Acute Ventilatory Failure

SECTION
MANAGEMENT OF
RESPIRATORY FAILURE
99
ACUTE VENTILATORY FAILURE

NICHOLAS S. HILL, MD
INTRODUCTION
PATHOPHYSIOLOGY OF ACUTE
VENTILATORY FAILURE
ACUTE VENTILATORY FAILURE DUE
TO INSUFFICIENT VENTILATORY
DRIVE
Congenital Causes
Acquired Causes
Pharmacologic Causes
Other Acquired Causes
Principles of Management

TO NEURAL TRANSMISSION
IMPAIRMENT
Cervical Spinal Cord Injury
Motor Neuron Disease
Injury or Disease Affecting the Phrenic
Nerve
Immunologic Neuropathies
Neuromuscular Junction Impairment
Neuromuscular Weakness Associated
with Critical Illness
Assessment of Need for Mechanical
Ventilation in Neuromuscular
Weakness
Principles of Ventilator Management
INTRODUCTION
Respiratory failure exists when the respiratory system
cannot maintain gas exchange, causing dysfunction in
other organs or threatening life. Such impairment primarily
affects oxygenation, manifested by hypoxemia, or affects
ventilation, manifested by hypercapnia and respiratory acidosis. This chapter deals with this latter circumstance, commonly called ventilatory failure.
Carbon dioxide (CO2) tension in the arterial blood (PaCO2)
is a function of alveolar ventilation ( V A ) and CO2 production
( V CO2), according to the following relationship.
PaCO2 = (V CO2 k) / V A
(1)
Total minute ventilation is the sum of both V A and dead
space ventilation. Either a decrease in total minute ventilation or an increase in dead-space ventilation can thus

TO CHEST WALL DEFECTS
Chest Wall Skeletal Abnormalities
Pleural Disease
Principles of Management
TO AIRWAY OBSTRUCTION
Upper Airway Obstruction
Chronic Obstructive Pulmonary Disease
Pathophysiology
Asthma
TO VASCULAR IMPAIRMENT
decrease V A . Any decrease in V A or increase in V CO2 relative to V A results in an increase in arterial PCO2. Because
bicarbonate retention by the kidney in response to hypercapnia is slow, a sudden increase in arterial PCO2 will not be
buffered quickly by bicarbonate and thus will abruptly
lower arterial pH. Ventilatory failure exists whenever arterial PCO2 is substantially elevated, and acute ventilatory
failure is present when the change from the patients baseline state develops rapidly enough to produce a clinically
important drop in arterial pH. Because patients with severe
chronic obstructive pulmonary disease (COPD), chronic neuromuscular disease, and other disorders may already have
hypercapnia at baseline, the presence of a component of
acute (acute-on-chronic) ventilatory failure is determined
not so much by the arterial PCO2 value as by the presence
of acidemia, typically to an arterial pH of less than 7.35.
The presence of acute ventilatory failure cannot be
1723
1724 PART 3 Clinical Respiratory Medicine
Excessive
ventilatory
demand
Inadequate ventilatory
output despite
increased effort
14
Hy
po
ve
60
nt
Figure 99-1 The physiologic mechanisms of acute ventilatory failure.

The two major causes of acute ventilatory failure are either a reduced
ventilatory effort or a reduced ventilatory output despite increased effort.
determined accurately by physical examination, pulse

oximetry, exhaled CO2, or other noninvasive tests. Thus,
making the diagnosis requires arterial blood gas analysis.1
PATHOPHYSIOLOGY OF ACUTE
VENTILATORY FAILURE
Alveolar ventilation becomes inadequate in relation to CO2
production either because of a failure of the patients ventilatory capability (pump failure) or ventilatory effort (drive
failure)2,3 (Fig. 99-1). These two mechanisms are distinct in
their clinical presentations. Patients with acute failure of
the ventilatory pump are dyspneic and tachypneic with
other signs of distress, whereas patients with failure of ventilatory drive are not short of breath and typically demonstrate bradypnea or apnea.
Although acute ventilatory failure is primarily a disorder
of alveolar ventilation, hypoxemia is also usually present.
Alveolar hypoventilation causes a proportional fall in alveolar oxygen pressure (PAO2), according to the alveolar gas
equation.
(2)
where arterial PCO2 is assumed to be nearly the same as

alveolar PCO2, PIO2 is the inspired PO2 (i.e., the inspired
oxygen fraction multiplied by the difference of barometric
pressure and 47 [water vapor pressure at body temperature]), and R is the respiratory exchange ratio. This relationship explains the fall in arterial PO2 that accompanies
alveolar hypoventilation, as shown in Figure 99-2.2 Calculating alveolar PO2 using Equation 2 permits determination
of the alveolar-arterial oxygen pressure difference ((Aa)PO2)
(commonly but imprecisely called the Aa gradient and
more precisely called the Aa oxygen tension difference).
This calculation distinguishes between pure hypoventilation as an explanation for hypoxemia (in which case, (Aa)
PO2 is normal) and the presence of other mechanisms such
ratios and right-to-left
as low ventilation-perfusion (V/Q)
shunt (in which case, (Aa)PO2 is increased).
Finally, hypercapnia can be a feature of hypoxemic
respiratory failure if the derangement in gas exchange is

