C L I N I C A L

Pediatric Emergency Medicine

Vol 9, No 3 Editor
Steven E. Krug,
FAAP MD,

September 2008

Feinberg School of Medicine, Northwestern University, Childrens Memorial Hospital, Chicago, IL

The Neonate
Praveen Kumar, MBBS, DCH, MD Guest Editor

129 . . . . . . . . Toward Emergency Department Preparedness: One Step at a Time Praveen Kumar
of 131 . . . . . . . . Perinatal Physiology and PrinciplesandNeonatal Resuscitation Satyan Lakshminrusimha Vivien Carrion

140 . . . . . . . . Evaluation and Management of the Critically Ill Neonate in the Emergency Department
U. Olivia Kim, David C. Brousseau, and G. Ganesh Konduri

149 . . . . . . . . The Jaundiced Newborn in the Emergency Department: Prevention of Kernicterus

Vinod K. Bhutani and Lois Johnson

Sepsis in the 160 . . . . . . . Neonatal T. Robinson,Emergency Department and Sandra B. Cadichon Daniel Praveen Kumar,

169 . . . . . . . Evaluation and Management of the Cyanotic Neonate

Robin H. Steinhorn

176 . . . . . . . . Neonatal Neurological Emergencies

Janine Yasmin Khan

184 . . . . . . . . Apparent Life-Threatening Events in the Young Infant and Neonate

Jean M. Silvestri

Birth: An 191 . . . . . . . . Complications After PretermGauthamOverview for Emergency Physicians Praveen Kumar and Suresh Disorders and the 200 . . . . . . . Neonatal SkinSethuraman andEmergency Medicine Physician Gomathy Anthony J. Mancini

W.B. Saunders

www.clinpedemergencymed.org

C L I N I C A L

Pediatric Emergency Medicine

Editor
Steven E. Krug, MD, FAAP
Northwestern University Feinberg School of Medicine Childrens Memorial Hospital Chicago, Illinois

Editorial Board
Jeffrey R. Avner, MD, FAAP Albert Einstein College of Medicine Childrens Hospital at Monteore Bronx, New York M. Douglas Baker, MD, FAAP Yale University Yale-New Haven Childrens Hospital New Haven, Connecticut Susan M. Fuchs, MD, FAAP, FACEP Northwestern University Feinberg School of Medicine Childrens Memorial Hospital Chicago, Illinois Marianne Gausche-Hill, MD, FAAP, FACEP UCLA School of Medicine HarborUCLA Medical Center Los Angeles, California Michael J. Gerardi, MD, FAAP, FACEP UMDNJ-NJ Medical School Childrens Medical Center and Morristown Memorial Hospital Morristown, New Jersey Daniel J. Isaacman, MD, FAAP Director, Clinical Affairs Global Medical Affairs Wyeth Pharmaceuticals Madison, New Jersey Nathan Kuppermann, MD, MPH, FAAP University of California at Davis U.C. Davis Medical Center Davis, California Jeffrey F. Linzer, Sr., MD, MICP, FAAP Emory University School of Medicine Childrens Healthcare of Atlanta at Egleston Altanta, Georgia Ronald I. Paul, MD, FAAP, FACEP University of Louisville School of Medicine Kosair Childrens Hospital Louisville, Kentucky Emory Petrack, MD, MPH, FAAP, FACEP Petrack Consulting, Inc. Case Western Reserve University Cleveland, Ohio Richard M. Ruddy, MD, FAAP, FACEP University of Cincinnati College of Medicine Childrens Hospital Medical Center Cincinnati, Ohio Joan E. Shook, MD, MBA, FAAP, FACEP Baylor College of Medicine Texas Childrens Hospital Houston, Texas Milton Tenenbein, MD, FRCPC, FAAP, FAACT, FACMT University of Manitoba Childrens Hospital Winnipeg, Manitoba, Canada Robert A. Wiebe, MD, FAAP, FACEP University of Texas, Southwestern Medical Center at Dallas Childrens Medical Center of Dallas Dallas, Texas Joseph L. Wright, MD, MPH, FAAP George Washington University School of Medicine and Health Sciences Childrens National Medical Center Washington, District of Columbia Martha S. Wright, MD Director, Residency Training Program Department of Pediatrics Attending Physician, Division of Pediatric Emergency Medicine Rainbow Babies and Childrens Hospital Case Western Reserve University School of Medicine

Toward Emergency Department Preparedness: One Step at a Time

Praveen Kumar, MBBS, DCH, MD

n 1993, the Institute of Medicine published a report on the state of emergency medical services across the nation and found that systems for the care of children were often fragmented and unable to meet the needs of children and thus recommended that all emergency departments (EDs) be prepared to provide pediatric emergency care [1]. These recommendations led to a critical appraisal of existing resources and ways to improve the quality of pediatric care in EDs. A subsequent study reported that the equipment necessary to provide optimal care was frequently unavailable in many EDs and that this problem was particularly more frequent in smaller lower pediatric volume EDs [2]. The results of a survey conducted around the same time by the Society for Academic Emergency Medicine suggested that emergency medicine residents' exposure to newborn resuscitation and care was limited and therefore merited further attention during pediatric emergency medicine training [3]. In response to these concerns, the American College of Emergency Physicians and the American Academy of Pediatrics published a policy statement in 2001 on the guidelines for preparedness of EDs that care for children [4]. The Society for Academic Emergency Medicine subsequently published a position statement in 2003 stating that physicians certified in emergency medicine possess the knowledge and skills required to provide quality emergency medical care to children [5]. However, in a more recent report released in 2006, the Institute of Medicine again identified pediatric emergency services as an area requiring special attention, noting that the level of emergency pediatric care throughout the nation was uneven, and recommended that every pediatric and emergency carerelated health professional credentialing

Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL. Division of Neonatology, Northwestern Memorial Hospital, Children's Memorial Hospital, Chicago, IL. Reprint requests and correspondence: Praveen Kumar, Northwestern Memorial Hospital, Prentice Pavilion, 333 East Superior St., Suite 404, Chicago, IL 60611-2950. (E-mail: p-kumar@northwestern.edu) 1522-8401/$ see front matter C 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2008.06.001

and certification body should define pediatric emergency care competencies and require practitioners to receive the appropriate level of initial and continuing education necessary to achieve and maintain those competencies [6]. The need to maintain an appropriate level of competency is especially acute in the area of neonatal care. Significant physiological changes necessary for a smooth transition from fetus to newborn occur at birth, and frequently encountered neonatal diseases such as perinatally acquired infections, ductal-dependent congenital heart defects, metabolic disorders, bilirubin encephalopathy, and congenital abnormalities of organ systems can have similar and/or nonspecific clinical presentations. These distinctive characteristics make it imperative for emergency physicians to be familiar with neonatal physiology and the differences in presentation of neonates compared to that of older children and adults. The commonly heard saying that children are not just little adults is thus particularly relevant; however, it is equally important to realize that neonates are not just little children either. Several studies have shown that early neonatal utilization of emergency services has risen significantly over the past 2 decades [7,8]. This shift has been attributed to shorter postpartum hospital stays and a combination of psychosocial factors such as primiparity, single marital status, young maternal age, and health insurance status [7-10]. Most neonatal visits to the EDs in these studies were for nonacute conditions and were self-referred by parents. Although the most frequent diagnoses were normal physiology, jaundice, feeding problems, or suspected sepsis, nearly 15% of neonates had a serious diagnosis such as congenital heart disease, seizures, bowel obstruction, hypoglycemia, or pneumonia [7]. In addition, nearly 10% to 30% of all neonates presenting to EDs were reported to require admission for further care [7,8], and in one study, nearly 6% required resuscitation [10]. These findings reaffirm that all ED physicians must be familiar with normal variations in newborn physiology 129

130 and be able to identify presentations of important neonatal conditions that may have the potential to cause serious sequelae, and even death, if not recognized and managed properly. This issue of Clinical Pediatric Emergency Medicine is dedicated to The Neonate and provides current information on neonatal physiology and some common neonatal conditions, both serious and benign, which may lead to an ED visit. The article on perinatal physiology and principles of neonatal resuscitation, for example, describes the transition from fetal to newborn period and reviews current Neonatal Resuscitation Program guidelines, controversies regarding the use of 100% oxygen in neonatal resuscitation, and alternative airway maintenance techniques in infants with difficult airways. The article on the evaluation and management of a critically ill neonate in the ED provides a review of the important aspects of the neonatal history and examination, the role of thermoregulation, and a brief overview of differential diagnoses in critically ill neonates. Furthermore, the article on complications after preterm birth provides a brief summary of common morbidities in critically ill neonates such as bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, and necrotizing enterocolitis. Other articles in this issue focus on important topics of particular interest and importance to ED physicians such as neonatal sepsis, neonatal jaundice, neurological emergencies in newborns, common skin lesions in newborns, evaluation, and management of the cyanotic neonate and newborns with an acute life threatening episode. I greatly appreciate and want to thank all the authors for the time and effort they have taken to prepare these articles

P. Kumar
and sincerely hope that this issue of Clinical Pediatric Emergency Medicine will bring us a step closer to providing quality emergency medical care to all neonates.

References
1. Durch JS, Lohr KN. From the Institute of Medicine. JAMA 1993;270: 929. 2. McGillivray D, Nijssen-Jordan C, Kramer MS, et al. Critical pediatric equipment availability in Canadian hospital emergency departments. Ann Emerg Med 2001;37:371-6. 3. Tamariz VP, Fuchs S, Baren JM, et al. Pediatric emergency medicine education in emergency medicine training programs. SAEM Pediatric Education Training Task Force. Society for Academic Emergency Medicine. Acad Emerg Med 2000;7:774-8. 4. American Academy of Pediatrics Committee on Pediatric Emergency Medicine, American College of Emergency Physicians Pediatrics Committee. Care of children in the emergency department: guidelines for preparedness. Ann Emerg Med 2001;37:423-7. 5. Lewis RJ. The Society for Academic Emergency Medicine position on pediatric care in the emergency department. Acad Emerg Med 2003; 10:1299. 6. Handel DA, Sklar DP, Hollander JE, et al. Executive summary: the Institute of Medicine report and the future of academic emergency medicine: the Society for Academic Emergency Medicine and Association of Academic Chairs in Emergency Medicine Panel: Association of American Medical Colleges annual meeting, October 28, 2006. Acad Emerg Med 2007;14:261-7. 7. Millar KR, Gloor JE, Wellington N, et al. Early neonatal presentations to the pediatric emergency department. Pediatr Emerg Care 2000;16: 145-50. 8. Sacchetti AD, Gerardi M, Sawchuk P, et al. Boomerang babies: emergency department utilization by early discharge neonates. Pediatr Emerg Care 1997;13:365-8. 9. Donovan EF, Perlstein PH, Atherton HD, et al. Prenatal care and infant emergency department use. Pediatr Emerg Care 2000;16:156-9. 10. Ung S, Woolfenden S, Holdgate A, et al. Neonatal presentations to a mixed emergency department. J Paediatr Child Health 2007;43:25-8.

Perinatal Physiology and Principles of Neonatal Resuscitation

Satyan Lakshminrusimha, MD, Vivien Carrion, MD
Successful transition at birth is dependent on establishment of the lungs as the organ of gas exchange. The objective of this review is to provide a general overview of the events during transition at birth, pathophysiology of asphyxia, and response to resuscitation. The basic steps of neonatal resuscitation are establishment of airway, ventilation, and circulatory support. The controversy about the use of room air vs oxygen at birth for resuscitation is discussed. Special conditions that may be encountered during neonatal resuscitation include choanal atresia, pneumothorax, diaphragmatic hernia, meconium aspiration, and anemia. Finally, guidelines for discontinuing, withdrawing, and withholding resuscitative efforts are reviewed. Clin Ped Emerg Med 9:131-139 C 2008 Published by Elsevier Inc. KEYWORDS neonatal resuscitation, oxygen, newborn

15-year-old girl visiting the city with her grandmother is brought to the emergency department (ED) with abdominal pain and cramps. The triage nurse gives her a cup for a sample of urine. She experiences more abdominal cramps and proceeds to deliver a premature infant weighing a little more than a pound in the restroom. The triage nurse brings this limp, apneic, and cyanotic baby to you for resuscitation. Unfortunately, this scenario is not very uncommon and most of us have experienced a similar situation in our ED. Although active resuscitation is required in only 1% to 2% of newborn infants, every ED should be prepared and equipped to deal with this emergency. Timely and appropriate resuscitation at birth can mean the difference between death, survival with neurologic impairment, or intact survival. In no other area of medicine are the benefits of prompt and correct action more rewarding and more immediate [1]. In this chapter, we will review the physiology of resuscitation and briefly outline the basic principles of

neonatal resuscitation. Some controversial areas of neonatal resuscitation are also briefly discussed. The approach to resuscitation of the newborn is well presented in the widely distributed Neonatal Resuscitation Program (NRP) textbook published by the American Academy of Pediatrics in conjunction with the American Heart Association [2].

Physiology of Resuscitation
Transition at Birth
Birth by vaginal delivery is a stressful process, but despite enduring this process for several hours, most newborn infants are pink and breathing regularly by 1 to 2 minutes of age [1]. Successful transition at birth is mainly dependent on establishment of the lungs as the site of gas exchange. The placenta performs respiratory, excretory, and endocrine functions during fetal life. As the cord is clamped, the neonate has to rapidly adapt and perform all of the above functions. The anatomical and physiologic changes that establish lungs as the site of exchange are shown in Table 1. The 3 events that initiate various changes occurring during transition include clamping of the umbilical cord, ventilation (initial breathing), and oxygenation (fetal PaO2 is in the low 20s and gradually increases to normal postnatal values after birth). Breathing movements are 131

State University of New York at Buffalo, Department of Pediatrics, Women and Children's Hospital of Buffalo, Buffalo, NY. Reprint requests and correspondence: Satyan Lakshminrusimha, MD, Division of Neonatology, Women and Children's Hospital of Buffalo, 219 Bryant St, Buffalo, NY 14222. (E-mails: slakshmi@buffalo.edu, vcarrion@upa.chob.edu) 1522-8401/$ - see front matter C 2008 Published by Elsevier Inc. doi:10.1016/j.cpem.2008.06.002

132
Table 1 Structure Alveolar type II cells Changes in cardiovascular and respiratory systems during transition at birth. Function During Fetal Life Chloride secretion and lung liquid formation Functional Change at Birth

S. Lakshminrusimha, V. Carrion

Comments

Alveolar type II cells

Synthesizes and releases surfactant

Pulmonary circulation Low flow (8%-10% of combined ventricular output), high resistance circuit Nutrition, gas exchange, Placenta and waste removal (low-resistance circuit) Ductus venosus Channels oxygenated blood from the placenta to the right atrium Foramen ovale Shunts oxygenated blood from the inferior vena cava to the left atrium Ductus arteriosus Blood from pulmonary artery to aorta to bypass the lungs and reach placenta

Sodium reabsorption and lung Impaired lung liquid clearance (common liquid clearance with elective cesarean delivery without labor) can result in transient tachypnea of newborn Increased surfactant release Impaired surfactant production (prematurity) can result in respiratory distress syndrome Increase in pulmonary blood Changes at birth mediated by oxygen, flow, drop in pulmonary ventilation, nitric oxide, and prostacyclin; arterial pressure impairment results in persistent pulmonary hypertension of newborn (PPHN) Spasm and closure of Removal increases systemic vascular umbilical vessels resistance and increases systemic blood pressure Constriction and reduction of Closure can worsen pulmonary venous obstruction in infradiaphragmatic total flow as umbilical venous anomalous pulmonary venous return flow decreases Closure may result in poorer mixing in Left atrial pressure (with increased pulmonary venous transposition, systemic venous obstruction in right heart obstruction, and pulmonary flow) closes the flap valve venous obstruction in left heart obstruction Increase in O2 and decrease Closure results in marked deterioration of ductal dependent pulmonary or systemic in prostaglandins result in circulations. Persistent patency results in ductal constriction (by 60 h respiratory distress and failure in in 93% of term infants) premature infants

intermittent in the fetus and inhibited during parturition. However, severe asphyxia can induce gasping movements, resulting in aspiration of meconium during delivery. Continuous breathing is triggered at birth by sensory stimulation such as cooling, rising PCO2, removal of placental humoral inhibitory factors (possibly prostaglandins), catecholamine surge, and oxygen [3]. With initiation of the first breath, air starts entering the alveoli. Expansion of the alveoli leads to release of surfactant with lowered surface tension. High negative inspiratory pressures are generated by term infants (30-50 cm H2O) during the first breath. During subsequent expiration, high positive pressures are created presumably by breathing against a closed glottis. This aids in clearing of liquid in the lungs and a more uniform distribution of air throughout the lung and establishment of functional residual capacity (FRC) [4-6].

initial period of primary apnea, appropriate sensory stimulus can initiate spontaneous ventilation. However, after 4 to 5 minutes, gasping became weaker, and secondary or terminal apnea occurred associated with bradycardia and hypotension. Approximately 8 minutes later, cardiac arrest was observed. After the onset of secondary apnea, assisted ventilation is usually necessary for resuscitation. Stimulation alone will not restart the baby's breathing. Delay in providing assisted ventilation to infants in secondary apnea prolongs the time to first gasp and spontaneous ventilation. It is also important to recognize that many causes other than asphyxia may delay the onset of respiration at birth (Figure 1 and Table 2).

Response to Resuscitation
The Apgar scoring system (Table 3) is widely used to assess cardiorespiratory status of the newborn in the delivery room [9]. Rapid achievement of higher Apgar scores has traditionally been considered the hallmark of a successful resuscitation, and persistent low Apgar scores may be related to poor prognosis [10]. The 5 components of the Apgar scoring system are indicators of different physiologic responses and therefore carry different significance [11]. Heart rate and respirations are the most important components. Heart rate (measured by listening to the heart with a stethoscope or palpating the pulse at the base of the umbilical cord) is the best way to assess response to

Primary Apnea and Secondary Apnea

In classic experiments done in the early 1960s, Dawes et al [7,8] described changes in pulse, respiration, and blood pressure in rhesus monkeys delivered by cesarean delivery and asphyxiated by tying of the umbilical cord and prevention of breathing. After a few shallow breathing movements, respiratory effort ceased resulting in primary apnea. After a few minutes of primary apnea, gasping started with increasing vigor and frequency. During this

Neonatal Resuscitation

133

Figure 1 Pathophysiology of asphyxia. The upper half of the figure shows physiologic events and consequences of asphyxia. The light blue line represents the respiratory pattern of the fetus/newborn infant. The red line represents heart rate and the pink area represents blood pressure. The solid lines indicate response to resuscitation and dashed lines represent lack of response to resuscitation. The colored text boxes show various interventions during neonatal resuscitation. The lower half of the figure shows response to resuscitation. In utero or peripartum asphyxia insults initially cause primary apnea. During primary apnea, maintaining patency of the airway and tactile stimulation is adequate to restore spontaneous breathing. If resuscitation is not effective, gasping and subsequently secondary apnea occur. During this period, tactile stimulation may not be adequate and assisted ventilation is required during resuscitation. Prolonged asphyxia results in cardiac arrest and acidosis necessitating assisted ventilation and chest compressions and in some cases medications such as volume boluses and epinephrine.

resuscitation. Muscle tone represents higher cerebral function, and reflex responsiveness is a brain stem response. Color is dependent on oxygenation and perfusion (heart rate and euvolemic circulation).

Neonatal Resuscitation
There are approximately 4.1 million births annually in the United States. Although 99% of these births occur in hospital delivery room settings, the remaining 1% may take
Table 2 Factors at birth that can delay the onset of effective respiration. Asphyxia Congenital malformations of airway or CNS Injury to nervous system Drugs depressing CNSnarcotics, magnesium Oligemia (anemia/hypovolemia) Sepsis Immaturity Surfactant deficiency/stiff lungs
CNS indicates central nervous system. Mnemonic: ACIDOSIS.

place in extramural settings including the home, automobiles, ambulances, and other locations [12]. This latter population invariably presents to the ED at times as a dyad of unknown prenatal and perinatal complications posing a unique challenge to the emergency physician. Every emergency physician should be prepared for the unexpected event of a delivery or out of hospital birth and arrival of a newborn into the ED.
Table 3 Apgar scoring system [9]. Score 0 Sign Heart rate Absent Respiratory Absent effort Muscle tone Limp Reflex irritability Color 1 b100 bpm Slow (irregular) 2 N100 bpm Good crying Active motion Cough or sneeze All pink

Some flexion of extremities No response Grimace Pink body, blue extremities

Blue, pale

134 Resuscitation of a newborn should follow the NRP guidelines [13]. This program had its origin in the late 1980s in the United States and evolved in the 1990s when more clinical research refined the initial resuscitation recommendations. The most recent changes to these recommendations include indications for suctioning for meconium, suctioning at the perineum, a greater emphasis on avoidance of hypothermia, the use of devices providing positive end-expiratory pressure (PEEP) for resuscitation in the delivery room and most recently clinical trials comparing room air vs O2 for newborn resuscitation. The initial resuscitation and stabilization of a newborn infant, whether delivered outside the hospital or in the ED, can be a difficult one. Anticipation and preparation are key to successful resuscitation of newborns in this setting. Personnel with expertise in airway, respiratory, and circulatory management need be available to resuscitate these infants. Ideally, 2 individuals should be in attendance one with complete resuscitation skills and one or more to assist. In addition, appropriate newborn equipment should be present in a designated area, which is both warm and clean, to ensure intubation, ventilation, fluid resuscitation, and when indicated, administration of drugs (Table 4). All the resuscitation supplies and equipment for neonatal resuscitation should be available in the ED [2,13]. Periodic review of the expiration date should be carried out and logged for these unexpected events. Despite an extensive list of conditions that can lead to a high-risk delivery, only 1% of newborns require major resuscitation that would necessitate the tools previously listed. Unlike adults, who in most circumstances experience a cardiac event as their precipitating resuscitative requirement, a newborn's primary need at birth is that of effective ventilation. Given the few occasions of ED births or immediate newborn arrivals to the ED, maintenance of newborn resuscitation skills is essential. Although many emergency physicians are certified in both pediatric and adult advanced life support (PALS/ACLS) and have opportunity to use this training on a frequent basis, this is not the case for newborn resuscitation. To this end, a physician who may be involved in newborn resuscitation benefits from certification in the NRP. The initial assessment of the newborn should be to assess whether resuscitative efforts are indicated given that most newborns are vigorous at birth. Newborn infants who do not require resuscitation can generally be identified by a rapid assessment of the infant. Infants born at term gestation, with clear amniotic fluid, breathing, and/or crying and with good muscle tone, need routine care that includes providing warmth, clearing of the airway (if needed), and keeping them dry. The compromised baby may exhibit cyanosis from insufficient O2 in the blood and/or bradycardia from insufficient delivery of oxygen to the heart muscle or brainstem [13]. Preterm delivery, meconium-stained amniotic fluid, an infant who is not crying or breathing, an infant who is cyanotic or
Table 4

S. Lakshminrusimha, V. Carrion
Neonatal resuscitation supplies and equipment.

Suction equipment Bulb syringe, mechanical suction and tubing, and meconium aspiration device Suction catheters, 5F or 6F, 8F, and 10F or 12F and 8F feeding tube and 20-mL syringe Bag-and-mask equipment Neonatal resuscitation bag with a pressure-release valve or pressure manometer (the bag must be capable of delivering 90%-100% oxygen) Face masks, newborn, and premature sizes (masks with cushioned rim preferred) Oxygen with flow meter (flow rate up to 10 L/min) and tubing (including portable oxygen cylinders) Intubation equipment Laryngoscope with straight blades, no. 0 (preterm) and no. 1 (term) Extra bulbs and batteries for laryngoscope Tracheal tubes, 2.5, 3.0, 3.5, and 4.0 mm internal diameter and stylet (optional)/scissors/tape or securing device for tracheal tube Alcohol sponges CO2 detector (optional)/laryngeal mask airway (optional) Medications Epinephrine 1:10 000 (0.1 mg/mL)3-mL or 10-mL ampules Isotonic crystalloid (normal saline or Ringers lactate) for volume expansion, 100 or 250 mL Sodium bicarbonate, 4.2% (5 mEq/10 mL) 10-mL ampules Naloxone hydrochloride, (0.4 mg/mL) 1-mL ampules or (1.0 mg/mL) 2-mL ampules Normal saline for flushes Dextrose 10%, 250 mL Feeding tube, 5F (optional) Umbilical vessel catheterization supplies Sterile gloves; scalpel or scissors; povidone-iodine solution; umbilical tape Umbilical catheters, 3.5F, 5F; 3-way stopcock Syringes, 1, 3, 5, 10, 20, and 50 mL Needles, 25, 21, and 18-gauge or puncture device for needleless system Miscellaneous Gloves and appropriate personal protection Radiant warmer or other heat source, firm, padded resuscitation surface Clock (timer optional)/warmed linens/stethoscope/tape, 1/2 or 3/4 inch Cardiac monitor and electrodes and/or pulse oximeter with probe (optional for delivery room) Oropharyngeal airways
Data from the American Academy of Pediatrics [13].

floppy, or an infant with weak or absent responses all need further assessment under a radiant warmer and likely intervention. The management of such infants is based on a rapid assessment of the infant's respiration, heart rate, and color [13]. The initial steps of resuscitation are to provide warmth by placing the infant under a radiant warmer, position the head in a sniffing position to open the airway, clearing the airway with a bulb

Neonatal Resuscitation
syringe or suction catheter, and drying the infant to reduce heat loss and to stimulate breathing [2]. Some key points that should be noted during initial resuscitation interventions follow.

135 an asphyxiated term infant has been studied in international clinical trials. A recent meta-analysis based on 7 studies and 2011 infants concluded that compared to the 100% O2 resuscitation group, neonates in the room air resuscitation group had a lower mortality both in the first week of life and at 1 month of age and beyond. The incidence of severe hypoxic ischemic encephalopathy in this meta-analysis (stage II and stage III) was similar between the 2 groups [20]. Current studies have not resolved the question of optimal O2 or no O2 administration for the term as well as the preterm infant [18]. The most recent NRP guidelines recommend the following. Babies Born at Term If a baby is cyanotic or when PPV is necessary, 100% supplementary O2 is recommended. If supplemental O2 is unavailable, room air can be used to deliver PPV. Research suggests that resuscitation with something less than 100% may be just as successful. If resuscitation is started with less than 100% O2, supplemental O2 up to 100% may be administered if there is no appreciable improvement within 90 seconds after birth. Babies Born at Less Than 32 Weeks of Gestation An oxygen blender and pulse oximeter are recommended during resuscitation. Positive pressure ventilation is initiated with an O2 concentration between 21% and 100% and adjusted up or down to achieve O2 saturation that gradually increases toward 90%. If O2 saturation is greater than 95%, the O2 concentration should be decreased. However, if the heart rate does not respond by increasing to greater than 100 bpm, ventilation problems should be corrected and 100% supplemental O2 should be used. For those facilities without a blender or pulse oximeter, the management described for the term baby may be used as present evidence does not support that a brief period of 100% O2 during resuscitation is detrimental.

Temperature Control
Very-low-birth-weight preterm infants are likely to become hypothermic despite the use of traditional techniques for decreasing heat loss [14]. For this reason, it is recommended that additional warming techniques be used, such as covering the infant in plastic wrapping/placing the infant torso in polyethylene bags [15,16] or placing under a radiant warmer. Warming mattresses have also been used, but care must be taken to avoid hyperthermia. The goal is to achieve normothermia, but at the same time, hyperthermia should be avoided. Induced hypothermia may reduce the extent of brain injury after hypoxia-ischemia. There is insufficient data to recommend routine use of selective head and/or systemic hypothermia after resuscitation of infants with suspected asphyxia [17]. Further clinical trials are needed to determine which infants would most benefit and which method of cooling is the most effective. Hyperthermia may worsen the extent of brain injury after hypoxia-ischemia. The goal should be to achieve normothermia and to avoid iatrogenic hyperthermia in resuscitated newborns.

Airway Management
Airway management remains a primary focus in neonatal resuscitation as greater than 80% of newborn arrests may be attributed to a respiratory etiology. Initial airway management should focus on lung inflation as well as adequate ventilation. If the infant appears vigorous, stimulation and transient face mask continuous positive airway pressure may be all that is needed, making sure the correct face mask size is applied (term vs preterm). There should be an adequate airway seal both when delivering continuous positive airway pressure as well as when the newborn requires positive pressure ventilation (PPV). An obstructed airway may be seen in newborns with choanal atresia, small mandibles, and large tongues. The current NRP guidelines no longer recommend routine intrapartum oropharyngeal and nasopharyngeal suctioning of infants delivered to mothers with meconium staining of amniotic fluid if the infant is vigorous at birth with strong respiratory efforts, good tone, and has a heart rate greater than 100 beats per minute (bpm).

Ventilation
In a depressed infant, PPV is indicated in the presence of apnea, heart rate less than 100 bpm, or persistent cyanosis. During PPV, one should use only the minimal pressure needed to achieve small chest wall excursions. Generally, peak pressures of 20 to 30 cm H2O are adequate. Preterm infants may require higher initial pressures because of surfactant deficiency and stiff lungs. However, high tidal volume breaths to a surfactantdeficient lung may induce lung injury. In most infants, FRC is gradually established in a stepwise fashion over several PPV breaths. However, when PPV is provided without PEEP, in the absence of spontaneous respiratory effort, FRC may not be established especially in surfactant deficient preterm infants [5]. Accumulating evidence indicates that it is important to hold the surfactantdeficient lung open with an adequate PEEP to minimize pulmonary edema and cytokine release and to improve

Use of O2 During Neonatal Resuscitation

There has been a growing concern about free radical damage induced by using 100% O2 during neonatal resuscitation [18,19]. The asphyxial process results in an increase in hypoxanthine, which serves as a substrate for the xanthinexanthine oxidase system with the resultant production of oxygen radicals upon the reintroduction of O2 to the tissues. The safety of room air for resuscitation of

136 compliance and the response to surfactant [4]. The use of a PEEP providing T-piece device (such as Neopuff, Fisher & Paykel Healthcare, Auckland, New Zealand) is currently recommended by the NRP. Placement of an orogastric tube may be necessary to avoid overdistension of the abdomen during PPV.

S. Lakshminrusimha, V. Carrion
Chest compressions are indicated for a heart rate less than 60 bpm despite adequate ventilation with supplemental oxygen for 30 seconds. Compression should be delivered on the lower third of the sternum, to a depth of approximately one third of anterior-posterior diameter of the chest. Chest compressions can be delivered either by a 2-thumb-encircling hand technique or by compression with 2 fingers with a second hand supporting the back. Compression and ventilation should be coordinated to avoid simultaneous delivery. There should be a 3:1 ratio of compressions to ventilations with 90 compressions and 30 breaths to achieve per minute to maximize ventilation. The chest should be permitted to fully reexpand during the relaxation phase of chest compressions for adequate ventilation, but the rescuer's thumb should remain in contact with the chest [13]. There should be continuous evaluation of the heart rate by auscultation and, if available, by pulse oximetry. Once the heart rate is greater than 60 bpm, chest compressions may be discontinued, but PPV should be continued at a rate of 40 to 60 breaths per minute until the heart rate is greater than 100 bpm and spontaneous ventilation is established. If there has been no improvement despite the above ventilation/ compression maneuvers then one should check to confirm that (a) the patient is intubated or the face mask has a good seal (with adequate chest rise), (b) oxygen is being administered, and (c) that chest compressions and ventilation are well coordinated.

Periodic Evaluation at 30-Second Intervals

After an initial assessment soon after birth and administration of the initial steps of resuscitation, further resuscitative efforts should be guided by simultaneous assessment of respiration, heart rate, and color every 30 seconds. Although Apgar scores (Table 3) are assigned at 1 and 5 minutes of postnatal life, resuscitative efforts should begin soon after initial stabilization and assessment. A newborn infant who is uncompromised will achieve and maintain pink mucous membranes without administration of supplemental O2.

Endotracheal Intubation
Intubation should be considered and PPV continued if the infant remains apneic or the heart rate remains less than 100 bpm despite 30 seconds of bag and mask ventilation. Endotracheal intubation is indicated at several points of neonatal resuscitation, including ineffective or prolonged bag and mask ventilation, during the performance of chest compressions or when endotracheal administration of medications is desired (Figure 2). Suggested endotracheal tube (ETT) size and depth of insertion at various birth weight and gestational age is shown in Table 5. To confirm ETT placement, an exhaled CO2 detector is strongly recommended. Change from a purple to yellow color confirms placement with the exception of a patient with poor cardiac output or diminished pulmonary blood flow. These situations may result in a false-negative reading. Adequate ventilation should result in an improvement in heart rate, color, muscle tone, and spontaneous breathing. Figure 3 gives an overview of special conditions that need appropriate and immediate management during resuscitation [13].

Drugs
Medications are rarely used in neonatal resuscitation but if the heart rate remains less than 60 bpm despite the above measures, then the insertion of an umbilical venous catheter and administration of epinephrine is indicated.

Insertion of an Umbilical Venous Catheter

The umbilical vein is the most quickly accessible vein in newborn infants and emergency physicians should be comfortable in inserting an umbilical venous catheter (Figure 3). Aseptic precautions should be taken while placing an umbilical vein catheter. A sterile, 3.5F or 5F end-hole catheter connected to a stopcock should be prefilled with normal saline. A loose tie of umbilical tape is placed around the base of the cord to stop bleeding. The cord is transversely cut with a sterile blade 1 to 2 cm from the skin line. The umbilical vein is usually in the 11 or 12-o'clock position, and the 2 arteries are at the 4 and 8-o'clock position. The position of these vessels may change farther away from the skin. The catheter is inserted to a distance of 2 to 4 cm (lesser in preterm babies) below the skin until good backflow of blood is noted with gentle aspiration. Advancing the catheter further carries the risk of placement within liver vessels. Umbilical vein catheters are used for the administration of epinephrine, naloxone, bicarbonate, and for volume expansion.

Laryngeal Mask Airway

There are select cases where intubation or even bag/mask ventilation may be difficult. This is more commonly seen in newborns with facial anomalies (eg, micrognathia, PierreRobin syndrome, macroglossia). The laryngeal mask airway may be effective in these situations and has been shown to be effective in term newborns. There is insufficient evidence to support use of laryngeal mask airways in very low birth weight newborns.

Circulation
Studies have demonstrated that auscultation is the superior method of assessing heart rate. Palpation of the umbilical cord or pulse is less reliable than auscultation.

Neonatal Resuscitation

137

Figure 2 Neonatal flow algorithm of resuscitation (produced with permission from the American Academy of Pediatrics) HR - heart rate.

138
Table 5 Suggested tracheal tube size and depth of insertion according to weight and gestational age. Gestational Age (wk) b28 28-34 34-38 N38 Tube Size (mm, internal diameter) 2.5 3.0 3.5 3.5-4.0 Depth of Insertion from Upper Lip (cm) 6.5-7 7-8 8-9 N9

S. Lakshminrusimha, V. Carrion
0.03 mg/kg per dose (0.1-0.3 mL/kg of 1:10 000 epinephrine) is the preferred route. While access is being obtained, administration of a higher dose (up to 0.1 mg/kg or 1 mL/kg of 1:10 000 epinephrine, drawn in a 3 or 5-mL syringe) through the ETT may be considered, but the safety and efficacy of this practice in newborns has not been evaluated [13].

Weight (g) b1000 1000-2000 2000-3000 N3000

Volume Expanders
Consider volume expansion when blood loss is suspected (abruption, placenta previa) or if the infant appears to be in shock (pale skin, poor perfusion, weak pulse) and has not responded adequately to other resuscitative measures. Isotonic saline is the solution of choice at a dose of 10 mL/kg that may be repeated if necessary. In premature infants, care should be taken to avoid giving volume expanders too rapidly.

General formula for depth of insertion from upper lip (6 + weight in kg) in cm.

Epinephrine
Epinephrine at doses of 0.01 to 0.03 mg/kg (0.1-0.3 mL/ kg of 1:10 000 epinephrine) will likely be ineffective via the ETT. Therefore, intravenous administration of 0.01 to

Figure 3 Special circumstances in resuscitation of the newly born infant. Clinical features (C/F) and management guidelines (Rx) for various conditions presenting during neonatal resuscitation. Insertion of an umbilical venous line with some indications is also shown.

Neonatal Resuscitation

139 improvement in heart rate is the best sign of successful neonatal resuscitation. Emergency physicians should be familiar with the principles and basics of neonatal resuscitation and maintain these skills with frequent mock codes.

Naloxone
Two criteria need to be fulfilled before administering naloxone (dose = 0.1 mg/kg). These include continued respiratory depression after PPV has restored a normal heart rate and color, and if there is a history of maternal narcotic administration within the past 4 hours. The intravenous route of administration is preferred. The intramuscular route is acceptable but has delayed onset of action. This medication should be avoided if maternal narcotic addiction is suspected as this may precipitate acute neonatal withdrawal.

Acknowledgments
American Academy of Pediatrics, Neonatal Resuscitation Program grant 2006/7 (SL).

References
1. Milner AD. Care around birthpart I: resuscitation of the newborn. In: Rennie JM, editor. Roberton's textbook of neonatology. 4th ed. Philadelphia (Pa): Elsevier Churchill Livingstone; 2005. p. 219. 2. American Heart Association, American Academy of Pediatrics. 2005 American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) of pediatric and neonatal patients: neonatal resuscitation guidelines. Pediatrics 2006;117:e1029-38. 3. Rigatto H. Control of breathing in fetal life and onset and control of breathing in the neonate. In: Polin RA, Fox WW, Abman SH, editors. Fetal and neonatal physiology, 3rd edition., vol. 1. Philadelphia (Pa): WB Saunders; 2004. p. 890. 4. Bloom R, Yost CC. A consideration of neonatal resuscitation. Pediatr Clin North Am 2004;51:669-84, ix. 5. Milner AD, Vyas H. Lung expansion at birth. J Pediatr 1982;101:879-86. 6. Vyas H, Field D, Milner AD, et al. Determinants of the first inspiratory volume and functional residual capacity at birth. Pediatr Pulmonol 1986;2:189-93. 7. Dawes GS, Jacobson HN, Mott JC, et al. The treatment of asphyxiated, mature foetal lambs and rhesus monkeys with intravenous glucose and sodium carbonate. J Physiol 1963;169:167-84. 8. Dawes GS, Mott JC, Shelley HJ, et al. The prolongation of survival time in asphyxiated immature foetal lambs. J Physiol 1963;168:43-64. 9. Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg 1953;32:260-7. 10. Nelson KB, Ellenberg JH. Apgar scores as predictors of chronic neurologic disability. Pediatrics 1981;68:36-44. 11. Saugstad OD. Physiology of resuscitation. In: Polin RA, Fox WW, Abman SH, editors. Fetal and neonatal physiology, 3rd edition, vol. 1. Philadelphia (Pa): WB Saunders; 2004. p. 765. 12. NCHS. Attendant, place and timing, and use of obstetric interventions of U.S. births change over past decade. Natl Center Health Stat 1999; 47:16. 13. Kattwinkel J. Textbook of neonatal resuscitation. 5th edition. Elk Grove Village (Ill): American Academy of Pediatrics; 2006. 14. Knobel R, Holditch-Davis D. Thermoregulation and heat loss prevention after birth and during neonatal intensive-care unit stabilization of extremely low-birthweight infants. J Obstet Gynecol Neonatal Nurs 2007;36:280-7. 15. Lenclen R, Mazraani M, Jugie M, et al. Use of a polyethylene bag: a way to improve the thermal environment of the premature newborn at the delivery room. Arch Pediatr 2002;9:238-44. 16. McCall EM, Alderdice FA, Halliday HL, et al. Interventions to prevent hypothermia at birth in preterm and/or low birthweight babies. Cochrane Database Syst Rev 2005:CD004210. 17. Kirpalani H, Barks J, Thorlund K, et al. Cooling for neonatal hypoxic ischemic encephalopathy: do we have the answer? Pediatrics 2007; 120:1126-30. 18. Richmond S, Goldsmith JP. Air or 100% oxygen in neonatal resuscitation? Clin Perinatol 2006;33:11-27, v. 19. Saugstad OD, Ramji S, Vento M. Oxygen for newborn resuscitation: how much is enough? Pediatrics 2006;118:789-92. 20. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation 2007; 72:353-63.

Bicarbonate
The use of bicarbonate is discouraged during brief cardiopulmonary resuscitation. Sodium bicarbonate is used in prolonged arrests unresponsive to other therapy and should be given only after establishing ventilation and circulation. The dose is 1 to 2 mEq/kg of 4.2% sodium bicarbonate by a slow intravenous infusion.

Discontinuation of Resuscitative Efforts

If there is no heart rate after 10 minutes of complete and adequate resuscitation efforts, and there is no evidence of other causes of newborn compromise, discontinuation of resuscitation efforts may be appropriate. Current data indicate that, after 10 minutes of asystole, newborns are very unlikely to survive, or the rare survivor is likely to survive with severe disability [13].

Resuscitation Skill Maintenance

Mock codes are planned practice resuscitation events usually organized and supervised by the director of the ED or at times by pediatric or neonatal subspecialists. These practice sessions should include mannequins, and standard resuscitation equipment allow physicians, nurses, and respiratory therapists an opportunity to maintain skills and assess performance in different case scenarios. Those conducting these mock codes should be either NRP certified or, ideally, NRP instructors. Mock codes, when performed on a quarterly or more frequent basis, should contribute toward efficiency in resuscitation and stabilization of newborns. This process also allows for review of recent recommended updates by the American Academy of Pediatrics/American Heart Association regarding cardiopulmonary resuscitation guidelines and continued comfort with specialized equipment use for these infants.

