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2 BASNET et al
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Literate parents signed the consent by trained study assistants who were dened as persistence of LCI or of any
form after they had read a written not otherwise involved in patient care. danger signs present at enrollment
statement in the local Nepali language. The zinc or placebo dispersions were despite 48 hours of treatment or ap-
For parents who were unable to read given as a single daily dose until dis- pearance of new danger signs or hyp-
or write, verbal informed consent was charge or for a maximum of 14 days. All oxia with deterioration of patients
obtained in the presence of a witness. children were observed for vomiting. clinical status anytime after initiation
After obtaining consent, blood was For children who vomited within the of treatment. A decision to change
collected for investigations, and the rst 15 minutes, a repeat dose was antibiotics was made only after con-
rst dose of intravenous antibiotics given. Children who vomited the second sultation with senior pediatricians in-
was administered. This was followed time were given the required amount in volved in the study. For children unable
by collection of nasopharyngeal aspi- 2 divided doses over a 24-hour period to eat/drink or breastfeed, intravenous
rate for identication of 7 respiratory from the next day onward. uids based on daily requirements
viruses. Details of the sampling tech- were initiated.19 Humidied oxygen
nique and the results of these analyses Outcome Denitions was given to children with documented
have been described in a separate The primary outcome, time to cessation hypoxia. During each physician visit,
publication20 of severe pneumonia, was dened as oxygen saturation was documented
the period starting from enrollment after a washout period of 5 minutes
Randomization, Intervention, and oxygen discontinued when they
and Blinding to the beginning of a 24-hour consec-
utive period of absence of LCI, hypoxia, were no longer hypoxic. The absence
The intervention was dispersible tab- and any danger signs. We used WHO of hypoxia was conrmed after a sec-
lets containing 10 mg of elemental zinc guidelines to dene hypoxia (SpO2 of ond reading taken 30 minutes later.
sulfate or placebo, manufactured and ,90%) and danger signs such as in- Study physicians were trained to as-
packed by Nutriset (Malaunay, France) ability to breastfeed or drink, vomit- sess and manage children with severe
in a blister pack with 15 tablets. Tablets ing everything consumed, convulsions, pneumonia, and their performance was
of both groups were identical in pack- lethargy, or unconsciousness.19 The monitored each day by experienced
aging, appearance, and inactive in- secondary outcome, treatment failure, pediatricians, who were also the inves-
gredients with no indication of group was dened as a requirement for tigators for this study. Standardization
identity and content. For each child in change in antibiotics, development of exercises were conducted before the
the study, there were 3 blister packs complications, such as empyema or start of the trial. Each physician was
with zinc or placebo tablets labeled pneumothorax requiring surgical in- assigned to record axillary tempera-
with a serial number to match the child tervention, or admission to the ICU ture, count respiratory rate, observe
study identication number. The ran- for ventilator or inotropic support. for LCI, and listen for wheezing and
domization list linking the treatment crepitations in at least 10 children.
groups to these identication numbers
Cointerventions Their ndings were matched against
was generated by and kept with a per- those of an experienced pediatrician un-
son not otherwise involved in the study. Enrolled children were admitted to
til the desired agreement was reached.
Children were allocated to either of the hospital and monitored by study
the 2 intervention groups by randomi- physicians at 8 hourly intervals un-
zation in blocks of 16 in a 1:1 ratio. til discharge. Benzyl penicillin (50 000 Data Management and Analysis
Randomization was stratied on age U/kg intravenously every 6 hours) and The completed forms with patient data
,12 months or $12 completed months gentamicin (7.5 mg/kg intravenously were collected by the study assistants
and on wheezing status before nebuli- once daily) were given until clinical on a daily basis. All forms were checked
zation. Study physicians selected blis- improvement, dened as absence of manually by 1 of the clinical supervi-
ter packs with the lowest number from danger signs, of hypoxia for 24 con- sors before data entry, which was done
a box specifying the stratum to which secutive hours and of LCI for a 48-hour within 48 hours. The data were double
each child belonged. Children ,12 period. Patients were then discharged entered into a database (Visual FoxPro
months were given 1 tablet and children with advice to continue oral amoxicillin 6.0, Microsoft Corp, Redmond, WA) with
$12 months were given 2 tablets dis- to complete treatment of a total dura- inbuilt logic, range, and consistency
solved in 5 mL of clean water or breast tion of 10 days. checks. Statistical analyses were under-
milk. The rst dose was dispensed by Antibiotics were changed to cefotax- taken by using Stata, version 10 (Stata
the study physician and subsequently ime in children with failure to improve, Corp, College Station, TX). Data cleaning,
4 BASNET et al
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TABLE 1 Baseline Demographic Characteristics of Children aged 2 to 35 Months in a Clinical Trial in reducing time to cessation of severe
Evaluating Efcacy of Zinc as Adjuvant Therapy for Severe Pneumonia
pneumonia dened as a 24-hour con-
Characteristic Zinc Group Placebo Group secutive period of absence of LCI, hyp-
n Value n Value oxia, and any other danger sign.