sufficiently severe. Both right-to-left shunt and low V/Q
ratios are present in the acute respiratory distress syndrome
115
ila
tio
Normal
40
90
tion
tila
rven
e
Hyp
20
Ventilatory
failure
PAO2 = PIO2 (PaCO2 /R)
80
65
PaO2 (mm Hg)
Reduced
ventilatory
effort
Impaired
neuromuscular
function
PaCO2 (mm Hg)
Reduced
drive
40
Figure 99-2 Relationship between arterial PO2 and arterial PCO2. There
is a reciprocal relationship between arterial oxygen pressure (PaO2) and
arterial carbon dioxide pressure (PaCO2) as ventilation increases or
decreases, assuming that the (Aa)PO2 difference does not change and the
respiratory exchange ratio is 0.8. (Redrawn from Pierson DJ, Kacmarek RM,
editors: Foundations of respiratory care. New York, 1992, Churchill Livingstone,
p 298.)
(ARDS) and can increase dead spacetotidal volume ratios

(VD/VT) as determined by the Bohr equation,4 thus impairing CO2 elimination and contributing to hypercapnia.
Table 99-1 classifies the typical clinical presentations of
acute ventilatory failure according to the site or type of
defect and the physiologic mechanism or category of disorder responsible. Not every listed example is discussed in this
chapter.
More than one mechanism may coexist in a given patient,
producing a life-threatening condition even when the individual processes are only moderate in severity. For example,
in decompensated obesity-hypoventilation syndrome, a
patient whose underlying respiratory drive is reduced
and whose obesity poses an increased elastic load on the
ventilatory pump may develop acute-on-chronic ventilatory failure in the presence of a relatively modest increase
in the work of breathing from an additional restrictive effect
of cardiomegaly and pleural effusions.

DUE TO INSUFFICIENT
VENTILATORY DRIVE
CONGENITAL CAUSES
Congenital disorders that may be associated with diminished hypoxic or hypercapnic ventilatory drive include
primary alveolar hypoventilation (or Ondines Curse),5
Prader-Willi syndrome,6,7 hypogonadism treated with exogenous testosterone,8 and Arnold-Chiari malformation.9
These disorders contribute to the development of acute ventilatory failure through diminished ventilator drive, often in
combination with other contributing mechanisms (such
as acute infection), and are most often seen in pediatric
settings.
ACQUIRED CAUSES
Decreased ventilatory drive is a frequent contributor to the
development of chronic ventilatory insufficiency but is
99 Acute Ventilatory Failure 1725
Table 99-1 Clinical Classification of Ventilatory Failure by Site

Site of Defect
Mechanism or Type
Clinical Examples
Ventilatory drive
Congenital
Acquired
Combination
Primary alveolar ventilation (Ondines Curse)

Drug overdose (opioids, sedatives, alcohol); general anesthesia
Cerebrovascular accident; neoplasm; carotid body resection
Obesity-hypoventilation syndrome; myxedema
Trauma
Vascular
Tumor
Other
Demyelinating
Phrenic nerve lesion
Pharmacologic
Autoimmune
Infectious/toxins
Congenital
Autoimmune
Acquired
Cervical spinal cord injury

Vascular accident
Primary or metastatic
Poliomyelitis; amyotrophic lateral sclerosis
Acute idiopathic demyelinating polyneuropathy (Guillain-Barr syndrome)
Trauma; cardiac surgery; neoplasm; idiopathic
Neuromuscular blocking agents
Myasthenia gravis
Botulism, tetanus, tick paralysis
Muscular dystrophy
Polymyositis; dermatomyositis
Hypophosphatemia; hypokalemia; hypomagnesemia; myxedema
Decreased mobility
Extrapulmonary restriction and
decreased mobility
Extrapulmonary restriction
Kyphoscoliosis; tight casts or bandages; ankylosing spondylitis; flail chest

Severe obesity
Obstruction
Obstruction

Increased dead space and very high V/Q
shunt
Very low V/Q;
General hypoperfusion
Epiglottitis, foreign body, tumor, vocal cord paralysis, tracheomalacia

COPD, acute severe asthma
COPD
Severe ARDS
Neural transmission
Spinal cord
Peripheral nerves
Neuromuscular
junction
Ventilatory muscles
Thoracic
Vertebrae and rib cage
Soft tissues
Pleura
Airways
Upper airways
Lower airways
Parenchyma
Pulmonary circulation
Other
Localized hypoperfusion
Increased CO2 production (inflammation;
hypermetabolism; muscle activity)
Exogenous CO2 inhalation
Pneumothorax; pleural effusion; pleural thickening; malignancy
Hypovolemic or cardiogenic shock, CPR, pulmonary hyperinflation