Summary
Occasionally, deliveries occur in extramural settings or in the ED. These newborn infants are often brought to the emergency physician for initial stabilization. Rapid decision making based on periodic evaluation of heart rate, respiration, and color will determine need for and appropriate steps of resuscitation. Ventilation of the lungs is the key and

Evaluation and Management of the Critically Ill Neonate in the Emergency Department
U. Olivia Kim, MD , David C. Brousseau, MD MS, G. Ganesh Konduri, MD
The care of a critically ill neonate in the emergency department setting presents a special challenge for practitioners who do not routinely encounter compromised neonates. This review will provide guidelines for the initial stabilization of these infants as well as identify differential diagnoses that should be considered. As with any critically ill patient, achieving physiologic stability of the neonate is the first priority. However, in addition to maintaining the airway, breathing, and circulation, thermoneutrality must be achieved for a successful outcome. Obtaining the history and initiating diagnostic evaluations should occur during or shortly after the course of stabilization to promptly initiate disease-specific therapies. The mnemonic NEO SECRETS may help focus the care and promote early identification of the cause of the infants deterioration. Clin Ped Emerg Med 9:140-148 C 2008 Elsevier Inc. All rights reserved. KEYWORDS neonatal emergency care, neonatal emergencies

apid evaluation and stabilization of a critically ill neonate is a required skill in the emergency department (ED). Neonates can acutely decompensate from a variety of causes. However, neonates have a limited repertoire of responses to stress and the presenting signs can be nonspecific. Therefore, a logical and multisystem approach to the evaluation and management of common causes is essential to stabilizing these infants. The following review summarizes our approach to a critically ill newborn in the setting of a busy ED. Although history, physical examination, and laboratory evaluation are described in sequence, it is understood that emergent cardiopulmonary stabilization takes precedence over detailed evaluation of the neonate for underlying causes. A rapid appraisal of the newborn for some of the more common diagnoses is essential though, for institution of specific therapies.

group B streptococcus [GBS] screens, and blood type) medications, complications during pregnancy and maternal illnesses. A birth history should follow and includes the gestational age at delivery, indication for delivery (maternal pregnancy induced hypertension, fetal distress, etc), the route of delivery including any instrumentation, complications during delivery, birth weight, and resuscitation required. The immediate neonatal course should also be reviewed for difficulties in transitioning to extrauterine life such as respiratory distress, hypoglycemia, feeding difficulties, jaundice, and length of hospital stay. The mother may remember the infant's discharge weight and this should be asked. The neonate's medical history consists of the time from discharge from the birth hospital to the time of presentation to the ED. Details on the infant's oral intake including the amount of water used to mix formula or any additives used should be obtained. The infant's urine output as well as stooling habits should also be assessed. If available,
Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI. Division of Emergency Medicine, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI. Reprint requests and correspondence: U. Olivia Kim, MD, Children's Corporate Center, Division of Neonatology, Suite C410, PO Box 1997, Milwaukee, WI 53201. (E-mails: okim@mcw.edu,dbrousse@mcw.edu, gkonduri@mcw.edu) 1522-8401/$ see front matter C 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2008.06.003

History
Initial evaluation of the critically ill neonate may be focused on immediate needs but should be orderly so as not to overlook significant signs or symptoms. The elements of a neonatal history should begin with a maternal history, such as maternal antenatal laboratory tests (status of rubella, hepatitis B, syphilis, human immunodeficiency virus, 140

Evaluation and management of the critically ill neonate

information from the first well child check should be obtained, either from the mother or the primary care provider's office. The neonate's examination and growth parameters from the last examination should be reviewed and compared with the weight obtained in the ED. Results of the state mandated newborn screening test results may be obtained from the primary physician's office, hospital of birth, or directly from the state newborn screening program. These test results are important in the evaluation of certain metabolic and endocrine causes of a neonate's acute illness as discussed later in this review.

141 malformation. Fixed and dilated pupils with a persistent oculocephalic response may indicate lidocaine toxicity, especially if there is a recent history of a circumcision or other medical procedure. The mouth, neck, shoulders, and arms should be assessed. Brachial pulses should be palpated and compared with femoral pulses to rule out a significant coarctation of the aorta. Examination of the chest may reveal a pronounced cardiac murmur, unequal breath sounds, or significant subcostal retractions. A distended, tender, and tympanic abdomen should prompt surgical consultation and a focused diagnostic search. The genitalia should be inspected. Testicular torsion or incarcerated inguinal hernias may be found. Ambiguous genitalia in a female infant or a hyperpigmented scrotum in a male infant may suggest congenital adrenal hyperplasia (CAH). Bloody stools may suggest gastrointestinal necrosis. All extremities should be palpated to ensure that bony structures are intact. A neurologic examination including evaluation of the primitive neonatal reflexes (root, suck, gag, Moro) should be done. The history, physical examination, and initial stabilization usually occur concurrently in a deteriorating infant and may easily be interrupted. Hence, care must be taken to ensure a thorough physical examination is completed on all critically ill infants.

Physical Examination
The physical examination of the neonate begins with inspection and an overall observation of the neonate's condition. It is important to remember that the presenting symptoms and signs can be nonspecific and common to a variety of diseases including sepsis, heart failure, and metabolic diseases. Therefore, it is important to consider a list of common disorders that present with immediate deterioration in the neonatal period. The overall appearance of the infant is often more significant in assessing the severity of the illness. A flexed posture with spontaneous movements and pink perfusion is reassuring. A flaccid posture with decreased spontaneous movements, cyanosis, and respiratory distress signifies a gravely ill neonate in need of immediate attention. Review of vital signs on admission may also provide an indication of distress. Axillary temperatures for neonates vary widely but are generally thought to be between 36.2C and 37.7C [1]. Heart rates between 110 and 160 beats per minute are normal for healthy term infants and may vary during sleep or active awake states [2]. Respiratory rates between 40 and 60 breaths per minute are also normal for a neonate [3]. Normal systolic blood pressures during the first month of life range from 65 to 75 mm Hg and diastolic pressures from 40 to 50 mm Hg [4]. An easy rule of thumb is that the mean blood pressure should approximate the estimated gestational age in weeks at the time of measurement. For example, a 2 week old former 38 week gestation infant's mean blood pressure should be around 40 mm Hg. Incorrect blood pressure readings may be obtained if the sphygmomanometer cuff is too small or large. Four extremity blood pressures should be obtained on all hemodynamically unstable neonates because discrepancies between upper and lower limb blood pressures may indicate a ductal dependent coarctation of the aorta. The remainder of the physical examination should follow and may suggest the source of illness. Inspection, palpation, and auscultation of the infant should occur from head to toe. The head should be palpated and carefully inspected for trauma in the encephalopathic neonate. The fontanelle should be auscultated to assess for a cranial bruit, especially if the neonate is hemodynamically unstable as this may be a sign of a cerebral arterio-venous

Initial Stabilization
As in all pediatric patients, stabilization prioritizes securing the airway, then establishing breathing and maintaining adequate circulation. Endotracheal intubation and fluid resuscitation are usually required in critically ill neonates, and these procedures, if indicated, should not be delayed while waiting for diagnostic evaluation. Establishing optimal ventilation and oxygenation is often sufficient to improve both respiratory and cardiac insufficiency; however, intravenous (IV) fluids and resuscitation may be required in the gravely ill neonate. An initial bolus of 10 mL/kg of isotonic fluid (0.9 NS) should be given over 10 to 15 minutes and repeated if necessary. If the umbilical stump is still present, this fluid may be given through an umbilical venous catheter [5]. If the physical examination identifies poor peripheral perfusion and cyanosis with or without a cardiac murmur, a continuous infusion of prostaglandins (PGE1, 0.010.05 g/kg per minute) should be promptly initiated and pediatric cardiology consulted. If abdominal distension or discoloration is noted on physical examination, a surgical abdomen must be considered. Bilious emesis and/or abdominal distention in the neonate should be treated as a surgical emergency and should be promptly evaluated with appropriate diagnostic tests and surgical consultation. Neonates with enteric emergencies often require additional fluid resuscitation as well as decompression of the gastrointestinal tract with a large bore repogle tube. Twoview abdominal radiographs should be done to assess the

142 bowel gas pattern and rule out perforation of a viscus. Pediatric surgery should be notified, and transfer to an appropriate facility should be initiated if necessary. Measures must be taken to promote thermoneutrality because this is essential for successful stabilization of a critically ill neonate. In vivo thermoregulation is an active process that requires oxygen, glucose, corticosteroids, and catecholamines [6]. A critically ill neonate who is hypoxic, hypoglycemic, or adrenally suppressed will be unable to maintain a normal body temperature and will become hypothermic. Prolonged hypothermia may result in cold stress that can affect all organ systems. The cold stressed infant may present with peripheral vasoconstriction to maintain heat, respiratory distress to increase oxygenation, metabolic acidosis due to hypoglycemia, and anaerobic metabolism if hypoxia persists, which further worsens the respiratory distress [7]. This vicious cycle of hypothermia and hypoxia will impede the response to resuscitation measures. For the cold infant, heat should be provided along with initial stabilization measures. Warmth can be initiated with a radiant warmer bed or overhead heat lamps. Although other methods such as chemical heating pads have been used, radiant heat is the most common and efficient in rewarming an infant [7]. In an ED setting, the radiant warmer also allows unrestricted access to the neonate for medical procedures. However, its use in the cold infant must be done with caution. Rapid warming can result in apnea, hypotension, and shock [8]. To prevent overheating of the neonate, use the servo-control option on the radiant warmer, set the skin temperature to 36.5C, and apply the skin probe to the anterior abdomen of the neonate. Oxygen consumption will increase as the infant's core temperature returns to normal. If the infant remains hypoxic because of respiratory or cardiac insufficiencies, rewarming may worsen tissue hypoxia. These complications must be monitored for, and if seen, the rewarming process should be slowed by resetting the servo-control skin temperature to 1C above the neonate's core temperature. Once the neonate achieves that temperature, the servo skin temperature is increased by 1C again until the neonate attains a core temperature of 36.5C. Care should be taken to avoid hyperthermia in neonates with suspected hypoxic ischemic encephalopathy because elevated core temperature can exacerbate neurologic injury in these cases.

U.O. Kim et al.

estimation and ionized calcium measurements should also be considered. Serum calcium, magnesium, phosphorus, blood ammonia, lactate and pyruvate, and cerebrospinal fluid studies should be performed if the neonate demonstrated central nervous system signs such as seizures and encephalopathy. Empiric use of IV broad-spectrum antibiotics is usually initiated in the ill appearing neonate after the initial blood work is obtained.

Differential Diagnoses
Once the neonate has recovered from the initial decompensation, efforts can be directed toward determining the etiology of the infant's condition. Working through the differential diagnosis in a critically ill neonate can be exhaustive and time-consuming. Commonly considered causes for a neonate's catastrophic deterioration are infection, congenital heart disease, and metabolic disorders (Table 1). However, there are other etiologies for critical illness in the neonate that must be considered as well. The following mnemonic, NEO SECRETS, may help focus the care and promote early identification of the cause of the infant's deterioration (Table 2).

Inborn Errors of Metabolism

Most neonates with inborn errors of metabolism become symptomatic after oral feeds and ingestion of the offending agent; therefore, most present between days 2 to 7 of life and may be erroneously diagnosed as having sepsis. Early suspicion of an inborn error of metabolism is essential for prompt diagnosis and the removal of the harmful metabolite. Affected neonates commonly demonstrate poor feeding with associated poor suck. Irritability, vomiting and failure to thrive, hepatosplenomegaly, jaundice, and abnormal
Table 1 Most common causes for catastrophic illness in the neonate. Ductal-Dependent Congenital Heart Disease (Require PGE1) Left-sided lesions: Coarctation of the aorta Interrupted aortic arch Aortic stenosis Hypoplastic left heart syndrome Right-sided lesions: Pulmonary atresia or stenosis Tetralogy of Fallot Tricuspid atresia

Infectious Diseases GBS Gram-negative bacilli Herpes simplex virus Enterovirus Respiratory syncytial virus

Metabolic Disorder Organic acidemias Hyperammonemias Fatty acid oxidation defects

Laboratory Evaluation
Laboratory evaluation of a critically ill neonate can be directed toward a specific etiology if suspected. In absence of a clear etiology, laboratory samples are also frequently obtained to help determine diagnosis and management. Appropriate routine laboratory work in a critically ill neonate consists of a complete blood count with a differential, blood and urine cultures, urinalysis, electrolytes including blood urea nitrogen and creatinine, glucose, and an arterial blood gas. Bedside blood glucose

For the purposes of this review article, this list is a brief outline of common diagnoses and is not meant to be comprehensive.

Evaluation and management of the critically ill neonate

Table 2 A mnemonic for the differential diagnoses of a critically ill neonate: NEO SECRETS. N E O S E C R E T S iNborn errors of metabolism Electrolyte abnormalities Overdose (toxin, poison) Seizures Enteric emergencies Cardiac abnormalities Recipe (formula, herbs, additives) Endocrine crisis Trauma Sepsis

143 all enteral feeds, initiation of IV fluids, and correction of associated acid-base and electrolyte abnormalities.

Electrolyte Abnormalities
Electrolyte abnormalities in the critically ill neonate are commonly the result of an underlying process rather than the initiating factor. However, delayed management may hinder any resuscitative efforts and may contribute to the neonate's ultimate demise. Water and electrolyte metabolism are closely associated, and the management of one may affect the other. Water balance in the neonate is primarily controlled by antidiuretic hormone whose action results in the uptake of water from the distal renal tubules as well as the cortical and medullary collecting ducts. This conservation of water is triggered by contraction of the intravascular volume and/or an increase in the serum osmolality. However, the renal response to antidiuretic hormone is diminished in neonates, thereby placing the critically ill neonate at high risk for imbalance [10]. Water requirements increase with advancing age. Neonates require 60 to 80 mL/kg per day in the first 2 days of life, 100 to 150 mL/kg per day during days 2 through 7, and 120 to 180 mL/kg per day thereafter until 28 days of life. For the dehydrated neonate, fluid resuscitation requires the replacement of the fluid deficit in addition to maintenance water requirements. The percentage of dehydration is simply calculated as follows: fluid deficit (L) = pre-illness weight (kg) illness weight (kg) [11]. For the neonate, the birth weight, hospital discharge weight, or the 2-week office visit weight should be available for comparison with the weight in the ED.

urine odors may be found. If the disease progresses unchecked, apnea, lethargy, a comatose state, and death may occur, and this deterioration can occur quickly [9]. Metabolic acidosis, persistent hypoglycemia, or a suggestive family history should increase the suspicion for an inborn error of metabolism. Prompt consultation with a neonatologist or medical specialist in genetics or inborn errors of metabolism is imperative. In addition to the initial stabilization blood work previously mentioned, directed laboratory evaluation includes serum amino acids, ammonia, pyruvate, lactate, urine organic acids, and urinalysis for ketones (Figure 1). If a confirmed serum ammonia level is more than 200 mol/L, immediate transfer to an intensive care unit with the ability to perform neonatal dialysis must be arranged. Specific treatments are indicated based on the final diagnosis and with the guidance of the medical specialist in genetics or inborn errors of metabolism. Immediate general measures will include the elimination of the inciting metabolite by stopping

Figure 1 Approach to the neonate with a suspected inborn error of metabolism. FAO, fatty acid oxidation; RTA, renal tubular acidosis.

144 Sodium balance in the neonate is primarily determined by the nephron. The fractional excretion of sodium is inversely proportional to gestational age. Although most healthy term infants have a mature basal sodium balance with a fractional excretion of sodium of less than 1%, certain conditions, including hypoxia and respiratory distress, can result in higher urinary losses of sodium and sodium imbalance [12]. Sodium supplementation in the first 24 hours of life is not necessary because hyponatremia at this time is due to excess free water and not sodium deficiency. During the remainder of the first week, neonates require 2 to 4 mEq/kg per day of sodium; this increases to 3 to 5 mEq/kg per day during the remainder of the first month of life. Similarly, potassium supplementation should be started on the second day of life. Potassium requirements in the first week of life are 1 to 2 mEq/kg per day and 2 to 3 mEq/kg per day for the remaining month of life. Hyponatremia, hyperkalemia, and metabolic acidosis may also be caused by congenital renal anomalies that are associated with progressive renal failure. The common
Table 3

U.O. Kim et al.

causes include autosomal recessive polycystic kidney disease, renal dysplasias, and renal tubular acidosis. These are usually accompanied by significant alterations in blood urea nitrogen and creatinine. The clinical signs and diagnostic evaluation of sodium and potassium abnormalities are shown in Table 3. The management of these derangements is the same: calculate the deficit and replace the losses while avoiding rapid correction. If the neonate is seizing because of hyponatremia, 4 to 6 mL/kg of 3% NaCl IV may be given rapidly without increased risk of central pontine myelinosis [13]. Hyperkalemia with electrocardiogram changes also requires additional measures: calcium gluconate 10% 100 mg/kg IV over 3 to 5 minutes, NaHCO3 (1-2 mEq/kg IV over 5-10 minutes), and insulin (0.1 U/kg/hr) IV infusion.

Overdose
Neonatal toxicology is very different from pediatric toxicology. Accidental ingestion is common in toddlers but rare in neonates. Their immature pharmacokinetics

Clinical presentation and diagnostic workup guidelines for common electrolyte abnormalities in a critically ill newborn. Signs and Symptoms Diagnostic Workup

If zK and shock, r/o CAH If AUOP and Aserum osmolality, r/o SIADH or renal defect If zUOP and dehydration, r/o improper mixing of formula Hypernatremia (Na+ >150 mEq/L) Lethargy or irritability If zUOP and Aurine specific gravity, r/o renal Seizures Seizures, decreased tone concentration defects If AUOP and z specific gravity, r/o breastfeeding failure, improper formula mixing Hypokalemia (K+ b3 mEq/L) Weakness If zurine K, r/o renal losses Ileus If hypertensive, r/o excess mineralocorticoids Hypertension or renin ECG changes: zP wave amplitude, If normotensive, r/o RTA, diuretics, inverted T waves GI losses or malnutrition Hyperkalemia (K+ N 6 mEq/L) Weakness If Aurine K+ and z17-OHP, r/o CAH Tetany If AUOP, r/o renal failure ECG changes: peaked T waves, If zchloride and metabolic acidosis, wide QRS, ST segment depression, V-fib r/o type IV RTA R/o metabolic acidosis because this can cause factitious hyperkalemia Hypocalcemia (total serum Clonic seizures, jerking or tetany If AMg+ correct Mg first Ca2+ b7 mg/dL, ionized Laryngospasm, stridor, weak cry If zserum Phos, r/o high Phos formula or cows Ca2+ b1.1 mmol/L) Prolonged QT interval milk ingestion, APTH If zserum Phos, zurine Ca, r/o renal failure If APTH, APhos, zAP, r/o Vit D abnormality If zPTH, APhos, zAP, r/o rickets If no thymus on CXR, r/o DiGeorge syndrome Hypoglycemia Lethargy Often symptom of other illness (serum glucose b40 mg/dL) Seizures (sepsis, asphyxia, shock, metabolic disorder) If zinsulin Ainsulin-like growth factor 1, r/o hyperinsulinemia
+

Hyponatremia (Na b130 mEq/L)

Edema Vomiting Muscle weakness Seizures and/or coma

r/o indicates rule out; UOP, urine output; SIADH, syndrome of inappropriate antidiuretic hormone; DTRs, deep tendon reflexes, RTA, renal tubular acidosis; ECG, electrocardiogram; V-fib, ventricular fibrillation; GI, gastrointestinal; 17-OHP, 17-hydroxyprogesterone; Ca, calcium; Mg, magnesium; Phos, phosphorus; PTH, parathyroid hormone; AP, alkaline phosphatase; Vit D, vitamin D; K, potassium; CAH, congenital adrenal hyperplasia; Na, sodium; CXR, chest x-ray.

Evaluation and management of the critically ill neonate

makes them more susceptible to toxins. Unique neonatal features include increased skin surface area-to-body weight ratio, immature hepatic and renal function resulting in impaired drug metabolism and excretion, and decreased plasma protein binding. All these factors allow drug toxicity at lower doses [14,15]. The routes of neonatal poisoning also differ from those of toddlers and include dermal exposure to toxins in addition to oral ingestion of contaminated breast milk. Dermal routes of exposure can occur if rubbing alcohol (isopropyl alcohol or ethanol) is used for antiseptic cord care or in baths for fever reduction. Systemic absorption of large amounts of topical diphenhydramine may also occur. Oral overdoses of diphenhydramine have been reported in cases of caregivers giving the antihistamine to sedate a fussy infant. Homeopathic colic remedies such as Gripe Water may contain sodium bicarbonate and ethanol and can cause toxicity if given in large quantities [16]. Ingestion of contaminated breast milk is another route for toxin exposure for the neonate. Morphine, methyl mercury, and pesticides have all been implicated in cases of acute neonatal deterioration and a complete maternal history including medications as well as complementary alternative medicines should be obtained for breast-fed infants.

145 metabolism is also regulated by several different hormones including glucagon and insulin. Surges of epinephrine and norepinephrine after birth contribute to the mobilization of hepatic glycogen [17], gluconeogenesis, and maintenance of plasma glucose concentration. Hepatic glucose production depends on the amount of glycogen stores, gluconeogenic precursors, gluconeogenic and glycogenolytic systems, and an intact endocrine system to coordinate these processes. Abnormalities in glucose metabolism reflects either exposure to irregular maternal glucose metabolism or intrinsic metabolic problems in the neonate [18]. Large for gestational age, which may be associated with diabetes mellitus in the mother, and small for gestational age infants are at increased risk of hypoglycemia. The clinical presentation and causes of hypocalcemia and hypoglycemia are detailed in Table 3. Similar to electrolyte abnormalities, treatment of hypocalcemia and hypoglycemia include supplementation of the deficient agent. Symptomatic hypocalcemia, which may present as seizures, requires an IV bolus of 100 to 200 mg/kg of 10% calcium gluconate followed by repeat boluses every 6 hours and/or a continuous calcium infusion. After the acute period, some neonates may need vitamin D supplementation and a low-phosphorus formula such as Similac PM 60/40 (Mead Johnson, Evansville, Indiana). Likewise, symptomatic hypoglycemia, which may also present as seizures, requires a 2 mL/kg IV mini-bolus of D10W to rapidly return the blood glucose level to normal without overshooting the desired glucose concentration [19]. This is then followed by a continuous glucose infusion. Determination of the glucose infusion rate (GIR) is determined by the following equation: GIR (mg/kg per minute) = [IV rate (mL/h) dextrose concentration (g/dL) 0.167] weight (kg). Most neonates will be euglycemic with a GIR of 5 to 8 mg/kg per minute. Infants requiring a higher GIR may have hyperinsulinemia. D25W boluses should be avoided. Congenital adrenal hyperplasia describes a group of disorders with an inherited defect in an enzyme required for the adrenocortical synthesis of cortisol from cholesterol [20]. The lack of glucocorticoids, and occasionally mineralocorticoids, in conjunction with the accumulation of premetabolites (commonly testosterone) result in the clinical manifestations of the affected neonate. The most common is 21-hydroxylase deficiency resulting in the inability to convert progesterone to aldosterone or cortisol and causing an accumulation of testosterone. Female infants classically present with ambiguous genitalia with varying degrees of virilization. However, a male infant may only have a hyperpigmented scrotum and no other physical abnormalities and can only be recognized by appropriate laboratory evaluation and results of the newborn screen if available. Affected infants classically have severe salt-wasting and hyperkalemia requiring aggressive fluid resuscitation and exogenous glucocorticoids and or mineralocorticoids. Some infants may be

Seizures
Neonatal seizures commonly manifest as subtle motor automatisms such as lip smacking, bicycling movements of the legs, tongue thrusting, apnea, and staring spells. The classic tonic-clonic movements are not typical in neonates, which may lure caretakers to overlook this diagnosis. The underlying etiology and treatment of the clinical seizures will dictate the outcome and ultimate neurologic development. Causes for neonatal seizures may include subarachnoid or subdural hemorrhages, intracranial infections, electrolyte abnormalities, and drug withdrawal. Less common causes are pyridoxine deficiency and local anesthetic toxicity. The diagnosis and management of seizures related to hyponatremia, hypocalcemia, and hypoglycemia are discussed in greater detail in the Electrolytes and Endocrine sections of this review. After electrolyte abnormalities are corrected and seizures continue, phenobarbital is the drug of choice, and 20 mg/kg IV should be given to halt seizure activity.

Endocrine Crisis
Endocrine emergencies such as hypoglycemia and hypocalcemia are relatively common in the neonatal period. Other disorders such as CAH and thyrotoxicosis are not routinely encountered in the ED setting but must be considered in critically ill neonates. Calcium metabolism is tightly regulated and involves the concerted effects of parathyroid hormone, vitamin D, and calcitonin on the targeted organs: intestines, kidneys, and bone. Glucose

146 hypertensive. If CAH is suspected, early consultation with a pediatric endocrinologist is recommended. Another cause of neonatal endocrine emergencies is thyrotoxicosis. Although rare, affected neonates can present from birth to 6 weeks of age with tachycardia, tremors, sweating, and irritability [21]. The most common cause of neonatal thyrotoxicosis is maternal Graves disease, which results in transplacental passage of thyroid-stimulating hormone receptor stimulating antibodies [22]. A complete history will also reveal the classic complaint of failure to thrive despite hyperphagia [20]. If neonatal thyrotoxicosis is suspected, early consultation with a pediatric endocrinologist is recommended.

U.O. Kim et al.

immediate evaluation by a pediatric cardiologist should be requested. Lesions with pulmonary overcirculation (atrial or ventricular septal defects, atrioventricular canal, truncus arteriosus, and partial anomalous pulmonary venous return) can present with evidence of congestive heart failure and respiratory distress; however, the deterioration in these infants is not as dramatic as with ductal dependent lesions. Congestive heart failure may also be due to supraventricular tachycardia and is suspected when the infant's heart rate is more than 220 bpm. A pediatric cardiologist should be consulted as soon as congenital heart disease is suspected.

Recipe
Incorrect mixing of formula may contribute to electrolyte imbalances in the neonate ranging from severe hypernatremia (not enough water added) to severe hyponatremia and water intoxication (not enough formula added) (see Electrolyte Abnormalities). A thorough history of the mixing of formula is essential. The recent trend of complementary and alternative medicine has promoted the use of natural foods including organic foods as well as the use of supplemental vitamins and homeopathic dietary additives. Nestle has released the first commercial infant formula with added probiotics (bifidobacteria) called Good Start Supreme with Natural Cultures to help support baby's healthy immune system. Although studies have yet to show a significant adverse effect of the commercially added probiotics (Lactobacillus, Bifidobacterium) [23-25], concern is raised regarding unregulated addition of probiotics to expressed breast milk or formula by well-meaning care takers. Because these additives are considered dietary supplements, there is no requirement to demonstrate safety, purity, or potency before marketing probiotics [26].

Cardiac Abnormalities
A decompensating neonate with a yet undiagnosed congenital cardiac defect is perhaps the most daunting patient for many emergency physicians. Most physicians remember the 5 classic cyanotic congenital heart defects: truncus arteriosus, transposition of the great arteries, tricuspid atresia, tetralogy of Fallot, and total anomalous pulmonary venous return. However, most of these patients become symptomatic during the first days of life and are most often diagnosed within the immediate newborn period. The emergency physician must be armed with a differential diagnosis of cardiac lesions that present after the immediate newborn period to provide appropriate therapy for an affected neonate. Ductal dependent lesions usually present in the first 2 weeks of life with severe hemodynamic compromise. The ductus arteriosus is usually patent in these infants in the immediate newborn period, and these infants can be asymptomatic at the time of discharge from the birth hospital. They remain wellappearing until they develop a dramatic hemodynamic collapse as the ductus arteriosus begins to close. Hence, neonates presenting with sudden appearance of shock require an immediate evaluation for ductal dependent congenital cardiac defects and should receive aggressive IV fluid resuscitation and prostaglandins to maintain the patency of the ductus arteriosus while awaiting evaluation from the cardiac specialists. The ductal dependent lesions are usually of 2 types: left-sided and right-sided obstructive lesions. Left-sided obstructive lesions (aortic stenosis, coarctation of the aorta, interrupted aortic arch, hypoplastic left heart syndrome) present with signs of severe systemic hypoperfusion with pallor, mottling, decreased or absent pulses, severe metabolic acidosis, and cardiomegaly with pulmonary congestion on chest radiograph (CXR). Right-sided obstructive lesions (pulmonary atresia, severe pulmonary stenosis, tetralogy of Fallot, tricuspid atresia) present with severe cyanosis, metabolic acidosis, and decreased perfusion of the lung fields on CXR. Prostaglandin infusion (PGE1 at a rate of 0.01-0.05 g/kg per minute) should be immediately started when neonates present with these signs, with or without a cardiac murmur, and an

Enteric Emergencies
Gastroschisis, omphalocele, tracheo-esophageal fistula, imperforate anus, meconium ileus, bowel atresias, and significant congenital diaphragmatic hernias are often diagnosed and addressed shortly after birth. Hence, they will not be included in the following discussion. Common enteric emergencies in neonates who were otherwise asymptomatic at home are discussed below. The suspicion of a surgical abdomen can be raised even with a limited history and physical exam. A history of feeding intolerance or bilious emesis with physical findings of a tender, distended abdomen with discoloration of the overlying skin should prompt immediate consultation with a surgeon skilled in neonatal care. A true surgical emergency is the neonate with malrotation with or without midgut volvulus. A contrast study, usually an upper GI, is required to rule out malrotation. Visualization of a dilated duodenum, abnormal positioned duodenojejunal junction with right-sided jejunal loops, and a malpositioned cecum

Evaluation and management of the critically ill neonate

on a contrast study confirms malrotation of the intestines [27]. If a corkscrew appearance of the jejunum is seen, midgut volvulus is present. Time is of the essence because intestinal necrosis can rapidly occur if there is a delay in making this diagnosis. Definitive surgical treatment consists of an exploratory laparotomy and Ladd's band procedure. If an neonate is previously premature, is an infant of a cocaine-using mother, or has a history of surgical closure of an abdominal wall defect, necrotizing enterocolitis must be considered. Abdominal radiographs may reveal intestinal dilatation and thickened bowel walls. The presence of pneumatosis intestinalis or portal venous gas is pathognomonic for necrotizing enterocolitis. If there is no free air or evidence of peritonitis, medical management should consist of IV antibiotics and bowel rest. If free air or peritonitis is found, surgical intervention is indicated. Hirschsprung disease should be considered in the neonate with a history of failure to pass meconium or infrequent stools and abdominal distension. A rectal biopsy is diagnostic and demonstrates the absence of ganglion cells. If there is rapid progression of abdominal distension and profuse vomiting, toxic megacolon must be assumed and emergent surgical treatment with a diverting colostomy may be necessary.

147 sepsis is a well-known cause of neonatal collapse. Common microbes of concern are GBS, Listeria monocytogenes, Escherichia coli, and Staphylococcus aureus. Maternal history of GBS status and penicillin prophylaxis at the time of delivery may be helpful but late-onset GBS is commonly community acquired. It is important to note that intrapartum and early neonatal antibiotic treatment does not prevent late-onset GBS meningitis, pneumonia, or sepsis. Maternal history of a cervical cerclage during pregnancy may increase the risk for gram-negative sepsis in the neonate, whereas a history of brown-colored amniotic fluid (which may be mistaken as meconiumstained fluid) may suggest Listeria. Prompt initiation of broad-spectrum IV antibiotics such as ampicillin and gentamycin or ampicillin and cefotaxime is essential. Ampicillin is effective against GBS, Listeria, and S aureus, whereas gentamycin is effective against most gram-negative bacilli. If ampicillin and cefotaxime are used, remember that several strains of lactamaseproducing E coli have become resistant to these drugs [29] and the threshold to add or change cefotaxime to gentamycin in the neonate with suspected gram-negative sepsis must be low. Viral infections include herpes simplex virus and enterovirus and can also compromise a neonate. Disseminated neonatal herpes simplex virus infection is clinically indistinguishable from sepsis and should be considered in the differential of sepsis. A history of maternal genital lesions or respiratory symptoms may be helpful but are often negative. If sepsis is highly suspected, consider a viral infection as well. In addition to blood cultures, send surface cultures and blood or cerebrospinal fluid for polymerase chain reaction assays for the suspected virus. Acyclovir should be started in septic-appearing neonates with signs of encephalopathy and/or disseminated intravascular coagulopathy. Because pleconaril is no longer available for the treatment of neonates with enteroviral infections, supportive treatment must be maximized. A detailed review of neonatal sepsis is presented later in the article on Evaluation and management of a newborn with sepsis.

Trauma (After the Perinatal Period)

Neonates are not immune from accidental injuries such as motor vehicle accidents, falls, and the antics of overzealous older siblings. Unfortunately, they may also be the victims of adult anger, frustration, and anxiety. An obtunded, encephalopathic neonate may have a metabolic disorder or sepsis, but trauma must also be considered. Intracranial pathology includes hemorrhage, edema, contusional tears, and diffuse axonal injury [28]. Other organs can be involved in trauma. The musculoskeletal system can also be affected as evidenced by fractures of varying degrees, but bony injury alone is rarely a cause of acute clinical deterioration of a neonate. However, if associated with a pneumothorax or liver laceration, emergent resuscitation may be required. Blunt abdominal trauma can result in adrenal hemorrhage, which can lead to hypovolemia and shock. Hence, radiographic imaging and ultrasonography play a crucial role in the evaluation of a critically ill neonate who has been the victim of a trauma. Pediatric neurosurgeons and pediatric general surgeons should be consulted early in the management of an injured neonate to help provide prompt surgical intervention if needed and collaborate with the medical team in maximizing the infant's outcome.

Summary
Neonatal symptoms of illness are limited and nonspecific, requiring the treating physician to be astute and complete in the care and management of these patients. Regardless of the diagnosis, the management of the critically ill neonate is still dependent on a rapid assessment and support of airway, breathing, and circulation. Although the history and physical examination may help narrow the differential diagnosis, beginning resuscitation and ensuring thermoneutrality are essential for the successful management of any critically ill neonate. Laboratory evaluation can be directed toward a specific diagnosis or can be broad enough to allow for the identification of a diagnosis or tracking changes in the status of the neonate. Although the

Sepsis
Sepsis is intentionally discussed last so as to give all other potential diagnoses careful consideration before attributing a neonate's deterioration to sepsis. Nonetheless, neonatal

148 differential diagnosis is extensive, a systematic approach to initial resuscitation, followed by application of the NEO SECRETS mnemonic will allow the treating physician to be focused and able to implement time-efficient interventions that will lead to the best possible outcome for the critically ill neonate.

U.O. Kim et al.

13. Sarniak AP, Meert K, Hackbarth R, et al. Management of hyponatremic seizures in children with hypertonic saline: a safe and effective strategy. Crit Care Med 1991;19:758-62. 14. Mendenhall AK, Eichenfield LF. Back to basics: caring for the newborn's skin. Contemp Pediatr 2001;17:98-114. 15. Spray A, Siegfried E. Dermatologic toxicology in children. Pediatr Ann 2001;30:197-202. 16. Blumenthal I. The gripe water story. J R Soc Med 2000;93:172-4. 17. Kawai Y, Arinze IJ. Activation of glycogenolysis in neonatal liver. J Biol Chem 1981;256:853-8. 18. Kalhan SC, Parimi PS. Disorders of carbohydrate metabolism. In: Fanaroff AA, Martin RJ, editors. Neonatal-perinatal medicine: diseases of the fetus and infant. 7th ed., vol 2. Philadelphia, PA: Mosby; 2002. p. 1351-76. 19. McGowan JE. Neonatal hypoglycemia. Pediatr Rev 1999;20:e6-e15. 20. Levine LS. Congenital adrenal hyperplasia. Pediatr Rev 2000;21: 159-67. 21. Foley Jr TP. Maternally transferred thyroid diseases in the infant: recognition and treatment. In: Bercu BB, Shulman DI, editors. Advances in perinatal thyroidology. New York, NY: Plenum Press; 1991. p. 209-26. 22. LaFranchi S. Evaluation and management of neonatal Grave's disease; 2008. Up to Date. Available at: http://patients.uptodate.com/topic. asp?file=pediendo/5108. Accessed 7-25-08. 23. Puccio G, Cajozzo C, Meli F, et al. Clinical evaluation of a new starter formula for infants containing live Bifidobacterium logum BL999 and prebiotics. Nutrition 2007;23:1-8. 24. Saavedra JM, Abi-Hanna A, Moore N, et al. Long-term consumption of infant formulas containing live probiotic bacteria: tolerance and safety. Am J Clin Nutr 2004;79:261-7. 25. Boehm G, Jelinek J, Stahl B, et al. Prebiotics in infant formulas. J Clin Gastroenterol 2004;38:s76-9. 26. Boyle RJ, Robins-Browne RM, Tang MLK. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 2000;83:1256-64. 27. Ryckman FC. Selected anomalies and intestinal obstruction. In: Fanaroff AA, Martin RJ, editors. Neonatal-perinatal medicine: diseases of the fetus and infant. 7th ed., vol 2. Philadelphia, PA: Mosby; 2002. p. 1276-307. 28. David TJ. Shaken baby (shaken impact) syndrome: non-accidental head injury in infancy. J Royal Soc Med 1999;92:556-61. 29. Paterson DL, Bonomo RA. Extended-spectrum b-lactamases: a clinical update. Clin Microbiol Rev 2005;18:657-86.

References
1. Ludwig-Beyer P, Heuther P. Pain, temperature, sleep, and sensory function. In: Huether S, McCance K, editors. Understanding pathophysiology. St. Louis, MO: Mosby-Year Book; 1996. p. 319-45. 2. Fletcher MA. General information. Physical diagnosis in neonatology. Philadelphia, PA: Lippincott, Williams & Wilkins; 1998. p. 3-28. 3. Southgate WM, Pittard III WB. Classification & physical examination of the newborn. In: Klaus MH, Fanaroff AA, editors. Care of the highrisk neonate. 5th ed. Philadelphia, PA: Saunders; 2001. p. 117. 4. Zubrow AB, Hulman S, Kushner H, et al. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group. J Perinatol 1995;15:470. 5. Kattwinkel J, editor. Textbook of neonatal resuscitation. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006. p. 6-4, 6-5. 6. Noerr B. Keeping the newborn warm: understanding thermoregulation. Mother Baby J 1997;2:6-12. 7. Hackman PS. Recognizing and understanding the cold-stressed term infant. Neonatal Netw 2001;20:35-41. 8. Perlstein PH, Edwards NK, Sutherland JM. Apnea in premature infants and incubator air temperature changes. N Engl J Med 1970; 282:461. 9. Zinn AB. Inborn errors of metabolism. In: Fanaroff AA, Martin RJ, editors. Neonatal-perinatal medicine: diseases of the fetus and infant. 7th ed., Vol. 2. Philadelphia, PA: Mosby; 2002. p. 1468-516. 10. McCance RA, Naylar NJ, Widdowson EM. The renal response of infants to a large dose of water. Arch Dis Child 1954;29:104. 11. Stone B. Fluids and electrolytes. In: Robertson J, Shilkofski N, editors. The Harriet Lane handbook: a manual for pediatric house officers. 17th ed. Philadelphia, PA: Mosby; 2005. p. 285. 12. Lorenz J, Kleinman LI, Ahmed G, et al. Phases of fluid and electrolyte homeostasis in the extremely low birth weight infant. Pediatrics 1995; 96:484-9.

The Jaundiced Newborn in the Emergency Department: Prevention of Kernicterus

Vinod K. Bhutani, MD, FAAP, Lois Johnson, MD, FAAPy
A jaundiced neonate in an emergency department can be a catastrophic emergency that necessitates expeditious care. Progressive and irreversible bilirubin neurotoxicity may be minimized by rapid reduction of serum bilirubin concentrations through a crash-cart approach: immediate administration of intensive phototherapy and preparation for a possible exchange transfusion. Onset of acute bilirubin encephalopathy (ABE) is initially nonspecific and insidious and may progress to irritability, painful tonic spasms, apnea, seizures, obtundation, coma, respiratory failure, and death. Early recognition of hyperbilirubinemia severity can facilitate rapid transition to treatment and overcome the major barriers to timely therapy. Emergency department personnel need to develop policies that define access to intensive phototherapy either on site or immediate access to a neonatal/pediatric critical care facility. This article reviews a systems strategy for a crash-cart approach that may be initiated in the emergency department for a safer transition to alternative facilities to manage and prevent ABE. Clin Ped Emerg Med 9:149-159 C 2008 Elsevier Inc. All rights reserved. KEYWORDS acute bilirubin encephalopathy, newborn jaundice, crash cart approach, intensive phototherapy, triage for newborn jaundice, severe neonatal hyperbilirubinemia

Clinical Case Report

The patient is currently a 5-year-old male with hearing loss (that has responded to cochlear implants), choreoathetosis, decidual teeth enamel dysplasia, and upgaze abnormalities. His story begins at birth as a normal healthy newborn. The patient's mother was admitted to a regional hospital at 7:30 PM, and the baby was delivered at 7:26 AM the next day (Thursday). His mother, aged 22 years, Hispanic and nonEnglish-speaking, had blood type AB, was Rh-positive, was hepatitis surface antigen negative, and was Rubella-immune. A marginal abruption of the placenta was noted by the obstetrician. Her HIV status was negative.
Stanford University School of Medicine and Lucile Packard Children's Hospital, Stanford, CA. Pennsylvania Center for Kernicterus, Philadelphia, PA. Reprint requests and correspondence: Vinod K. Bhutani, MD, Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Lucile Packard Children's Hospital, 750 Welch Ave #315, Stanford, CA 94304. (E-mail: bhutani@stanford.edu) 1522-8401/$ - see front matter C 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2008.06.004

At birth, the newborn was noted to be term gestation at 38 weeks and appropriate for gestational age. The Apgar scores were 10 at 1 and 5 minutes. The birth weight was 2715 g, the length was 48.5 cm, and the head circumference was 32.5 cm. The newborn was examined at 8:10 AM, with vitals signs including a pulse rate of 156/min and a respiratory rate of 36/min. The examination was recorded as normal, and no clinical risk factors were noted. He was admitted to the well baby nursery and declared a stable newborn by a nurse. At age 24 hours (Friday), the skin color was noted as pink. Mother and baby were discharged from the maternity floor at an infant age of about 29 hours. No discharge orders were provided other than to return to see the obstetrician 6 weeks later and to the pediatrician in 2 weeks. On Sunday, at an infant age of approximately 74 hours, the patient was seen at the emergency department (ED) at the birthing hospital. He was alert, oriented, and conscious, with a heart rate of 160/min, respiratory rate of 39/min, and a temperature of 39C. The ED chart lists him as well, baby has turned yellow, good startle reflex child jaundiced. The patient's parents left the ED 149

150 before completion of care because they were frustrated with lack of attention about 2 hours later. The patient then presented to the ED at the Children's Hospital at age 77 hours. At age 78 hours, the infant was examined by the ED physician and noted to have good tone. Urine and blood tests were obtained while the infant was alert and active. The total serum bilirubin (TSB) of 44.1 mg/dL was reported at age 81 hours. At this time, the infant was very yellow but alert. The neonatal intensive care unit (NICU) was notified. The infant was admitted to the NICU at age 83 hours. Vital signs upon admission were the following: HR = 134/min, RR = 48/min, T = 37.3C, BP = 71/38 mm Hg (mean = 58). The infant is now described as having orange jaundice, was very icteric, and was irritable. Between ages 83 and 86 hours, he was noted to be jittery at times, with decreased tone in leg, and when supine infant tend(ed) to turn trunk to head and shoulders and arms to the right and keep lower extremities midline. He was administered phototherapy. Consent for blood exchange transfusion was obtained at age 87 hours. After discharge from the intensive care nursery, there was no further recurrence of jaundice, and no specific cause for the hazardous hyperbilirubinemia was identified. At age 3 months, auditory brainstem response testing showed sensorineural hearing loss. Examination at age 18 months was consistent with kernicterus.