Mean age in months (SD) 299 7.8 (6.0) 299 7.1 (5.6) In a study undertaken in Bangladesh,7
Age groups (months)
26, n (%) 299 167 (55.9) 299 185 (61.7)
children who received zinc recovered
711, n (%) 299 78 (26.1) 299 63 (21.1) faster, and fewer had treatment fail-
1223, n (%) 299 45 (15.1) 299 45 (15.0) ure and duration of severe pneumonia
2435, n (%) 299 9 (3.0) 299 6 (2.0)
lasting .72, 96, or 120 hours. The re-
Male subjects, n (%) 299 177 (59.2) 299 190 (63.6)
Mean age of mother, y (SD) 292 24.7 (4.2) 294 24.1 (4.1) sults from our trial were in the same
Illiteratea mother (%) 292 79 (27.1) 294 75 (25.5) direction but smaller. Another trial in
Illiteratea father (%) 293 20 (6.8) 295 18 (6.1) South India8 failed to show any bene-
Unemployedb mother (%) 290 205 (70.7) 294 213 (72.5)
Unemployedb father (%) 289 10 (3.5) 291 9 (3.1) cial effect of zinc on duration of illness
Child still breastfeeding 299 283 (94.6) 299 288 (96.3) in young children with severe pneu-
a No schooling with inability to read part or whole of a sentence. monia. In another study from Kolkatta,
b No work/housework.
India,21 although zinc was efcacious in
boys, the overall effect as well as the
TABLE 2 Baseline Clinical Characteristics of Children Aged 2 to 35 Months Enrolled in a Clinical interaction between gender and zinc
Trial on the Efcacy of Zinc as Adjuvant Therapy for Severe Pneumonia
administration was not statistically
Characteristic Zinc Placebo
signicant. All these studies, like our
n Value n Value study, were double-blind randomized
Mean duration of cough in days (SD) 299 4.0 (2.0) 299 4.2 (2.2) controlled trials assessing the efcacy
Mean duration of difculty breathing in hours (SD) 299 30.2 (20.2) 299 29.6 (18.3) of zinc in children with severe pneu-
Mean duration of fever in days (SD) 264 3.5 (2.0) 279 3.5 (2.1)
Wt for length/height #2 z scorea (%) 296 86 (29.1) 298 71 (23.8) monia. Inherent differences in the pop-
Length/height for age #2 z scorea (%) 299 28 (9.4) 299 22 (7.4) ulations studied and differences in the
Mean hemoglobin in g/dL (SD) 299 11.0 (1.4) 299 10.9 (1.4) illness characteristics including pre-
Mean axillary temperature in C (SD) 299 37.7 (0.8) 299 37.7 (0.9)
Febrileb (%) 299 46 (15.4) 299 46 (15.4)
enrollment duration and denition of
Mean respiratory rate in breaths per minute (SD) recovery would explain the discrepancy
211 mo 245 64 (12) 248 65 (12) between studies.
1235 mo 54 60 (13) 51 63 (10)
Mean oxygen saturation (SD) 299 86 (8) 299 87 (9) In the current trial, the proportion of
Oxygen saturation (%) children with wheezing was 82% com-
,90% 299 186 (62.2) 299 187 (62.5)
pared with 37% in the Bangladeshi7
,93% 299 255 (85.3) 299 249 (83.3)
Wheezing (%) 299 244 (81.6) 299 248 (82.9) and 62.5% in the South Indian trial.8
Crepitations (%) 299 273 (91.3) 299 276 (92.3) Because children with reactive airway
Endpoint consolidation on CR 258 60 (23.3) 262 66 (25.2) disease would meet criteria for inclu-
Symptoms of severe pneumonia
Child unable to drink/breastfeed (%) 299 30 (10.0) 299 24 (8.0) sion in our study, we excluded children
History of convulsions (%) 299 1 (0.3) 299 2 (0.7) with a history of recurrent wheezing
Vomiting everything child eats (%) 294 9 (3.1) 292 5 (1.7) and enrolled others only if LCI per-
Child unconscious/lethargic (%) 299 25 (8.4) 299 30 (10.0)
Signs of severe pneumonia sisted after salbutamol administration.