V.K. Bhutani, L. Johnson

5. Symptomatic jaundiced infants and those with severe hyperbilirubinemia should be directly and promptly referred to neonatal and pediatric intensive care facilities, and in certain centers might even bypass the ED.

Introduction
Jaundice is the commonest clinical diagnosis in neonatal medicine and is due to elevated unconjugated (indirect) and/or conjugated (direct) bilirubin levels [2]. Confirmation is by a total serum (plasma) blood test for bilirubin (TSB) or transcutaneous bilirubin (TcB). Bilirubin is a known antioxidant at low levels (in vitro) and a potent neurotoxin at high levels (in vivo). Estimated incidence in the United States is tabulated in Table 1 [3]. Elevated bilirubin concentrations may occur due to increased bilirubin production (breakdown of heme moiety of hemoglobin) and/or delayed bilirubin elimination (hepatic and intestinal), as well as, by a unique neonatal phenomenon of enterohepatic reabsorption of bilirubin. Bilirubin and carbon monoxide are the major degradation products of heme. The nonwater-soluble unconjugated bilirubin (bound to albumin) is processed in the hepatocyte to the excretable water-solubleconjugated bilirubin by the enzyme uridine-diphospho-glucuronosyl-transferase (UGT). With decreased gastrointestinal activity and/or starvation in the immediate postnatal period, some of this conjugated bilirubin is reconverted to unconjugated bilirubin in the gut and reabsorbed in the circulation (enterohepatic recirculation). The neurotoxic effect of bilirubin does not correlate well with TSB levels because it is influenced by the ability of unconjugated bilirubin (mg/dL) to bind with albumin (g/dL) at ratio of about 8:1. Bilirubin binding to albumin is influenced by acidosis, hypoalbuminemia, lower gestational age, postnatal age (age b3 days), and interference by drugs (especially sulfas and some cephalosporins). Neurologic injury, assessed by magnetic resonance imaging, is evident in the basal ganglia (globus pallidus and subthalamic nuclei), brainstem nuclei (especially, auditory, and cochlear nuclei), inferior colliTable 1 Current known incidence of severe hyperbilirubinemia in the United States [3]. TSB Levels at Age > 72 h N17 mg/dL (N95th percentile) significant N20 mg/dL (N98th percentile) severe in late preterm infants N25 mg/dL (N99.9th percentile) severe N30 mg/dL (N99.99th percentile) hazardous ABE Incidence 8.1%-10% 1%-2% 0.16% 0%-0.032% 1 in 10 1 in 70 1 in 700 1 in 10,000

Lessons Learned From the Case Report

In this formerly healthy newborn infant's hyperbilirubinemia and acute bilirubin encephalopathy (ABE) experiences, there were multiple lapses in the health care provided during his first 4 days of life (particularly on a weekend). These delays were augmented by absence of an identified and accessible medical home. We conducted a root cause analysis of this self-referred admission to the ED and other similar cases directed from physician's offices [1]. Lessons from this case are discussed in this article and include the following: 1. Progressive or suddenly recognized jaundice with TSB concentrations N25 mg/dL (severe hyperbilirubinemia for term infants) and/or signs of ABE in newborn infants are medical emergencies. 2. These infants require prompt and immediate implementation of bilirubin reduction strategies that include intensive phototherapy and/or preparation for possible blood exchange transfusion. 3. Transition from progressive hyperbilirubinemia to ABE is often rapid and unpredictable. There is a very narrow margin of safety, and time matters. 4. Each ED that attends to a neonatal population should have a triage policy to identify infants at risk for ABE (within 1 to 2 hours of presentation) and a process for direct and prompt transfer to a specialty neonatal/pediatric facility for specific care.

1 in 40,000 to 70,000 live births (estimate)

The jaundiced newborn in the ED

culus, the cerebellum and the hippocampus (especially the CA2 sector). Acute clinical manifestations of bilirubin neurotoxicity are those of ABE: progressive changes in infant's cry pattern, muscle tone, apnea, seizures, and behavioral changes. If unmonitored or with delayed treatment, irreversible posticteric sequelae, known as kernicterus, may manifest during infancy. These are characterized by movement disorders of dystonia, athetosis and choreoathetosis, sensorineural hearing loss, oculomotor abnormalities of strabismus, and gaze palsies (especially, upgaze). Kernicterus is one of the most easily preventable forms of neonatal brain damage [2-9].

151 often daily, follow-up until the bilirubin concentrations decline substantially [1]. Common clinical predisposing factors include those that aggravate hemolysis, promote functional immaturity of the liver, or delay elimination and are outlined in Table 2 [10,11]. Red blood cell breakdown occurs from a number of conditions in newborns and increases the risk of severe hyperbilirubinemia. Infants with ABO or Rh blood group incompatibilities may develop severe hyperbilirubinemia within the first 24 hours after birth. Increased hemolysis results from maternal antibodies reacting with fetal and neonatal antigens. Rh incompatibilities may occur when the infant is Rh-positive and the mother is Rh-negative. With the introduction of Rh immunoglobin in the 1960s, the incidence of Rh incompatibility dropped significantly. Today, ABO incompatibilities have become the main blood group incompatibility. ABO incompatibilities may occur when the infant has type A, B, or AB blood and the mother has type O. Less frequently, incompatibility of minor group blood types may lead to significant hemolysis. Glucose6-phosphate dehydrogenase (G6PD) deficiency is also frequently associated with neonatal hyperbilirubinemia. Although increased hemolysis may clearly contribute to

Predisposing Clinical Risk Factors

Neonatal jaundice is common, so it is important that clinicians recognize and understand the factors that place infants at increased risk of developing severe hyperbilirubinemia. A predischarge TSB/TcB, plotted on the hourspecific bilirubin nomogram at the time of infant's discharge from the birthing hospital, accurately predicts the postnatal risk of severe hyperbilirubinemia (Figure 1). Infants with bilirubin concentrations in the high-risk zones of the nomogram require a more rigorous and frequent,

Figure 1 Serial values of TSB before (x), during (), and subsequent () to intensive phototherapy in a late preterm (36 and 4/7 weeks gestational age) infant with a birthweight of 3840 g and discharged at age 37 hours, as shown on a hour-specific bilirubin nomogram [2]. He was seen in the pediatrician's office the next day. On Sunday morning, the family was concerned about the infant's color and poor feeding. He was brought to the birthing hospital ED. Within an hour, he was transferred to the NICU, placed under intensive phototherapy, and initiated on an intravenous fluid correction for dehydration. An automated auditory brainstem response was abnormal in the right ear. Clinical signs of lethargy and irritability with a normal muscle tone were consistent with a diagnosis of early ABE. Preparations were made for an exchange transfusion. Within 3 hours, there was a substantial decline in the TSB concentration. The repeat automated auditory brainstem response within 4 hours of treatment was normalized. Infant had done well on long-term follow-up at age 18 months. (Nomogram reprinted with permission.)

152
Table 2 Some of the common causes for neonatal hyperbilirubinemia [1 1]. Clinical Conditions

V.K. Bhutani, L. Johnson

Biological Basis Increased bilirubin production

1. IsoimmunizationRh, ABO, and minor group incompatibilities 2. RBC enzyme defectsG6PD deficiency, pyruvate kinase deficiency, hexokinase deficiency; congenital erythropoietic porphyria; etc 3. RBC structural defectshereditary spherocytosis (autosomal dominant; especially if 1 parent has splenomegaly or had splenectomy); hereditary elliptocytosis; infantile pyknocytosis 4. Sepsisbacterial; viral (such as CMV); protozoal 5. Extravasated bloodbruising, cephalohematoma, subgaleal bleed, subdural hematoma, hemangiomas 6. Polycythemia Increased enterohepatic 1. Prematurity circulation 2. Starvation 3. Decreased gastrointestinal activity 4. Delayed bacterial colonization of the gut 5. Pyloric stenosis, GI immotility or obstruction Decreased elimination 1. Crigler-Najar syndrome: (type 1 UGT)autosomal recessive, diagnose by liver biopsy 2. Gilbert syndrome: neonatal variant often confused as breast milk jaundice. Sometimes coinherited with G6PD deficiency 3. Arias syndrome (type II UGT)autosomal dominant with variable penetrance 4. Transient familial neonatal hyperbilirubinemia (Lucey-Driscoll) syndromerare, caused by inhibitor of UGT from mother
Abbreviations: RBC, red blood cell; CMV, cytomegalovirus; GI, gastrointestinal; UGT, uridine-diphospho-glucuronosyl-transferase; G6PD, glucose-6-phosphate dehydrogenase.

the hyperbilirubinemia in some G6PD-deficient populations, in other populations, decreased conjugation is the main contributor to hyperbilirubinemia. Decreased bilirubin conjugation, the result of a variant promoter for the gene UGT1A1 encoding the B-UGT enzyme (as seen in Gilbert's syndrome), has been shown to contribute significantly to the development of hyperbilirubinemia in neonates with the Mediterranean type of G6PD deficiency. Thus, it is likely that G6PD-deficient neonates who develop bilirubin toxicity have a combination of increased bilirubin production rates and the variant UGT1A1 promoter gene that diminishes the capacity for bilirubin conjugation. Presently, neonatal screening for G6PD deficiency is not routine. Evaluation for G6PD deficiency needs to be considered among infants with progressive hyperbilirubinemia and ethnic or racial risk factors and, those infants who respond poorly to phototherapy. The G6PD enzyme deficiency should be suspected in any infant with unexplained severe hyperbilirubinemia or in those from regions including South and Eastern Asia, African coasts, the Mediterranean, and parts of the Middle East. Population migrations and multiracial ancestry have changed the global patterns of G6PD deficiency. History of exposure to agents that trigger a hemolytic reaction (such as mothballs, fava beans, antimalarial drugs) should be elicited from mothers of known G6PD carriers or from those who are at risk because of ethnicity or race. Perinatal factors can increase an infant's risk for developing hyperbilirubinemia. Bruised infants and those with a cephalohematoma are more likely to experience hyperbilirubinemia due to increased red cell break down. Pitocin has been linked to hyperbilirubinemia, although

the mechanism underlying this relationship is not clearly understood. Infants with perinatal sepsis and asphyxia are more vulnerable to bilirubin toxicity and neuronal susceptibility at lower concentrations of bilirubin. Breast-feeding and its association with newborn jaundice are complex. An evidence-based review of issues surrounding neonatal hyperbilirubinemia found that among the identified cases of kernicterus, almost all of the infants were breast-fed. Root cause analysis of lactation failure in infants with kernicterus identified inadequate (a) clinician-initiated education, (b) on-site certified consultants, (c) documentation of infant latching, (d) measure of milk transfer, and (e) follow-up and record of urine and stool pattern changes. Thus, a suboptimal lactation experience and exclusive breast-feeding may be considered as a predictive risk factor for hyperbilirubinemia. Inadequate intake and dehydration slow bilirubin elimination and increase enterohepatic circulation. Conversely, good milk transfer and infant weight gain are reassuring signs in a breast-fed infant and suggest that severe hyperbilirubinemia is less likely to occur. Approximately 20% to 40% of women have a high level of -glucoronidase in their breast milk that may potentiate hyperbilirubinemia by increasing enterohepatic circulation of bilirubin. However, this is an area that requires further investigation because some studies have not found increased -glucoronidase levels present in breast-fed infants with hyperbilirubinemia. A population-based study demonstrated that bilirubin levels for appropriately breast-fed infants are only marginally higher than those in exclusively formula fed infants. Late preterm gestation infants born between 34 and 36 and 6/7 weeks of gestation are at high risk of severe

The jaundiced newborn in the ED

Table 3 Clinical risk factors for severe neonatal hyperbilirubinemia [2]. Risk Factors Major 1. Predischarge TSB/TcB N95th percentile 2. Jaundice at age b24 h 3. Blood group incompatibility 4. Gestational age 35-36 wk 5. Sibling received phototherapy 6. Cephalohematoma or significant bruising 7. Exclusive but suboptimal breast-feeding 8. East Asian race Minor 9. Predischarge TSB/TcB: 75th-95th percentile 10. Gestational age 37-38 wk 11. Jaundice observed before discharge 12. Sibling with jaundice 13. Macrosomic infant of a diabetic mother 14.Maternal age z25 y 15. Male sex Assessment Laboratory test Clinical observation Laboratory test Clinical examination History Clinical examination History and observation History Laboratory test Clinical examination Observation History History Examination History

153 coloration of the sclera, usually evident in adults, is often a late observation in newborn infants. It is often difficult to visualize the sclera during the first few days after birth. Progression of recognition of jaundice may be cephalocaudal or it can fade in and out like a tan. It is important that clinicians do not estimate severity of hyperbilirubinemia based on skin color; several studies have confirmed the inability of the human eye to accurately predict the level of bilirubinemia based on skin color [14].

Risk of Bilirubin Neurotoxicity

Clinical risk factors for neurotoxicity include prematurity, asphyxia, sepsis, hypoalbuminemia, lethargy, and temperature instability. The neonatal brain has a unique blood-brain barrier that slows the equilibrium between plasma and brain and is generally protective. When the blood-brain barrier is intact, as in the healthy newborn, the rate of bilirubin uptake by the brain is likely to be determined by the (1) concentration of unbound bilirubin, (2) structural and genetic vulnerability of the brain, (3) duration of exposure, (4) ability of bilirubin to bind to albumin, and (5) local cerebral blood perfusion. In healthy late-preterm and term infants, the risk of bilirubininduced neuronal injury is related to the concentration of unbound or free unconjugated bilirubin and hydrogen ions (pH) in the blood. Free unconjugated bilirubin occurs when the albumin binding capacity is exceeded or when other displacing substances compete for bilirubin binding sites on albumin. If the blood-brain barrier is disrupted, as can occur in infants who are sick, asphyxiated, or who have experienced brain hemorrhage, bilirubin bound to albumin can move rapidly into the extracellular space in the brain. When the concentration of unbound bilirubin is high, entry of bilirubin into neuronal cells can produce a sequence of cellular events that may lead to neurotoxicity and ultimately to cell death. However, because the injurious effects of bilirubin on neuronal cells depend on both duration and magnitude of the exposure, it is possible that minimal harmful exposure may be reversed. The extent to which cellular defense mechanisms contribute to variations of toxic effects of bilirubin remains uncertain [15].

hyperbilirubinemia, dehydration, and ABE. In California, they account for nearly 25% of the readmissions for healthy infants during the first month of age. The risk for bilirubin neurotoxicity occurring at lower levels of hyperbilirubinemia has been attributed to lower albumin levels and immature livers that are less able to eliminate bilirubin. Infants with diminished albumin binding sites are at risk for bilirubin neurotoxicity [12]. The 2004 American Academy of Pediatrics (AAP) guidelines provide a listing of major and minor clinical risk factors for severe hyperbilirubinemia (Table 3). Of these, gestational immaturity and the predischarge TSB/TcB are the best predictors [13].

Acute Bilirubin Encephalopathy

The neurotoxic effects of bilirubin can lead to ABE. Because the earliest signs of ABE are subtle and nonspecific, they may be missed. The classic signs of ABE are increasing hypertonia, especially of extensor muscles with retrocollis and opisthotonos, in association with varying degrees of drowsiness; poor feeding; hypotonia; alternating tone; and high-pitched or absent cry. These signs can be described in terms of the infant's mental status, muscle tone, and cry [16]. Signs of ABE should be determined by close clinical observation and by direct questioning of parents. The rate of progression of clinical signs depends on the rate of bilirubin rise, the duration of

Recognition and Follow-Up of Jaundice

Jaundice is recognized by blanching the skin over the forehead, sternum, hip, knees and ankles with digital pressure to reveal the underlying skin and subcutaneous tissue color. Skin color varies from healthy pink, lemony yellow, to orange and sienna. Assessment is limited by skin pigmentation, plethora, decreased ambient light, and prior exposure to sun or phototherapy. Melanin skin pigmentation is variable among individuals and is influenced by ancestry, ethnicity, and individual responses to sunlight exposure. If jaundice cannot be clearly excluded, one may assess the mucosal areas such as the gum margins. Yellow

154 hyperbilirubinemia, the adequacy of albumin binding reserves, the level of unbound bilirubin, host susceptibility, and the presence of comorbidities. Prompt and effective intervention when ABE symptoms appear can prevent chronic kernicteric sequelae. A combination of intensive phototherapy and exchange transfusion may be used to rapidly reduce the bilirubin load and potentially the extent of brain damage. Late signs of ABE include cessation of feeding, bicycling movements, inconsolable irritability and crying, respiratory failure, progressive coma, or intractable seizures. The likelihood of kernicteric sequelae is increased when late signs are present. Acute bilirubin encephalopathy may also lead to death after respiratory failure, apnea, seizures, and/or coma. Clinical risk factors for bilirubin neurotoxicity are used as guidelines to tailor the bilirubin thresholds for initiation of intensive phototherapy and are useful to manage an infant until the availability and validation of objective tests such as the unbound bilirubin and auditory brainstem responses can be obtained. Overall, current laboratory and clinical data indicate bilirubin damages brain tissue cells via necrosis and apoptosis, either alone or in combination, in a neuroanatomic distribution dependent on the amount, duration, and developmental timing of exposure of sensitive brain tissue to free bilirubin. As described by Shapiro [17], the extent of neuronal injury depends on (1) the amount and duration
Table 4 Options Assess risk (triage management)

V.K. Bhutani, L. Johnson

of exposure to free bilirubin (high level, short duration exposure not necessarily the same as lower level, long duration exposure), (2) the susceptibility of the developing nervous system, (3) the relative amount of necrosis vs apoptosis produced, and (4) whether surviving neurons will be functionally normal or more susceptible to other stressors either at the time of hyperbilirubinemia or afterwards.

Timing of Interventions to Reduce Excessive Bilirubin Load

Is the outcome of an infant with ABE different if phototherapy and/or exchange transfusion is provided sooner? The timing of bilirubin reduction strategies impacts the outcome of severe hyperbilirubinemia complicated by ABE. Early implementation of strategies to rapidly and effectively reduce the excessive bilirubin load before the onset of neurologic signs, in all likelihood, would prevent chronic posticteric sequelae or kernicterus [18]. Once the clinical signs of bilirubin neurotoxicity are evident, emergent intervention to expeditiously reduce the bilirubin load is the only known recourse in clinical practice. To date, exchange transfusion remains the only known clinical option. Although there is no predictive evidence that a specific bilirubin level will or will not cause neurotoxic damage, the critical bilirubin level, in

Steps for a crash-cart approach to manage hazardous hyperbilirubinemia [8]. Most Effective Means to Minimize Brain Damage

1. Rapid clinical examination to check (a) severity of jaundice, (b) TcB test, (c) neurologic examination for muscle tone, behavior, and cry pattern. 2. Plot TcB and recent TSB level on the AAP bilirubin nomogram for risk assessment and for exchange transfusion. [2] 3. Weigh against the potential risk of ABE and timeliness/safety of interventions (experience is essential). 4. Communicate with families regarding potential of imminent risk. Laboratory tests (do not wait for results TSB and direct bilirubin level, serum albumin, serum electrolytes to start phototherapy) Blood type (ABO, Rh), direct antibody test (Coombs) CBC, differential and smear for cell morphology; reticulocyte count G6PD enzyme assay (quantitative) Urine for reducing substances and other tests: as needed Immediate Interventions Start intensive phototherapy (while procedures are being done). Consider immune globulin (IVIG) for isoimmune hemolytic disease. Albumin infusion (1 g/kg) for hypoalbuminemia (b3 g/dL) just before exchange transfusion has been used but concerns remain of its safety. Definitive procedure Isovolume double volume exchange (170 mL/kg in term, 190 mL/kg in preterm). Indications: For presence or onset of any neurologic signs, failed automated auditory brainstem response, if TSB approaches exchange threshold or bilirubin (mg) to albumin (g) ratio is N7 (mg/g) or failure of intensive phototherapy to substantially reduce TSB levels. Duration of procedure Exchange transfusion may be accomplished within 3 to 4 hours (informed consent, laboratory evaluation, central catheters and access and other procedures). Ideal location: neonatal/pediatric intensive care facility. Technical problems A single volume exchange transfusion may be adequate while intensive phototherapy is being delivered.

The jaundiced newborn in the ED

any healthy baby, is influenced by postnatal age, maturity within the range of term gestational age, duration of hyperbilirubinemia, and rate of TSB rise. Hansen [19] and Watchko [20] have recently summarized the scientific evidence and mechanism of bilirubin neurotoxicity. These indicate that bilirubin kills specific neurons by causing necrosis; in vitro studies show that it induces apoptosis and support in vivo observations in older literature showing neuroanatomic changes consistent with apoptosis. Evidence also suggests that bilirubin interferes with intracellular calcium homeostasis by altering function and expression of calcium/calmodulin kinase II, by selectively decreasing calcium-binding proteins in susceptible brainstem areas and increasing intracellular calcium in cultured neurons, and by sensitizing the cell to other injuries or triggering apoptosis. Bilirubin may also kill cells by causing neuronal hyperexcitability, perhaps via excitatory amino acid neurotoxicity, or it may have other membrane or neurotransmitter effects. Finally, it may act by interfering with mitochondrial respiration and energy production. Thus, interventions that reduce bilirubin exposure to the neonatal brain have been shown to prevent bilirubin neurotoxicity. The timing of interventions does matter.

155 5. Treatmentinitiate intensive phototherapy (or transfer for therapy) within about an hour of arrival.

Emergency Interventions for Rapid Reduction of Bilirubin Concentrations

Rapid bilirubin reduction strategies include intensive phototherapy, double volume blood exchange transfusion, and the occasional need for pharmacologic agents, often used in combination. Once progressive ABE has occurred, there are no neuroprotective agents that have been investigated; thus, prevention remains the key strategy. Brief descriptions of emergency interventions are provided here, and the reader is referred to detailed sources for implementation materials. Intensive Phototherapy Phototherapy is the current intervention of choice to reduce the severity of neonatal unconjugated hyperbilirubinemia, regardless of its etiology, in a matter of 2 to 4 hours [2]. Optimal use of phototherapy has been defined by specific ranges of TSB thresholds that have been configured to an infant's postnatal age (in hours) and potential risk for bilirubin neurotoxicity. Effective phototherapy implies its use as a drug with specific blue light wavelengths at a specific peak wavelength (460 nm) and a range of emission spectrum (400-520 nm), preferably in a precise (narrow) bandwidth that is delivered at an irradiance (dose) of 30 to 35 W/cm2 per nanometer to 80% of an infant's body surface area (BSA). There are several commercial devices and delivery methods for phototherapy for use at both the hospital and home. Blue lights in the 425 to 475 nm range (Phillips F-20 T12/BB or NeoBlueTM) should be easily and rapidly accessible and periodically inspected and maintained to ensure proper functioning. These may be complemented with white halogen lights to cover a wider surface area; avoid shadows created with multiple lights. Clinical response to a specific modality is also dependent on a number of factors that include ongoing rate of bilirubin production, maturation of enterohepatic elimination processes, performance of the device, and operational barriers to effective administration. The efficacy is additionally influenced by (a) optimization of light administration to achieve a minimum distance between the device and the patient such that the foot print of light covers maximum BSA with minimal physical barriers; (b) infant characteristics such as the severity of jaundice, BSA proportions, as well as dermal thickness, pigmentation, and perfusion; (c) the duration of treatment to a specific bilirubin threshold. As described by Maisels and McDonagh [23], the absorption of light by the normal form of bilirubin (4Z,15Z-bilirubin) generates transient excited-state bilirubin molecules. These fleeting intermediates can react with oxygen to produce colorless products of lower molecular weight, or they can undergo rearrangement to become structural isomers (lumirubins) or

Crash-Cart Management for Hazardous Hyperbilirubinemia and ABE

An infant presenting with signs of ABE or with bilirubin levels that exceed thresholds for severe hyperbilirubinemia requires urgent and expert attention [8,21,22]. A clinical algorithm [22] may be used to guide the efforts of the ED care team (Table 4) to coordinate the ensuing interventions that will appear to be suddenly invasive and intrusive to a family that was just at home and celebrating a birth. To prevent permanent sequelae, the acute evaluation and interventions need to be implemented in a matter of couple of hours (Figure 2). If the TSB level is approaching or is at hazardous levels or onset of ABE is recognized, the goal of therapy is to dramatically reduce the bilirubin load, promptly, safely, and expeditiously. Triage for a Jaundiced Newborn Arriving at the ED The triage process should be guided by ongoing staff clinical education, development and implementation of a local protocol, and action plan (Figure 2). The key components follow: 1. Suppliesthere must be ready access to devices, equipment, and a transport isolette. 2. Clinical assessmentthis should identify risk factors and include a rapid neurologic examination. 3. TestingTcB testing and other STAT laboratory studies (if essential). 4. Informed consentone must advise the parents of the medical emergency.

156

V.K. Bhutani, L. Johnson

Figure 2 An algorithm for ED management as proposed by Smitherman et al [22] (reprinted with permission).

The jaundiced newborn in the ED

isomers in which the configuration of at least one of the 2 Z-configuration double bonds has changed to an E configuration. Isomerization processes occur more quickly than photooxidation. Phototherapy converts bilirubin to yellow photoisomers and colorless oxidation products that are less lipophilic than bilirubin and do not require hepatic conjugation for excretion. Photoisomers are excreted mainly in bile and oxidation products predominantly in urine. Sunbathing is no longer recommended in newborn infants as a means to treat jaundice [23]. Exchange Transfusion Exchange transfusion is a critical and invasive procedure that can significantly reduce a bilirubin level in a matter of 1 to 2 hours [2]. Trained personnel in neonatal/pediatric intensive care facilities with full monitoring and resuscitation capabilities should perform this procedure. Exchange transfusion should be considered and anticipated when there are signs of ABE (even if TSB is falling) or if there are significant concerns of neurotoxicity. Concerns for neurotoxicity are heightened in an asymptomatic infant when (a) the TSB level exceeds 30 mg/dL; (b) intensive phototherapy fails to produce a significant TSB reduction in an infant with severe hyperbilirubinemia (a progressive TSB decline of at least N0.5 mg/dL per hour or N2 mg/dL drop in 4 hours should be expected); or (c) an infant who had an earlier successful hearing screen and fails an automated auditory brainstem response screen. Before an exchange transfusion is initiated, the health care team should review the risks and benefits of the procedure with the parents, so they can provide informed parental consent. The adverse effects of an exchange transfusion include neonatal morbidities such as apnea, anemia, thrombocytopenia, electrolyte and calcium imbalance, risk of necrotizing enterocolitis, hemorrhage, infection, complications related to the use of blood products, and catheterrelated complications. Exchange transfusion also carries the risk of neonatal mortality, especially in sick infants. Pharmacologic Options Pharmacologic options and chemoprevention strategies have been reviewed in recent articles [2,8,10,11,24]. Pharmacologic interventions have a limited role in the ED management of a sick infant. Possible interventions and their usefulness and limitations are briefly discussed. Albumin Infusion. At times, an albumin infusion (1 g/kg) is considered before an exchange transfusion, especially if serum albumin is low (b3 g/dL), or immune globulin (IVIG) may be administered when the hyperbilirubinemia is attributed to isoimmunization. Exchange transfusion is performed as an isovolumic procedure, preferably with concurrent withdrawal from an arterial line and infusion through a venous line. Double volume exchange (170 mL/kg) is ideal, but in the event of technical difficulties, a single volume exchange transfusion may be adequate if supplemented with intensive phototherapy. The

157 entire process should be accomplished within 4 to 6 hours of the identification of the medical emergency [2]. Intravenous Gamma Globulin. For infants with severe hyperbilirubinemia due to blood group incompatibilities, administration of IVIG (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or if the TSB is within 2 to 3 mg/dL (34-51 mol/L) of the exchange level. If necessary, this dose can be repeated in 12 hours. Intravenous gamma globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease. Although data are limited, it is reasonable to assume that IVIG will also be helpful in the other types of Rh hemolytic disease such as anti-C and anti-E. Phenobarbital. Phenobarbital can accelerate bilirubin excretion by increasing hepatic clearance. However, this drug is no longer recommended because it has limited or no clinical effect when administered to infants less than 32 weeks of gestation and is ineffective when given before 12 hours of age. The adverse effects of this therapy include sedation, risk of hemorrhagic disease, and the potentially addictive nature of phenobarbital. This drug has a slow onset of effect (usually several days) and a long duration of action (1 to 2 weeks) after its discontinuation. For all of these reasons, the use of phenobarbital is no longer recommended. Tin Mesoporphyrin. Stannic porphyrins, in particular tin mesoporphyrin, inhibit the enzyme heme oxygenase and block the transformation of heme to biliverdin and bilirubin and have been noted to cause photosensitization (especially with intense white light phototherapy). Tin mesoporphyrin has been investigated in clinical pharmacologic and toxicological studies and is effective in reducing bilirubin levels in infants at risk for severe hyperbilirubinemia with no significant side effects. Most infants do not need further phototherapy after tin mesoporphyrin is administered. Tin mesoporphyrin is currently being evaluated for safety, and the Food and Drug Administration has not yet approved its use in the United States. Other strategies that warrant further investigation and clinical trials are use of agents that interrupt the enterohepatic circulation and bilirubin accumulation from the continued action of -glucoronidase. Chemoprevention with use of casein supplements or other agents such as L-aspartic acid could decrease intestinal reabsorption of bilirubin and may play a potential preventive or adjunctive clinical role. Supportive Interventions The first repeat TSB level should be checked within 2 to 4 hours of initiation of therapy to document a substantial response in TSB level. It should be repeated every 3 to 4 hours if TSB is rising and 8 to 12 hours if declining. If there is evidence of dehydration (serum sodium N153 mEq/ L and/or weight loss N15% of birthweight), enteral milk intake, with expressed breast milk, should continue unless the infant is undergoing an exchange transfusion.

158 Parenteral fluids should be administered for dehydration or when oral intake is in question. Continuous and uninterrupted intensive phototherapy is recommended until TSB levels decline substantially. Breast-feeding may be resumed after TSB has declined. Phototherapy may be interrupted briefly to facilitate breast-feeding.

V.K. Bhutani, L. Johnson

ness, gait abnormality, failure of fine stereognosis, gaze abnormalities, poor coordination, and exaggerated extrapyramidal reflexes. Follow-up should include neurologic and neurodevelopmental evaluation, neuroimaging with magnetic resonance imaging, and auditory evoked brainstem responses. Prior inattention to quality of care to newborn jaundice and kernicterus has led this newborn condition to be a public health issue [27-29]. Information for parents and health providers is available at the Center for Disease Control and Prevention Web site [30]. Summary Severe hyperbilirubinemia and ABE are continuing risks for infants born in the United States and also for those discharged as healthy from their birth hospital. Because the margin of safety between a specific TSB level and the onset of ABE is narrow and often unpredictable, prevention of ABE is the only safe medical option. Awareness, recognition, and identification of the subtle neurologic signs in

Follow-up of Infants with Severe Neonatal Hyperbilirubinemia

Posticteric sequelae are often unrecognized, mislabeled, or misdiagnosed. These errors have led to prolonged diagnostic and health-seeking odysseys for families [25,26]. Because such presentations to the ED are uncommon, it may be useful to initiate an internal root cause analysis (Table 5) to look for opportunities to improve local practices. Infants with TSB levels greater than 25 mg/dL and those who receive an exchange transfusion should be followed through infancy until school age for awkward-

Table 5 Review of antecedent events for a case of near-miss kernicterus referred to an ED that way cared for by multiple providers at multiple sites. Age Birth 33 h 60 h Site Health Related Events Potential Opportunities Mom had prenatal care at an antenatal clinic and seen for follow-up at the clinic (close to home). 1. Prenatal meeting with pediatric staff to outline the first week postnatal plan of actions. 2. Birthing hospital and clinic to create a coordinated process for transfer of health information within 48 h of birthing. 3. Clinic/Birthing hospital to track no-show patients for first scheduled appointment within 2 to 3 d of birthing hospital discharge 4. Front-office education: front office to verify nature of appointment and target scheduling for appointments at age 3 to 5 d.

Birthing Hospital Primigravida, Spanish-onlyspeaking mom. She had chosen to breast-feed. Birthing Hospital Routine Tbili: 7.3 mg/dL (low-intermediate risk zone) Birthing Hospital Discharged; follow-up appointment made at Birthing Hospital clinic Birthing Hospital No-show at office visit clinic Medical Home # First postbirthing appointment made by first visit front office staff when infant was 3 d old

5d

8d

Age 8 d: chronological events 10:30 AM Medical Home # Examined by family nurse practitioner. first visit TSB ordered and parents requested to await instructions.

1:00

PM

Medical Home # Parents return home, frustrated with wait first visit Home Parents called with results and asked to return to pick up referral slip Referral Hospital Parents arrive at Referral Hospital NICU with a slip that states his TSB is 20 mg/dL; referred by RN to the ED

3:30 5:30

PM PM

6:30 PM Referral Hospital Waiting in the ED (no medical care) -10:00 PM ED 10:30 PM Referral Hospital Admitted to NICU NICU

5. Recognition of jaundice severity (including TcB measurements) 6. Optimize infant blood sample and request for urgent results (optimal sample to result interval being b2 h) 7. Parents to receive education about jaundice. 8. MD to review clinical assessment before infant leaving premises without intervention. 9. Direct parents to NICU 10. Fax referral to health care site (NICU) 11. Clinic and Hospital staff awareness of process for direct admission to NICU for specific neonatal emergencies: fever, jaundice, sepsis, hypoglycemia, shock, and heart defects. 12. Triage and treatment policies for neonates arriving to any ED Baby admitted with acute kernicterus. Responded to intensive phototherapy with rapid reversal of signs for ABE.

The jaundiced newborn in the ED

any infant with severe jaundice and/or hyperbilirubinemia are crucial to a successful outcome. Current evidence suggests that ABE is reversible with timely, rapid, and effective bilirubin reduction strategies in its early and intermediate phases. Infants with hazardous hyperbilirubinemia and ABE treated with intensive phototherapy and an exchange transfusion in a timely and prompt manner have escaped long-term neurologic sequelae. Thus, in an infant with ABE, rapid, timely, and effective reduction of total bilirubin load could influence long-term outcome.

159
12. Bhutani VK, Johnson L. Kernicterus in late preterm infants cared for as term healthy infants. Semin Perinatol 2006;30:89-97. 13. Keren R, Luan X, Friedman S, et al. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics 2008;121: e170-9. 14. Johnson LH, Bhutani VK. Guidelines for management of the jaundiced term and near-term infant. Clin Perinatol 1998;25: 555-74. 15. Wennberg RP, Ahlfors CE, Bhutani VK, et al. Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics 2006;117:474-85. 16. Johnson L, Brown AK, Bhutani V. BINDa clinical score for bilirubin induced neurologic dysfunction in newborns. Pediatrics 1999;104: 746. 17. Shapiro SM. Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND). J Perinatol 2005; 25:54-9. 18. Hansen TW. Acute management of extreme neonatal jaundice the potential benefits of intensified phototherapy and interruption of enterohepatic bilirubin circulation. Acta Paediatr 1997;86: 843-6. 19. Hansen TW. Mechanisms of bilirubin toxicity: clinical implications. Clin Perinatol 2002;29:765-78. 20. Watchko JF. Kernicterus and the molecular mechanisms of bilirubininduced CNS injury in newborns. Neuromolecular Med 2006;8: 513-29. 21. Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: for a safer first week. Pediatr Clin North Am 2004;51:843-61. 22. Smitherman H, Stark AR, Bhutani VK. Early recognition of neonatal hyperbilirubinemia and its emergent management. Semin Fetal Neonatal Med 2006;11:214-24. 23. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008;358:920-8. 24. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med 2001;344:581-90. 25. Sheridan SE. Testimony to the National Summit on Medical Errors and Patient Safety Research, Washington, DC, 11 September 2000. Available at: www.quic.gov/summit/wsheridan.htm (21 March 2003). 26. Sheridan SE. Parents of infants and children with kernicterus. J Perinatol 2005;25:227-8. 27. Joint Commission Accrediting Hospital Organizations (JCAHO). Revised guidance to help prevent kernicterus. Sentinel Event Alert 2004;31:1-2. 28. Bhutani VK, Donn SM, Johnson LH. Risk management of severe neonatal hyperbilirubinemia: to prevent kernicterus. Clin Perinatol 2005;32:125-39. 29. Blackmon LR, Fanaroff AA, Raju TN, et al. Research on prevention of bilirubin-induced brain injury and kernicterus: National Institute of Child Health and Human Development conference executive summary. 2003. Pediatrics 2004;114:229-33. 30. Center for Disease Control and Prevention. Jaundice/Kernicterus. http://www.cdc.gov/ncbddd/dd/kernichome.htm. Accessed 8/2/08.

Acknowledgments
The work for this article was also supported in part by funds from the Sandy Eglin Fund and her generous support of the Pilot Kernicterus Registry at Pennsylvania Hospital, Philadelphia. This study was supported in part by AAMC/CDC PERT grant MM-0448.

References
1. Johnson L, Brown AK, Bhutani VK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;93:488-94. 2. American Academy of Pediatrics. Clinical practice guideline: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316. 3. Bhutani VK, Johnson LH, Maisels MJ, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol 2004;24:650-62. 4. Van Praagh R. Diagnosis of kernicterus in the neonatal period. Pediatrics 1961;28:870-4. 5. Jones MH, Sands R, Hyman CB, et al. Longitudinal study of the incidence of central nervous system damage following erythroblastosis fetalis. Pediatrics 1954;14:346. 6. Perlstein M. Neurologic sequelae of erythroblastosis fetalis. Am J Dis Child 1950;79:605-6. 7. Volpe JJ. Bilirubin and brain injury. In: Volpe JJ, editor. Neurology of the Newborn. 4th ed. Philadelphia, PA: W. B. Saunders Co.; 2001. 8. Bhutani VK, Johnson L, Keren R. Acute bilirubin encephalopathy before it is too late. Contemp Pediatr 2005:54-74. 9. Bhutani VK, Johnson L. Kernicterus: a preventable neonatal brain injury. J Arab Neonatal Forum 2005 Available at: http://www.fmhs. uaeu.ac.ae/neonatal/iss003/pap03.asp. Accessed 8/2/08. 10. Ip S, Chung M, and the Subcommittee on Hyperbilirubinemia. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 2004;114:e130-53. 11. Hyperbilirubinemia in the neonate: risk assessment, screening and management, Association of Women's Health, Obstetrics and Neonatal Nurses. Available at: http://www.awhonn.org/awhonn/ product.detail.do?productCode=HNPP-CD-2NDI. Accessed 8/2/08.

Neonatal Sepsis in the Emergency Department

Daniel T. Robinson, MD, Praveen Kumar, MBBS, DCH, MD, FAAP, Sandra B. Cadichon, MD
Despite significant improvements in the care and management of acutely ill infants, septicemia remains one of the top 10 causes of neonatal death. Neonates can present either shortly after birth or later with subtle signs to suggest infection. Early diagnosis and prompt intervention are essential to prevent serious morbidity and mortality in neonates (<28 days of age) and infants (>28 days of age) with sepsis. Unlike older children, a young infant is often incapable of demonstrating clinical evidence of illness, and even a wellappearing infant may have a bacterial or viral disease. The immaturity of the newborns immune system may increase the susceptibility of these patients to infections. The following article is a review of the clinical presentation, differential diagnosis, and evaluation and management of a neonate presenting to the emergency department with suspected sepsis. Clin Ped Emerg Med 9:160-168 C 2008 Elsevier Inc. All rights reserved. KEYWORDS neonatal sepsis, bacterial and viral infection, emergency department, immune system

epsis is ranked as the sixth leading cause of death among neonates and the eighth leading cause of death for infants through the first year of life [1]. The incidence of neonatal sepsis is 1 to 5 per 1000 live births [2]. These vulnerable patients present to the emergency department (ED) or their primary care provider's office with nonspecific symptoms and are unable to articulate their concerns. Quite often, the only presenting symptom is fever, and not uncommonly, these infants are described as well appearing. Neonatal sepsis is classified as either early or late based on the timing of presentation. In the literature, however, there is no definitive consensus as to what age limits apply, with early-onset sepsis ranging from 48 hours to 6 days after delivery [3]; late-onset sepsis generally occurs beyond the first week of life. The clinical relevance of this distinction is that early-onset disease is often due to organisms acquired during delivery. Late-onset disease is only occasionally a result of vertical transmission and is more frequently caused by organisms acquired after delivery (nosocomial or community sources) [3]. Characteristics of early and late neonatal sepsis are summarized in Table 1.

Risk Factors and Pathogenesis

Although no significant sex difference has been reported, it was noted as early as the 1960s that male infants had a higher incidence of neonatal sepsis than females, which may be related to X-linked immunoregulatory genes [2]. Early-onset sepsis occurs primarily via vertical transmission, and the most common risk factors are prolonged rupture of membranes (>18 hours before delivery), maternal fever (>100.5C), chorioamnionitis, and preterm birth (<37 weeks estimated gestational age). The infant can either become colonized with bacteria during passage through an infected or colonized birth canal or via the

Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL. Division of Neonatology, Children's Memorial Hospital, and Northwestern Memorial Hospital, Chicago, IL. Reprint requests and correspondence: Sandra B. Cadichon, MD, Division of Neonatology, Children's Memorial Hospital, 2300 Children's Plaza Box 45, Chicago, IL 60614. (E-mails: daniel-robinson@northwestern. edu, p-kumar@northwestern.edu, s-cadichon@northwestern.edu) 1522-8401/$ - see front matter C 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2008.06.005

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Neonatal sepsis in the emergency department

Table 1 Characteristics of neonatal sepsis. Early Onset (<7 d) Intrapartum complications Transmission Clinical manifestation Case fatality rate Often present Vertical; organism often acquired from mothers genital tract Fulminant course, multisystem involvement, pneumonia common 5%-10% Late Onset (7 d to 3 mo) Usually absent Vertical or via postnatal environment Insidious, focal infection, meningitis common 5%

161

Very Late Onset (>3 mo) Varies Usually postnatal environment Insidious Low

Reprinted with permission from Fanaroff and Martin [2].

upward spread of infection after rupture of membranes. The pathogens that cause late-onset disease may be acquired vertically in the peripartum period or horizontally from fomites in the environment or from colonized caregivers after delivery [2]. Other risk factors for neonatal sepsis include a history of immune deficiency disorders such as severe combined immunodeficiency syndrome and some inborn errors of metabolism such as galactosemia, which may present in the first week of life with Escherichia coli (E. coli) sepsis or urosepsis. The presence of a ventriculoperitoneal (VP) shunt, central line, and need for recurrent bladder catheterization (as in infants with a neurogenic bladder as a result of myelomeningocele) also increase the risk for infection. Regardless of the risk factor, sepsis or bacteremia occurs when the skin or mucosal barrier become compromised and allow entry of organisms into the blood stream.

Immunological Basis for Increased Susceptibility to Infection in Newborns

The immunologic system consists of 2 main defense mechanisms, innate and acquired immunity. Innate immunity consists of the natural barriers that do not require prior exposure to microbes or antigen and includes intact skin or mucous membranes, gastric acid, and digestive enzymes. The phagocytic cells beneath these layers constitute the next line of defense if microorganisms somehow breach the cutaneous and/or the mucosal barriers. Acquired immunity consists of the cell-mediated (T lymphocyte) and humoral (B lymphocyte and immunoglobulin) systems. Compared with older children and adults, all newborns have a developmentally immature immune system and increased susceptibility to invasive microbial infection [4]. After birth, immunoglobulin (Ig) A contributes significantly to the neonate's immune defense and is one example of the developmental evolution of the immune system and exemplifies how neonates and infants differ from older children and adults. Secretory IgA is a polymeric form of IgA that prevents bacterial adhesion to mucosal sites and therefore inhibits colonization. Some studies have demon-

strated low levels of secretory IgA in saliva of human neonates in the first few days of life (adult levels in secretions are not generally achieved before 6 to 8 years of age) [5]. This low level of IgA is thought to allow for colonization and thus predispose newborns to invasive infections. Another important component of humoral defense for the fetus and newborn is IgG. Maternal transfer of IgG begins around 22 weeks of gestation and continues throughout the third trimester. Type-specific antibody plays a major role in the clearance of not only viral organisms but also group B Streptococcus (GBS) and other pathogenic bacteria from the circulation as well [5]. The importance of type-specific antibody in immunity to GBS was demonstrated by Lancefield et al [8], and an association was proven for GBS types Ia, Ib, and III in the human neonate [6-9]. Type-specific antibodies appear to offer protection to some neonates born to mothers with colonized genital tracts who have higher antibody titers to GBS compared with the low level of protective antibody in the serum of pregnant women who are not colonized with GBS [5]. The remainder of the immunoglobulins (IgM, IgA, IgD, and IgE) do not cross the placenta and are of fetal or neonatal origin, and the presence of these immunoglobulins in the newborn circulation implies a fetal or newborn response to a particular pathogen and can be used as a tool to diagnose certain infections. T-cell function is also developmentally immature in neonates. This is best exemplified by neonatal infections with Listeria monocytogenes. Listeria is an anaerobic facultative motile gram-positive intracellular bacillus that affects primarily neonates, immunocompromised adults, and the elderly. Although neonatal sepsis from Listeria is rare, if infected, neonates are at increased risk for developing overwhelming sepsis and meningitis without appropriate therapy. Listeria in neonates repels phagosome killing through its major virulence factor, listeriolysin O; cell-cell transmission of the organism occurs rapidly without exposure to the humoral antibodies or neutrophils. T lymphocytes provide the only natural recognition and immunity toward L. monocytogenes, and because cellular immunity is suppressed during pregnancy and is naturally deficient during early neonatal life, this predisposes the neonate to severe infections [10,11].

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Table 2 Host responses to bacterial infection in the neonate. Function Opsonization, chemoattraction Status in Neonate Decreased complement components, especially in preterm infants C8, C9, and alternative pathway components are decreased more than others IgG concentration A in preterm infants, term infants have higher concentration than adults; only IgG is transported across the placenta IgA absent from secretions Impaired migration, impaired binding to chemotactic factors Impaired up-regulation of adhesive glycoproteins Decreased deformability Normal with sufficient quantities of opsonin Normal in healthy neonates, A in stressed neonates Superoxide production is normal Hydroxyl radical formation is decreased Decreased Controversial Controversial

D.T. Robinson et al.

Component Complement

Clinical Significance A production of chemotactic factors,A opsonization of bacteria

Antibody

Opsonization, complement Activation

Lack of antibody to specific pathogens results in z risk of infection z risk of mucosal colonization with potential pathogens A inflammatory response, inability to localize infection

Neutrophil

Chemotaxis

Phagocytosis Bacterial killing

Monocyte

Chemotaxis Phagocytosis Bacterial killing

A inflammatory response Uncertain Uncertain

Modified and reprinted with permission from Polin and St Geme [5].

Other host responses to bacterial infections are delineated in Table 2.

Etiology
The spectrum of organisms causing neonatal sepsis has changed over time. Since the late 1960s to early 1970s, Streptococcus agalactiae (GBS) has emerged as a major pathogen associated with neonatal sepsis and meningitis. Many infants with invasive GBS disease present with earlyonset sepsis and are often identified and treated before discharge after birth. As a result of guidelines prepared by the Center for Disease Control and Prevention, the American Academy of Pediatrics, and the American College of Obstetrics and Gynecology [12], the attack rate of earlyonset sepsis due to GBS in the United States has gradually declined since 1996 from 2 per 1000 live births to 0.36 per 1000 live births in 2005 [13]. However, many infants are discharged home before 48 hours and may present as outpatients with this serious disease. One study of febrile infants younger than 3 months presenting to their primary care physician's office found that GBS was the second most frequently isolated organism in this age group [14]. A second large study found that among infants younger than 3 months presenting to an ED with a serious bacterial illness, 20% were positive for gram-positive organisms and 6% were positive for GBS [15]. Other gram-positive organisms causing disease in young infants include Staphylococcus aureus, Enterococcus species, Streptococcus pneumoniae, and less frequently, L. monocytogenes [14,15]. The most commonly isolated bacterial organisms in young febrile infants are gram-negative organisms [14-16].

E. coli is the most common gram-negative organism found in infants presenting with fever. Other gram-negative organisms include Klebsiella species, Enterobacter species, Salmonella, Citrobacter species, and Neisseria species. In addition to bacterial etiologies, viruses are a significant cause of morbidity and mortality in neonates and young infants. There are numerous viruses known to cause infection in man, and most tend to occur in a seasonal fashion, and community outbreaks can increase one's index of suspicion. In 2004, Byington et al [15] found that 35% of infants (n = 1385) who presented with fever to the ED were positive for one or more viruses; the most frequently isolated viruses were respiratory syncytial virus (RSV) and enterovirus (EV). An equally important consideration is whether febrile infants with viral illnesses could have a concomitant serious bacterial infection. During the 1970s to 1990s, several studies of infants and children up to 3 years old with RSV infection found a concomitant serious bacterial infection in 0% to 1.9% [15]. In a similar, but more recent, evaluation of infants 1 to 90 days old presenting to the ED with fever, the authors found that viral positive infants had a lower risk for serious bacterial infection in general and specifically a lower occurrence of bacteremia, urinary tract infection (UTI) (2.5% of the infants positive for RSV had a bacterial UTI), and soft tissue infection. Conversely, those who were virus negative were nearly 3.5 times more likely to have a serious bacterial infection (10.4% of the infants who were negative for viral infections had a bacterial UTI) [15]. The viruses isolated in this study were EV, RSV, influenza A or B, parainfluenza 1, 2, or 3, rotavirus, adenovirus, herpes simplex virus (HSV), and varicella virus.

Neonatal sepsis in the emergency department

Enterovirus and herpes viral infections are important causes of neonatal morbidity and mortality. Enterovirus is an RNA virus from the Picornaviridae family. Five species of EV are known to infect humans (EV types A, B, C, D and poliovirus), which include 68 serotypes traditionally classified as polioviruses, echoviruses, coxsackieviruses, and numbered EVs [17]. Each year, an estimated 10 to 15 million symptomatic enteroviral infections occur in the United States. During 1970 to 2005, 44.2% of reported cases occurred in infants younger than 1 year, and the proportion of reports with fatal outcome had a bimodal distribution by age with peaks for ages less than 1 year and greater than 45 years [18]. According to the National Enterovirus Surveillance System report from 1970 to 2005, two thirds of reported cases of EV in infants younger than 1 year were caused by coxsackie B1. There are 2 types of HSV, types 1 and 2, which are known pathogens that can cause significant morbidity and mortality in the neonate. Herpes simplex virus is a DNA virus and humans are the only known reservoir [19]. The incidence of neonatal HSV infection ranges from 1:1400 to 1:30 000 deliveries, resulting in 1500 to 2200 cases of neonatal HSV infection each year in the United States [19]. Transmission of HSV results from close personal contact either at times of symptomatic disease, or more commonly, during periods of asymptomatic viral shedding [19]. The risk of vertical transmission of HSV relates to maternal serologic status; the risk is highest with primary HSV-2 infection and lowest with recurrent/reactivation of HSV-2 infection in the mother. The lower transmission rate in recurrent disease is attributed to the lower viral titer, transplacentally protective antibodies, and lower frequency of cervical viral shedding during recurrent infection [19]. Fungal infections are rare in healthy infants but may occur in infants with central line access, VP shunts, and infants requiring recurrent bladder catheterization. Fungemia in a healthy infant should raise concern for immunodeficiency beyond the developmental physiologic immunodeficiency of infancy.

163 concerning, if not more so, than sustained fever. Therefore, a systematic approach as described in the article in this issue on the evaluation and management of the critically ill neonate is necessary for an appropriate assessment. In general, neonatal sepsis, both early and late, can present with temperature instability, feeding difficulties, diarrhea, respiratory instability such as tachypnea or apnea, lethargy, hypoglycemia, and persistent unexplained jaundice. In some cases, skin lesions may provide an important clue to the diagnosis, such as the presence of microabscesses in L. monocytogenes and grouped vesicular lesions in neonatal herpes. Late-onset bacterial sepsis differs from early-onset disease in that a significant number of infants with late-onset disease present with meningitis and UTIs. Viral illnesses may also present with nonspecific symptoms in the neonate. Clinical presentation may range from a well-appearing infant with fever, cough, or rhinorrhea to a critically ill-appearing infant with coagulopathy, hypotension, and in severe cases, congestive heart failure and myocarditis. In addition, viral myocarditis may present with tachycardia (in the absence of fever), ST changes on electrocardiogram, and poor left ventricular function on echocardiogram. The neonate presenting in septic shock must be recognized promptly because early intervention can significantly decrease morbidity and mortality [20]. Careful attention to the history and physical examination can provide important clues to the presence of shock. Vital sign abnormalities such as fever and tachycardia are common in infants with sepsis, but shock must be considered when these signs present with changes in mental status, an indicator of decreased cerebral perfusion. The neurologic finding of mental status change in a neonate may range from an irritable infant to one who is lethargic or unable to be aroused [21]. Bradycardia is unique to neonates and infants in septic shock as compared with older pediatric patients and adults and could be related to hypothermia (<36C), which is frequently seen. Hypothermia may blunt tachycardia. The cardiovascular examination can indicate altered perfusion through abnormal capillary refill (sluggish, >2 seconds or flash) as well as altered pulses (weak or bounding). Other findings suggestive of shock include cool extremities and oliguria (urine output <1 mL/kg per hour). The diagnosis of shock does not require that a neonate be hypotensive. It is a late finding in septic shock in neonates, and its presence confirms decompensated shock [21,22]. A consensus panel on sepsis and organ dysfunction suggested vital sign parameters, which may help in identifying neonates with shock: heart rate less than 100 or greater than 180 beats per minute, respiratory rate greater than 50 breaths per minute for newborns in the first week of life and greater than 40 from 1 week until 1 month of age, and systolic blood pressure lower than 65 mm Hg within the first week of life and lower than 75 mm Hg from 1 week until 1 month old [22].

Clinical Assessment
A detailed history and a complete physical examination are equally important in the assessment of an ill infant. Laboratory evaluations and diagnostic tests are also essential because it is important to remember that many ill infants present with nonspecific signs. An infant presenting with respiratory distress may demonstrate distress as a result of infection, congenital heart disease, or an inborn error of metabolism. Similarly, fever is a common reason for a caregiver to seek medical attention, but this too is a nonspecific finding in that dehydration, drug withdrawal, and extensive hematomas can also result in pyrexia [2]. Sick newborns and infants often present with temperature instability, and this may be as

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activated partial thromboplastin times as well as low fibrinogen levels that may require transfusion. Individual or combinations of laboratory tests would ideally identify infected neonates and distinguish between bacterial, viral, and other types of infections, with the goal of decreasing antibiotic exposure and unnecessary admissions to the hospital. Examples of these tests are the WBC count, absolute band count, UA, C-reactive protein (CRP), interleukins, and procalcitonin. These examples represent an abbreviated list of investigated markers. We include a brief discussion of some of these, keeping one important caveat in mind for the neonate: regardless of preliminary laboratory results, standard clinical practice includes initiation of antibiotics after obtaining cultures and then admission of infants 28 days or younger to the hospital if infection is a concern [23]. Leukocyte counts have been well studied in the workup for infection. Studies have used different ranges for risk assessment, commonly using 5000 to 15 000-20 000/mm3 as a range for placing infants in a low-risk category. However, even WBC counts in those low-risk ranges have been shown to have poor negative predictive value for serious bacterial infections in the neonate [26]. Counts above and below those levels may have relatively high predictive values for infection, but they are not specific to bacterial infection. The presence of immature cells has also been relied upon for identifying infected patients. Cutoff levels used to help rule out infection include an absolute band count of 1500/mm3 and an immature-to-total (I:T) neutrophil ratio of 0.2 or lower. Interlaboratory variability, with particular reference to the absolute band count, makes widespread application of single-center studies difficult [27]. Also, the determination of a neutrophil band form is a subjective assessment [28]. White blood cell and immature cell counts, therefore, cannot be relied upon alone for predicting the presence of infection. C-reactive protein is a nonspecific marker of inflammation produced by the liver. An acute phase reactant produced by hepatocytes, this protein is often used as an aid in diagnosing infection as well as in deciding the duration of therapy [29]. For the immediate perinatal period, it is an attractive aid because intrapartum antibiotic administration may cloud blood culture results. In the ED, an isolated CRP may be of little value because the statistical correlations used to link CRP with infection, whether they be sensitivity, negative predictive value or others, show increased reliability with serial values [30]. For instance, in 134 infants with culture-proven late-onset sepsis, the sensitivity rose from 61.5% to 84.4% by obtaining a second CRP, and the negative predictive value rose from 82% to 94.6%. Specificity and positive predictive values at best were 74.6% and 47.4%, respectively [30]. This improved accuracy may be partly due to the fact that the increase in CRP lags after onset of infection because transcription of this protein is under direction of other cytokines. Theoretically, a low CRP in the ED may result from

Laboratory Testing
As discussed earlier, identification of infants with serious infections on the basis of presenting signs is difficult. Therefore, accepted practice is to obtain a complete blood cell count, blood culture, urinalysis (UA), urine culture, and cerebrospinal fluid (CSF) from all neonates presenting with possible sepsis [23]; 1-2 mL is acceptable for a blood culture in neonates. The urine culture should be obtained via sterile urethral catheterization or suprapubic aspiration. A UA showing 10 or greater white blood cells (WBCs)/high-power field (HPF) and/or bacteria on Gram stain suggests a UTI. Normal values for CSF in neonates differ not only from those of older children but also between preterm and term babies. Accepted normal range values for preterm and term neonates respectively are 0-25, 0-22 cells/mm3 (WBC); 65-150, 20-170 mg/dL (protein); 24-63, 34-119 mg/dL (glucose) [24]. Whether to obtain additional diagnostic studies is case dependent. In the past, a workup for sepsis meant routinely obtaining a chest radiograph. It is no longer the norm for every patient in which infection is a concern but is suggested in those who present with respiratory symptoms and/or have fever. If the history, time of year, or examination findings raise concern for specific organisms, focused diagnostic testing should be ordered. For example, testing for RSV, influenza, or adenovirus requires sampling nasopharyngeal secretions for the antigen. For pertussis, culture of the nasopharynx would be the gold standard, but polymerase chain reaction may be available to some EDs. Latex agglutination to test for bacterial antigen may be helpful when a patient has already received antibiotic therapy; however, it should not replace obtaining a blood culture. Although this technology has been used on both urine and CSF, a retrospective study of older infants and children who had CSF agglutination tests showed that the test provided no added value to CSF Gram stain and culture in diagnosing or excluding meningitis in those treated before cultures were obtained [25]. When concerned about enteroviral or herpes meningoencephalitis, polymerase chain reaction should be ordered on the CSF specifically for those viruses. Additional sites to culture for herpes include the mouth, nasopharynx, conjunctiva, rectum, and any suspicious skin lesions. The blood buffy coat may also grow the virus. Enterovirus can be cultured from the throat, rectum, stool, and potentially from the blood and urine. Electrolytes, blood glucose, an arterial blood gas, and coagulation studies are worth obtaining because metabolic and hematologic derangements are observed in sepsis. Hypocalcemia and hypoglycemia, when detected, should be corrected. A blood gas will help establish the degree of metabolic acidosis as well as the presence of respiratory failure as a result of sepsis. Disseminated intravascular coagulation is another consequence of sepsis, and patients may have thrombocytopenia, prolonged prothrombin and

Neonatal sepsis in the emergency department

obtaining the test too close to onset of infection. To make this test of greater value, it might be prudent to discuss the practices of the inpatient services that care for neonates within the same facility as the ED. If the inpatient services routinely use serial CRPs, it may be worth obtaining the initial value in the ED. Cytokines such as proinflammatory interleukins 6 and 8 and antiinflammatory interleukin 10 show promise as useful diagnostic aids for infection [28,31]. Interleukin levels rise early in the inflammatory response to an infection as opposed to CRP, providing an earlier signal of infection [32]. However, these tests also do not have acceptable sensitivity or specificity, and they may be elevated in situations other than infection. Another consideration is that the half-lives of these cytokines are short. Interleukins may drop to low levels after acute increases even when infection persists [28,34]. It is conceivable that levels may have already decreased depending on the time between onset of infection and presentation to the ED. The peptide procalcitonin is another marker applied to the diagnosis of sepsis. Its relation to infection is unclear and, as with other markers, can be elevated in situations outside sepsis [33]. In fact, elevations occur in healthy neonates in the immediate postnatal period. The sensitivity of this test has been reported to be as low as 50% and as high as 99%; variation in study results stems from the heterogeneous methods used in different studies, including subjects of wide age ranges, varied definitions of sepsis, as well as different threshold levels used for procalcitonin [33]. This test may best be used in conjunction with other laboratory information. More markers including cell surface antigens (CD64, CD69, HLA-DR), granulocyte colony-stimulating factor, and adhesion molecules are being evaluated as aids in diagnosing infection in neonates [28,31,34]. The rise of antibiotic resistance alone brings value to discovering accurate indicators that would confirm or refute the presence of infection. To date, most studies looking at indicators of infection in neonates occur in the inpatient setting. For application in the ED, future investigations should pursue the applicability of these tests to potentially septic neonates presenting to the ED as well as the ability to distinguish between bacterial and other infectious etiologies. Currently, no test seems reliable entirely on its own in the ED evaluation of a neonate for sepsis. These diagnostic markers are more often useful in conjunction with one another and in series.

165 (defined in this study as a rectal temperature of 38.2C or higher) and found that two thirds of those with bacterial disease appeared well to the examining attending physician. Bonadio et al [36] sought to determine the reliability of observation variables in distinguishing infectious outcomes of febrile infants aged 0 to 8 weeks. In this prospective study, 7 observational variables (level of activity, level of alertness, respiratory status/effort, peripheral perfusion, muscle tone, affect, and feeding pattern) were assigned a score; the higher the score, the greater the degree of compromise. All infants (n = 233) received physical examinations and sepsis evaluations (lumbar puncture, complete blood count, blood culture, and UA/ urine culture). There were 29 infants with serious bacterial infection (10 with bacterial meningitis, 12 with bacteremia, 7 with UTIs), and 45 cases had aseptic meningitis. Two of the infants with serious bacterial infections had normal observation scores and appeared well; however, both had abnormal laboratory findings suggestive of infection. The variables that best identified the presence of serious bacterial illness were as follows: affect or change in mental status, respiratory status/effort, and peripheral perfusion [36]. In a more recent study, 11 of 15 infants younger than 3 months (2 were <1 month old) presenting to the ED with fever were well appearing but were found to be blood culture positive (one with Citrobacter freundii meningitis had a temperature of 38.5C and a negative blood culture) [37]. Thus, caution is advised when assessing a febrile neonate who is well appearing to the clinician. Three main studies emerged between 1985 and 1994 which sought to avoid unnecessary hospitalization by defining low-risk criteria to assist in determining whether infants younger than 3 months presenting to the ED would require definitive hospital admission and antibiotic treatment, or if these infants could be discharged home from the ED with close outpatient follow-up [35,38,39]. The Philadelphia group studied 29 to 60-day-old infants with fever higher than 38.2C who were well appearing and had low-risk criteria defined as having WBC less than 15 000/mm3, band-neutrophil ratio less than 0.2, UA less than 10 WBC/HPF with negative Gram stain, CSF cell count less than 8 WBC/mm3 with negative Gram stain, and a negative chest radiograph [35]. The Rochester study included well-appearing infants younger than 60 days with fever higher than 38.0C who were term with unremarkable perinatal history and uncomplicated discharge to home after delivery. Additional low risk criteria included WBC 5000-15 000/mm3, absolute band count <1500/mm3 and UA <10 WBC/HPF [39]. The Boston study included infants aged 28 to 89 days who were nontoxic-appearing previously healthy term infants with uncomplicated newborn nursery stays and had laboratory criteria including WBC less than 20 000/mm3, UA less than 10 WBC/HPF, negative chest radiograph, and CSF WBC of less than 10/mm3 [38]. All infants from these 3 studies had close follow-up as a requirement; the Boston group gave empiric

Limitations of Clinical and Laboratory Assessment in Identifying Infants With Sepsis

Several studies have concluded that even detailed clinical and laboratory assessment may not identify all infants with serious illness. In 1993, Baker et al [35] studied 747 infants who were 29 to 56 days of age presenting with fever

166 antibiotics in addition to requiring follow-up. All 3 studies concluded that infants meeting the low-risk criteria as defined in their respective studies could be discharged home from the ED with close follow-up. The 3 studies mentioned above evaluated infants older than 29 days; younger infants, however, are in a different risk category. Applying the low-risk criteria from the above studies, Kadish et al [16] sought to identify febrile infants 1 to 28 days with low risk for serious bacterial illness. They concluded that based on these criteria, 3% of infants with serious bacterial illness would have been assessed to be at low risk at the time of presentation and would have been sent home without treatment. They concluded that these guidelines could not safely be recommended for febrile neonates. Similarly, Baker and Bell [40] applied the Philadelphia protocol to febrile infants from birth to 1 month old and concluded that these criteria lacked the sensitivity and negative predictive value to identify neonates at low risk for serious bacterial illness.

D.T. Robinson et al.

ducts or between intramuscular ceftriaxone and intravenous or oral calcium-containing products. More details on this advisory can be obtained at either the Federal Drug Administration (http://www.fda.gov/cder/drug/InfoSheets/ HCP/ceftriaxone.htm) or Roche (http://rocheusa.com/products/rocephin/rocephin-hcp-letter.pdf) Web sites [44]. Antibiotic resistance is surely changing the epidemiology of invasive pathogens. Still, even with the emergence of organisms such as methicillin-resistant S. aureus and ampicillin-resistant Enterococcus, wide use of medications such as vancomycin for neonates in the ED at this time is not warranted. Childrensuitedtoreceive vancomycin whenbeing evaluated for infection are those with indwelling devices such as central venous catheters and VP shunts. Physicians must maintain a high index of suspicion for herpes infection and promptly initiate antiviral therapy with acyclovir if the clinical scenario is suggestive. Acyclovir should be administered at 60 mg/kg per day intravenously (IV), divided into 3 doses. This regimen has improved morbidity and mortality from disseminated disease and mortality from encephalitis but, unfortunately, has not impacted morbidity among survivors of HSV encephalitis [45]. In addition to antimicrobial administration, treatment must support compromised organ systems. Septic neonates will need vascular access. This will allow for correction of fluid deficits, electrolyte and acid-base disturbances as well as hematologic abnormalities amenable to transfusion therapy.

Treatment
Because of the difficulties in accurately identifying neonates with sepsis after a careful evaluation, it is recommended that all neonates presenting to the ED with possible sepsis should receive antimicrobial therapy. Although there are no data to support a particular antibiotic regimen [41], consideration of the potential organisms helps tailor the drugs chosen. For the coverage of gram-positive organisms, ampicillin is suggested. It is particularly justified given concerns for Listeria [42]. Ampicillin has also been a therapy used for E. coli infection; however, there is considerable resistance now, and careful attention must be paid to patterns of sensitivities within individual institutions or communities [43]. Because gram-negative organisms are potential pathogens, therapy should include either an aminoglycoside or a third-generation cephalosporin. Based on the reports of neonatal deaths related to the interaction between ceftriaxone and calcium-containing products, the Federal Drug Administration and Roche (Nutley, NJ), manufacturer of Rocephin (ceftriaxone sodium), recently released new guidelines for administration of this frequently used cephalosporin. These guidelines recommend that ceftriaxone should not be reconstituted or mixed with a calcium-containing product, such as Ringer's or Hartmann's solution or parenteral nutrition containing calcium, and ceftriaxone and intravenous calcium-containing products including parenteral nutrition should not be administered to any patient, particularly neonates, by the same or different infusion lines or sites within 48 hours of each other. Although there are no reported cases of ceftriaxone-calcium precipitates in patients other than neonates, there is a potential for the interaction between ceftriaxone and calcium-containing products in patients of any age. There are no data on interactions between intravenous ceftriaxone and oral calcium-containing pro-

Management of Septic Shock

The American College of Critical Care Medicine published guidelines for intervention in neonates, infants, and children who present in septic shock [21]. The goal is the restoration of circulation and perfusion and adherence to these guidelines has been shown to improve survival [46]. Two algorithms were recommended, one for neonates and one for infants. There are common interventions and time goals for both algorithms, and practitioners should be familiar with them (Figure 1). The goal is to restore circulation within 60 minutes. Within the first 5 minutes of presentation, shock should be recognized and a stable airway maintained and access obtained. By 15 minutes from presentation, fluid resuscitation with isotonic or colloid boluses to a maximum volume of 60 mL/ kg should be accomplished. In addition, hypoglycemia and hypocalcemia should be corrected. The appropriate intervention for hypoglycemia is 10% dextrose solution at 2 mL/kg IV push and hypocalcemia may be treated with slow IV administration of calcium gluconate at a dose of 100 mg/kg. Should fluid resuscitation restore perfusion, the next appropriate step is observation in an ICU setting. If shock persists, central venous and arterial access should be obtained and vasoactive agents should be started, with dopamine as a first-line agent. If after the first hour circulation is not restored with further pressor support,

Neonatal sepsis in the emergency department

167

Figure 1 Recommendations for stepwise management of hemodynamic support in term newborns. Modified and reprinted with permission from Carcillo and Fields [21]. PDE, phosphodiesterase; ECMO, extra corporeal membrane oxygenation; NRP, neonatal resuscitation program; CVP, central venous pressure; LV, left ventricle; RV, right ventricle.

concern for adrenal insufficiency should be raised and the need for hydrocortisone therapy should be considered. As mentioned earlier, practitioners must also consider other diseases that may present with shock in the neonatal period, such as ductal-dependent congenital heart disease, and support the patient as needed [47].

Summary
An estimated 7% of neonates presenting to the ED are diagnosed with sepsis [48]. Neonatal physiology makes this patient population more susceptible to sepsis compared with older pediatric patients. After considering other diseases that may present with a picture similar to that of

sepsis, emergency physicians should try to differentiate between potential pathogens to focus laboratory investigations and tailor therapy. The combination of individual laboratory tests may further increase sensitivity and specificity, but an optimal panel of tests is yet to be identified. Crucial steps in the ED care of the septic neonate are identification of patients in septic shock and then rapid restoration of their circulation to improve outcomes.

References
1. Heron M. Deaths: leading causes for 2004. Natl Vital Stat Rep 2007; 56:1-95. 2. Fanaroff A, Martin RJ. Neonatal-perinatal medicine, diseases of the fetus and infant. 8th ed. St Louis: Mosby; 2006.

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3. Vergnano S, Sharland M, Kazembe P, et al. Neonatal sepsis: an international perspective. Arch Dis Child Fetal Neonatal Ed 2005;90: F220-4. 4. Clapp DW. Developmental regulation of the immune system. Semin Perinatol 2006;30:69-72. 5. Polin RA, St Geme III JW. Neonatal sepsis. Adv Pediatr Infect Dis 1992;7:25-61. 6. Baker CJ, Kasper DL. Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection. N Engl J Med 1976;294:753-6. 7. Klegerman ME, Boyer KM, Papierniak CK, et al. Estimation of the protective level of human IgG antibody to the type-specific polysaccharide of group B Streptococcus type Ia. J Infect Dis 1983; 148:648-55. 8. Lancefield RC, McCarty M, Everly WN. Multiple mouse-protective antibodies directed against group B streptococci. Special reference to antibodies effective against protein antigens. J Exp Med 1975;142: 165-79. 9. Gotoff SP, Papierniak CK, Klegerman ME, et al. Quantitation of IgG antibody to the type-specific polysaccharide of group B Streptococcus type 1b in pregnant women and infected infants. J Pediatr 1984;105: 628-30. 10. Vazquez-Boland JA, Kuhn M, Berche P, et al. Listeria pathogenesis and molecular virulence determinants. Clin Microbiol Rev 2001;14: 584-640. 11. Issekutz TB, Evans J, Bortolussi R. The immune response of human neonates to Listeria monocytogenes infection. Clin Invest Med 1984;7: 281-6. 12. Schrag S, Gorwitz R, Fultz-Butts K, et al. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep 2002;51(RR-11):1-22. 13. Perinatal group B streptococcal disease after universal screening recommendationsUnited States, 2003-2005. MMWR Morb Mortal Wkly Rep 2007;56:701-5. 14. Pantell RH, Newman TB, Bernzweig J, et al. Management and outcomes of care of fever in early infancy. JAMA 2004;291:1203-12. 15. Byington CL, Enriquez FR, Hoff C, et al. Serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections. Pediatrics 2004;113:1662-6. 16. Kadish HA, Loveridge B, Tobey J, et al. Applying outpatient protocols in febrile infants 1-28 days of age: can the threshold be lowered? Clin Pediatr 2000;39:81-8. 17. Khetsuriani N, Lamonte A, Oberste MS, et al. Neonatal enterovirus infections reported to the national enterovirus surveillance system in the United States, 1983-2003. Pediatr Infect Dis J 2006;25:889-93. 18. Khetsuriani N, Lamonte-Fowlkes A, Oberst S, et al. Enterovirus surveillanceUnited States, 1970-2005. MMWR Surveill Summ 2006;55:1-20. 19. Enright AM, Prober CG. Neonatal herpes infection: diagnosis, treatment and prevention. Semin Neonatol 2002;7:283-91. 20. Carcillo J, Han K, Lin J, et al. Goal-directed management of pediatric shock in the emergency department. Clin Pediatr Emerg Med 2007:165-75. 21. Carcillo JA, Fields AI. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002;30:1365-78. 22. Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8. 23. American College of Emergency Physicians. Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med 2003;42:530-45. 24. McMillan J, DeAngelis CD, Feigin RD, et al, editors. Oski's pediatrics: principles and practice. 3rd ed. Philadelpia, PA: Lippincott, Williams & Wilkins; 1999. 25. Nigrovic LE, Kuppermann N, McAdam AJ, et al. Cerebrospinal latex agglutination fails to contribute to the microbiologic diagnosis of

D.T. Robinson et al.

pretreated children with meningitis. Pediatr Infect Dis J 2004;23: 786-8. Brown L, Shaw T, Wittlake WA. Does leucocytosis identify bacterial infections in febrile neonates presenting to the emergency department? Emerg Med J 2005;22:256-9. Luxmore B, Powell KR, Diaz SR, et al. Absolute band counts in febrile infants: know your laboratory. Pediatrics 2002;110(1 Pt 1):e12. Ng PC, Lam HS. Diagnostic markers for neonatal sepsis. Curr Opin Pediatr 2006;18:125-31. Philip AG, Mills PC. Use of C-reactive protein in minimizing antibiotic exposure: experience with infants initially admitted to a well-baby nursery. Pediatrics 2000;106:E4. Benitz WE, Han MY, Madan A, et al. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998;102:E41. Malik A, Hui CP, Pennie RA, et al. Beyond the complete blood cell count and C-reactive protein: a systematic review of modern diagnostic tests for neonatal sepsis. Arch Pediatr Adolesc Med 2003;157:511-6. Santana Reyes C, Garcia-Munoz F, Reyes D, et al. Role of cytokines (interleukin-1beta, 6, 8, tumour necrosis factor-alpha, and soluble receptor of interleukin-2) and C-reactive protein in the diagnosis of neonatal sepsis. Acta Paediatr 2003;92:221-7. van Rossum, Wulkan RW, Oudesluys-Murphy. Procalcitonin as an early marker of infection in neonates and children. Lancet Infect Dis 2004;4:620-30. Mishra UK, Jacobs SE, Doyle LW, et al. Newer approaches to the diagnosis of early onset neonatal sepsis. Arch Dis Child Fetal Neonatal Ed 2006;91:F208-12. Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. N Engl J Med 1993;329: 1437-41. Bonadio WA, Hennes H, Smith D, et al. Reliability of observation variables in distinguishing infectious outcome of febrile young infants. Pediatr Infect Dis J 1993;12:111-4. Bachur RG, Harper MB. Predictive model for serious bacterial infections among infants younger than 3 months of age. Pediatrics 2001;108:311-6. Baskin MN, O'Rourke EJ, Fleisher GR, et al. Outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone. J Pediatr 1992;120:22-7. Dagan R, Powell KR, Hall CB, et al. Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis. J Pediatr 1985;107:855-60. Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age. Arch Pediatr Adolesc Med 1999;153:508-11. Gordon A, Jeffery HE. Antibiotic regimens for suspected late onset sepsis in newborn infants. Cochrane Database Syst Rev 2005:CD004501. Brown JC, Burns JL, Cummings P. Ampicillin use in infant fever: a systematic review. Arch Pediatr Adolesc Med 2002;156:27-32. Byington CL, Rittichier KK, Bassett KE, et al. Serious bacterial infections in febrile infants younger than 90 days of age: the importance of ampicillin-resistant pathogens. Pediatrics 2003;111(5 Pt 1):964-8. Information for healthcare professionals: ceftriaxone (marketed as Rocephin), September 11, 2007. Available at http://www.fda.gov/cder/ drug/InfoSheets/HCP/ceftriaxone.htm2007 Accessed 04-23-2008. Kimberlin DW. Management of HSV encephalitis in adults and neonates: diagnosis, prognosis and treatment. Herpes 2007;14:11-6. Han YY, Carcillo JA, Dragotta MA, et al. Early reversal of pediatricneonatal septic shock by community physicians is associated with improved outcome. Pediatrics 2003;112:793-9. Colletti JE, Homme JL, Woodridge DP. Unsuspected neonatal killers in emergency medicine. Emerg Med Clin North Am 2004;22:929-60. Millar KR, Gloor JE, Wellington N, et al. Early neonatal presentations to the pediatric emergency department. Pediatr Emerg Care 2000;16: 145-50.

26.

27. 28. 29.

30. 31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41. 42. 43.

44.

45. 46.

47. 48.

Evaluation and Management of the Cyanotic Neonate

Robin H. Steinhorn, MD
The infant presenting to the emergency department with cyanosis requires rapid assessment, diagnosis, and initiation of therapy. In this article, the potential challenges in recognizing cyanosis are discussed, including the presence of higher concentrations of fetal hemoglobin and its oxygen binding characteristics. A systematic approach to the diagnosis of cyanosis is presented, based on an understanding of the normal transitional physiology, and how diseases of the airway, lung, and circulatory system may disrupt these processes. Strategies for initial emergency department management of lung and cardiac disease are presented. Clin Ped Emerg Med 9:169-175 C 2008 Elsevier Inc. All rights reserved. KEYWORDS oxygen transport, fetal hemoglobin, pulmonary circulation, congenital heart disease, oxygen therapy, prostaglandin therapy, cyanosis

yanosis, derived from the Greek word kuaneos meaning dark blue, refers to the bluish discoloration of the skin, nailbeds, or mucous membranes. If cyanosis is limited to the extremities, it is referred to as acrocyanosis or peripheral cyanosis. This is relatively common in young infants and is generally a physiologic finding owing to the large arteriovenous oxygen difference that results during slow flow through peripheral capillary beds. In contrast to acrocyanosis, central cyanosis is present throughout the body and is evident in the mucous membranes and tongue. Central cyanosis indicates the presence of potentially serious and life-threatening disease, and requires immediate evaluation. The clinician will need to rapidly consider respiratory, central nervous system, hematologic, cardiac, and metabolic causes [1]. It is often a challenge to define an optimal PaO2 in the newborn with mild cyanosis or respiratory distress. The focus should not necessarily be on achieving an exact number, but rather on avoiding tissue hypoxia by providing adequate oxygen transport to the body tissues. Oxygen is carried in the blood in 2 forms. Virtually all of the oxygen content in the blood is that carried by

Division of Neonatology, Children's Memorial Hospital and Northwestern University, Chicago, IL. Reprint requests and correspondence: Robin H. Steinhorn, MD, Division of Neonatology, Children's Memorial Hospital and Northwestern University, 2300 Children's Plaza #45, Chicago, IL 60614. (E-mail: r-steinhorn@northwestern.edu) 1522-8401/$ see front matter C 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2008.06.006

hemoglobin: each gram of hemoglobin can combine with 1.34 mL of oxygen. In contrast, the amount of oxygen dissolved in the plasma (0.003 mL per 100 mL of plasma) is clinically insignificant. Therefore, the goal should be to achieve adequate hemoglobin saturation and perfusion of the tissues. While oxygenated hemoglobin is bright red, reduced hemoglobin is dark blue or purple in color and is what produces the dusky or blue color of the skin and mucous membranes. An important concept is that cyanosis is dependent upon the absolute concentration of reduced hemoglobin, rather than on the oxygen saturation or the ratio of reduced hemoglobin to oxyhemoglobin [2]. With careful observation, cyanosis may become apparent when the deoxygenated hemoglobin content is as little as 3 g per 100 mL. Therefore, infants with polycythemia may exhibit cyanosis at relatively high arterial saturations, whereas it is more difficult to discern cyanosis in a severely anemic infant unless the oxygen saturation is extremely low (Table 1). In general, the relatively high hemoglobin of the normal infant tends to facilitate the recognition of cyanosis. At the same time, the relative concentration of fetal hemoglobin and its unique characteristics of oxygen binding need to be considered, as these factors may impair the recognition of cyanosis. The ratio of fetal to adult hemoglobin varies from infant to infant, and the proportions of each hemoglobin affect the oxygen saturation resulting at any given PaO2. Thus, if a baby has mostly adult hemoglobin, central cyanosis (arterial saturation, 169

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Table 1 Effect of hemoglobin concentration on the recognition of cyanosis. Hgb (g) 20 8 Reduced Hgb (g) 3 3 Sao2 85 62 Total Hgb-reduced Hgb/total Hgb (20-3)/20 (8-3)/20

R.H. Steinhorn
Functional closure of the ductus occurs over the first several hours of life, largely in response to the increased oxygen tension. Left atrial pressure also increases leading to closure of the foramen ovale. These events therefore eliminate the fetal right to left shunts and establish the normal postnatal circulatory pattern of pulmonary and systemic circulations. Within 24 hours after birth, pulmonary artery pressure typically decreases to approximately 50% of mean systemic arterial pressure and continues to drop over the next 2 to 6 weeks until adult values are attained.

These data show the expected levels of saturation for 2 hypothetical babies: one with a normal hemoglobin (20 g/dL ) vs one with a low hemoglobin (8 g/dL). Both babies have a fixed reduced hemoglobin level of 3 g. The infant with the hemoglobin of 20 will have a saturation of 85% and may appear cyanotic. However, the severely anemic infant may not appear cyanotic until the saturation is critically low.

75% to 85%) will be observed when the PaO2 falls below 50 mm Hg. In contrast, if the baby has mostly fetal hemoglobin, central cyanosis may not be observed until the PaO2 drops well below 40 mm Hg. Thus, infants with a high proportion of fetal hemoglobin may have a serious reduction in oxygenation before cyanosis is clinically apparent (Figure 1).

The ABCs of Differential Diagnosis in the Cyanotic Infant

Using an airway, breathing, circulation (ABC) algorithm of evaluation will allow the emergency department (ED) practitioner to systematically consider the most common causes of cyanosis in the newborn period (Table 2).

A: Airway-Upper and Lower Airway Disease

Normal Cardiopulmonary Adaptation at Birth

At birth, profound changes in the cardiovascular and respiratory systems occur to allow the infant to adapt to air breathing. An understanding of these normal transitional changes is important in evaluating a cyanotic infant, as their disruption is likely to lead to cyanosis [3]. The fetus has a unique circulatory pattern because the placenta, not the lung, serves as the organ of gas exchange. Less than 10% of the cardiac output is circulated through the pulmonary vascular bed, and the placenta, as the organ of gas exchange, receives nearly half of the cardiac output. Pulmonary blood flow remains low owing to elevated pulmonary vascular resistance; pulmonary pressure is equivalent to systemic pressure because of active vasoconstriction. Fetal circulation shunts blood from the right to the left atrium across the foramen ovale and from the pulmonary artery to the descending aorta through the ductus arteriosus providing direct blood flow to the placenta. The fetal lungs produce fluid that fills the alveoli, bronchi, and trachea. At birth, catecholamines and other hormones that increase during labor cause a rapid switch from net secretion to net absorption of liquid in alveolar spaces. As the lungs fill with air, lung fluid is removed via the trachea and absorption by the pulmonary capillaries and lymphatics. Pulmonary vascular resistance drops dramatically and permits an 8- to 10-fold rise in pulmonary blood flow. Simultaneously, the low vascular resistance bed of the placenta is removed and systemic vascular resistance increases. As pulmonary pressure falls to less than systemic pressure, pulmonary blood flow increases and blood flow through the patent ductus arteriosus reverses direction.