Nasal aring (%) 298 116 (38.9) 299 116 (38.8) Brooks et al reported that in children
Grunting (%) 299 60 (20.1) 299 71 (23.8) without wheezing, administration of zinc
Head nodding (%) 299 65 (21.7) 299 73 (24.4)
Central cyanosis (%) 299 1 (0.3) 299 2 (0.7) resulted in earlier resolution of clinical
a Derived by using the recent WHO Child Growth Standards.17 signs.7 The effect of zinc was not modi-
b Dened as axillary temperature of .38.5C. ed by wheezing status in our subgroup
analysis (Fig 2), a nding similar to that
only marginally. The proportion of chil- DISCUSSION reported from South India.8 However,
dren who vomited after the rst dose This study on zinc as adjunct therapy because there were only 106 children
of supplement was higher (14%) in inchildrenwithseverepneumonia shows without wheezing, we had insufcient
the zinc than in the placebo group (9%; a modest but not statistically signif- power to detect an effect of zinc in this
P = .052). icant effect of daily zinc administration subgroup.
6 BASNET et al
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a measureable effect of zinc. Using CRs an aspect that needs to be taken into and the study physicians for their contri-
to improve the diagnosis enabled us to account when the results from this trial bution to the study aswell as other staff of
identify only 24% with radiographic as well as those of other completed, the Child Health Research Project. We
pneumonia. It is also noteworthy that ongoing, and planned studies are in- thank the director of the Kanti Children
there was signicant benecial effect of terpreted and summarized to deter- Hospital and staff of the Emergency, Ob-
zinc in this subgroup. Future studies are mine the role of zinc in the treatment servation, Acute Respiratory Illness/Oral
needed exploring the role of zinc in se- of severe pneumonia. Rehydration Therapy, Medical, Paying
vere pneumonia in which children with and Special Cabin wards for their invalu-
wheezing are excluded and CR, micro- able support. We also thank the head
biologic, and inammatory markers are ACKNOWLEDGMENTS of the Department of Child Health, Pro-
used in an attempt to arrive at a more The Zinc Severe Pneumonia Study Group fessor Pushpa Raj Sharma, and other
specic diagnosis.24 is: RameswarMan Shrestha, MD; Uday Raj faculty members for their support, the
Upadhaya, DCH; Chandeshwar Mahaseth, Department of Microbiology, Tribhuvan
MRCP; Rojen Sundar Shrestha, DCH; University Teaching Hospital, Kathmandu,
CONCLUSIONS Puja Shrestha, MBBS; Geetika KC, MBBS; for providing the laboratory facilities and
This trial yielded a small but not sta- Yagya Ratna Shakya, MBBS; Ujma Shrestha, Dr Dhiraj Man Shrestha for interpreta-
tistically signicant efcacy estimate MBBS. tion of chest radiographs. We thank Sol-
for zinc in the resolution of severe pneu- We thank all the children and their fam- frid Vikren for excellent administrative
monia in hospitalized 2- to 35-month-old ilies who took part in the study. We are support and Hans Steinsland for gen-
children. All study participants received indebted to eld assistants Mahesh erating the randomization list and main-
optimized antibiotic and other therapies, Kumar Thapa and Ram Krishna Khatri taining it until the end of the study.
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8 BASNET et al
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A Randomized Controlled Trial of Zinc as Adjuvant Therapy for Severe
Pneumonia in Young Children
Sudha Basnet, Prakash S. Shrestha, Arun Sharma, Maria Mathisen, Renu Prasai, Nita
Bhandari, Ramesh K. Adhikari, Halvor Sommerfelt, Palle Valentiner-Branth, Tor A.
Strand and members of the Zinc Severe Pneumonia Study Group
Pediatrics; originally published online March 5, 2012;
DOI: 10.1542/peds.2010-3091
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