Although airway conditions will generally present shortly after birth, these should be considered during the initial evaluation of the infant presenting to the ED with respiratory distress [4]. Choanal atresia occurs in 1:5000 infants, with unilateral disease being more common. Choanal atresia should be suspected when an infant's distress is more obvious in a quiet state and

Figure 1 Representation of the different characteristics of oxygen binding in fetal vs adult hemoglobin. For a hypothetical PaO2 of 45, the saturation of adult hemoglobin would fall below 80%, typically creating a cyanotic appearance. However, the binding characteristics of fetal hemoglobin would allow for the saturation to remain in the mid-80s, which may not be associated with overt cyanosis.

Evaluation and management of the cyanotic neonate

Table 2 Causes of cyanosis. A Airway Choanal atresia Micrognathia Pierre Robin sequence Laryngomalacia Vocal cord paralysis Tracheal stenosis Vascular slings/rings Cystic hygroma Hemangioma Other neck masses B Breathing Pneumonia Congenital diaphragmatic hernia Congenital cystic adenomatoid malformation Pulmonary sequestration Congenital lobar emphysema Pulmonary hypoplasia Phrenic nerve palsy Hypoventilation C Circulation

171

Oxygen carrying capacity Polycythemia Anemia Methemoglobinemia Congenital heart disease Decreased pulmonary blood flow Tricuspid atresia Pulmonary atresia Pulmonary stenosis Tetralogy of Fallot Ebsteins anomaly Inadequate mixing Transposition of the great arteries Persistent pulmonary hypertension

improves during crying. It can be confirmed by the inability to pass a suction catheter through the nares into the oropharynx, as well as via medical imaging, with computed tomography scanning currently serving as the radiographic procedure of choice. Placement of an oral airway should provide immediate improvement. Other associated anomalies are very common; in particular, CHARGE sequence (coloboma, heart disease, atresia of choana, retarded growth and development, genitourinary anomalies, ear/hearing anomalies) should be considered. Micrognathia, retrognathia, or the Pierre Robin sequence generally presents early in life and will be obvious on physical examination. The airway obstruction from the posterior tongue is more pronounced in the supine position. When present, a cleft palate does not cause respiratory distress unless feeding difficulties are severe. These infants may require tracheostomy for several years until the mandible grows enough to maintain the tongue in a more anterior position. Laryngomalacia is a congenital abnormality of the larynx and is the most common cause of inspiratory stridor in infants. Although it may be noted immediately after birth, it commonly presents at several weeks of age. Airway symptoms typically worsen with crying, feeding, and respiratory infections. Gastroesophageal reflux is a common association. Subglottic stenosis may occur as a congenital malformation or be acquired after prior airway manipulation. Infants present with stridor, respiratory distress, or obstructive apnea. Vocal cord paralysis may be associated with birth or surgical trauma and is another common cause of stridor in the newborn. It is typically unilateral, causing a hoarse cry and minimal respiratory symptoms. In contrast, bilateral vocal cord paralysis can cause severe respiratory distress, and a tracheostomy may be required. In these cases, central nervous system anomalies such as the Arnold-Chiari malformation should be considered.

Other conditions may cause intrinsic or extrinsic compression of the trachea. Tracheal stenosis is characterized by expiratory stridor, respiratory distress, wheezing, or persistent cough. Symptoms typically worsen after an upper airway infection. The diagnosis is confirmed by direct bronchoscopic visualization. Tracheal stenosis is often associated with complete tracheal rings, which may require extensive surgical repair in case of multiple rings or long segment stenosis. A number of conditions may produce extrinsic airway compression. Vascular rings and slings caused by abnormal development of mediastinal vessels can compress or deviate the trachea causing airway obstruction. An anomalous distal origin of the innominate artery from the aortic arch is the most common cause, but other anomalies include double aortic arch or an aberrant right subclavian artery. Specialized cardiac computed tomography or magnetic resonance imaging studies are helpful in accurately defining the anatomy. Neck or mediastinal masses such as teratomas and cystic hygromas represent large lesions that can cause extrinsic compression of the trachea; these are typically associated with visible neck masses. Subglottic hemangiomas should be considered in infants that have skin hemangiomas. As hemangiomas typically increase in size over the first 6 to 12 months of life, symptoms often emerge after an initially benign history.

B: BreathingLung Disease
Neonatal pneumonia is most commonly acquired at the time of birth and usually causes diffuse rather than lobar infiltrates. The initial radiograph is frequently indistinguishable from the ground glass appearance of respiratory distress syndrome, although pleural effusions are more characteristic of pneumonia. Bacterial pneumonia is most common, and frequent pathogens include group B -hemolytic streptococci and Gram-negative

172 enteric bacilli (Escherichia coli, Klebsiella, Enterobacter). Important elements of the maternal history will include colonization with group B -hemolytic streptococci with or without adequate intrapartum prophylaxis (N2 doses of penicillin before delivery), as well as a history of prolonged rupture of membranes (N18 hours), or a history of maternal fever or chorioamnionitis. Herpes simplex and cytomegalovirus are viral causes of neonatal pneumonia, but typically present as components of disseminated infections. Congenital chlamydia infections can cause pneumonia that presents between 2 and 8 weeks of age, typically with upper respiratory symptoms associated with a cough and apnea. Congenital lung abnormalities are rare but important causes of respiratory distress in the newborn [4]. In many cases, infants are initially asymptomatic, with respiratory distress developing over time. Careful review of the chest x-ray should reveal these lesions. Congenital diaphragmatic hernia is a relatively common birth defect, but because of its frequent association with significant pulmonary hypoplasia and significant pulmonary hypertension, it almost always presents shortly after birth. Congenital cystic adenomatoid malformations are extremely rare lung abnormalities composed of cystic lung tissue with communication to the bronchial tree. Medical imaging will help to differentiate this lesion from a congenital diaphragmatic hernia. Pulmonary sequestration is a rare condition characterized by nonfunctioning primitive lung tissue that does not communicate with the tracheobronchial tree and receives vascular supply from the systemic circulation (thoracic or abdominal aorta). Sequestrations may occasionally present in the neonatal period with signs of congestive heart failure owing to the run-off circulation, but more commonly present later in life with recurrent infections. Congenital lobar emphysema is an overinflated, hyperplastic area of the lung surrounded by otherwise normal lung tissue. These are most common in the upper lobes. Symptoms are typically progressive, but may be rarely present at birth. Surgical excision is usually curative, although overinflation of remaining lung areas can occur. It is important to remember that respiratory failure and cyanosis may occur secondary to other organ system dysfunction. For instance, birth injury associated with neurologic depression or hypoxic-ischemic encephalopathy is commonly associated with hypoventilation. Phrenic nerve injury may cause diaphragmatic paresis. In addition, excessive oral secretions and inadequate swallowing may obstruct the airway and cause respiratory distress. Hypoglycemia may cause central nervous system depression and secondary respiratory distress; this is most commonly seen in small-for-gestational-age infants, large-for-gestational-age infants, infants of diabetic mothers, birth asphyxia, or in rare cases due to primary hyperinsulinism (eg, nesidioblastosis or Beckwith-Wiedemann syndrome). Abdominal distension may

R.H. Steinhorn
compress the thorax and interfere with normal respiration. This may be seen as a result of gastrointestinal pathology (obstruction) or large intra-abdominal mass effect (renal/genitourinary masses, severe ascites). Finally, late preterm (34 - 37 weeks gestation) or even term infants may present with apneic episodes as a cause of cyanosis.

C: CirculationCardiac and Circulatory Causes

The hemoglobin circulating in the vasculature plays an important role in oxygenation. Both high and low levels of hemoglobin may lead to cyanosis, although for different reasons. Polycythemia can cause pulmonary hypertension owing to increased viscosity of the blood interfering with pulmonary perfusion. This may be seen in infants of diabetic mothers, delayed clamping of the umbilical cord, chronic fetal hypoxia (eg, placental insufficiency, preeclampsia); in recipient twins of a twinto-twin transfusion syndrome; and in conditions such as trisomy 21. Conversely, severe anemia can cause respiratory distress because inadequate oxygen delivery to tissues can lead to cellular hypoxia. Anemia may be due to hemolytic disease of the newborn, fetal blood loss due to external hemorrhage (placental abruption, umbilical cord rupture), or fetal-maternal hemorrhage, or may be seen in donor twins in twin-to-twin transfusion syndrome. Abnormalities of the hemoglobin molecule itself may interfere with the normal chemical combination of hemoglobin with oxygen. The most common cause is methemoglobinemia, which results from the oxidation of hemoglobin molecules from the normal ferrous to ferric state. Infants are more susceptible as fetal hemoglobin is more easily oxidized than is adult hemoglobin, and because levels of methemoglobin reductase are relatively low in infants. Methemoglobinemia may result from exposure to oxidants (eg, nitrites, sulfonamides, prilocaine, metoclopropamide) or rarely from congenital deficiency of methemoglobin reductase. The characteristic clinical scenario is a blue-grayappearing infant without respiratory distress who has decreased oxygen saturation, but normal arterial oxygen tension. Severe cyanosis is a prominent feature in congenital heart disease associated with diminished pulmonary blood flow or in babies with separate circulations and poor mixing [5]. Diminished pulmonary blood flow is characteristic of tricuspid atresia, pulmonary atresia, pulmonary stenosis, tetralogy of Fallot (TOF), and Ebstein's anomaly. Tetralogy of Fallot represents approximately 10% of cases of congenital heart disease and is one of the most common cyanotic congenital heart lesions presenting in the newborn period. The pulmonary outflow stenosis in TOF tends to be progressive, meaning that clinically significant cyanosis

Evaluation and management of the cyanotic neonate

is present at birth in approximately 25% of infants, but 75% become cyanotic by 1 year of age. In all of these conditions, pulmonary blood flow will initially be dependent on blood directed to the lungs through a patent ductus arteriosus. Therefore, cyanosis worsens at the time of ductal closure and tends to improve rapidly after the ductus is reopened after initiation of prostaglandin E1 (PGE1). Transposition of the great arteries (TGA) is another relatively common congenital heart lesion that presents with severe cyanosis. The systemic and pulmonary circulations are normally in series with each other, but in complete transposition, the circulations are in parallel. Therefore, deoxygenated systemic venous blood returns to the right atrium, enters the right ventricle, and exits through the aorta. Infants with TGA are dependent on communications between these 2 circuits for mixing. If the ventricular septum is intact, life-threatening cyanosis will develop when the foramen ovale and ductus arteriosus close in the hours or days after birth. Although a patent ductus arteriosus will improve atrial mixing to a variable degree, adequate inter-atrial communication is what allows for adequate mixing and oxygenation. Infants with a large ventricular septal defect may present to the ED after the first few days of life because there is more potential for mixing even as other shunts close. Cardiac disease associated with complete mixing may be associated with a variable degree of cyanosis. Examples include truncus arteriosus and total anomalous pulmonary venous return, lesions which are characterized by pulmonary overcirculation. Because pulmonary blood flow is normal to increased, cyanosis is usually not as significant and does not respond to PGE1. In fact, measures that increase pulmonary blood flow (PGE1, supplemental oxygen) should be avoided as they may worsen pulmonary overcirculation and thus decrease systemic blood flow. In rare cases, total anomalous pulmonary venous return may be associated with obstruction, which leads to decreased pulmonary blood flow and severe cyanosis. Persistent pulmonary hypertension of the newborn (PPHN) describes the failure of the normal circulatory transition that occurs after birth [3]. It is characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left extrapulmonary shunting of blood through fetal channels (foramen ovale and ductus arteriosus). The combination of inadequate pulmonary perfusion and extrapulmonary shunting leads to refractory hypoxemia. Persistent pulmonary hypertension often complicates parenchymal lung disease in newborn infants, because pulmonary vessels readily constrict in response to alveolar hypoxia. However, PPHN can also occur idiopathically in the absence of underlying parenchymal disease. In these cases, the syndrome is believed to be the result of an abnormally remodeled vasculature that develops in utero in response to prolonged fetal stress, hypoxia, and/or pulmonary hypertension. PPHN is

173 commonly associated with lung hypoplasia, as seen in congenital diaphragmatic hernia.

Initial Evaluation
The evaluation should systematically assess the infant for airway, pulmonary, and circulatory causes as described above. The history should include an assessment of the pregnancy, labor, and newborn risk factors. A history of maternal diabetes increases the risk of congenital heart disease, as well as polycythemia and hypoglycemia, which may be associated with lethargy and hypoventilation. The presence of oligohydramnios may suggest renal abnormalities associated with hypoplastic lungs, whereas polyhydramnios may suggest airway, esophageal, or neurologic abnormalities. Screening results for cervical colonization of group B streptococcus should be sought, although it is important to realize that infection is possible even if the antenatal culture was negative. Prolonged rupture of membranes may suggest bacterial infection, and a history of a difficult delivery may result in intracranial hemorrhage or phrenic nerve paralysis. The physical examination should be performed when the infant is appropriately warmed and quieted. The growth characteristics should be noted, as infants who are small or large for gestational age are more prone to polycythemia. The primary focus will be on determining the degree of respiratory distress, as its absence will suggest the presence of congenital heart disease or methemoglobinemia. Respiratory insufficiency due to pulmonary disease is typically characterized by rapid respirations accompanied by retractions and nasal flaring. Neurologic conditions are potential causes of cyanosis because of hypoventilation and may be associated with slow or irregular respirations. It is also important to evaluate the infant's tone and activity, and to assess the infant for periodic breathing and/or apneic spells. The examination may reveal findings of birth trauma, such as an Erb's palsy or stridulous cry. The cardiac exam should include an assessment of the infant's heart rate, peripheral pulses, and perfusion. Auscultation of the heart should focus on the second heart sound, which will be loud and single (or narrowly split) in pulmonary hypertension, as well as in transposition and pulmonary atresia. The auscultation of heart murmurs is often not helpful: serious lesions such as transposition are not associated with murmurs, and loud murmurs are frequently due to a relatively benign lesion such as a small ventricular septal defect. A notable exception is that a harsh ejection murmur is characteristic of pulmonary stenosis. As noted above, the oxygen saturation is the percent of hemoglobin that is chemically combined with oxygen, which represents the vast majority of oxygen content in the blood. Pulse oximetry provides excellent noninvasive and continuous assessment of oxygen saturation. New

174 generation pulse oximeters appear to improve performance during low perfusion states. It is often useful to obtain simultaneous measurements from the right hand and a foot to determine flow patterns through the ductus arteriosus. As the left subclavian artery may have a preductal or postductal origin from the aorta, it is best not to use the left hand for pulse oximetry monitoring. Although measurement of arterial blood gas oxygen tension is standard practice, the pain of an arterial puncture may produce agitation and changes in ventilation and oxygenation. A venous blood gas may be useful for the assessment of pH and PaCO2, but should not be used to determine oxygenation. In either case, the presence of a significant metabolic acidosis may indicate cardiac failure, sepsis, asphyxia, or metabolic disorders. Many microsampling blood-gas analyzers now include lactate in their measured parameters, providing additional useful information about global perfusion and oxygenation. A chest radiograph is an integral part of the initial assessment of the cyanotic newborn. The locations of stomach, liver, and heart should be determined to rule out dextrocardia and situs inversus. Examining the lung fields may reveal parenchymal lung disease (remembering that the newborn with pneumonia typically has diffuse rather than focal infiltrates) or lung abnormalities such as cystic adenomatoid malformation. Elevation of either hemidiaphragm by more than 2 intercostal spaces relative to the opposite side suggests diaphragmatic paralysis due to phrenic nerve injury. Hyperinflated lung fields are seen occasionally in lobar emphysema or cystic lesions of the

R.H. Steinhorn
lungs. Decreased pulmonary vascular markings are characteristic of pulmonary stenosis or pulmonary atresia with inadequate ductal shunting and may be seen in infants with idiopathic persistent pulmonary hypertension of the newborn (Figure 2). The size and shape of the heart may yield some clues to the diagnosis: for instance, the boot shape heart of TOF, and the egg on string appearance of transposition, and the characteristic massive cardiomegaly of Ebstein's anomaly. An electrocardiogram is useful for the diagnosis of cardiac arrhythmias. However, normal newborns have a predominance of right-sided forces, and moderate right ventricular hypertrophy is a common finding with many types of respiratory and cardiac disease. Therefore, the electrocardiogram is seldom helpful in the evaluation of the infant with congenital heart disease and is often completely normal even in infants with serious disease such as transposition. A notable exception would be the infant with left axis deviation due to left ventricular hypertrophy, which would strongly suggest tricuspid atresia. Some advocate for the hyperoxia test as a clinical tool to differentiate between pulmonary and cardiac disease in cyanotic infants. The test is based on the principle that in the absence of fixed cardiac shunts, 100% oxygen will increase alveolar PO2, leading to an increase in pulmonary venous and systemic arterial PO2. In cyanotic congenital heart disease (eg, decreased pulmonary blood flow or TGA), little or no rise in PaO2 would be expected after breathing 100% O2. However, the same finding may occur in infants with significant pulmonary hypertension if significant right-to-left shunting persists through extrapulmonary shunts (ductus arteriosus and foramen ovale). Given the wide availability of echocardiography, the hyperoxia test should rarely (if ever) be necessary and should only be considered after discussion with a cardiologist.

Initial Management in the Emergency Department

Severe cyanosis requires urgent supportive therapy while a diagnosis is established. This will include intravenous fluids and withholding of enteral feedings. The infant should be maintained in a thermoneutral environment using a radiant warmer. Hypoglycemia is common in critically ill infants, therefore glucose levels should be monitored and glucose infusions provided to maintain a blood glucose of greater than 55 mg/dL. An airway and assisted ventilation should be considered for infants with respiratory distress, but may be deferred for the comfortable infant. Severe acidosis should be corrected with infusions of sodium bicarbonate, but only after adequate gas exchange has been established. If the infant is less than 10 days old and the umbilical stump is still attached, umbilical venous and arterial lines can frequently be placed

Figure 2 Chest x-ray of an infant with idiopathic persistent pulmonary hypertension. Note the clear lung fields with decreased vascularity. Similarly, oligemic lung fields would also be expected in conditions with low pulmonary blood flow, such as pulmonary atresia.

Evaluation and management of the cyanotic neonate

by experienced practitioners for rapid central access. Hypocalcemia is often associated with cardiac disease and critical illness, and should be corrected based on the ionized calcium. Oxygen should be provided, although there are increasing concerns about the potential risks associated with this therapy [6]. Even brief (30-minute) exposures to extreme hyperoxia are increasingly recognized to increase oxidative stress and potentially damage lung parenchymal and vascular function, even in term infants [7,8]. Therefore, the use of 100% O2 should generally be avoided at the outset. Initiating oxygen therapy with 40% to 60% O2 will allow the caregiver to provide support, assess for improvement, and seek advice from a cardiologist. This point is particularly important if an infant has only a minimal response to oxygen, as this may indicate potential cardiac disease and need for PGE1. In addition, it is important to remember that oxygen may promote ductal closure. This may not be a major concern for lesions that limit pulmonary blood flow, as the pulmonary venous PO2 would not be expected to rise. However, admixture lesions such as hypoplastic left heart syndrome may present with moderate cyanosis. These conditions are dependent on a patent ductus to maintain systemic blood flow. Oxygen may not only promote ductal closure, but may increase pulmonary and decrease systemic blood flow. In the infant who does not require assisted ventilation, oxygen may be delivered via a head hood or nasal cannula [9]. A head hood is the only method that allows the FiO2 to be determined precisely. The oxygen concentration should be measured by an oxygen analyzer placed near the baby's mouth. Relatively high flows are needed achieve adequate concentrations of oxygen and avoid carbon dioxide accumulation, although humidification is generally not necessary. Although head box oxygen is generally well tolerated, this method limits the infant's mobility, and oxygen concentrations fall quickly when the hood is lifted to provide care to the infant. Therefore, this method is typically not used when prolonged oxygen treatment is required. Oxygen is frequently delivered by a nasal cannula. The disadvantage of this method is that the infant entrains variable amounts of room air around the nasal cannula. Therefore, it cannot provide 100% oxygen, and the oxygen concentration in the hypopharynx (a good proxy for the tracheal concentration) will be much lower than the concentration of oxygen at the cannula inlet. Both the oxygen concentration and the cannula flow rate will be the major factors that will determine the fraction of oxygen actually delivered. Therefore, it is generally better to titrate delivery to achieve the desired oxygen saturation levels, generally 90% to 95% by pulse oximetry.

175 Prostaglandin E1 is clinically effective for infants dependent on ductal patency to maintain pulmonary blood flow or sufficient mixing. It is given intravenously by constant infusion, and the initial dose is typically 0.05 g/kg per minute. Apnea is a common side effect after initiation of PGE1, and some recommend intubation if the infant will require transport shortly after beginning the infusion. Other common side effects include flushing and diarrhea. There are no absolute contraindications to beginning prostaglandin, although it may worsen the pulmonary edema associated with obstructed total anomalous pulmonary venous return.

Summary
The infant presenting to the ED with cyanosis requires urgent assessment, diagnosis, and initiation of therapy. A systematic, rational approach to the diagnosis of neonatal cyanosis is essential. An understanding of the normal transitional physiology, and how diseases of the airway, lung, and circulatory system may disrupt these processes, will enable the ED practitioner to determine whether the underlying cause is related to airway obstruction, parenchymal disease, hypoventilation due to central nervous system disease or apnea, or due to cardiac disease. Management is based on the clinical diagnosis and attention to hemodynamic stability, judicious oxygen administration, and referral to the appropriate inpatient hospital setting. Although prognosis depends on the diagnosis, it is generally good with prompt recognition and intervention.

References
1. Sasidharan P. An approach to diagnosis and management of cyanosis and tachypnea in term infants. Pediatr Clin North Am 2004;51: 999-1021. 2. Lees MH. Cyanosis of the newborn infant. Recognition and clinical evaluation. J Pediatr 1970;77:484-98. 3. Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO: focus on PPHN. Semin Perinatol 2005;29:8-14. 4. Porta NF. Respiratory disorders of the newborn. In: Green T, Franklin W, Tanz R, editors. Pediatrics: Just the Facts. New York: McGraw-Hill; 2005. p. 99-108. 5. Zahka K, Lane J. Approach to the neonate with cardiovascular disease. In: Martin RJ, Fanaroff A, Walsh MC, editors. Fanaroff and Martin's Neonatal-Perinatal Medicine. 8th ed. Philadelphia, PA: Mosby; 2005. p. 1112-20. 6. Saugstad OD, Ramji S, Vento M. Oxygen for newborn resuscitation: How much is enough? Pediatrics 2006;118:789-92. 7. Lakshminrusimha S, Russell JA, Steinhorn RH, et al. Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen resuscitation. Pediatr Res 2006;59:137-41. 8. Lakshminrusimha S, Russell JA, Steinhorn RH, et al. Pulmonary hemodynamics in neonatal lambs resuscitated with 21%, 50%, and 100% oxygen. Pediatr Res 2007;62:313-8. 9. Frey B, Shann F. Oxygen administration in infants. Arch Dis Child Fetal Neonatal Ed 2003;88:F84-8.

Neonatal Neurological Emergencies

Janine Yasmin Khan, MD
Encephalopathy, or an altered state of consciousness, presents a diagnostic challenge to clinicians involved in the care of neonates. Unlike older age groups where neurological dysfunction almost invariably suggests central nervous system disease, the neonate will present with an acute encephalopathy when severe illness arises within or outside the central nervous system. This article is intended to highlight the various neonatal conditions that may present with disturbed neurological function (seizures and altered states of consciousness) to the emergency department, and emergency physicians must be aware of the extensive differential diagnoses associated with such presentations. It cannot be overemphasized that a detailed history from a caregiver and a thorough physical examination are essential to identify potentially treatable etiologies. Clin Ped Emerg Med 9:176-183 C 2008 Elsevier Inc. All rights reserved. KEYWORDS neurological emergency, seizures, neonatal, encephalopathy

nfants presenting with a neurological emergency, often display nonspecific signs that create significant diagnostic difficulties. In the neonatal period, neurological dysfunction may present as seizures, lethargy, or coma, and the underlying cause may be related to disturbances in organ systems other than the central nervous system. Although nonaccidental injury may predispose the neonate to acute neurological dysfunction and should be considered when the history is suggestive of such an injury, it is the nontraumatic conditions that remain important causative factors in this age group. Regardless of the cause of the presenting encephalopathy, affected infants tend to present with signs of an overwhelming illness requiring immediate supportive care. Prognosis of infants presenting with an encephalopathy varies depending on the specific underlying etiology.

Neonatal Seizures
Seizures are the most common neonatal neurological emergency encountered in the emergency department (ED) and require prompt diagnosis and treatment. Seizures occur more often in the neonatal period than at any other time of life. The precise frequency is unknown but estimated to occur in approximately 1-5:1000 live births [1]. A seizure represents the most frequent manifestation of neurological disorder in the newborn and may be related to significant illness. Its presence may reflect a potentially 176

treatable etiology, and immediate evaluation to determine the underlying cause is essential because seizures may precipitate hypoxemia, acidemia, alterations in glucose homeostasis, and hemodynamic changes in blood pressure and heart rate and can potentially contribute to further brain injury [2]. Although most neonatal seizures are acute and reactive and associated with a particular etiologic condition, some seizures occur without an identifiable cause and are termed idiopathic [3]. Clinical diagnosis of seizure activity in the neonate is assisted by the recognition that some seizures may only be associated with changes in respiration, heart rate, and blood pressure. Most neonatal seizures are focal in origin because of the delay in generalization of electrical activity secondary to lack of myelination, together with incomplete dendritic and synaptic formation in the immature brain. Neonatal seizures result as a manifestation of a wide range of conditions that fall into 1 of 5 broad categories: neonatal encephalopathy, metabolic disturbances, central nervous system (CNS) or systemic infections, inborn errors of metabolism, and structural brain lesions. The common

Feinberg School of Medicine, Northwestern University, Children's Memorial Hospital and Northwestern Memorial Hospital, Chicago, IL. Reprint requests and correspondence: Janine Yasmin Khan, MD, Division of Neonatology, 2300 Children's Plaza, Box 45, Chicago, IL 606143394. (E-mail: j-khan@northwestern.edu) 1522-8401/$ - see front matter C 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2008.06.007

Neonatal neurological emergencies

Table 1 Frequent causes of neonatal seizures.

177 neuronal cells, which may result from different mechanisms. Disturbance in energy production with resultant failure of the sodium-potassium pump is seen in hypoxia, ischemia, and hypoglycemia. Alternatively, alteration in the neuronal membrane may affect sodium permeability, as seen in hypocalcemia and hypomagnesemia. Normal calcium and magnesium levels are usually protective to the neuronal membrane by causing a decrease in intracellular sodium, whereas low levels would enhance depolarization by increasing sodium influx. A third mechanism involves excess of excitatory vs inhibitory neurotransmitters, which may also lead to increased depolarization. The N-methyl-D-aspartic acid glutamate receptor is the most important excitatory amino acid receptor in the neonatal period, related in part to their enhanced physiological activity in the immature brain. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors mediate fast excitatory neurotransmission by triggering an influx of sodium. This causes depolarization resulting in the opening of voltage-sensitive calcium channels, thereby contributing to the cytosolic accumulation of calcium. Both N-methyl-D-aspartic acid and alphaamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors enhance neuronal excitability at term gestation, and peak seizure susceptibility occurs in the second postnatal week in many animal seizure models [7].

Hypoxic-Ischemic encephalopathy Intracranial hemorrhagesubarachnoid, intraventricular, and subdural hemorrhages Intracranial infectionsgroup B streptococcus, Gram-negative bacteria, HSV, cytomegalovirus, and coxsackie virus Cerebral infarction Metabolic abnormalitieshypoglycemia, hypocalcemia, hypomagnesemia, hypo/hypernatremia, hyperammonemia Inborn errors of metabolism Drug withdrawal Developmental migrational disorderslissencephaly Benign neonatal convulsions/benign familial neonatal convulsions

causes of neonatal seizures are listed in Table 1. Mizrahi and Kellaway [4] found that the most frequent cause of seizure in the neonate was hypoxic-ischemic injury (32%), followed by intracranial hemorrhage (17%), CNS infections (14%), cerebral infarction (7%), metabolic disturbances (6%), inborn errors of metabolism (3%), and unknown (10%). Hypoxic-ischemic encephalopathy is the most common cause of neonatal seizures; however, it is unusual for infants with this condition to present initially to the ED. Instead, affected infants tend to present to the neonatal intensive care unit within 6 to 12 hours of birth with a history of perinatal complications with associated low Apgar scores, metabolic abnormalities, and clinical signs of encephalopathy (lethargy, decreased spontaneous activity, hypotonia, abnormal reflexes, weak/absent suck, seizures). There are 2 neonatal epileptic syndromes that are considered benign and therefore associated with a good prognosis: benign neonatal convulsions and benign familial neonatal convulsions. The former is usually a self-limiting idiopathic seizure syndrome, also known as fifth day fits, with brief seizures commonly appearing between the fourth and sixth days of life, recurring during a period of 24 to 48 hours, followed by complete resolution. Seizures rarely persist beyond the first week of life, and the neurological examination is normal between seizures; however, this is a diagnosis of exclusion and extensive investigation for a specific etiology is necessary [4,5]. Benign familial neonatal convulsion is an autosomal dominant disorder with 85% penetrance. Seizures are brief and may recur for 2 to 3 months with subsequent spontaneous resolution; however, an association with post neonatal epilepsy has been reported [6]. In the ED, initial evaluations are directed at infectious and metabolic causes because they are most likely to be responsive to treatment, and delayed diagnosis may result in significant morbidity and mortality.

Clinical Presentation
Clinical manifestations of seizures in the neonate differ from those in the older infant/child. Identification and characterization of the seizure is important, including location, extent of limb, face or truncal involvement, duration and progression of the seizure, and timing of recurrence. Neonatal seizures have been classified as subtle or fragmentary, clonic, tonic, and myoclonic and may be subclassified as focal, multifocal, or generalized [8]. Subtle seizures, although difficult to detect, may represent significant brain dysfunction and include abnormalities in ocular movements (horizontal or vertical deviation of the eyes, repetitive fluttering of eyelids), oralbuccal-lingual movements, swimming and cycling movements of upper and lower extremities, respectively, and/or apneic episodes in term infants. Autonomic dysfunction with periodic changes in blood pressure, heart rate, oxygen saturation, and respiration are more frequently seen in association with subtle seizures. Tonic seizures are characterized by tonic extension of all extremities and are usually generalized with associated ocular signs or apnea. On the other hand, multifocal clonic seizures are characterized by clonic movements originating in one extremity, then spreading to involve other areas. Focal clonic seizures are characterized by localized rhythmic jerking movements and are usually associated with focal traumatic or ischemic injury but may also be seen in generalized cerebral insults including metabolic encephalopathies.

Pathophysiology
Seizures result from excessive repetitive depolarization of neurons due to an increased influx of sodium into

178 Myoclonic seizures represent single or multiple jerks of flexion, involving upper or lower extremities. These are sometimes confused with benign myoclonic jerks in the newborn, a condition that occurs during sleep in the first few weeks of life and are associated with a normal neurological examination and electroencephalogram (EEG). It is important to differentiate between jitteriness and seizure activity because these conditions are often confused and the diagnosis has important implications regarding management. Jitteriness indicates tremulous movements that are stimulus-sensitive and independent of autonomic changes and may be differentiated from seizures by the absence of abnormal ocular movements with cessation of abnormal movements by passive flexion of the affected limb. Status epilepticus is a common medical neurological emergency, with no precise estimate of its incidence in the neonatal population. The definition of status epilepticus has changed over time and according to the International Classification of Epileptic Seizures refers to ongoing seizure activity for at least 30 minutes duration or frequently repeated seizure activity during which the infant fails to regain consciousness between seizures [9]. More recent definitions have proposed seizures of shorter duration of 10 to 15 minutes, as studies have shown that the longer-lasting seizures tend to be associated with delayed treatment response [10]. There is also ongoing concern regarding the effect of repetitive or prolonged seizures on brain development and brain injury [11]. Status epilepticus is a life-threatening condition with serious neurological sequelae [10].

J.Y. Khan
diagnosis in the ED. Because neonatal seizures are acute and reactive events, initial screening laboratory tests seek to identify the underlying etiology and include a complete blood count, glucose, sodium, potassium, calcium, ionized calcium, and magnesium. A lumbar puncture to exclude intracranial infections, meningitis and encephalitis, is usually undertaken, and a cranial computerized tomography scan to exclude intracranial hemorrhage/infarction should be considered. The EEG is the preferred investigation to confirm seizure activity and may be a helpful guide to treatment and prognosis. The approach to a neonate presenting with a seizure includes management of the airway, administration of oxygen, cardiovascular support, and establishing parenteral access (ABC's of resuscitation). Etiology-specific therapy may be adequate in cases of metabolic disturbances. Anticonvulsant therapy is not necessary in all cases, and emergency physicians must decide whether to start antiepileptic therapy. Hypoglycemia, hypocalcemia, and hypomagnesemia management can be found in Table 2. Careful attention should be directed at the infusion site and the infant's heart rate and blood pressure during administration of these solutions. It is important to realize that in cases of hypocalcemia resistant to treatment, when there is associated hypomagnesemia, it may be necessary to normalize the magnesium level before normocalcemia is achieved. In cases of seizures refractory to antiepileptic drug (AED) therapy, pyridoxine-dependent seizures should be considered. This is a rare, autosomal recessive disorder with no specific laboratory tests and is a diagnosis of exclusion. The management of these seizures is outlined in Table 2. Pyridoxine dependence is confirmed by the termination of seizures on EEG within 2 to 6 minutes after intravenous (IV) administration. The side effects most commonly seen during a trial of pyridoxine include apnea, lethargy, and hypotonia;

Management
Although clinical recognition of seizure activity may be difficult in the neonate due to clinical and EEG variation compared to older children, it remains the basis of

Table 2

Etiology-specific therapy in metabolic disturbances. Treatment Comments

Condition Hypoglycemia Hypocalcemia

Hypomagnesemia

Pyridoxine dependence trial

10% dextrose solution at 2 mL/kg over 5-10 min Followed by maintenance glucose infusion rate * of 6-8 mg/kg per minute Repeat as needed. 10% calcium gluconate solution at 100 mg/kg or 1 mL/kg, IV, over 15 min. Alternatively, 10% This is especially useful when fluid restriction calcium chloride at 20 mg/kg or 0.2 mL/kg, IV, is necessary. Following acute management, calcium gluconate should be added to over 15 min maintenance IV fluid Before administration, dilute 50% solution to 50% magnesium sulfate solution IV 25 mg/mL (to give a 20% solution). May repeat 20-50 mg/kg/dose (0.2-0.4mEq/kg/dose) every 8-12 hours for 2-3 doses, check level before over 2 hours redosing. Maintenance 0.25-0.5mEq/kg/day. Do not give in infants with renal failure. Pyridoxime 100 mg/kg given by slow IV injection, Concurrent EEG, cardiorespiratory, and pulse then 100 mg every 10 min (up to 500 mg) oximetry monitoring

Glucose infusion rate GIR %dextrose rateml=hour 0:167 : weightkg

Neonatal neurological emergencies

Table 3 Drug Phenobarbital Phenytoin (fosphenytoin) Lorazepam Midazolam Antiepileptic drug therapy for neonatal seizures. Loading Dose 20 mg/kg IV over 15-20 mins, followed by 10 mg/kg doses to maximum of 40 mg/kg 20 mg PE/kg IV, slowly over 30 minutes titrate effect with 10 mg PE/kg aliquots 0.050.10 mg/kg/dose over 5 minutes, may repeat in 10-15 mins 0.10.2 mg/kg IV Maintenance 3-5 mg/kg/day given once daily

179

3-4 mg/kg/day may be given in 2 divided doses.

Pyridoxine

50-100 mg IV, then 100 mg every 10 min (up to 500 mg)

Followed by a continuous infusion of 60 microgr/kg/hour. May Increase dose every 15-30 minutes by 60microgr/kg/hour and titrate to cessation of clinical seizure activity. Concurrent EEG monitoring is essential

therefore, concomitant cardiorespiratory and pulse oximetry monitoring is necessary because these infants may require respiratory support. First-line AEDs and dosing schedules are shown in Table 3. Phenobarbital remains the first drug of choice. A loading dose of 20 mg/kg IV is given at a rate of 1 to 2 mg/kg per minute [12]. If seizures persist, repeat phenobarbital at 10 mg/kg dose for a total of 40 mg/kg. If seizures are controlled, maintenance phenobarbital is commenced at 3 to 5 mg/kg per day. Phenobarbital is effective in approximately 50% of newborns with seizures [13]. Phenytoin is usually added when there is inadequate control of seizures with phenobarbital and should be infused at less than 1 mg/kg per minute to avoid hypotension and cardiac arrhythmias. The new formulation fosphenytoin, the prodrug of phenytoin, is currently recommended and preferred because it is less irritating to veins, therefore less likely to lead to soft-tissue injury, and has a lower risk of cardiac complications. It is usually prescribed as phenytoin equivalent (PE), where 1.5 mg/kg of fosphenytoin is equivalent to 1 mg/kg of phenytoin. The loading dose is 20 mg(PE)/kg IV, usually followed by additional 5 to 10 mg (PE)/kg doses as required for continued seizure activity maintenance therapy of 3 to 4 mg/kg per day may be given in 2 divided doses. Lorazepam is usually given when there is inadequate response to sequential use of phenobarbital and phenytoin, at a dose of 0.05 to 0.10 mg/kg, and the dose may be repeated as needed. Refractory status epilepticus in neonates should be managed with continuous EEG monitoring and may be treated with midazolam at a loading dose of 0.1 to 0.2 mg/kg IV, followed by a continuous infusion of 60 microgr/kg per hour. The dose may be increased every 15 to 30 minutes by 1 to 2 micrograms/kg/minute and titrated to cessation of clinical seizure activity. All anticonvulsants may produce significant respiratory depression; therefore, close cardiorespiratory monitoring is necessary and respiratory support provided as needed. Neonatal stroke usually presents with focal seizures, and most clinically apparent strokes involve areas of distribu-

tion of the middle cerebral artery. It is therefore essential to have a low threshold for neuroimaging in a neonate presenting with an acute neurological symptom. The prognosis of neonatal seizures is determined by the underlying cause of the seizures, with 42% to 59% of infants showing residual abnormalities on neurological examination. There is a reported incidence of early death associated with neonatal seizures of approximately 30%, and long-term outcomes have included developmental delay in 55% [14] and mental retardation and cerebral palsy in 40% and 43% respectively [15]. Only 20% of infants with neonatal seizures were without neurological sequelae on long-term follow-up in 1 study [16], and epilepsy in the postneonatal period has been reported in 20% to 30% of affected infants, increasing to approximately 56% in infants with high-risk factors (hypoxic-ischemic encephalopathy, infection, hemorrhage) for neurological injury [17].

Alteration of Sensorium and Coma

Central nervous system dysfunction can be caused by a variety of conditions that result in an altered state of
Table 4 Common causes of alteration of sensorium and coma. Traumatic Nonaccidental injury (eg, shaken baby syndrome) Accidental injury Non-traumatic Infection Inborn errors of metabolism Metabolic disorders Status epilepticus Congenital heart disease Hypertensive encephalopathy Kernicterus Brain malformations Hypoxic-Ischemic injury Exogenous toxins

180 consciousness and coma. Infants presenting with coma or altered consciousness should be managed as a medical emergency, during which investigations and treatment should be undertaken concurrently. The differential diagnosis of coma is extensive (Table 4) and may be broadly subdivided into traumatic and nontraumatic causes. Nontraumatic causes are more frequent in the neonate, with the most common etiologies being infection, congenital heart disease and inborn errors of metabolism. Infectious etiologies include meningitis and encephalitis. The most common organisms in the neonatal period include group B streptococcus, Escherichia coli, herpes simplex (HSV), and enteroviruses. The diagnosis of encephalitis should be considered in an infant presenting with fever, seizures, and encephalopathy. In these infants, HSV infection should always be in the differential diagnosis, and the appropriate testing with a lumbar puncture should include a cerebrospinal fluid sample for HSV polymerase chain reaction (PCR), which is currently considered the most sensitive test for HSV encephalitis, and acyclovir should not be withheld. In addition, broad spectrum antibiotics should be instituted immediately. The clinical diagnosis of an inborn error of metabolism presents a challenge to the ED physician and requires a high index of suspicion as affected neonates will present with nonspecific signs. Although these disorders are individually rare, with most having an incidence of 1 per 100,000 births, together they constitute a significant number of potential admissions to the ED with an incidence approaching 1 per 800 to 2500 births. Recently, tandem mass spectrometry has resulted in early diagnosis and treatment of many of these disorders including organic acidurias, aminoacidopathies, and disorders of fatty acid oxidation, however there are some inborn errors that will not be recognized through newborn screening, and others that may be missed on tandem mass spectrometry. It is recommended that physicians develop a systematic approach to the neonate presenting with altered consciousness or coma because many of these disorders are amenable to treatment [18]. The treatable disorders are usually those inborn errors of intermediary metabolism where infants may present with poor feeding, vomiting, lethargy, liver failure, and/or coma preceded by an uneventful neonatal course. These disorders include the aminoacidopathies (eg, maple syrup urine disease and tyrosinemia type 1), most organic acidemias (eg, methylmalonic isovaleric and proprionic acidemias), urea cycle defects, and disorders of carbohydrate metabolism (eg, galactosemia, hereditary fructose intolerance). Inborn errors of intermediary metabolism result in accumulation of toxic metabolites proximal to the defective enzyme and usually require early intervention with special diets; however, exchange transfusion, peritoneal dialysis or hemofiltration may also be required in the acute phase. Lethargy and coma may also occur in infants with fatty acid oxygenation defects and mitochondrial disorders; however, severe hypoglycemia is

J.Y. Khan
usually an associated finding in these infants, due in part to a deficiency of energy metabolism. Various metabolic abnormalities may contribute to neurological dysfunction and coma, including hypoglycemia, hyperglycemia, hypernatremia, hyponatremia, hyperammonemia, and uremia. Hypoglycemia in neonates can contribute to worsening neurological outcome and therefore requires prompt diagnosis and treatment. Hyperammonemia is usually seen in infants with urea cycle defects and branched-chain organic acidemias; but the latter also tends to be associated with severe ketoacidosis. Affected neonates typically present with acute neurological deterioration with altered sensorium, coma, and/or intractable seizures. It is necessary to identify and rapidly treat hyperammonemia because an elevated ammonia level is neurotoxic and may be life-threatening if significantly elevated (N400-500 mol/L). Recently, hyperbilirubinemia and kernicterus have reemerged as important clinical concerns partly because of the widespread practice of early discharge of late preterm infants (34-36 weeks gestational age), together with a lack of understanding of the effect of bilirubininduced neurological dysfunction in these infants, which might lead to permanent neurological sequelae [19]. A severely hyperbilirubinemic infant presenting in the ED will more likely have nonspecific signs of decreased feeding, lethargy, irritability, and intermittent arching. If untreated, clinical signs will progress to hypertonia, drowsiness, inconsolable irritability with a high-pitched cry, and eventually to seizures and possible coma. The progression of acute bilirubin encephalopathy is predictive of the severity of neurological sequelae, whereas appropriate intervention with intensive phototherapy and/or exchange transfusion in the early stage of acute bilirubin encephalopathy can reduce the extent of brain injury [20]. A neonate with an elevated total serum bilirubin level presenting to the ED, should be considered a neonatal emergency and promptly evaluated and treated. An altered state of consciousness can be seen in neonates with underlying systemic conditions, other than primary CNS disorders (for example, neonatal hypertension, congenital or acquired cardiac disease, cerebral infarction, congenital hyperlipidemia, toxin ingestion); therefore, a detailed history and systematic examination are essential in all affected infants, thus allowing management to be guided by significant findings.

Management
The clinical approach to a neonate presenting with coma or an altered state of consciousness begins with resuscitation (airway, breathing, circulation) and supportive measures together with continuous physiological monitoring. Concurrent laboratory investigations should be carried out with simple bedside tests including glucose estimation, electrolytes, and blood gas performed immediately after

Neonatal neurological emergencies

Table 5 Investigation of coma in the neonate.

181 immediate intensive phototherapy (following American Academy of Pediatrics treatment guidelines for term and near-term infants) in the ED and transition to the care of a neonatologist once stabilized. Status epilepticus, which is discussed earlier, is a lifethreatening emergency that requires prompt treatment with basic resuscitation measures to support the airway, ventilation, and perfusion, together with AEDs to treat seizures and a systematic approach to identify the etiology. In the neonate, status epilepticus is more likely to be symptomatic, and treatment of the underlying cause may prevent ongoing neurological injury and facilitate seizure control.

Blood Blood count Electrolytes including ionized calcium, glucose, uric acid Ammonia level Blood culture Blood gas including lactate level Liver panel including total and direct bilirubin level Coagulation panel Plasma amino acids Acylcarnitine profile Urine Color, odor, urinalysis, and urine culture Reducing substances Urine organic acids Lumbar punctureCSF cell count, protein, glucose, bacterial and viral cultures, HSV PCR Chest and abdominal x-rays Electrocardiography Cardiac echocardiography Cranial imaging Electroencephalography
CSF, cerebrospinal fluid; HSV, herpes simplex virus; PCR, polymerase chain reaction.

Neurophysiological Monitoring in the Neonate

The primary techniques of assessing brain injury in the neonatal period involve various neuroimaging tools, the commonest in the ED are cranial computerized tomography and magnetic resonance imaging, Functional monitoring of the brain via continuous standard, multichannel electroencephalography (EEG) monitoring, has not been feasible because it requires considerable expertise for preparation, recording, and interpretation of results. However, it is becoming increasingly evident that real-time information regarding neonatal brain function during periods of critical illness is important in minimizing postnatal brain injury in the immature nervous system. Although continuous neurophysiological monitoring is not yet possible in the ED, it is highlighted in this article because the ED is often the first point of contact for severely ill neonates presenting with various primary problems that may potentially impact neurodevelopmental outcome. The neonatal period represents a critical time in brain development and maturation and is characterized by rapid brain growth, during which neuronal migration, differentiation, myelination, and synaptogenesis occur [25]. During this period, the developing neuronal circuitry is more susceptible to insult than at any other time in life. Interventions that improve the potentially harmful neurological and cognitive consequences of cerebral hypoxia and/or ischemia are desirable. There is an increasing need for continuous noninvasive bedside cerebral monitoring of neurophysiological function, which can be easily interpreted in a timely manner to allow appropriate intervention without compromise to necessary medical and nursing care. Neuromonitoring in the neonate is currently being explored as a potential tool to be added to other physiological monitoring parameters (electrocardiography, heart rate, respiratory rate, blood pressure, oxygen saturation, and temperature), which are routinely measured in critically ill neonates in the ED. An emerging change in clinical practice in neonatal intensive care units

admission. In many cases, further testing may be necessary, and Table 5 gives a list of suggested initial investigations. This is by no means a comprehensive list, and additional testing may be necessary as initial investigation results become available. Treatment is supportive, and initial fluid resuscitation with a dextrose/electrolyte solution is preferred. Although specific treatment measures are dictated by the underlying cause, immediate aggressive intervention may be lifesaving and prevent long-term neurological sequelae. Hypoglycemia should be treated emergently as discussed in the previous section. Severe hyperammonemia is lifethreatening, and recent evidence suggests that the duration of high levels is perhaps a more important risk factor than peak level in determining outcome; therefore, rapid resolution is critical for a favorable neurodevelopmental outcome [21,22]. A multidisciplinary team approach is advised for supportive management. Sodium benzoate or sodium phenylbutyrate, orally or IV, together with L-arginine and L-carnitine have been used to enhance nitrogen excretion in cases with ammonia levels at 3 to 4 times the upper limit. However, significantly higher levels require aggressive intervention [23], and current literature supports the early institution of hemodialysis, which results in rapid and efficient removal of ammonia and remains the mainstay of treatment [24]. It is important that busy EDs establish a protocol, in collaboration with neonatology, for recognition of hyperbilirubinemia and early institution of treatment for affected infants, thereby promoting timely admission to a pediatric/neonatal unit. Furthermore, critically ill, unstable infants with hyperbilirubinemia should start

182 is continuous neurophysiological surveillance provided by amplitude-integrated EEG (aEEG) and near-infrared spectroscopy (NIRS) that monitor neuronal function and tissue oxygenation, respectively. Critically ill neonates have a predilection for cerebral dysfunction as evidenced by clinically-silent, abnormal electrocerebral activity that raises concern regarding subsequent cognitive and motor delays. Adverse outcomes may be attributable to physiological disorders, such as hypotension and hypoxia-ischemia, which may occur with a variety of severe illnesses (sepsis, congenital heart disease, encephalopathies with various primary problems) and may lead to brain injury and dysfunction [26,27]. The development of the cerebral function monitor provides continuous neurophysiological and seizure activity monitoring via an aEEG. The EEG signal for the aEEG is recorded from 1 channel via 2 symmetrical parietal or temporal electrodes. The signal is then filtered to attenuate artifacts, semilogarithmically compressed, and rectified to reflect variations in minimum and maximum EEG amplitude. The output is a representation of the overall electrocortical background activity of the brain and readily shows critical changes of brain perfusion or metabolism. Research groups have investigated its use in neonates and have shown that the cerebral function monitor has a high-sensitivity, specificity and predictive value for long-term severity of hypoxic-ischemic encephalopathy and is useful in detection of seizures in term neonates. Continuous monitoring is especially useful in neonates with suspected seizure activity for diagnosis and subsequent evaluation of anticonvulsive therapy. The latter has been shown to promote electroclinical dissociation, that is, suppression of clinical seizures with continuation of electrophysiological seizure activity [28]. Further studies have shown that the commonly used AEDs are only effective in approximately half of infants treated for seizures [13]. Near-infrared spectroscopy is a newer technology that is increasingly being applied to neonates because it allows noninvasive bedside monitoring. Clinical monitoring with NIRS has been limited by its inability to generate reliable absolute values between time points in an individual infant and also between different infants; this is compounded by a lack of large studies that evaluate and support its use. However, in an effort to assess changes in oxygenation and hemodynamics in the brain and somatic organs (skeletal muscle, kidneys), newer cerebral oximeters have focused on regional saturation of oxygen and are designed to address the question of cerebral and somatic oxygen delivery and consumption at the tissue level. Continuous real-time trends in regional saturation of oxygen sometimes prove helpful in prompting earlier intervention to lessen or prevent potential complications. The underlying principle of NIRS is that light in the near infrared range (7001000 nm) easily penetrates soft tissue/bone and is

J.Y. Khan
absorbed by chromophores (eg, circulating hemoglobin) at quantifiably different amounts depending on the oxygenation state, thus allowing for direct measurement of changes in oxygen saturation in the blood in the capillary bed just below the sensor and, therefore, also providing information regarding perfusion of the underlying vascular beds [29]. In finding ways of using these technologies effectively, we may ultimately understand how to modify therapy in the ED to appropriately address neurological and somatic stress factors in a timely manner, to minimize their effects, thereby reducing the overall morbidity burden for individual neonatal patients.

References
1. Volpe JJ. Neonatal seizures. Neurology of the newborn. 4th ed. Philadelphia (Pa): WB Saunders; 2001. p. 178-214. 2. Walton NY. Systemic effects of generalized convulsive status epilepticus. Epilepsia 1993;34:54-8. 3. Mizrahi EM, Watanabe K. Symptomatic neonatal seizures. In: Roger J, Bureau M, Dravet C, et al, editors. Epileptic syndromes of infancy, childhood and adolescence. 4th ed. John Libbey, Eurotext Ltd; 2005. p. 17-38. 4. Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia (Pa): Lippincott-Raven; 1998. p. 181. 5. Cunniff C, Wiedlin N, Jones KL. Autosomal dominant benign neonatal seizures. Am J Med Genet 1988;30:963-6. 6. Ronen GM, Rosales TO, Connolly M, et al. Seizure characteristics in chromosome 20 benign familial neonatal convulsions. Neurology 1993;43:1355-60. 7. Sanchez RM, Jensen FE. Maturational aspects of epilepsy mechanisms and consequences for the immature brain. Eplipesia 2001;42: 577-85. 8. Volpe JJ. Neonatal seizures. Clin Perinatol 1977;4:43-63. 9. Berg A, Shinnar S, Levy S, et al. Status epilepticus in children with newly diagnosed epilepsy. Ann Neurol 1999;45:618-23. 10. Eriksson K, Metsaranta P, Huhtala H, et al. Treatment delay and the risk of prolonged status epilepticus. Neurology 2005;65:1316-8. 11. Holmes GL, Ben-Ari Y. The neurobiology and consequences of epilepsy in the developing brain. Pediatr Res 2001;49:320-5. 12. Lockman LA, Kriel R, Zaske D, et al. Phenobarbital dosage for control of neonatal seizures. Neurology 1979;29:1445-9. 13. Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999; 341:485-9. 14. Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117:1270-80. 15. Brunquell PJ, Glennon CM, DiMario FJ, et al. Prediction of outcome based on clinical seizures type in newborn infants. J Pediatr 2002;140: 707-12. 16. Ortibus EL, Sum JM, Hahn JS. Predictive value of EEG for outcome and epilepsy following neonatal seizures. Electroencephalogr Clin Neurophysiol 1996;98:17. 17. Clancy RR, Legido A. Postnatal epilepsy after EEG-confirmed neonatal seizures. Epilepsia 1991;32:69-76. 18. Saudubray JM, Nassogne MC, de Lonlay P, et al. Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol 2002;7:3-15. 19. Smitherman H, Stark AR, Bhutani VK. Early recognition of neonatal hyperbilirubinemia and its emergent management. Semin Fetal Neonatal Med 2006;11:214-24.

Neonatal neurological emergencies

20. Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: for a safer first week. Pediatr Clin North Am 2004;51:843-61. 21. Picca S, Dionisi-Vici C Abeni D, et al. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol 2001;11:862-7. 22. Yoshino M, Sakaguchi Y, Kuriya N, et al. Neuropediatrics 1991;22: 198-202. 23. Prietsch V, Lindner M, Zschocke J, et al. Emergency management of inherited metabolic diseases. J Inherit Metab Dis 2002;25:531-46. 24. Rutledge SL, Havens PL, Haymond MW, et al. Neonatal hemodialysis: effective therapy for the encephalopathy of inborn errors of metabolism. J Pediatr 1990;116:125-8.

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25. Rakic P. Images in neuroscience. Brain development, VI: radial migration and cortical evolution. Am J Psychiatry 1998;155: 1150-1. 26. Hellstrom-Westas L, Rosen I, Svenningsen NW. Silent seizures in sick infants in early life. Diagnosis by continuous cerebral function monitoring. Acta Pediatr Scand 1985;74:741-8. 27. Clancy RR, Legido A, Lewis D. Occult neonatal seizures. Epilepsia 1988;29:256-61. 28. Scher MS, Alvin J, Gaus L, et al. Uncoupling of EEGclinical neonatal seizures after antiepileptic drug use. Pediatr Neurol 2003;28: 277-80. 29. Wolfberg AJ, duPleiss AJ. Near-infrared spectroscopy in the fetus and neonate. Clin Perinatol 2006:707-28.

Apparent Life-Threatening Events in the Young Infant and Neonate

Jean M. Silvestri, MD
An apparent life-threatening event (ALTE) is characterized by some combination of apnea, change in color and tone, choking, or gagging. It is frightening to the observer and presents a difficult clinical challenge. There is no standard evaluation for an infant with an ALTE, with history and physical examination being the keys to directing the diagnostic workup. In young infants, prematurity plays a significant role in the diagnostic possibilities that include gastrointestinal, neurologic, and infectious conditions. The goal is to identify a treatable cause that will define the expected natural history. Evidence is lacking regarding the true risk of subsequent events and death vs the perceived risk of death, which is complicated by the heterogeneity of the group of infants with ALTE. The presentation, differential diagnosis, plan for evaluation, and management of the young infant with ALTE will be reviewed, as well as the relationship of ALTE and sudden infant death syndrome and the literature regarding ALTE in the newborn infant. Clin Ped Emerg Med 9:184-190 C 2008 Elsevier Inc. All rights reserved. KEYWORDS apparent life-threatening event, apnea, gastroesophageal reflux

n apparent life-threatening event (ALTE) was defined in 1986 by the National Institutes of Health Conference on Infantile Apnea and Home Monitoring as an episode that is frightening to the observer that is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking or gagging. In some cases, the observer fears that the infant has died [1]. A large amount of information has been amassed in the 20 years since an ALTE was defined. However, ALTE as a clinical syndrome is open to considerable interpretation, initially on the part of the observer of the event as well as upon presentation to a physician's office or emergency department (ED). This diagnosis is especially difficult because the patients represent diverse pathophysiology; however, they often appear well and normal at the time of ED presentation. Because there is no standard evaluation or minimal workup for an infant with ALTE [2], the physician's challenge is to create a management plan to identify those infants who may be at subsequent risk for significant morbidity and death. The ALTEs typically occur in children younger than 12 months, with the median age 184

of presentation at about 2 months [3-7]. The focus of this article will be to review the presentation, differential diagnosis, plan for evaluation, and management of the young infant with ALTE and examine the literature regarding ALTE in the newborn infant.

Clinical Presentation
An ALTE should not be regarded as a specific diagnosis but as a chief complaint that requires medical attention and evaluation. As per definition, the presentations are characterized by a combination of breathing irregularities that may include apnea; difficulty breathing; color change (typically cyanosis); altered tone; and, in an infant, altered level of consciousness. The initial history provided by the witness is of extreme importance in directing the investigation and determining the severity of the event to
Department of Pediatrics, Rush University Medical Center, Rush Children's Hospital, Chicago, IL. Special Care Nursery, Rush Children's Hospital, Chicago, IL. Reprint requests and correspondence: Jean M. Silvestri, MD, Pediatrics, Rush University Medical Center, Rush Children's Hospital, 1653 West Congress Parkway, Chicago, IL 60612. (E-mail: jean_m_silvestri@rsh.net) 1522-8401/$ see front matter C 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2008.06.008

Apparent life-threatening events in the young infant and neonate

determine disposition. Although there are no data concerning reliability of parental reporting of ALTE, one could extrapolate from the data of the reliability of parental reports of apnea occurrence in infants on home monitoring that demonstrate that there may be considerable observer error [8]. Caretaker anxiety may overestimate the event, and lack of professional experience may underestimate the event especially when the infant appears well. In all cases, the event must be taken seriously.

185 After a description of the event, a complete history should be obtained that includes questions about the pregnancy and perinatal period, particularly critical in the neonate and young infant. Special attention should be given to determining the gestational age of the infant. This is especially important in the late preterm infant. Without detailed probing of the due date, the infant's relative immaturity may not be appreciated; and prematurity contributing to the etiology of the event might be overlooked. Other pertinent newborn history includes prior history of admission or short stay in a newborn intensive care unit or observational nursery, birth trauma, antibiotic use, significant jaundice, and possible risk for anemia, all of which may be indicative of an evolving or unresolved neonatal problem. Identifying when the newborn screening was obtained and ensuring that the newborn screening was indeed sent are important in that a very small amount of blood may hold the key to several diseases with significant morbidity. A feeding history is also important to determine if there is interest in feeding; the feeding pattern; and associated gagging, coughing, or arching behaviors. Additional questions should include sick contacts, medications given, recent immunizations, and trauma, both accidental and intentional. The infant's developmental history, behavior, and sleep patterns should be reviewed. A family history is important to identify genetic, metabolic, cardiac, or neurologic conditions or other early infant deaths that may be a manifestation of these conditions. A social history that includes alcohol, tobacco, or substance use as well as medications in the home may raise the index of suspicion for an unintentional or intentional ingestion of a toxin. After the history is obtained, a careful and thorough physical examination should be performed. The general impression of the infant's wellness after the event is important and may direct further investigation and the disposition of the infant. The physical examination is directed to determine underlying etiologies. Specific areas to focus on include growth parameters, especially in the preterm infant, and recent newborn discharge to ensure normal growth. Vital signs are essential. Pulse oximetry has become almost routine monitoring in the ED, although no study has examined the systematic use of oximetry in evaluating ALTE infants. Evidence of trauma should be assessed, which would include bruising, fontanel size and fullness, and conjunctival or retinal hemorrhages. The importance of the history and physical examination is demonstrated by a prospective study of 243 infants admitted to a tertiary care academic center after an ALTE [7]. A cause was identified based on the history and physical examination alone in 21% of cases. In another 49%, the history and physical examination suggested a cause that was confirmed by testing. The next challenge is which diagnostic tests to order to identify a cause of the ALTE.

Etiologies
Depending upon the case series, more than 50% of ALTE infants ultimately have a cause identified [3,4,6,7,9]. The challenge is that infants may have multiple coexistent diagnoses, and 1 specific diagnosis may not account for the life-threatening event. Among the etiologies, the 3 most common are gastrointestinal (GI) conditions, neurologic problems such as seizures, and infections, typically in the lower respiratory tract. Less common diagnoses include cardiovascular disease, breath-holding spells, inborn errors, metabolic problems, child abuse, and a variation of normal physiology. Some of these diagnoses will be considered in further detail as they relate specifically to the neonate and young infant. If no cause is determined, then the ALTE is considered idiopathic. The term apnea of infancy is reserved for an infant greater than 37 weeks' gestation at birth in which no specific cause can be identified for the ALTE and is related to the onset of pathologic apnea [1].

Evaluation: History and Physical Exam

A detailed history and physical examination are the basis from which to start sorting through the myriad of possible diagnoses and directing a diagnostic evaluation. Therefore, key components of the history are a description and duration of the event and the intervention. Description of the ALTE includes infant state (awake or asleep); color change location (eg, circumoral, peripheral, or whole body); location, position, and activity of the infant; respiratory effort; tone; and associated noise of choking, cough, gagging, wheezing, stridor, or emesis. Description of the intervention that terminated the event could include minimal or no intervention, gentle stimulation or blowing in the face, vigorous stimulation, or mouth-to-mouth resuscitation. This description is especially important in the young infant in that a caretaker may observe normal physiologic patterns and consider them pathologic. Periodic breathingrespiratory pauses with or without a sigh for up to 20 secondsmay appear frightening to the inexperienced observer and may even prompt resuscitation, and needs to be accurately described to be reassuring to all involved. Another important prognostic factor is to determine if there were similar events in the last 24 hours or in the past.

186

J.M. Silvestri
150 patients [5] were admitted for observation after an ALTE. This study also supported admission of all patients, and 8% of those hospitalized required medical interventions during their admission after an unremarkable ED evaluation. Prematurity appeared to be a significant risk factor for the occurrence of an intervention during hospitalization. A prospective study [11] was designed to develop criteria to identify infants with an ALTE who may be safely discharged from the ED. High-risk infants were those who required hospitalization because of subsequent events, significant interventions, and treatment of specific diagnoses (such as sepsis). Among 59 infants presenting to the ED with an ALTE, 8 (14%) infants experienced significant events or interventions (apnea, seizures, infections, ventilation) during their hospitalization. Multiple ALTEs within the 24 hours before admission and age not exceeding 1 month identified this high-risk subgroup of infants requiring admission. Another factor that was found to be predictive of subsequent events was prematurity. A larger validation set will be required to substantiate these criteria for differentiating high-risk infants (eg, younger than 1 month with multiple ALTEs in the 24 hours before admission) and low-risk infants (eg, older than 30 days and who experienced a single ALTE) and outpatient vs inpatient disposition. In those infants who do not meet the high-risk criteria, care must still be individualized. In considering discharge from the ED, the infant must appear well, there should be no family or social issues or concerns that would be suspicious for nonaccidental injuries, and appropriate follow-up care should be identified. For infants who are admitted, investigations and observations often include cardiorespiratory monitoring as well as oximetry. Some centers may have an ALTE protocol requiring formal studies of multichannel recordings or polysomnography in those infants without an identified etiology to direct further workup at the time of admission. From a study of 73 admitted infants (88% with an idiopathic ALTE), events of apnea and bradycardia that were documented during the initial hospitalization predicted subsequent events recorded at home [12]. To reiterate, it is imperative that all ALTEs be taken seriously. In those infants with physiologic compromise, or who appear ill, or who required significant stimulation or resuscitation, a period of hospitalization for further observation and evaluation is clearly indicated. These observations will then assist in creating an individualized discharge plan.

Evaluation: Diagnostic Testing

At present, there is no evidence-based standard evaluation of the infant with ALTE. In the prospective study of 243 patients noted above [7] of which almost half (n = 120) were younger than 2 months, 3776 tests were ordered (mean of 15.5 5.2 tests per patient). Only 18% of these tests were positive, and only 6% contributed to the diagnosis. In this series, 70% of infants had an etiologic diagnosis for their ALTE. Among the remaining 30% (n = 72) of patients, the further tests led to identification of an occult cause in 14% (n = 33); and in the remaining 16% (n = 39), no cause was found. The 6 tests that identified a cause in these 33 patients were a white blood cell count, urine analysis and culture, chest x-ray, screening for gastroesophageal reflux (GER), multichannel recording, and brain neuroimaging. A larger patient sample will be needed to determine if a battery of tests would be useful in the infant who does not have suggestive findings on the initial history and physical examination. One must also balance the risks of testingincluding a potentially invasive procedure, a financial burden, an emotional burden, possible unnecessary testing that may have complications, or acquisition of nosocomial infections with the benefits of securing a diagnosis vs the potential of a delayed or missed diagnosis. There has been no study that has supported a standard testing strategy [2,7]. With such a small yield from a significant amount of diagnostic testing (only 6% of the 3776 tests ordered in the previously mentioned study) contributing to a diagnosis, it begs the question as to whether too many tests are being done, or perhaps not the correct tests; and thus, the whole approach needs to be reexamined. A retrospective study using a large database on hospital admissions for ALTE from 12 067 patients aged 3 days to 5 months from 36 children's hospitals across the United States enrolled in the Pediatric Health Information System highlights significant variability in length of hospital stay, use of medications, and diagnostic testing [10]. These data strongly support further research for an alternative strategy to improve quality of care for these infants.

Admission and Hospitalization

Most of the investigations to determine an underlying etiology are done after admission to the hospital. Many reviews of ALTEs have reported data from hospital admissions [4,6,7,10] but did not examine the question of who should be admitted. In 1 study published in 1999, 83% of the 130 patients [3] were admitted with an ALTE. However, the study offered a recommendation that, until management guidelines were developed, all infants should be admitted for a period of observation because there was concern that etiologic diagnoses changed from the ED to the ward and that diagnoses made in the ED may be made on insufficient evidence. In a later study from 2004, 77% of

Potential Etiologies of ALTE in the Neonate and Young Infant

The Convalescing Preterm Infant
Former preterm infants who are not yet at least 1 month postterm may continue to have the maturational delay associated with prematurity that may contribute to their

Apparent life-threatening events in the young infant and neonate

ALTE. In 1 retrospective study, a series of 150 infants with ALTE in which 33% were less than 37 weeks' gestation, prematurity was a risk factor for the need for significant medical intervention[5]. Although infants with apnea of prematurity typically resolve by 37 weeks' gestation, some may continue to have apnea until several weeks past term [1]. In infants of 24 to 28 weeks' gestation, apnea of prematurity frequently persists beyond term [13]. Data from the large Collaborative Home Infant Monitoring Evaluation (CHIME) that monitored 1079 infants (infants with idiopathic ALTE, siblings of infants who died of sudden infant death syndrome [SIDS], symptomatic and asymptomatic preterm infants with birthweight less than 1750 g, and healthy term infants) demonstrated that conventional events (defined as apnea 20 seconds; if b44 weeks, heart rate b60 beats per minute [bpm] for at least 5 seconds or b80 bpm for at least 15 seconds; if 44 weeks, heart rate b50 bpm for at least 5 seconds or b60 bpm for at least 15 seconds) were common among all groups of infants and that preterm infants had an increased risk of extreme events (defined as apnea 30 seconds; if b44 weeks, heart rate b60 bpm for 10 seconds; if 44 weeks, heart rate b50 bpm for 10 seconds). Preterm infants had increased risk of extreme events until 43 weeks postconceptional age [14]. This is why identifying the correct gestational age of the infant is of key importance. The preterm infant may have a number of resolving issues of prematurity such as lung disease, anemia, poor suck-swallow coordination with increasing volume of feeding, along with a maturing cardiorespiratory pattern. Individually, these conditions may not precipitate an ALTE but in sum may create a vulnerability that might result in an ALTE. Anemia may contribute to the problem especially at a time when an infant may be approaching his or her physiologic nadir. Thus, a comprehensive view of the infant is required to determine if causality of the ALTE can be attributed to any one of these multiple issues. In scenarios where 1 underlying etiology cannot be identified, the infant is still immature, the ALTE required vigorous stimulation or resuscitation, and the physician cannot determine the true risk for morbidity, monitoring may be chosen to aid characterizing and documenting the frequency, severity, and resolution of the ALTE events.

187 contributed to the ALTE, and the data can be compared with the observer's account of the ALTE.

Gastroesophageal Reflux
This is one of the most common diagnoses associated with ALTEs in infants. The question becomes whether the ALTE is associated with or caused by GER. In a systematic review of 8 studies involving 643 infants, GER was the most common diagnosis found in 227 (35%) infants [9]. However, the criteria for GER were variable and based on clinical grounds, pH studies, and radiological studies. A large prospective study from 1 site [7] found GER (based upon pH probe and upper GI series findings) in 69 (28%) of 243 infants evaluated. Evaluation for GER was 1 of 6 studies that aided in the establishment of a diagnosis when the history and physical examination were noncontributory. In a large multicenter study [10] using a database from 36 children's hospitals, the most common discharge diagnosis among 12 067 infants was GER; GER was diagnosed in 33.9% (4091 of 8964) of infants younger than 2 months and 45.8% (1421 of 3103) of infants aged 2 to 5 months. Again, there was a great deal of variability in diagnostic testing for GER, with sleep apnea testing, pH probe, and upper GI studies used. The problem with these findings is that GER is a common problem in infants. Gastroesophageal reflux, or frequent regurgitation without physiologic compromise, should also be differentiated from gastroesophageal reflux disease, which has physiologic compromise that may include esophagitis, growth failure, and respiratory problems. Despite the frequency of the finding of GER in infants with ALTE, there is an abundant literature that presents a convincing argument that there is only a weak association between GER and documented apnea and bradycardia [15-17]. Among a subset of 21 infants being evaluated for apnea by polysomnography and pH probe monitoring for GER (defined as pH b4 for 6 seconds), of 741 apneas events, only 19% (n = 140) were associated with reflux: 94% of the apneas (67% obstructive) preceded reflux, and only 6% followed the episode of reflux [15]. This lack of temporal relationship of ALTE and GER was also demonstrated in preterm infants [17]. Among 119 infants (gestational age mean SD of 28 2 weeks at birth and 37 4 weeks at time of study), there were 6255 episodes of GER, with only 1% of these events associated with apnea of at least 15 seconds. There was no difference in the apnea rate before, during, or after GER; and GER did not prolong apnea duration. These investigations raise the question as to the role of GER and its association with apnea and, as a result, the ability of GER to cause an ALTE. Studies are limited in that a clinically significant ALTE did not necessarily occur at the time of the recordings. The mechanism of a GER related ALTE may be through stimulation of laryngeal chemoreceptors resulting in a reflex response of apnea, bradycardia, and pallor or through laryngospasm resulting in

Monitored Infants
Preterm infants who are discharged on home monitoring for resolving apnea of prematurity may also present to the ED as an ALTE and may manifest as increased alarms. In those cases, it is imperative to review the monitor's alarm settings. Numerous alarms occur if the apnea alarm is set at 15 seconds, as short apnea is common [14] and not necessarily pathologic. Baseline heart rate decreases with advancing age, and bradycardia limits should be adjusted appropriately. Home memory monitors may be downloaded to review and identify events that may have

188 obstructive apnea. One must use caution in interpreting GER as the cause of an ALTE especially if there are coexistent diagnoses. However, ALTE may be related to GER when there are episodes that occur when the infant is awake and that are associated with gross emesis or regurgitation at the time of the ALTE. The history of formula in the nose and mouth or similar findings on the physical examination would support this diagnosis and lead to diagnostic testing for GER and a treatment plan for reflux.

J.M. Silvestri
Therefore, seizures may be the presenting diagnosis in the ED but not be the final diagnosis upon hospital discharge. A description of the event may include eye fluttering, staring, eye deviation, or stiffening; but often, the young infant may only have apnea and/or cyanosis as the presenting signs of a seizure. Electroencephalogram (EEG) recordings may not be diagnostic because the interictal EEG is generally normal, and repeated recordings or a video EEG recording over a prolonged period may be necessary.

Infection
In the young infant, one must consider late-onset sepsis or meningitis as a possible cause of ALTE in the first weeks to first 3 months of life. Thus, a detailed history of the pregnancy, delivery, and newborn hospitalization is indicated. Etiologies may reflect the maternal, nursery, or postnatal environment; and the workup is directed to identifying an infection and appropriate antibiotic treatment. The more common infections reported in infants with ALTEs are those related to the lower respiratory tract, with bronchiolitis, pertussis, and respiratory syncytial virus (RSV) being the most frequent [3,7,9]. Respiratory syncytial virus infection may present with prolonged apnea or as an ALTE more commonly in the young infant and those infants with a history of prematurity [18,19]. Passive immunization for RSV has reduced but not eliminated the disease; and RSV should remain in the differential of an infant presenting with an ALTE with a history of congestion, cough, or a sick contact. Rapid diagnostic testing for RSV along with other laboratory data can assist in making the diagnosis. Apnea related to RSV is typically self-limited and resolves with the resolution of the illness [19]. However, preterm infants who still have cardiorespiratory immaturity may have a longer period of resolution and may require monitoring.

Child Abuse
Although less common, there should be a low threshold for the consideration of child abuse as an etiology. When there is a history of recurrent ALTEs, especially in an infant requiring resuscitation while in the care of the same person, the suspicion of child abuse, Munchausen syndrome by proxy, or intentional suffocation should be raised. In 1 study, abusive head injury was identified in 6 (2.5%) of 243 patients, of which 2 subsequently died in hospital [21]. Another study demonstrated intentional suffocation in 18 (12%) and fabrication in 7 (5%) of 157 patients with an ALTE who required cardiopulmonary resuscitation [22]. So that the diagnosis of child abuse is not overlooked, there must be continued vigilance. The history may reveal a caretaker (typically the mother) who appears dedicated, may have a health care background, and may have a personal history of unusual illnesses. Identification of child abuse is less complicated when signs of trauma or neglect are evident on physical examination. A fundoscopic examination [23], skeletal survey, neuroimaging, and toxicology screens may be revealing. These screens have been used to identify abuse as the cause for an ALTE, but have not been applied in a consistent manner to a study population of idiopathic ALTEs to determine if there is underreporting of child abuse among ALTE infants. Urine toxicology studies are useful to identify recent intentional or unintentional exposure to drugs, and long-term exposure may be identified by hair analysis. Investigators have also used covert video recordings to confirm suspected cases of intentional suffocation and Munchausen syndrome by proxy [22,24]. In all these scenarios, the safety of the infant is of paramount importance to avoid returning the infant to an unsafe environment.

Seizures
Neurologic problems that are frequently diagnosed in infants with ALTE include intracranial hemorrhage, hydrocephalus, infection, or malformations. A history of birth trauma or prematurity is important to elicit. Breathholding spells are also reported [7,9] and may be confused with a seizure. Although the onset of breath-holding spells is typically between 6 to 12 months of age, in a series of 95 patients with severe spells, 12% presented in the first 6 months and 5% within the perinatal period [20]. The history may reveal an inciting event that results in crying followed by apnea, which may result in pallor or cyanosis with altered tone and consciousness and is thus quite frightening to the observer. A positive family history may also support the diagnosis [20]. One of the most common neurologic diagnoses made in ALTE is seizures, both febrile and afebrile. Seizures can also be the result of a hypoxic event or prolonged apnea from another etiology such as RSV or pertussis bronchiolitis.

The Term Infant with ALTE in the First Week of Life

Apparent life-threatening events occurring in newborns have been reported in the literature. A report from Sweden [25] over a 5.5-year period identified 13 infants aged 9 to 91 hours of life who experienced an ALTE: 3 did not survive the resuscitation, no cause was found in 7, and 4 died later, 2 of which had neonatal sepsis. Another report from a tertiary referral center [26] identified over a

Apparent life-threatening events in the young infant and neonate

5-year period 10 previously healthy term infants aged 15 hours to 3.5 days who experienced an ALTE: 5 of these neonates died; and in the other 5, the workup was unrevealing. Over a 3-year period with 15 000 births at a hospital in Washington, DC, there were 20 previously healthy term infants with an ALTE in the first 3 days of life, with half of the events occurring on day 1 [27]. Potential causes were found in 40% of infants, which included airway obstruction, delayed transition, and neurologic disorders. These studies highlight that ALTEs do occur in the early newborn period although infrequently. They occur in a heterogeneous group of infants who require a thorough investigation and may have a high risk for mortality. In an effort to better define and separate events that may be related to transition to extrauterine life, the definition of a postnatal age of greater than 12 hours may be a useful addition to the diagnosis of an ALTE [14] in the newborn period.

189 with both ALTE and SIDS. In addition, comparing risk factors of those infants with an ALTE enrolled in the CHIME with known SIDS risk factors demonstrated that the CHIME ALTE infants were younger, less frequently of low birth weight or growth restricted, and had fewer teenage mothers, suggesting that the 2 populations are different [29]. Risk reduction strategies (such as the Back to Sleep Campaign) that have been effective in reducing the incidence SIDS have not altered the incidence of ALTEs [6,30]. Currently, no conclusive evidence establishes a definitive link between ALTE and SIDS.

Discharge Planning and Follow-up

The treatment and discharge plan should be tailored to the underlying etiology. Infants who demonstrate cardiorespiratory instability during their hospitalization should demonstrate stability before discharge. There may be infants as noted in the prior discussion of the convalescing preterm infant who may benefit from in-home monitoring because of resolving cardiorespiratory immaturity. In addition, monitoring may be indicated in some infants [31] because of the increased risk of sudden death. Home memory monitoring has been useful in identifying an underlying pathology in infants with recurrent ALTEs when the initial evaluation was unremarkable and the diagnosis was determined to be idiopathic ALTE [22]. Clinical characteristics at the time of initial presentation such as skin color, tone, behavioral state, or degree of resuscitation were not significant factors predicting the recurrence risk of a subsequent event [32]. The risk of recurrence has not been well defined. Among 147 infants in a monitoring program (73 with ALTE), 53 (36%) had significant events and 46 (87%) experienced their first subsequent event within the first month of monitoring [12]. All infants being monitored for an idiopathic ALTE (107 term and 45 preterm infants) in CHIME had an increased risk for repeated extreme episodes; the difference only achieved significance for the preterm ALTE infants. When repeated events occurred, they occurred within 6 weeks of the prior event [14]. These studies support a duration of monitoring of 4 to 6 weeks after the initial event. The decision to use home monitoring should be individualized. Thus, in certain infants, home monitoring may be a useful tool to help infants make the transition to home and to help the physician clarify the underlying mechanisms, natural history, and frequency of recurrence of ALTEs. As a standard of care, all home monitors should have event-recording capability [1] set with ageappropriate bradycardia alarms (80 bpm for an infant 34-44 weeks' gestation and 60 bpm for an infant greater than 44 weeks' gestation) and apnea thresholds (apnea alarms set at 20 seconds to alarm and record). Parents should be informed that there are no data indicating that monitors save lives and must understand that the purpose of monitoring is to alert the caretaker to a potentially life-

Relationship Between ALTE and Sudden Infant Death Syndrome

The complete definition of ALTE in 1986 by the National Institutes of Health Conference on Infantile Apnea and Home Monitoring included that in some cases, the observer fears that the infant has died. Previously used terminology such as aborted crib death or near-miss sudden infant death syndrome (SIDS) should be abandoned because it implies a possibly misleading close association between this type of spell and SIDS [1]. It has taken 20 years since that conference, amid significant controversy, to attempt to abandon the close association of ALTE and SIDS. Earlier studies described an association of increased mortality in infants with prior ALTE and recurrent apnea [28], and prior ALTE events occurred in less than 7% of infants who died of SIDS [1]. It is important to note that most SIDS victims do not experience a prior ALTE. Earlier studies have had methodologic differences that include reliance on parent reports that are subject to recall bias. Another obscuring factor is the lack of adequate death scene investigations. Subsequent data have emerged that argue against the relationship of ALTE and SIDS. Infants with ALTE typically have a benign outcome but are a heterogeneous group, and some infants may have an increased risk of death; but there is no evidence that the mechanism is similar to SIDS. A different time course is evident for SIDS and ALTE. Most infants with ALTE experience their events at a younger age (8 weeks) than those who die of SIDS (18 weeks) [6]. Data from the CHIME study that monitored 1079 infants (detailed above) demonstrated that the resolution of extreme events occurred before the time of the peak incidence of SIDS, suggesting that extreme events were not a precursor to SIDS [14]. In a prospective, population-based study [6], smoking was the only risk factor that was found to overlap

190 threatening event. There should be a support system in place for the family with appropriate teaching, cardiopulmonary resuscitation training, and directions for monitor use. Appropriate techniques for stimulation or resuscitation of an infant should be highlighted to reinforce that an infant should not be shaken. In addition, all caregivers should be instructed in safe infant sleep practices that should include supine sleeping with the face uncovered and to avoid overheating. A safe sleep environment also requires a firm sleeping surface, no loose bedding or soft crib toys in the crib, and a smoke-free environment.

J.M. Silvestri
9. McGovern MC, Smith MBH. Causes of apparent life threatening events in infants: a systematic review. Arch Dis Child 2004;89:1043-8. 10. Tieder JS, Cowan CA, Garrison MM, et al. Variation in inpatient resource utilization and management of apparent life-threatening events. J Pediatr 2008;152:629-35. 11. Claudius I, Keens T. Do all infants with apparent life-threatening events need to be admitted? Pediatrics 2007;119:679-83. 12. Ct A, Hum C, Brouillette RT, et al. Frequency and timing of recurrent events in infants using home cardiorespiratory monitors. J Pediatr 1998;312:783-9. 13. Eichenwald EC, Aina A, Stark AR. Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks. Pediatrics 1997; 100:354-9. 14. Ramanathan R, Corwin MJ, Hunt CE, et al. Cardiorespiratory events recorded on home monitors. Comparison of healthy infants with those at increased risk for SIDS. JAMA 2001;285:2199-207. 15. Arad-Cohen N, Cohen A, Tirosh E. The relationship between gastroesophageal reflux and apnea in infants. J Pediatr 2000;137:321-6. 16. Mousa H, Woodley FW, Metheny M, et al. Testing the association between gastroesophageal reflux and apnea in infants. JPGN 2005;41: 169-77. 17. DiFiore JM, Arko M, Whitehouse M, et al. Apnea is not prolonged by acid gastroesophageal reflux in preterm infants. Pediatrics 2005;116: 1059-63. 18. Bruhn FW, Mokrohisky ST, McIntosh K. Apnea associated with respiratory syncytial virus infection in young infants. J Pediatr 1977;90:382-6. 19. Church NR, Anas NG, Hall CB, et al. Respiratory syncytial virus related apnea in infants. Am J Dis Child 1984;138:247-50. 20. DiMario FJ. Prospective study of children with cyanotic and pallid breath-holding spells. Pediatrics 2001;107:265-9. 21. Altman RL, Brand DA, Forman S, et al. Abusive head injury as a cause of apparent life-threatening events in infancy. Arch Pediatr Adolesc Med 2003;157:1011-5. 22. Samuels MP, Poets CF, Noyes JP, et al. Diagnosis and management after life threatening events in infants and young children who received cardiopulmonary resuscitation. Br Med J 1993;306:489-92. 23. Pitetti RD, Maffei F, Chang K, et al. Prevalence of retinal hemorrhages and child abuse in children who present with an apparent life threatening event. Pediatrics 2002;110:557-62. 24. Southall DP, Plunkett MCB, Banks MW, et al. Covert video recordings of life-threatening child abuse: lessons learned for child protection. Pediatrics 1997;100:735-60. 25. Polberger S, Svenningsen NW. Early neonatal sudden infant death and near death of full term infants in maternity wards. Acta Paediatr Scan 1985;74:861-6. 26. Burchfield DJ, Rawlings DJ. Sudden death and apparent lifethreatening events in hospitalized neonates presumed to be healthy. Am J Dis Child 1991;145:1319-22. 27. Grylack LJ, Willimas A. Apparent life-threatening events in presumed healthy neonates during the first three days of life. Pediatrics 1996;97: 349-51. 28. Oren J, Kelly D, Shannon DC. Identification of a high-risk group for sudden infant death syndrome among infants who were resuscitated for sleep apnea. Pediatrics 1986;77:495-9. 29. Esani N, Hodgman JE, Ehsani N, et al. Apparent life-threatening events and sudden infant death syndrome: comparison of risk factors. J Pediatr 2008;152:365-70. 30. Gershon WM, Besch NS, Franciosi RA. A comparison of apparent lifethreatening events before and after the back to sleep campaign. Wis Med J 2002;101:39-45. 31. American Academy of Pediatrics Committee on the Fetus and Newborn. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics 2003;111:914-7. 32. Steinschneider A, Richmond C, Ramaswamy V, et al. Clinical characteristics of an apparent life-threatening event and the subsequent occurrence of prolonged apnea and prolonged bradycardia. Clin Pediatr 1998;37:223-30.

Summary
An infant presenting to the ED with an ALTE remains a difficult clinical challenge. The history and physical examination are key to directing the diagnostic workup. There is no standard evaluation for an infant with an ALTE. Currently, in-hospital observation and monitoring remain an accepted treatment for young infants and especially for those with repeated ALTEs. In young infants, prematurity plays a significant role in the diagnostic possibilities that include GI, neurologic, and infectious disorders. The goal is to identify a treatable cause that will serve to define the expected natural history. Evidence is lacking regarding the true risk of subsequent events and death vs the perceived risk of death. Diagnosis and treatment are complicated by the heterogeneity of the group of infants with ALTE. Collaborative multicenter studies are needed to develop and refine best practice guidelines, to improve coding and diagnostic criteria for infants with ALTE, and to identify the true risk of adverse outcomes.

Acknowledgments
The author would like to acknowledge the editorial assistance of Jill and William J Malan in preparing this article.

References
1. National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring, Sept 29 to Oct 1, 1986. Pediatrics 1987;79:292-9. 2. Kahn A. Recommended clinical evaluation of infants with an apparent life-threatening event. Consensus document of the European society for the study and prevention of infant death, 2003. Eur J Pediatr 2004; 163:108-15. 3. Gray C, Davies F, Molyneux E. Apparent life-threatening events presenting to a pediatric emergency department. Pediatr Emerg Care 1999;15:195-9. 4. Davies F, Gupta R. Apparent life-threatening events in infants presenting to an emergency department. Emerg Med J 2002;19:11-6. 5. DePiero AD, Teach SJ, Chamberlain JM. ED evaluation on infants after an apparent life-threatening event. Am J Emerg Med 2004;22:83-6. 6. Kiechl-Kohlendorfer U, Hof D, Peglow UP, et al. Epidemiology of apparent life threatening events. Arch Dis Child 2004;90:297-300. 7. Brand DA, Altman RL, Purtill K, et al. Yield of diagnostic testing in infants who have had an apparent life-threatening event. Pediatrics 2005;115:885-93. 8. Steinschneider A, Santos V. Parental reports of apnea and bradycardia: temporal characteristics and accuracy. Pediatrics 1991;88:1100-5.

Complications After Preterm Birth: An Overview for Emergency Physicians

Praveen Kumar, MBBS, DCH, MD, Gautham Suresh, MD, DM, MS
Nearly 65000 very low-birth-weight infants are born each year in the United States. Survival of these very premature infants has significantly increased over time with improvements in obstetric and neonatal care such as use of antenatal steroid and postnatal surfactant therapy, improved resuscitation and ventilation strategies, and use of early enhanced parenteral nutrition. However, a significant proportion of these infants develop either one or more complications of prematurity and may require ongoing care after their discharge. It is estimated that nearly 25% very low-birth-weight infants and as many as 80% extremely low-birth-weight infants have at least one readmission to the hospital. Many of these infants present to the emergency department with an illness that may be related to the complications of prematurity, and a basic understanding of these morbidities will allow emergency department physicians to provide optimal care to these infants. This article provides a brief summary of common morbidities seen in these high-risk infants. Clin Ped Emerg Med 9:191-199 C 2008 Elsevier Inc. All rights reserved. KEYWORDS preterm, very low birth weight, extremely low birth weight, intraventricular hemorrhage, periventricular leukomalacia, apnea of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity

early 13% of all babies are born preterm in the United States each year, and the proportion of live births with birth weight not exceeding 1500 g (very low-birthweight [VLBW] infants) has increased gradually from 1.17% to 1.48% over the last 3 decades [1]. This would suggest that, with approximately 4.3 million live births each year, nearly 65000 VLBW infants are born each year in the United States. Over this same period, there has been a significant reduction in mortality rates for this group of infants, with more than 85% of VLBW infants now surviving to discharge [2]. Nearly one third of these

Division of Neonatology, Northwestern Memorial Hospital, Children's Memorial Hospital, Chicago, IL. Neonatal Division, Department of Pediatrics, Dartmouth Hitchcock Medical Center, Lebanon, NH. Reprint requests and correspondence: Praveen Kumar, MBBS, DCH, MD, 250 E Superior St, Room 05-2159, Northwestern Memorial Hospital, Chicago, IL 60611. (E-mails: p-kumar@northwestern.edu, gautham.suresh@hitchcock.org) 1522-8401/$ - see front matter C 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2008.06.009

surviving high-risk infants have had one or more complication of prematurity during their initial hospital stay that may or may not have completely resolved by the time of their discharge from the neonatal intensive care unit (NICU). This increase in the number of preterm births combined with increased survival means that an increasing number of these NICU graduates present to primary care physicians and emergency departments (EDs) across the country for their postdischarge care. Many of these visits to EDs are frequently related to an underlying complication after preterm birth such as complications of a ventriculoperitoneal (VP) shunt in an infant with posthemorrhagic hydrocephalus (PHH) or respiratory distress in an NICU graduate with bronchopulmonary dysplasia (BPD). It is estimated that nearly 25% of VLBW infants and as many as 80% of extremely low-birth-weight (birth weight 1000 g) infants have at least 1 hospital readmission after their discharge from the NICU over the first 2 years of life [3]. This trend makes it imperative that all physicians providing care for these 191

192 infants be familiar with the pathophysiology and morbidities unique to these infants. This article will review some of the common complications after preterm birth.

P. Kumar, G. Suresh
on cranial ultrasound screening with no identifiable clinical signs. However, in others, a major IVH can be associated with significant deterioration in clinical status with new-onset severe metabolic acidosis, significant drop in hematocrit, hyperglycemia, and worsening cardiopulmonary and neurologic status. A bulging fontanelle and other signs of increased intracranial pressure are seen only in a small group of patients with the most severe IVH. Cranial ultrasonography is the neuroimaging modality of choice for the diagnosis because of its portability, high resolution, and lack of ionizing radiation. Cranial ultrasound in high-risk infants (usually infants younger than 32 weeks' gestation or birth weight 1500 g) is usually recommended at 4 to 7 days of age or earlier in the presence of clinical suspicion. Definitive neuroimagining with magnetic resonance imaging (MRI) in any infant with any grade of IVH before discharge has been suggested to be helpful in defining both the nature and extent of cerebral injury and/or impaired cerebral development [9]. The presence of IVH places an infant at higher risk for neurodevelopmental delays. The long-term neurodevelopmental outcome of infants with IVH depends on IVH severity and associated parenchymal injury. The most common neuromotor abnormality associated with IVH in preterm infants is spastic hemiplegia or spastic diplegia with lower extremities being affected more than the upper extremities. This finding is related to the fact that the descending motor fibers controlling lower extremity function are near the lateral ventricles and are more prone to injury in infants with IVH. In 1983, Papile et al [10] reported the outcome of 198 VLBW infants and found a major handicap in 9% of infants with grade I IVH, 11% with grade II IVH, 36% with grade III IVH, and 76% with grade IV IVH. The incidence of major handicap in VLBW infants with no IVH was reported to be 10%. Subsequent studies confirmed the initial findings that IVH grades I and II did not significantly increase the risk of major handicap in VLBW infants [11,12]. However, some recent studies suggest that even grades I and II IVHs are associated with as much as a 2-fold increase in the risk of lower cognitive performance and a 2.6-fold increase in the risk of neuromotor abnormalities [13]. Another large recent study from France reported an incidence of cerebral palsy of 28% and 60% in all infants born between 22 and 32 weeks' gestation with grades III and IV IVHs, respectively [14]. This study reported exclusively on the prevalence of cerebral palsy at 2 years of age, and it is important to note that the overall incidence of major handicap in this large study would have been higher if cognitive delays were also included.

Intraventricular Hemorrhage
Intraventricular hemorrhage (IVH) is the most common intracranial hemorrhage in premature infants. The incidence of IVH in premature infants declined steadily from the late 1970s to mid-1990s but has remained essentially unchanged since then [2,4]. This initial decrease was related to improvements in obstetric and neonatal care as well as the widespread use of antenatal corticosteroids to induce lung maturation in preterm infants that has been shown to reduce the incidence and severity of IVH as well [5]. The current incidence of any IVH and major IVH in VLBW infants was reported to be 27% and 12%, respectively, in a large cohort of infants [4]. The incidence and severity of IVH are inversely related to gestational age and birth weight, and IVH is rarely seen in infants born after 34 weeks' gestation. For example, the incidence of all IVHs and major IVHs is 41% and 24%, respectively, in infants with a birth weight of 501 to 750 g as compared with 18% and 5%, respectively, in infants with a birth weight of 1251 to 1500 g [4]. Other risk factors for developing IVH include: perinatal asphyxia, need for resuscitation, need for mechanical ventilation, pneumothorax, sudden and rapid changes in blood pressure and intravascular volume, chorioamnionitis, disseminated intravascular coagulation, and patent ductus arteriosus (PDA). Conversely, pregnancy-induced hypertension in mothers and early postnatal use of indomethacin in infants have been associated with a lower incidence of IVH [6,7]. The primary site of bleeding in IVH is the subependymal germinal matrix, which is richly vascular, highly cellular, and gelatinous in texture and has little support for blood vessels in early preterm infants who are at highest risk for developing IVH. The initiation of bleeding from these poorly supported capillaries within the germinal matrix is complex and influenced by many different intravascular, vascular, and extravascular factors. Intraventricular hemorrhage is graded as follows: grade Iisolated germinal matrix hemorrhage with no intraventricular extension, grade IIgerminal matrix hemorrhage with extension into the ventricular system but without any ventricular dilatation, grade IIIIVH with ventricular dilatation, and grade IVcharacterized by intraparenchymal hemorrhage [8]. Grades I and II are also referred to as minor IVHs, whereas grades III and IV are considered major IVHs. Nearly half of all cases of IVH occur during the first 24 hours of life, and nearly 90% occur before 4 days of age. The clinical presentation of IVH is variable, but the most common clinical sign is an unexplained drop in the hematocrit. In most cases, the diagnosis of IVH is made

Posthemorrhagic Hydrocephalus
Posthemorrhagic hydrocephalus is defined as the development of ventriculomegaly after IVH in a preterm infant

Complications following preterm birth: an overview for emergency physicians

with an otherwise anatomically normal ventricular system. The incidence of PHH is closely and directly related to the severity of IVH. Some ventricular enlargement after IVH has been reported in as many as 50% of infants, but nearly half of these have no progression and resolve without any intervention [15]. The overall incidence of progressive ventricular dilatation after IVH in a preterm infant has been reported to be in the range of 15% to 25%, but it is much higher in infants with grades III and IV IVH and is reported to occur in nearly 50% to 70% of survivors with a major IVH [15,16]. It is also important to remember that, although the incidence of IVH in preterm infants has declined over the last 3 decades, the absolute numbers of survivors with IVH and PHH are likely to be either unchanged or even increased because of improved survival rates of extremely low-birth-weight infants who are at greatest risk for complications of prematurity. Both lower gestation and major IVH are independent risk factors for the development of PHH in preterm infants with IVH [15]. Although rapid ventricular dilatation and acute clinical deterioration can occur in a small number of infants with a large amount of IVH, more commonly, PHH develops gradually over weeks as a result of obliterative arachnoiditis in the posterior fossa. In most cases, PHH is of the communicating type with obstruction beyond the fourth ventricle; but obstruction at the level of the aqueduct can be seen in some cases. The development of PHH can cause or contribute to preexisting white matter injury in these infants. The mechanisms of damage to the periventricular white matter secondary to PHH are poorly understood but are likely to be related to ischemia due to raised intracranial pressure and parenchymal compression, oxidative stress due to generation of free radicals, and the actions of inflammatory cytokines [17]. The initial management of an infant with PHH requires careful monitoring of head circumference and serial cranial ultrasounds to monitor for ventricutomegaly. In a large study of 248 VLBW infants with IVH, spontaneous arrest of ventricular dilatation without any treatment was reported in 38% of infants. Of the remaining 62% with persistent progressive ventricular enlargement, 48% required only nonsurgical treatment, 34% received surgical treatment, and 18% died [15]. Nonsurgical treatment options in infants with PHH include serial lumbar punctures and pharmacologic interventions such as carbonic anhydrase inhibitors and osmotic diuretics, but their role in the management of these infants is unproven and may even be harmful [18]. Surgical treatment options include cerebrospinal fluid drainage by placement of a ventricular reservoir and VP shunt. These interventions are only used if spontaneous arrest and resolution of PHH are considered to be unlikely based on serial cranial ultrasounds and clinical examinations. The optimal timing for placement of a ventriculoperitoneal (VP) shunt remains controversial; however, very early placement in the presence of a blood clot and cellular debris may

193

increase the risk of shunt obstruction and infection. The development of PHH in preterm infants is associated with increased mortality and an adverse impact on neurodevelopmental outcome that is even worse if surgical interventions are required. The mortality for infants with PHH is reported to be in the range of 15% to 25%; and in one study, up to 90% of surviving infants with PHH had subsequent neuromotor disability, 76% exhibited pronounced disability, and 56% had multiple impairments [19]. In another study, less than 30% of all infants with PHH and less than 20% of those requiring a VP shunt were normal on follow-up [16]. The main predictors of poor outcome were need for shunt placement, repeated shunt infections and revisions, and associated white matter injury on neuroimaging studies. Many of these infants present to the ED, and VP shunt complications such as infection and shunt failure should be considered and treated promptly to mitigate their impact on the neurodevelopmental outcome of these infants.

Periventricular Leukomalacia
Periventricular leukomalacia (PVL) refers to necrosis of white matter in the periventricular region. It is the most common hypoxic-ischemic lesion seen in preterm infants but is also seen in term infants with hypoxic-ischemic insults. This lesion is primarily due to arterial ischemia in the watershed area of the cerebral arteries and should be differentiated from the periventricular necrosis seen in infants with grade IV IVH that is secondary to venous congestion and subsequent hemorrhagic infarction. Periventricular leukomalacia is usually bilateral and symmetric, and it can be focal or diffuse. The true incidence of PVL in preterm infants remains unclear and varies in different studies depending on neuroimaging modality and the definition of PVL. Cranial ultrasound is the primary neuroimaging modality, but MRI has been shown to be more sensitive in identifying these lesions. The incidence of cystic PVL on cranial ultrasounds in VLBW survivors is about 3% [4]. However, MRI studies of the survivors and autopsy findings in nonsurviving VLBW infants suggest that the true incidence of PVL in these infants is probably much higher. The incidence of PVL is also inversely related to gestational age and is higher in infants with evidence of chorioamnionitis before birth and in infants with cardiorespiratory instability and IVH in the postnatal period. Other predisposing risk factors include perinatal asphyxia, hypocarbia, PDA, and postnatal sepsis. The lesions of PVL begin as focal areas of coagulation necrosis after an ischemic insult to the white matter followed by microglial infiltration, astrocytic proliferation, and eventual cyst formation. Ultrasound diagnosis is primarily based on the identification of these cysts, and it takes about 2 to 3 weeks for cysts to appear after the initial insult. The size of these cysts varies depending on the severity of the initial insult and timing of the

194 neuroimaging studies, as the size of cavities diminishes over time secondary to progression of gliosis. Eventually, the cysts resolve; and thinning of periventricular white matter with compensatory mild ventriculomegaly may be the only residual findings. These cysts are detected by ultrasound only when they are approximately 0.5 cm or greater in size. Periventricular leukomalacia is typically located posteriorly and dorsolateral to the external angles of the lateral ventricles. This area includes motor costicospinal tracts with fibers responsible for lower extremity function located close to the ventricles; and therefore, the most common clinical correlate of this lesion is spastic diplegia in which lower limb function is more severely affected and upper extremities are relatively spared. Another common complication in these infants is visual deficits related to involvement of the nearby optic radiations. Intellect and cognitive function are also frequently affected because of interference with normal cerebral organization. Periventricular leukomalacia has been shown to be a strong predictor of future neurodevelopmental delays. Cognitive and motor impairments invariably occur in infants with large bilateral cysts; but even small, focal, unilateral cysts are associated with a 50% to 80% risk of deficits. The EPIPAGE (tude Epidmiologique sur les Petits Ages Gestationnels) study group reported that 35% of infants with unilateral cystic PVL and 75% of infants with bilateral cystic PVL developed cerebral palsy on follow-up [14]. In another study, 74% of infants with small, localized cystic changes and 96% of infants with extensive cystic PVL had signs of cerebral palsy at 24 months of age [20].

P. Kumar, G. Suresh
cases, especially in infants who are born at less than 28 weeks' gestation [22-24]. Apnea of prematurity is traditionally classified into 3 categories. Central apnea is characterized by total cessation of inspiratory effort with no evidence of obstruction. Obstructive apnea occurs when there is collapse of the airway and no airflow takes place despite continued breathing effort. Mixed apnea consists of airway obstruction in association with a central pause [23]. The site of obstruction in obstructive apnea is mostly in the pharynx; however, it may also occur at the larynx. Mixed apnea accounts for more than half of all apneic episodes, followed in decreasing frequency by central and obstructive apnea [23]. Apnea of prematurity is primarily a result of immaturity in the regulation of breathing as a result of immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors [23,25]. Swallowing occurs with increased frequency during all types of apnea, extending the duration of apnea through reflex inhibition of respiration [25]. Other clinical findings associated with apnea may include oxygen desaturations, clinical cyanosis, pallor, bradycardia, and hypotonia. Apnea of prematurity is a diagnosis of exclusion, and other conditions should be considered and excluded in an infant with new-onset or increased frequency of apnea. Other conditions that can present with apnea as a presenting sign include (a) central nervous system disorders such as intracranial hemorrhage, seizures, and meningitis; (b) infections such as sepsis, pneumonia, meningitis, and respiratory syncytial virus infection; (c) hematologic disorders such as anemia; (d) metabolic disorders such as hypoglycemia, hypocalcemia, and metabolic acidosis; (e) gastrointestinal disorders such as necrotizing enterocolitis (NEC), abdominal distension, and gastroesophageal reflux (GER); (f) cardiopulmonary disorders such as PDA, pulmonary hemorrhage, and pulmonary congestion; and (g) miscellaneous causes such as temperature instability, drug overdose (eg, opiates and magnesium sulfate), and positional compromise of the airway. Apnea of prematurity should only be considered in infants in whom all other causes of apnea have been excluded. Gastroesophageal reflux is frequently considered a cause for apnea in the convalescent preterm infant. However, the current research indicates that, although both apnea and GER are often seen together in premature infants, this relationship is often coincidental rather than causal and that pharmacologic treatment of GER should be reserved for infants who exhibit other signs of GER such as significant emesis and failure to thrive, regardless of whether apnea is present [23]. General measures to control apnea should include appropriate infant positioning to maintain airway and maintenance of a thermoneutral environment. Methylxanthines (eg, aminophylline, theophylline, caffeine) have

Apnea of Prematurity
Apnea in a preterm infant is defined as a respiratory pause for 20 seconds or longer, or any pause associated with cyanosis or bradycardia. Apnea of prematurity is a diagnosis of exclusion, and other conditions should be considered and excluded in an infant with apnea. Apnea of prematurity also needs to be differentiated from periodic breathing, which is defined as recurrent sequences of pauses in respiration lasting 5 to 10 seconds and followed by 10 to 15 seconds of rapid respiration. Periodic breathing is considered a normal event in preterm infants and is not usually associated with any color or heart rate changes. Periodic breathing is reflective of the immaturity of the respiratory control system and does not require any intervention. Apnea of prematurity usually begins later in the first week of life but can occur on the first day of life in some cases. The incidence of apnea of prematurity increases with decreasing gestational age, occurring in 7% of babies born at 34 to 35 weeks' gestation, 15% at 32 to 33 weeks, 54% at 29 to 31 weeks, and in nearly all infants born at less than 29 weeks' gestation [21,22]. Apnea of prematurity frequently resolves by 37 weeks of gestational age but may persist until 43 to 44 weeks of gestational age in some

Complications following preterm birth: an overview for emergency physicians

been the mainstays of pharmacologic therapy for apnea of prematurity. Caffeine has become the drug of choice because of its lower toxicity, high therapeutic index, and long half-life that allows once a day dosing. Doxapram is another respiratory stimulant that has been shown to be effective, although no better than methylxanthines, for the reduction of apnea in preterm infants. Nonpharmacologic approaches include use of continuous positive airway pressure, high-flow nasal cannula, and mechanical ventilation that is necessary only in refractory cases. Most preterm infants are apnea-free by the time they are ready for discharge from the NICU. An apnea-free observation period ranging from 3 to 7 days has been used by various units as a prerequisite for discharge in these infants. The persistence of these cardiorespiratory events may delay discharge in a small number of infants who can either remain hospitalized until resolution of apnea and bradycardia episodes or be discharged home on cardiorespiratory monitors. The decision to discharge such an infant on home monitoring should be made after careful discussion with both parents. Home monitoring is usually recommended until 43 to 44 weeks of gestational age. These parents should receive cardiopulmonary resuscitation training before discharge. Although there is enough evidence to suggest that apnea of prematurity is neither predictive of nor a precursor to sudden infant death syndrome, the impact of apnea of prematurity on neurodevelopmental outcome remains unclear and unresolved [23].

195

Anemia of Prematurity
Anemia of prematurity is a normocytic, normochromic anemia with low absolute reticulocyte counts and the presence of bone marrow erythroid hypoplasia. The bone marrow becomes the main site for erythropoiesis by 22 weeks' gestation, but the liver continues as an erythropoietic organ until term; and a significant increase in hematopoietic output in late gestation or early postnatal period requires extramedullary hematopoiesis. Erythropoiesis in the fetus is independent of maternal erythropoiesis. The primary regulator of erythropoiesis in late gestation is erythropoietin. Fetal red blood cell production begins early in gestation, resulting in a hemoglobin concentration of approximately 9 g/dL by 10 weeks and about 14 g/dL by 24 weeks of gestation, compared with an average cord hemoglobin concentration of 17 g/dL in term infants. In addition to lower hemoglobin levels at birth than term infants, the rate and degree of decline in hemoglobin levels are also more pronounced in preterm infants and are inversely related to gestational age at birth. During the first weeks of life, all infants, term and preterm, experience a decline in circulating red blood cell mass. In healthy term infants, the nadir hemoglobin value usually is 11.4 0.9 g/dL at an age of approximately 8 to 12 weeks, but rarely falls to less than 9 g/dL. However, the decline

occurs much earlier and is more pronounced in premature infants even in the absence of any complicating illnesses; and the mean hemoglobin concentration can fall to as low as 8 g/dL in infants weighing 1000 to 1500 g and 7 g/dL in infants weighing less than 1000 g at birth [26]. The various factors responsible for anemia of prematurity include physiologic changes, blood loss, and other iatrogenic factors. The physiologic factors responsible for anemia of prematurity include expanding blood volume, shortened red blood cell survival, and blunted erythropoietin response to anemia. Although rapidly increasing body mass and plasma volume can cause a hemodilutional effect on hemoglobin concentration, it is generally agreed that the primary reason for the fall in hemoglobin concentration is the actual decrease in the red cell mass rather than just a hemodilutional effect of expanding plasma volume. The rapid decline of hemoglobin partially reflects shorter red blood cell survival time in the presence of a striking decrease in hematopoietic activity. The halflife of erythrocytes is approximately 35 to 50 days in preterm infants and 60 to 70 days in term infants as compared with 120 days in adults. Another important cause of anemia in preterm infants during the first few days and weeks of life is blood loss. The blood loss in these infants could occur before delivery because of fetomaternal hemorrhage or twin-to-twin transfusion; or it could be due to an obstetric accident, traumatic delivery, and excessive bruising during delivery. A higher incidence of intracranial and pulmonary hemorrhage in VLBW infants can further exacerbate their anemia. Probably the most important mechanism of blood loss in preterm infants is the need for repeated blood sampling to monitor these critically ill neonates. These phlebotomy losses are maximum in the smallest premature infants. Despite micromethods for laboratory testing, cumulative blood losses can exceed the circulating red cell mass for many infants receiving intensive care. It is important to remember that 1 mL of blood in a 1000-g infant is equivalent to removing about 70 mL of blood from an adult; and in the presence of diminished erythropoietic response, such losses can lead to severe anemia in a short time. Another key reason for anemia in preterm infants is diminished bone marrow response in the face of progressive anemia, and the cause of hyporesponsive bone marrow in preterm infants is inadequate erythropoietin production [27]. Premature infants produce erythropoietin in response to anemic hypoxia, but the magnitude of the response is much less than expected for their degree of anemia. One mechanism to explain this observation is that the fetus and premature infants during the first weeks of life rely on the liver as the primary site for erythropoietin production [27]. Hepatic erythropoietin-producing cells are less sensitive to hypoxia compared with the kidney and produce 1/10 the erythropoietin in response to similar degree of hypoxic stimuli [27]. In summary, an altered bone marrow response due to a relative lack of erythropoietin and

196 iatrogenic blood loss secondary to sampling for laboratory tests are the primary reasons and determinants of the severity of anemia in preterm infants. The commonly observed signs associated with anemia of prematurity include pallor, poor feeding, lethargy, tachycardia, tachypnea, apnea/bradycardia, failure to gain weight, and increased work of breathing and oxygen requirement. These indicators of physiologically significant anemia are often nonspecific. Furthermore, the level of hematocrit tends to correlate poorly with these signs in many infants [27]. Various studies have attempted to assess the relationship between clinical signs and the degree of anemia by evaluating the effect of packed red blood cell transfusions on cardiovascular indices, respiratory irregularities, and/or weight gain in preterm infants with anemia of prematurity; and these studies have failed to consistently demonstrate benefits of transfusion [27,28]. A comprehensive approach to the management of anemia of prematurity includes concerted efforts to minimize phlebotomy losses, conservative and judicious use of erythrocyte transfusions, optimal intake of calories and proteins for catch-up growth, adequate supplementation of nutrients such as iron, and optimal use of recombinant human erythropoietin if necessary [28]. Recombinant human erythropoietin administration in preterm infants has been shown to stimulate erythropoiesis with no significant associated adverse effects; however, the questions related to optimal dose and frequency, cost benefit, and role of supplemental iron have not been answered fully. Based on our observations and a review of the current literature, we consider that 2 to 3 times a week administration of recombinant human erythropoietin at a dose of 600 to 750 U/kg/wk in conjunction with 6 mg/kg/d of oral iron supplementation is adequate and safe in stable preterm infants with anemia of prematurity [28].

P. Kumar, G. Suresh
Bronchopulmonary dysplasia is of multifactorial etiology, with contributory conditions including fetal infection or inflammation (usually associated with maternal chorioamnionitis), oxidant stress (preterm infants are deficient in antioxidant enzymes), ventilator-induced lung injury, postnatal inflammation, poor nutrition, pulmonary fluid overload, development of a PDA, genetic factors, and abnormal growth-factor signaling [31]. The pathology of BPD is characterized by interstitial edema, fibrosis, and atelectasis and narrowing of small airways resulting in decreased lung compliance and increased airway resistance [32]. Airflow restriction is often worsened by associated tracheobronchomalacia. In severe or late stages of BPD, there are often areas of lung hyperinflation and air trapping. The damage to the airways and distal lungs in BPD is not uniform, which results in different time constants in different lung areas. The pulmonary vasculature is also affected in BPD, with abnormal muscularization of the walls of small pulmonary arteries, and increased pulmonary vasoreactivity (exaggerated vasoconstriction), with resultant pulmonary hypertension. These pathophysiologic changes result in ventilation-perfusion mismatch, hypoxia, hypercarbia, and respiratory acidosis. The increased pulmonary vascular resistance can lead to poor right ventricular function, impaired cardiac output, pulmonary edema, cor pulmonale, and an increased risk of sudden death [33]. The clinical manifestations of BPD include increased respiratory rate, retractions, use of accessory muscles of respiration, and diffuse crackles and wheezes on auscultation. Infants with severe BPD can have BPD spells, which manifest as sudden-onset hypoxic episodes associated with decreased chest wall movement and an increased need for respiratory support. Because of respiratory compromise, infants with BPD often have difficulty with oral (breast or bottle) feeding. Infants with BPD often have exacerbations of their respiratory distress; and they can be very sensitive to fluid intake, with even the slightest increase in the amount of fluid intake sometimes leading to an increase in respiratory distress. Bronchopulmonary dysplasia is a marker of associated comorbidity, including neurodevelopmental impairment. Infants with BPD have a higher prevalence of cerebral palsy and cognitive impairment than BPD-free gestation-matched controls [33]. Bronchopulmonary dysplasia is usually treated with fluid restriction, diuretics, supplemental oxygen, and respiratory support with continuous positive airway pressure or mechanical ventilation. Bronchodilators are often used in affected infants, without good evidence for their effectiveness, and may worsen airway narrowing in the presence of tracheobronchomalacia. Dexamethasone has been used in severe cases of BPD; but this is associated with an increased risk of neurodevelopmental impairment, and its use is currently discouraged [34]. Optimal nutrition and developmental care are also important components of management. Bronchopulmonary dysplasia can result in a

Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia is the most common chronic respiratory disease in infancy. It is a common cause of morbidity in preterm neonates, affecting up to 85% of infants with a birth weight of less than 700 g and smaller proportions of higher-birth-weight infants, with a wide variation in the incidence across different NICUs [29]. Based on recent National Institutes of Health criteria, BPD is diagnosed if a neonate has received treatment with greater than 21% supplemental oxygen for 28 days or longer [30]. This criterion for duration of oxygen treatment is assessed at a gestational age of 36 weeks in neonates born at less than 32 weeks' gestation. In those with a gestational age of 32 weeks or greater at birth, it is assessed at a postnatal age of greater than 28 days but less than 56 days. If an infant with at least 32 weeks' gestation is discharged before 56 days of age, the assessment is made at discharge.

Complications following preterm birth: an overview for emergency physicians

prolonged need for supplemental oxygen therapy, and some infants with BPD are discharged home on supplemental oxygen. A few infants with severe BPD may go home on mechanical ventilation, and these infants usually will have a tracheostomy. After discharge, infants with BPD are prone to serious respiratory illness with relatively minor viral respiratory tract infections; and they should therefore be protected from such infections with good hand hygiene, avoidance of crowds, avoidance of contact with adults or children with respiratory illness, prevention of exposure to environmental pollutants including tobacco smoke, routine pediatric immunizations, and the use of palivizumab to prevent hospitalization from respiratory syncytial virus infection [35]. Approximately half of all infants with BPD are readmitted to the hospital after discharge from the NICU. This occurs more often in the first year of life than in subsequent years. Their respiratory reserve can be quite limited. Chronic cough and wheezing also are common. Airway function may deteriorate in the first year of life. These respiratory problems usually subside over time, by around school age, although even BPD survivors without overt symptoms or signs often still have abnormalities on pulmonary function testing [36].

197

Retinopathy of Prematurity
Retinopathy of prematurity (ROP) is a common and potentially serious condition among VLBW infants. It is characterized by abnormal retinal vascular development and can lead to retinal detachment and blindness in the most serious (fortunately infrequent) cases. It occurs in up to 68% of infants with a birth weight less than 1251 g, and approximately one third of these cases are severe [37]. During normal retinal development in the fetus, blood vessels migrate centrifugally from the optic disc, beginning at approximately 16 weeks of gestation. Mature blood vessels extend to the nasal ora serrata by 36 weeks of gestation and to the temporal ora serrata by 39 to 41 weeks of gestation [38]. The retina is fully developed at birth in a term infant; therefore, ROP does not occur. Preterm infants are born before retinal development is complete and are therefore at risk for ROP. The shorter the gestation at birth the greater the degree of retinal immaturity and, likewise, the consequent risk of ROP. As retinal vascularization proceeds symmetrically from the optic disc to the ora serrata, there is an advancing circumferential border between vascular and avascular retina. It is within this border area that acute ROP develops [39]. Retinopathy of prematurity usually does not manifest with any overt clinical signs; and preterm infants at risk (those born at a gestational age of 32 weeks or less or with a birth weight of 1500 g or less, and selected infants with a higher gestation or birth weight) should be routinely screened for ROP with indirect ophthalmoscopy, using current guidelines endorsed by pediatric and ophthalmol-

ogy professional societies [40]. The initial screening should be done at a gestational age of 31 weeks or a chronological age of 4 weeks, whichever is later. Such screening is usually performed during the NICU stay and ensures early identification of the disorder and timely treatment when required. Screening should be done by a qualified and experienced ophthalmologist. The findings of the retinal examination should be described according to the International Classification of Retinopathy of Prematurity [41]. The geographic location of the ROP lesions on the retina is described using zones, concentric circles centered on the optic disc. Zone I, the innermost zone, is a circular area around the fovea. Zone II is the concentric area immediately outside zone I that extends as far as the nasal ora serrata. Zone III is the residual crescentic retinal area anterior to zone IIit is absent nasally and extends temporally to the periphery of the retina. The severity of ROP lesions is described using 5 stages, based on the appearance of the lesions, with higher stages representing more severe disease (Table 1). The cumulative extent of the disease across the real estate of the retina is measured in terms of clock hours. Plus disease is defined as dilation and tortuosity of the posterior retinal blood vessels as defined by a standard photograph. Preplus disease is defined as vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but demonstrate more arterial tortuosity and more venous dilatation than normal. Over time, the vessel abnormalities of preplus disease may progress to frank plus disease as the vessels dilate and become more tortuous [41]. Infants with lower stages of ROP on routine screening should undergo frequent repeated examinations at intervals of 1 to 3 weeks until retinal vascularization is complete. Screening examinations can be stopped in infants in whom (a) retinal vascularization has reached the ora serrata or is within 1 disk diameter of it, (b) vascularization has progressed into zone III without previous zone II ROP, or (c) a postmenstrual age of 45 weeks is reached without the development of prethreshold ROP or worse. However, all preterm infants will need periodic ophthalmologic examinations through childhood to identify other ocular
Table 1 Stage 1 2 Stages of ROP. Description Thin demarcation line separating the vascular and avascular zones of the retina A ridge that has height and width and extends above the plane of the retina in the region of the demarcation line Extraretinal fibrovascular proliferation or neovascularization extends from the ridge into the vitreous. Partial retinal detachment Total retinal detachment

4 5

198 problems such as refractive errors, strabismus, and impaired vision [42]. Infants whose ROP is at an advanced stage are at high risk for visual impairment and should undergo laser photocoagulation, which has replaced cryotherapy as the ablative modality of choice (retinopexy). With either therapy, the goal is destruction of the peripheral immature unvascularized portion of the retina because it is the source of growth factors that are thought to cause the retinopathy. This permits regression (healing) of the ROP. A recent study, the Early Treatment for Retinopathy of Prematurity Randomized Trial, confirmed the efficacy of treatment of severe ROP and showed beneficial effects of treatment at an earlier stage of ROP than previous criteria, leading to revised indications for treatment [43]. Current criteria for retinal ablative treatment are as follows: (a) zone I ROP any stage with plus disease; (b) zone I ROPstage 3, no plus disease; and (c) zone IIstage 2 or 3 with plus disease [40]. Complications of laser retinopexy include anterior segment ischemia; cataract; and burns of the cornea, iris, or tunica vasculosa lentis [38]. Although there are yet no definitive interventions to prevent ROP (except prevention of prematurity), accumulating evidence from observational studies indicates that, in preterm infants on supplemental oxygen therapy, there may be beneficial effects to maintaining the oxygen saturation at levels below those commonly used in most NICUs and to reducing wide fluctuations in oxygen saturation during the hospital course. In most of these studies, attempts to maintain oxygen saturation levels in preterm infants at less than 90% were associated with less frequent and less severe ROP [44].

P. Kumar, G. Suresh
intestine, representing intramural gas), intestinal wall thickening, intestinal dilation, loss of the normal mosaic pattern, development of rounded or elongated loops, and air in the portal venous system or in the biliary tree [48]. In advanced cases with intestinal perforation, clinical and radiological signs of pneumoperitoneum are seen [48]. With serious disease, the infant can be critically ill, with hypotension, acidosis, extensive capillary leak, thrombocytopenia, and disseminated intravascular coagulation. Survivors of NEC are at risk for complications such as cholestasis, intestinal strictures, short-bowel syndrome, and neurodevelopmental impairment. Treatment of NEC consists of cessation of enteral feeds, use of parenteral nutrition, and antibiotic therapy for periods ranging from 3 to 21 days, depending on the severity of the illness at presentation. Infants who develop intestinal perforation and pneumoperitoneum require abdominal surgery, with either insertion of a peritoneal drain or a laparotomy with possible intestinal resection [49]. After the surgery, the infant may be left with an ileostomy, a colostomy, or both until the bowel is reanastomosed during a subsequent surgery. Prevention of NEC has been elusive. The risk of NEC is decreased with breast milk compared with formula feeding. Recently, the use of probiotics has shown promising results in clinical trials of NEC prevention. During enteral feeding of preterm infants, the volume of milk feeds in preterm infants should be increased cautiously. A maximum enteral feeding volume increase of 20 to 25 mL/kg body weight per day is commonly accepted as safe [50].

Summary Necrotizing Enterocolitis

Necrotizing enterocolitis is a potentially life-threatening disorder that usually affects preterm infants in the NICU but can also affect term neonates. It affects approximately 12% of infants with a birth weight less than 1500 g, is seen in 1% to 5% of all NICU admissions, and has a mortality of 12% to 30% [45,46]. It can also affect clusters of infants in a NICU. Necrotizing enterocolitis is a condition characterized by intestinal ischemia (usually of the small intestine) and, in the most serious cases, can result in necrosis of large segments of the intestine. Although the exact etiology of NEC is unknown despite extensive research, the main contributory factors are thought to be prematurity, intestinal ischemia, bacterial colonization, and enteral feeding [47]. Presenting clinical features include feeding intolerance (increased volume of gastric residuals), bilious or blood-stained gastric aspirates, hematochezia, abdominal distension, erythema of the abdominal wall, abdominal tenderness, and decreased intestinal motility. The diagnosis is made primarily on abdominal radiography, with the characteristic signs including pneumatosis intestinalis (radiolucent round or linear areas in the walls of the Neonatal intensive care unit graduates may have one or more unresolved morbidity at the time of their discharge from the NICU and may require care from multiple subspecialists. They remain at high risk for visits to the ED and subsequent rehospitalization. These infants, with their unique set of morbidities, may offer an unusual challenge and may overwhelm an ED physician unfamiliar with the various complications after preterm birth. We hope that this article will provide ED physicians with a basic understanding of some of these common complications after preterm birth.

References
1. Martin JA, Kung HC, Mathews TJ, et al. Annual summary of vital statistics: 2006. Pediatrics 2008;121:788-801. 2. Fanaroff AA, Hack M, Walsh MC. The NICHD neonatal research network: changes in practice and outcomes during the first 15 years. Semin Perinatol 2003;27:281-7. 3. Wilson-Costello D. Is there evidence that long-term outcomes have improved with intensive care? Semin Fetal Neonatal Med 2007;12: 344-54. 4. Fanaroff AA, Stoll BJ, Wright LL, et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007;196:147.e1-8.

Complications following preterm birth: an overview for emergency physicians

5. Shankaran S, Bauer CR, et al. Prenatal and perinatal risk and protective factors for neonatal intracranial hemorrhage. National Institute of Child Health and Human Development Neonatal Research Network. Arch Pediatr Adolesc Med 1996;150:491-7. 6. Perlman JM, Risser RC, Gee JB. Pregnancy-induced hypertension and reduced intraventricular hemorrhage in preterm infants. Pediatr Neurol 1997;17:29-33. 7. Ment LR, Oh W, Ehrenkranz RA, et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics 1994;93:543-50. 8. Papile LA, Burstein J, Burstein R, et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92:529-34. 9. Inder TE. Neurodevelopmental impact of low-grade intraventricular hemorrhage in very preterm infants. J Pediatr 2006;149:152-4. 10. Papile LA, Munsick-Bruno G, Schaefer A. Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J Pediatr 1983;103:273-7. 11. Pinto-Martin JA, Riolo S, Cnaan A, et al. Cranial ultrasound prediction of disabling and nondisabling cerebral palsy at age two in a low birth weight population. Pediatrics 1995;95:249-54. 12. Roth SC, Baudin J, McCormick DC, et al. Relation between ultrasound appearance of the brain of very preterm infants and neurodevelopmental impairment at eight years. Dev Med Child Neurol 1993;35:755-68. 13. Patra K, Wilson-Costello D, Taylor HG, et al. Grades I-II intraventricular hemorrhage in extremely low birth weight infants: effects on neurodevelopment. J Pediatr 2006;149:169-73. 14. Ancel PY, Livinec F, Larroque B, et al. Cerebral palsy among very preterm children in relation to gestational age and neonatal ultrasound abnormalities: the EPIPAGE cohort study. Pediatrics 2006;117:828-35. 15. Murphy BP, Inder TE, Rooks V, et al. Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome. Arch Dis Child Fetal Neonatal Ed 2002;87:F37-41. 16. Cherian S, Whitelaw A, Thoresen M, et al. The pathogenesis of neonatal post-hemorrhagic hydrocephalus. Brain Pathol 2004;14: 305-11. 17. Futagi Y, Suzuki Y, Toribe Y, et al. Neurodevelopmental outcome in children with posthemorrhagic hydrocephalus. Pediatr Neurol 2005; 33:26-32. 18. Whitelaw A, Kennedy CR, Brion LP. Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation. Cochrane Database Syst Rev 2001:CD002270. 19. Randomised trial of early tapping in neonatal posthaemorrhagic ventricular dilatation: results at 30 months. Ventriculomegaly Trial Group. Arch Dis Child Fetal Neonatal Ed 1994;70:F129-36. 20. Pierrat V, Duquennoy C, van Haastert IC, et al. Ultrasound diagnosis and neurodevelopmental outcome of localised and extensive cystic periventricular leucomalacia. Arch Dis Child Fetal Neonatal Ed 2001; 84:F151-6. 21. Henderson-Smart DJ. The effect of gestational age on the incidence and duration of recurrent apnoea in newborn babies. Aust Paediatr J 1981;17:273-6. 22. Eichenwald EC, Aina A, Stark AR. Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks. Pediatrics 1997; 100(3 Pt 1):354-9. 23. Martin RJ, Abu-Shaweesh JM, Baird TM. Apnoea of prematurity. Paediatr Respir Rev 2004;5(Suppl A):S377-82. 24. Ramanathan R, Corwin MJ, Hunt CE, et al. Cardiorespiratory events recorded on home monitors: comparison of healthy infants with those at increased risk for SIDS. JAMA 2001;285:2199-207. 25. Stokowski LA. A primer on apnea of prematurity. Adv Neonatal Care 2005;5:155-70. 26. Stockman III JA. Anemia of prematurity. Current concepts in the issue of when to transfuse. Pediatr Clin North Am 1986;33:111-28.

199

27. Kumar P, Krishanan R. Anemia of prematurity: etiology and pathophysiology. Asian J Pediatr Pract 2002;6:19-24. 28. Kumar P, Krishanan R. Anemia of prematurity: management strategies and role of recombinant erythropoietin. Asian J Pediatr Pract 2002;5:41-6. 29. Rojas MA, Gonzalez A, Bancalari E, et al. Changing trends in the epidemiology and pathogenesis of chronic lung disease. J Pediatr 1995;126:605-10. 30. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. J Respir Crit Care Med 2001;163:1723-9. 31. Chess PR, D'Angio CT, Pryhuber GS, et al. Pathogenesis of bronchopulmonary dysplasia. Semin Perinatol 2006;30:171-8. 32. Coalson JJ. Pathology of bronchopulmonary dysplasia. Semin Perinatol 2006;30:179-84. 33. Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet 2006;367:1421-31. 34. American Academy of Pediatrics Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002;109:330-8. 35. American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 2003;112(6 Pt 1):1442-6. 36. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007;357:1946-55. 37. Good WV, Hardy RJ, Dobson V. Early Treatment for Retinopathy of Prematurity Cooperative Group. The incidence and course of retinopathy of prematurity: findings from the Early Treatment for Retinopathy of Prematurity study. Pediatrics 2005;116:15-23. 38. Recchia FM, Capone Jr A. Contemporary understanding and management of retinopathy of prematurity. Retina 2004;24:283-92. 39. Fielder AR, Reynolds JD. Retinopathy of prematurity: clinical aspects. Semin Neonatol 2001;6:461-75. 40. Section on Ophthalmology, American Academy of Pediatrics, American Academy of Ophthalmology and American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2006; 117:572-6. 41. International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited. Arch Ophthalmol 2005;123:991-9. 42. O'Connor AR, Fielder AR. Visual outcomes and perinatal adversity. Semin Fetal Neonatal Med 2007;12:408-14. 43. Good WV. Early Treatment for Retinopathy of Prematurity Cooperative Group. The early treatment for retinopathy of prematurity study: structural findings at age 2 years. Br J Ophthalmol 2006;90: 1378-82. 44. Lutty GA, Chan-Ling T, Phelps DL, et al. Proceedings of the third international symposium on retinopathy of prematurity: an update on ROP from the lab to the nursery. Mol Vis 2006;12:532-80. 45. Srinivasan PS, Brandler MD, D'Souza A. Necrotizing enterocolitis. Clin Perinatol 2008;35:251-72. 46. Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet 2006;368: 1271-83. 47. Hunter CJ, Upperman JS, Ford HR, et al. Understanding the susceptibility of the premature infant to necrotizing enterocolitis. Pediatr Res 2008;63:117-23. 48. Epelman M, Daneman A, Navarro OM, et al. Necrotizing enterocolitis: review of state-of-the-art imaging findings with pathologic correlation. Radiographics 2007;27:285-305. 49. Moss RL, Dimmitt RA, Barnhart DC, et al. Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. N Engl J Med 2006;354:2225-34. 50. Patole S. Prevention and treatment of necrotising enterocolitis in preterm neonates. Early Hum Dev 2007;83:635-42.

Neonatal Skin Disorders and the Emergency Medicine Physician

Gomathy Sethuraman, MD, Anthony J. Mancini, MD
Neonatal skin may play host to a variety of dermatological conditions, ranging in spectrum from benign, self-limited disorders to severe and/or life-threatening disease. Neonatal skin disorders may be of concern to parents and physicians alike, and may initially be evaluated in the urgent care clinic or emergency department, where specialty consultation may not always be readily available. In this paper, several neonatal skin conditions are briefly reviewed, including vesiculopustular disorders; those presenting with bullae, erosions and ulcerations; vascular and pigmented birthmarks; and disorders which present with skin erythema and scaling. This brief discussion is intended as a starting point for the emergency physician who may be the bfront lineQ clinician faced with the evaluation of a neonate or infant with skin disease. Clin Ped Emerg Med 9:200-209 C 2008 Elsevier Inc. All rights reserved. KEYWORDS neonatal, skin disorders, emergency medicine

he skin of the neonate may exhibit several differences from that of the adult, both anatomically and physiologically, and may play host to a variety of dermatological conditions, representing a wide array of severities from mild and self-limited to severe and/or lifethreatening. These conditions may include (but are not limited to) transient or physiologic phenomena, findings related to perinatal or obstetrical trauma, disorders of pigmentation, infectious diseases, inflammatory conditions, genetic disorders, and malignancies. Skin disorders in the infant may be a source for concern to parents and physicians alike and may present for initial evaluation to the pediatric clinic, urgent care, or emergency department. Practitioners in these settings should be familiar with neonatal skin disorders, as immediate specialty consultation may not always be readily available. What follows is a brief discussion of several select neonatal skin disorders. The reader is referred to other sources for a more comprehensive review of these and other conditions.

is that of vesiculopustular lesions, which can be the presenting feature for a variety of infectious, inflammatory, genetic, and transient neonatal disorders (Table 1) [1,2]. Bullae, erosions, and ulcerations may be caused by several disorders listed in Table 1, as well as staphylococcal scalded skin syndrome, congenital syphilis, epidermolysis bullosa, mastocytosis, bullous forms of ichthyosis, autoimmune blistering disease, aplasia cutis congenita, and several even less common conditions [1,2]. Some distinct categories of neonatal skin lesions include pigmented (ie, melanocytic nevus, Mongolian spots, nevus of Ota, caf au lait macules) and vascular (ie, infantile hemangioma, port wine stain) birthmarks, and those presenting with erythema and scaling (Table 2). Several disorders from each of these categories are briefly discussed here.

Types of Neonatal Skin Lesions

Although there is no widely accepted and consistent classification, skin lesions in neonates may present as papules, plaques, patches, pustules, vesicles, bullae, erosions, or ulcerations. The most common presentation 200

Division of Pediatric Dermatology, Children's Memorial Hospital, Chicago, IL. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL. Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL. Reprint requests and correspondence: Anthony J. Mancini, MD, Division of Pediatric Dermatology, 2300 Children's Plaza #107, Chicago, IL 60614. (E-mail: amancini@northwestern.edu) 1522-8401/$ see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cpem.2008.06.010

Neonatal skin disorders and the emergency medicine physician

Table 1 Causes of vesiculopustular skin eruptions in neonates.

201

Noninfectious Erythema toxicum neonatorum Miliaria (prickly heat) Neonatal acne Eosinophilic pustular folliculitis Acropustulosis of infancy Transient neonatal pustular melanosis Langerhans cell histiocytosis Incontinentia pigmenti Infectious Bacterial Staphylococcus aureus Streptococcus pyogenes/other streptococci Pseudomonas aeruginosa Listeria monocytogenes Aspergillus infection Viral Herpes simplex virus Varicella zoster virus Cytomegalovirus Fungal Candida albicans Infestations Scabies (Sarcoptes scabiei ) infestation
Adapted from Curr Opin Pediatr. 1997;9:396-405 and Gilliam et al [2].

Figure 1 Erythema toxicum neonatorum. Blotchy erythematous wheals, papules, and papulopustules in a newborn.

performed and usually reveals abundant eosinophils. Peripheral eosinophilia may be seen in 15% to 18% of patients [5]. Erythema toxicum neonatorum usually resolves spontaneously over several days, and no treatment is required.

Miliaria
Miliaria is commonly seen during the first few weeks of life and is due to eccrine (sweat) duct obstruction. Predisposing factors include excessive warming in incubators, fever, warm clothing, and overswaddling. Two types of miliaria can occur in neonates, depending on the level of obstruction. In miliaria crystallina, the obstruction is very superficial, at the level of stratum corneum, which results in accumulation of sweat beneath it. Clinically, it presents as fragile, tiny, superficial, clear vesicles resembling water droplets that can easily be wiped away. Miliaria rubra, more commonly known as prickly heat and representing the most common form of miliaria, is due to obstruction of the sweat duct at the mid epidermis. Clinically, tiny erythematous papules, vesicles or papulopustules are present. Although miliaria can occur anywhere on the body surface, it is most common on occluded surfaces and in intertriginous areas. Treatment for miliaria is supportive, with avoidance of overheating, tepid to cool baths, and use of air conditioning when feasible [1,5].

Vesiculopustular Disorders
Erythema Toxicum Neonatorum
Erythema toxicum neonatorum is the most common cause of vesiculopustular lesions in neonates [3-5]. This benign, self-limited condition is usually seen in full-term infants and appears 24 to 72 hours after birth, although it occasionally exhibits a delayed onset. Erythema toxicum neonatorum presents as erythematous macules, wheals, papules, and pustules, which may involve the face, trunk, and proximal extremities (Figure 1). The palms and soles are usually spared. The blotchy erythema commonly waxes and wanes, similar to an urticarial eruption. Erythema toxicum neonatorum is diagnosed on a clinical basis, but if there is a question, a smear of pustular contents can be
Table 2 Conditions associated with neonatal skin erythema and scaling. Seborrheic dermatitis Atopic dermatitis Diaper dermatitis Nutritional/metabolic disorders Ectodermal dysplasia Immunodeficiency Collodian baby/ichthyoses Psoriasis Neonatal lupus erythematosus Congenital/neonatal candidiasis

Neonatal Acne
Neonatal acne is seen in up to 20% of newborns [1]. It begins during the first few weeks of life and is believed to be related to the effects of maternal hormones on the newborn sebaceous glands. Malassezia species have also been hypothesized as a possible cause, in which case the eruption has been termed neonatal cephalic pustulosis [6,7]. Neonatal acne presents with erythematous papules and pustules limited usually to the face. Comedones are characteristically absent. Mild cases do not require therapy, and the process usually resolves spontaneously by 3 to

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eosinophils. Although the etiology is unclear, a postscabies hypersensitivity phenomenon may be responsible of IA in some patients [9]. Treatment for IA includes use of antihistamines and potent topical corticosteroids during flare-ups. The flares of IA become less frequent and less intense until the process resolves completely, usually by 3 years of age [9].

Transient Neonatal Pustular Melanosis

Transient neonatal pustular melanosis (TNPM) is an uncommon benign neonatal skin disorder, seen primarily in black infants. It often presents in the immediate postnatal period and is characterized by vesiculopustules without associated erythema, which helps to distinguish it from more concerning vesiculopustular disorders such as herpes, varicella, Candida or staphylococcal/streptococcal infection. The pustules of TNPM (which contain primarily neutrophils) rupture easily, leaving behind hyperpigmented macules which may be surrounded by a characteristic collarette of scale (Figure 3) and may persist for several weeks to months. The most commonly affected sites include the forehead, chin, neck, upper chest, and back. The palms and soles may also be involved. Some infants with TNPM may present only with hyperpigmented macules, and it is assumed that the pustules ruptured in utero in these patients. No therapy is required [1,5,8].

Figure 2 Infantile acropustulosis. Tense, pruritic pustules on the plantar and medial foot of a 3-month-old male.

6 months of age [1,8]. More severe cases may be treated with low strength (ie, 2.5%) benzoyl peroxide gel or topical erythromycin. In patients where Malassezia is playing a pathogenic role, topical antifungal agents may speed resolution of the lesions [1].

Acropustulosis of Infancy
Acropustulosis of infancy (or infantile acropustulosis [IA]) is a pustular disorder characterized by recurrent crops of intensely pruritic, vesiculopustular lesions on the acral extremities. Lesions most often occur on the palms and soles (Figure 2), with occasional extension to dorsal surfaces as well as the wrists and ankles. Infantile acropustulosis can begin at any point between birth and the first year of life. Similar to eosinophilic pustular folliculitis, the lesions of IA tend to occur in crops and may wax and wane. However, pustular smears from patients with IA show mainly neutrophils, with occasional

Impetigo
Impetigo is the most common bacterial skin infection in children, and it may occur in neonates as early as the first few days of life. It occurs in 2 forms: bullous and nonbullous [10,11]. Both Staphylococcus aureus and Streptococcus pyogenes can cause nonbullous impetigo, whereas most cases of bullous impetigo are caused by S aureus. Nonbullous (also known as crusted) impetigo presents with erythematous papules and vesicles with a

Figure 3 Transient neonatal pustular melanosis. Peripheral collarettes of scale mark areas of ruptured pustules in this newborn. Note the associated hyperpigmented macules.

Figure 4 Bullous impetigo. Flaccid and ruptured bullae, with the characteristic peripheral collarette of the blister roof.

Neonatal skin disorders and the emergency medicine physician

honey-colored crust [10]. It is the lesser common form in neonates. Bullous impetigo, which can be considered a localized form of staphylococcal scalded skin syndrome (SSSS), is caused by infection with an epidermolytic toxinproducing strain of S aureus. Clinically, it presents with fragile vesicles and bullae which rupture easily to form superficial erosive patches surrounded by a pathognomonic peripheral remnant of the blister roof (Figure 4) [12]. Common locations include the diaper, periumbilical, and intertriginous regions. A subset of bullous impetigo is staphylococcal pustulosis, which presents with fragile pustules with surrounding erythema that also rupture easily and leave a denuded erythematous macule with a peripheral rim of scale. Possible complications of neonatal impetigo include cellulitis, osteomyelitis, septic arthritis, pneumonia, and bacteremia. The diagnosis can be confirmed by Gram stain and culture, and treatment consists of an appropriate antimicrobial agent [10-12].

203

Figure 5 Congenital candidiasis of the nails. Yellow discoloration, ridging and periungal erythema were the only manifestations of congenital candidiasis in this newborn boy. Note the distal nail plate separation.

Neonatal Herpes
Neonatal herpes is one of the most potentially severe infections of the infant and occurs in 1 in 20 000 to 1 in 3000 live births [13]. It is usually caused by herpes simplex virus type 2 and results from vertical transmission from an infected mother or via acquisition from passage through an infected birth canal [14]. Neonates can also acquire herpes infection postnatally by direct contact with infected persons. The risk of transmission of herpes to the newborn is higher with primary maternal genital infection (up to 50% transmission rate) than with recurrent infection (2%5%) [15,16]. Neonatal herpes occurs in 3 traditional forms: (i) skin, eyes, and mouth disease; (ii) central nervous system infection; and (iii) disseminated herpes. Skin, eyes, and mouth disease is seen in 40% of patients [17], although infants with this presentation may often progress to more disseminated involvement. Skin lesions may be present in roughly 77% and 60% of the infants with disseminated and central nervous system infection, respectively [18]. Neonatal herpes skin lesions present as erythematous macules and discrete or grouped vesicles on an erythematous base. The vesicles may transition to pustules over 1 to 2 days, and a more diffuse, vesiculobullous, and erosive dermatitis may also be noted in some patients. The lesions of neonatal herpes occur most commonly on the scalp and face and may also reveal a predominance in the region of the presenting part(s) [18]. Early recognition, prompt confirmation of diagnosis, and institution of therapy are crucial. Options for confirming the diagnosis from skin lesions include obtaining scrapings for a Tzanck smear, direct fluorescent antibody test, and/or viral culture. The direct fluorescent antibody, if available, is highly sensitive and specific and has the added advantage of a rapid turnaround (ie, hours) for results [19]. Viral cultures should also be obtained on blood, conjunctivae, nasopharynx, cerebrospinal fluid, and urine, and polymerase chain reaction studies of cerebrospinal fluid are now a standard component of the evaluation. High-dose parenteral acyclovir (60 mg/kg per day) is the treatment of choice for neonatal herpes [20].

Congenital and Neonatal Candidiasis

In congenital candidiasis, lesions present between birth and 1 week of age, whereas in neonatal candidiasis, they present after 1 week of age. Congenital cutaneous candidiasis is acquired in utero and results from ascending infection with Candida albicans (and rarely other Candida species). Risk factors include premature labor, history of maternal vulvovaginitis, and presence of intrauterine foreign devices (such as cervical cerclage or intrauterine device). Invasive perinatal procedures and instrumentation, as well as extremely low birth weight, may predispose to more severe, disseminated forms of congenital candidiasis [21-23]. Congenital cutaneous candidiasis presents with scattered erythematous macules, papules, and papulopustules, which often number in the hundreds. Relative sparing of the diaper area is common, and oral thrush is rarely noted. Palm and sole involvement are commonly seen, and nail changes (yellow discoloration, ridging, and periungal erythema, Figure 5) are frequently present. Diffuse desquamation may eventually become more prominent, as the multiple pustules begin to rupture. Term infants without other risk factors tend to do well, often with infection limited to the skin [8,24]. However, in premature infants, dissemination is more likely. One notable population is extremely low-birth-weight infants, in whom widespread erosive changes and burn-like redness may occur in what has been termed invasive fungal dermatitis [25]. These infants are at high risk for invasive disease, including fungemia, urinary tract infection, and meningitis.

204 The diagnosis of congenital candidiasis can be made with a bedside scraping and potassium hydroxide microscopic examination, which reveals budding spores and pseudohyphae. Fungal culture from intact pustules or other tissues can further confirm the diagnosis, and the findings of abscesses or funisitis on placental examination may also be useful. Topical antifungal agents often suffice in term infants with congenital cutaneous candidiasis and no risk factors for dissemination. Newborns with disseminated candidiasis or with known risk factors for disseminated disease require systemic antifungal therapy [26]. Neonatal candidiasis, which is seen after the first week of life, is usually acquired by passage through an infected maternal birth canal. It presents most often as oral thrush or diaper dermatitis but may also be associated with more severe or disseminated disease in newborns with other risk factors. Oral thrush is characterized by curd-like, white membranous patches on the tongue and oral mucous membranes. It can be confirmed by gentle scraping with a tongue blade, which reveals a friable erythematous mucosa underlying the removed patch [8]. Other vesiculopustular disorders which are not discussed here, and which may be seen in neonates, include EPF and neonatal scabies.

G. Sethuraman, A.J. Mancini

Disorders Presenting With Bullae, Erosions, and Ulcerations

Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded skin syndrome is a toxin-mediated blistering disease caused by S aureus [12,27-29]. The blisters are caused by epidermolytic toxins which separate the epidermal cells via specificity for the adhesion molecule desmoglein 1 [29]. Staphylococcal scalded skin syndrome begins with localized infection, usually around the umbilicus, perioral region (Figure 6A), conjunctivae, or perineum. Toxin is produced at the primary site of infection and then spreads in a hematogenous fashion, mediating the disease process at distant (nonprimary) sites. Clinically, it is characterized by widespread erythema associated with superficial fragile blisters (Figure 6B) and tender denudation. There is a predilection for the flexures, and radial crusting and fissuring around the mouth, nose, and ears may be noted. However, the oral mucous membranes are characteristically spared in SSSS. Accompanying symptoms include fever, irritability, decreased feeding, and lethargy [12]. The diagnosis of SSSS is often a clinical one, although the organism may be isolated in cultures of primary sites of cutaneous infection, the conjunctivae, the nasopharynx, or the blood. Although SSSS may be mild in older children, it tends to be a severe process in affected neonates and can be associated with significant morbidity or even mortality. Outbreaks of SSSS have been reported
Figure 6 Staphylococcal scalded skin syndrome. This infant had initial infection characterized by perioral, perinasal and periorbital erythema with crusting (A). The ruptured, superficial blister on the toe (B) was one of the earliest manifestations of his generalized disease and is mediated by hematogenous spread of toxin.

in intensive care nurseries [30]. Treatment with a parenteral antistaphylococcal agent is indicated, along with meticulous wound care, pain control, and attention to fluid and electrolyte status.

Epidermolysis Bullosa
Epidermolysis bullosa (EB) is a group of inherited blistering diseases caused by mutations in different genes encoding the various structural proteins of the cutaneous basement membrane zone. The key feature in all forms of EB is the formation of blisters following abrasional skin trauma [31]. Depending on the level of blistering, EB is divided into 3 types: EB simplex (epidermolytic EB), junctional EB, and dystrophic (or dermolytic) EB [31-35]. Neonates presenting with EB often have mucocutaneous blisters and erosions at the time of birth or shortly thereafter. Some may be born with large areas of denuded skin (congenital localized

Neonatal skin disorders and the emergency medicine physician

205 secondary infections, severe dental caries, and increased risk for squamous cell carcinoma [32]. Treatment for all forms of EB is primarily supportive, with attention to wound care, treatment of secondary infections, nutritional support, pain control, and psychologic support [36]. Prenatal diagnosis for subsequent pregnancies is available for all forms of EB [31].

Vascular Birthmarks
Vascular birthmarks are divided into vascular tumors and vascular malformations (Table 3). Vascular tumors are proliferative neoplasms of the vasculature, the most common of which is the infantile hemangioma. Vascular malformations represent developmental anomalies of blood vessels without any proliferative changes and may include capillary, venous, lymphatic and/or arterial elements [37,38]. Infantile hemangiomas and capillary malformations are briefly discussed here.

Figure 7 Epidermolysis bullosa. This newborn female presented with congenital localized absence of skin. She was found to have recessive dystrophic epidermolysis bullosa, based on evaluation of skin biopsy with immunomapping studies.

Infantile Hemangiomas
absence of skin or CLAS) (Figure 7). The subtype of EB cannot be confirmed based on clinical examination alone and requires studies such as skin biopsy with immunofluorescence mapping, electron microscopy, and/ or mutation analysis. Epidermolysis bullosa simplex is the mildest and the most common form of EB. There are several different subtypes of this autosomal dominant disorder, including Weber-Cockayne (with blisters primarily occurring in an acral distribution), Koebner, and Dowling-Meara, among others. Weber Cockayne is the most common variant of EB simplex. In the more severe form, Dowling-Meara EB, the blisters are widespread and large, may occur in a grouped pattern (hence, the other name, EB herpetiformis), and may be associated with significant oral and esophageal mucosal involvement. Epidermolysis bullosa simplex lesions tend to heal without scarring, given the superficial plane of the blistering [32,33]. Junctional EB is an autosomal recessive form which tends to be more severe. There are 3 major types, including the Herlitz form, the non-Herlitz form, and junctional EB with pyloric atresia. The Herlitz form of junctional EB is the most severe, with death often occurring by 2 years of age. Junctional EB often involves the nails, mucous membranes, and dental enamel. Affected sites often reveal atrophy and scarring, and growth retardation is common in those who survive the neonatal period [32]. Dystrophic EB can be either dominantly (dominant dystrophic EB) or recessively (recessive dystrophic EB) inherited. Both of these forms are associated with scarring and milia (tiny white cyst) formation. Dominant dystrophic EB is the more mild form, whereas recessive dystrophic EB is a severe variant characterized by widespread mucocutaneous disease, mitten-hand deformities, growth failure, recalcitrant anemia, esophageal stenosis, Infantile hemangiomas (IH) represent the most common benign skin/soft tissue tumor in children. They often begin to become evident during the first few weeks of life, although they may occasionally be congenital. They occur in superficial, deep, or mixed patterns. Superficial hemangiomas are bright red and grow out from the surface of the skin, whereas deep hemangiomas present as partially compressible nodules with an overlying bluish hue, venous prominence, and/or telangiectasia. In mixed lesions, both superficial and deep components are seen. Infantile hemangiomas undergo 3 phases in their natural history: the proliferative phase (from birth to approximately 10-12 months of age; this is the period of active growth), the plateau phase (a period of stability, usually occurring between 12 and 18 months of age), and the involution phase (spontaneous resolution, which occurs over the following 5-10 years). Most hemangiomas do not require therapy [37]. Congenital hemangiomas may represent a typical IH with early onset, or one of 2 distinct subtypes. The noninvoluting congenital hemangioma presents as a blue nodule or tumor with coarse surface telangiectasias and a surrounding
Table 3 The classification of vascular birthmarks. Vascular malformations Capillary malformation Nevus simplex (salmon patch) Nevus flammeus (port wine stain) Venous malformation Lymphatic malformation Arteriovenous malformation Combined lesions Capillary-venous Capillary-lymphatic-venous

Vascular tumors Infantile hemangioma Tufted angioma Kaposiform hemangioendothelioma Pyogenic granuloma Hemangiopericytoma

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Nevus flammeus (or portwine stain [PWS]), is a congenital CM that presents as a pink or bright red vascular patch. These lesions may occur as an isolated skin finding or in association with a variety of syndromes. Portwine stain has a static course during the first few years but may darken progressively over a period of many years and rarely develops secondary proliferative blebs. Syndrome associations include SturgeWeber syndrome (V1 PWS in combination with glaucoma, leptomeningeal angiomatosis, and seizures), Klippel-Trenaunay syndrome (PWS, venous varicosities, and soft tissue/bony overgrowth; usually involves an extremity), Proteus syndrome (PWS, epidermal nevi, palmoplantar cerebriform hyperplasia, lipomas, macrodactyly, and hemimegalencephaly), and Cobb syndrome (dermatomal PWS with corresponding spinal cord vascular malformation) [40].

Figure 8 Non-involuting congenital hemangioma. This lesion is characterized by a blue hue, peripheral pallor, and coarse surface telangiectasias.

rim of pallor (Figure 8). These lesions persist indefinitely without spontaneous involution. The rapidly involuting congenital hemangiomas may present in a variety of patterns and is characterized by very rapid involution in early life, often with residual skin atrophy [37]. Infantile hemangiomas in certain locations may be associated with complications, including functional compromise, ulceration, bleeding, psychosocial concerns (later in life), and internal disease. Potentially concerning distribution patterns include the periocular, nasal tip, lip, anogenital, and ear regions. In addition, extensive and large (segmental) hemangiomas, those in a facial beard distribution, and large facial or lumbosacral lesions may have extracutaneous associations [37,38]. PHACES (Posterior fossa malformation, Hemangioma, Arterial anomalies, Cardiac defects and aortic Coarctation, Eye abnormalities, Sternal clefting and Supraumbilical abdominal raphe) syndrome (MIM 606519) refers to the constellation of extensive facial IH in association with defects in other systems, including the eyes, brain, heart, and arteries [39]. In addition, infants with multiple hemangiomas (ie, N5) are at risk for internal hemangiomatosis, most commonly involving the liver and gastrointestinal tract. Children with any of these forms of IH should be promptly referred to a specialist familiar with their evaluation and therapy [37,38].

Pigmented Birthmarks
Mongolian Spot
Mongolian spots represent nevomelanocytes in the dermis, which underwent an arrest in migration from the neural crest to the epidermis. They are seen in most black infants and become proportionately less common with lighter skin types. They present as blue-to-gray patches, most often distributed over the buttocks and sacrum and occasionally more widespread. These benign lesions usually resolve spontaneously over the first few years of life. Extensive Mongolian spots have been reported in association with GM1 gangliosidosis type 1, Hunter syndrome, and Hurler syndrome [41,42].

Nevus of Ota
Nevus of Ota is a periorbital dermal melanocytosis, which is congenital in 50% of the patients [3]. It presents as irregular, gray-to-blue macules and patches of the periorbital region, temple, forehead, and malar region. It is usually unilateral, and ophthalmic involvement may be noted as bluish and patchy discoloration of the sclera. Malignant degeneration (melanoma) is rarely reported, and therapy is quite difficult, although laser treatment may improve the appearance [43]. Nevus of Ito is a similar dermal melanocytosis seen in the supraclavicular, scapular, and deltoid regions.

Capillary Malformations
Capillary malformations (CM) are the most common type of vascular malformation. The nevus simplex (salmon patch) is, by far, the most common vascular lesion of infancy. These dull red pink macules and patches are most common on the glabella, superior eyelids, and inferior scalp. No treatment is necessary for these benign lesions, and most resolve spontaneously over several years. The exception is the inferior scalp CM (stork bite), which may persist indefinitely [40].

Cafe Au Lait Macules

Caf au lait macules are epidermal pigmented macules seen in 0.3% to 18% of neonates [3]. They present as light tan to brown, round, or oval macules and patches and can occur anywhere on the body. Their size may vary from a few millimeters to several centimeters. Most often, caf au lait macules are sporadic and are not associated with a syndrome. However, multiple lesions may be associated with neurofibromatosis (requires 6 lesions measuring

Neonatal skin disorders and the emergency medicine physician

over 5 mm in the prepubertal child and accompanied by at least one other type 1 neurofibromatosis diagnostic feature), McCune-Albright syndrome (usually large unilateral lesions with a sharp respect for the midline, in association with precocious puberty and bony fibrous dysplasia), and other rare disorders [44].

207

Disorders Presenting With Skin Erythema and Scaling

There are several disorders which may present with skin erythema and scaling (Table 2). A few of these disorders are discussed here.

Atopic Dermatitis
Atopic dermatitis (AD) is an extremely common skin disorder, affecting an estimated 17% of all children in the United States [45]. Children with AD often have an atopic familial predisposition, as well as an increased risk for other atopic disorders including allergic rhinoconjunctivitis, asthma, and food allergy. Atopic dermatitis is often the initial manifestation of the atopic march to these other atopic diseases [46]. In neonates and infants, AD presents as scaly, erythematous patches and plaques of the extensor surfaces of the extremities, the trunk and the face (especially cheeks). Oozing and crusting may be present. When facial involvement is diffuse, the nose and perinasal areas are often spared, a pathognomonic finding termed the headlight sign. The diaper area is characteristically spared, and pruritus is a consistent feature. Scalp involvement may be present, and the areolae may be edematous, scaly, and crusted. It may be difficult to distinguish seborrheic dermatitis from atopic dermatitis in the infant; however, involvement of the diaper and umbilical areas favor the former. Characteristic antecubital and popliteal accentuation of AD is seen later, usually during the toddler years [46,47]. Secondary superinfection with S aureus is very common in AD and usually presents with pustules and crusts (although the classic honey color is often lacking). Other infections which may occur with increased frequency include herpes simplex virus (eczema herpeticum), molluscum contagiosum, and warts. The management of neonatal/infantile AD includes brief daily baths, emolliation, topical corticosteroids (usually low-potency, occasionally mid-potency for more severe nonfacial, nonfold areas), and oral antihistaminic agents for control of pruritus. Secondary infection, when present, should be treated as well [46,47].

Figure 9 Neonatal lupus erythematosus. Erythematous, slightly scaly, annular plaques on sun-exposed areas of the face and scalp. Early recognition of this condition is vital, given the potential association with congenital heart block.

eclabium, ectropion, and distortion of the ear helices. This presentation may occur in association with a variety of disorders. The membrane is gradually shed over days to weeks but should be allowed to do so spontaneously in the setting of a humidity-controlled isolette. Potential complications for collodion babies include respiratory distress (secondary to chest restriction), fluid loss, electrolyte imbalances, and temperature instability. The majority of collodion babies turn out to have a form of ichthyosis termed nonbullous congenital ichthyosiform erythroderma. Other disorders which may present as a collodion baby include lamellar ichthyosis, X-linked recessive ichthyosis, Netherton syndrome, ectodermal dysplasia, and Gaucher disease. Occasionally, the skin appears and remains normal after shedding of a collodion membrane [48].

Neonatal Lupus Erythematosus

Neonatal lupus erythematosus (NLE) is an acquired disorder caused by transplacental transfer of maternal antibodies against the RNA proteins (Ro/SS-A and La/ SS-B). A minority of affected infants have antibodies against U1 ribonucleoprotein. The risk of infants having NLE is 1% to 20% in mothers with anti Ro/La antibodies [49,50]. The skin is involved in approximately 50% of infants, and these changes may be present at birth or develop within the first few weeks of life [49,50]. Neonatal lupus erythematosus presents with erythematous, slightly scaly patches, which may also reveal subtle atrophy and/or telangiectasia. The patches may be annular (ie, have central clearing) and prominent involvement of the periorbital areas may lead to the appearance of raccoon eyes (Figure 9). The face, head and neck are most commonly involved. The importance of prompt recognition of NLE is its association with irreversible congenital heart block, of which it is the most common

Collodion Baby/Ichthyoses
The term collodion baby refers to a newborn who is born encased in a shiny membrane that covers the entire skin surface. Its presence may result in flexion contractures,

208 cause. Transient liver involvement and hematologic cytopenias may also occur [51]. Mothers of infants with NLE have an increased risk of systemic lupus erythematosus, Sjogren syndrome, and mixed connective tissue disease, as well as a recurrence risk of 25% for NLE (especially the heart block) in future pregnancies [52].

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of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N Engl J Med 1987;316:240-4. Handsfield HH, Waldo AB, Brown ZA, et al. Neonatal herpes should be a reportable disease. Sex Transm Dis 2005;32:521-5. Friedlander SF, Bradley JS. Viral infections. In: Eichenfield L, Frieden IL, Esterly NB, editors. Neonatal Dermatology. 2nd ed. London: Saunders Elsevier; 2008. p. 195. Pouletty P, Chomel JJ, Thouvenot D, et al. Detection of herpes simplex virus in direct specimens by immunofluorescence assay using a monoclonal antibody. J Clin Microbiol 1987;25:958-9. Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of highdose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 2001;108:230-8. Hernandez-Machin B, Reyes CS, Vargas MM, et al. Picture of the month: congenital cutaneous candidiasis. Arch Pediatr Adolesc Med 2007;161:907-8. Gibney MD, Siegfried EC. Cutaneous congenital candidiasis: a case report. Pediatr Dermatol 1995;12:359-63. Darmstadt GL, Dinulos JG, Miller Z. Congenital cutaneous candidiasis: clinical presentation, pathogenesis, and management guidelines. Pediatrics 2000;105:438-44. Aldana-Valenzuela C, Morales-Marquec M, Castellanos-Martnez J, et al. Congenital candidiasis: a rare and unpredictable disease. J Perinatol 2005;25:680-2. Rowen JL, Atkins JT, Levy ML, et al. Invasive fungal dermatitis in the b or = 1000-gram neonate. Pediatrics 1995;95:682-7. Heukelbach J, Feldmeier H. Scabies. Lancet 2006;367:1767-74. Yamasaki O, Yamaguchi T, Sugai M, et al. Clinical manifestations of staphylococcal scalded-skin syndrome depend on serotypes of exfoliative toxins. J Clin Microbiol 2005;43:1890-3. Faden H. Neonatal staphylococcal skin infections. Pediatr Infect Dis J 2003;22:389. Nishifuji K, Sugai M, Amagai M. Staphylococcal exfoliative toxins: molecular scissors of bacteria that attack the cutaneous defense barrier in mammals. J Dermatol Sci 2008;49:21-31. El Helali N, Carbonne A, Naas T, et al. Nosocomial outbreak of staphylococcal scalded skin syndrome in neonates: epidemiological investigation and control. J Hosp Infect 2005;61:130-8. McGrath JA, Mellerio JE. Epidermolysis bullosa. Br J Hosp Med (Lond) 2006;67:188-91. Bruckner AL. Epidermolysis bullosa. In: Eichenfield L, Frieden IL, Esterly NB, editors. Neonatal dermatology. 2nd ed. London: Saunders Elsevier; 2008. p. 159-73. Uitto J, Richard G. Progress in epidermolysis bullosa: genetic classification and clinical implications. Am J Med Genet 2004;131: 61-74. Fine JD, Eady RAJ, Bauer EA, et al. Revised classification system for inherited epidermolysis bullosa: report of the second International Consensus meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad Dermatol 2000;42:1051-2. Uitto J. Molecular diagnostics of epidermolysis bullosa: novel pathomechanisms and surprising genetics. Exp Dermatol 1999;8: 92-5. Bello YM, Falabella AF, Schachner LA. Management of epidermolysis bullosa in infants and children. Clin Dermatol 2003;21:278-82. Bruckner AL, Frieden IJ. Hemangiomas of infancy. J Am Acad Dermatol 2003;48:477-93. Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med 1999;341:173-81. Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol 1996;132:307-11. Mancini AJ. Vascular disorders of infancy and childhood. In: Paller AS, Mancini AJ, editors. Hurwitz Clinical Pediatric Dermatology. 3rd ed. London: Elsevier; 2006. p. 322-31.

17. 18.

19.

When To Worry About Immunodeficiency

Skin eruptions may be the presenting feature for various forms of immunodeficiency. In this setting, patients may present with atopic- or seborrheic-like dermatitis, erythroderma, and/or severe intertrigo (redness in the fold areas). In addition, cutaneous infections may also point to an underlying immune defect, especially those that are severe or which are caused by unusual organisms. Clues to underlying immunodeficiency include severe and recalcitrant skin eruptions, poor response to therapy, cutaneous graft versus host disease on histologic examination (when skin biopsy is performed), and recurrent infection. In addition, growth failure, diarrhea, recurrent sinopulmonary infections, and alopecia may be other salient features.
20.

21.

22. 23.

24.

25. 26. 27.

References
1. Wagner A. Distinguishing vesicular and pustular disorders in the neonate. Curr Opin Pediatr 1997;9:396-405. 2. Gilliam AE, Pauporte M, Frieden IJ. Vesiculobullous and erosive diseases in the newborn. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. 2nd ed. New York, NY: Elsevier; 2008. p. 475-8. 3. Conlon JD, Drolet BA. Skin lesions in the neonate. Pediatr Clin North Am 2004;51:863-88. 4. Nanda S, Reddy BS, Ramji S, et al. Analytical study of pustular eruptions in neonates. Pediatr Dermatol 2002;19:210-5. 5. Van Praag MC, Van Rooij RW, Folkers E, et al. Diagnosis and treatment of pustular disorders in the neonate. Pediatr Dermatol 1997;14:131-3. 6. Niamba P, Weill FX, Sarlangue J, et al. Is common neonatal cephalic pustulosis (neonatal acne) triggered by Malassezia sympodialis? Arch Dermatol 1998;134:995-8. 7. Johr RH, Schachner LA. Neonatal dermatologic challenges. Pediatr Rev 1997;18:86-94. 8. Smolinski KN, Shah SS, Honig PJ, et al. Neonatal cutaneous fungal infections. Curr Opin Pediatr 2005;17:486-93. 9. Mancini AJ, Frieden IJ, Paller AS. Infantile acropustulosis revisited: history of scabies and response to topical corticosteroids. Pediatr Dermatol 1998;15:337-41. 10. Martin JM, Green M. Group A streptococcus. Semin Pediatr Infect Dis 2006;17:140-8. 11. Sandhu K, Kanwar AJ. Generalized bullous impetigo in a neonate. Pediatr Dermatol 2004;21:667-9. 12. Stanley JR, Amagai M. Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N Engl J Med 2006;355: 1800-10. 13. Gupta R, Warren T, Wald A. Genital herpes. Lancet 2007;370:2127-37. 14. Gardella C, Handsfield HH, Whitley R. Neonatal herpesthe forgotten perinatal infection. Sex Transm Dis 2008;35:22-4. 15. Brown ZA, Vontver LA, Benedetti J, et al. Effects on infants of a first episode of genital herpes during pregnancy. N Engl J Med 1987;317: 1246-51. 16. Prober CG, Sullender WM, Yasukawa LL, et al. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time

28. 29.

30.

31. 32.

33.

34.

35.

36. 37. 38. 39.

40.

Neonatal skin disorders and the emergency medicine physician

41. Ochiai T, Suzuki Y, Kato T, et al. Natural history of extensive Mongolian spots in mucopolysaccharidosis type II (Hunter syndrome): a survey among 52 Japanese patients. J Eur Acad Dermatol Venereol 2007;21:1082-5. 42. Mendez HM, Pinto LI, Paskulin GA, Ricachnevsky N. Is there a relationship between inborn errors of metabolism and extensive Mongolian spots? Am J Med Genet 1993;47:456-7. 43. Taeb A, Boralevi F. Hypermelanoses of the newborn and of the infant. Dermatol Clin 2007;25:327-36. 44. Korf BR. Diagnostic outcome in children with multiple caf au lait spots. Pediatrics 1992;90:924-7. 45. Laughter D, Istvan JA, Tofte SJ, et al. The prevalence of atopic dermatitis in Oregon schoolchildren. J Am Acad Dermatol 2000;43:649-55. 46. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol 2003;112(6 Suppl):S118-27.

209
47. Eigenmann PA. Clinical features and diagnostic criteria of atopic dermatitis in relation to age. Pediatr Allergy Immunol 2001;14 (12Suppl):69-74. 48. Van Gysel D, Lijnen RL, Moekti SS, et al. Collodion baby: a follow-up study of 17 cases. J Eur Acad Dermatol Venereol 2002; 16:472-3. 49. Lee LA. Neonatal lupus erythematosus. J Invest Dermatol 1993;100: 9S-13S. 50. Silverman ED, Laxer RM. Neonatal lupus erythematosus. Rheum Dis Clin North Am 1997;23:599-618. 51. Lee LA. Neonatal lupus: clinical features and management. Pediatr Drugs 2004;6:71-8. 52. McCune AB, Weston WL, Lee LA. Maternal and fetal outcome in neonatal lupus erythematosus. Ann Intern Med 1987;106: 518-23.