(intrinsic PEEP)
Pulmonary thromboembolism; venous air embolism
Fever; sepsis; burns; severe trauma; shivering; tetany; seizures; malignant
hyperthermia
Laboratory or industrial accident; therapeutic use; rebreathing
ARDS, acute respiratory distress syndrome; CO2, carbon dioxide; COPD, chronic obstructive pulmonary disease; CPR, cardiopulmonary resuscitation; PEEP,
ventilation-perfusion ratio.
positive end-expiratory pressure; V/Q,
typically not the sole mechanism for acute ventilatory

failure, except for those patients presenting with druginduced suppression.
PHARMACOLOGIC CAUSES
Depression of the drive to breathe by drugs is by far the most
common circumstance of this form of acute ventilatory
failure. The opioids are potent depressors of both hypoxic
and hypercapnic ventilatory drive; however, any sedative,
hypnotic, or anxiolytic agent causes respiratory depression
if administered in sufficient quantity.10 Propofol, in particular, is a potent respiratory depressant used commonly for
sedation during procedures or during mechanical ventilation and must be dosed with caution in patients breathing
spontaneously.11 Respiratory depression resolves as the
drug is cleared from the body or is pharmacologically antagonized, as signaled by the return of spontaneous breathing
efforts. Because the central nervous system effects of some
agents may wax and wane due to the enterohepatic circulation, lipid storage, or other mechanisms, patients should be
observed until it is clear that the ventilatory drive has been
reestablished before they are weaned from ventilatory
support. In the case of drug overdoses and other poisoning,
identifying the specific agent or agents involved and the use

of any specific therapies available, such as antidotes or dialysis, is important to expedite the weaning process from ventilatory support.10 Patients who fail to wean from mechanical
ventilation because of inadequate drive from depressant
drugs breathe slowly or not at all when ventilatory support
is briefly discontinued. The much more common reason for
difficulty weaning after drug overdose is that other mechanisms (e.g., aspiration pneumonia or sepsis) intervene. In
these circumstances, with a return of respiratory drive,
patients become tachypneic and manifest signs of respiratory distress when ventilatory support is discontinued.12
OTHER ACQUIRED CAUSES

Myxedema13,14 may present with hypercapnia related to
acquired depression of ventilatory drive, and hypothyroidism may be a cofactor when patients present with worsening hypercapnia. Thyroid function testing should be done
routinely in patients with new or worsening hypercapnia,
especially when a clear physiologic explanation is inapparent. Patients with underlying abnormalities of ventilatory
drive who develop respiratory infections, congestive heart
failure, or other acute illnesses are more likely to develop
acute ventilatory failure compared with individuals without

such defects.
The obesity-hypoventilation syndrome, discussed in
Chapter 89, is characterized by blunted responses to hypoxia
and hypercapnia15 and is one disorder in which patients
may first present in acute ventilatory failure. Typically, such
patients have a history of recent weight gain and are found
to be markedly fluid-overloaded, with features of cor pulmonale. The increased work of breathing from decreased chest
wall compliance, cardiomegaly, and often large pleural effusions, as well as worsening hypoxemia, all contribute to
respiratory muscle fatigue and the development of severe
hypercapnia and respiratory acidosis. Hypoventilation and
acute ventilatory failure related to obesity are more common
among hospitalized patients with severe obesity than has
previously been reported.16,17 As the prevalence of obesity
increases, ventilatory failure from decompensation of the
obesity-hypoventilation syndrome is likely to be encountered more frequently.
Acute stroke is another setting in which disordered ventilatory drive may contribute to acute ventilatory failure,
even though other processes are usually present, especially
the inability to protect the lower airway and to clear respiratory tract secretions.18,19 The prognosis of patients with
ischemic and hemorrhagic strokes who require intubation
and mechanical ventilation is poor both in the short and
long term, with a survival rate of 50% at 30 days and
30% after 1 year.18,20,21 Prognosis is especially unfavorable
after basilar artery occlusion due not only to depressed
respiratory drive but also to the swallowing impairment
and problems with secretion clearance seen with brain
stem injury.22
Although data are not encouraging and the mortality
rate is still high, American Heart Association guidelines
recommend mechanical ventilation for patients with acute
stroke if needed (Level IC).23 Of course, this necessitates an
ethical discussion with the patient and/or family to determine the patients wishes regarding aggressive support (see
Chapter 104).
PRINCIPLES OF MANAGEMENT
Because the underlying physiologic defect is inadequate
ventilatory drive despite a presumably normal ventilatory
pump, management focuses on restoring normal alveolar
ventilation. Although noninvasive ventilation (NIV) is being
applied in an increasing number of clinical settings to
augment alveolar ventilation, its utility lies mainly in maintaining respiration in patients with failure of the ventilatory
pump, whereas endotracheal intubation is generally necessary following acute failure of respiratory drive. NIV can be
quite effective in treating chronic congenital or acquired
central hypoventilation in outpatients, but in the setting of
acute loss of respiratory drive, invasive mechanical ventilation restores alveolar ventilation more rapidly and reliably
and is more effective for airway protection and secretion
clearance than is NIV.
Because of the patients impaired ventilatory drive, a
ventilator mode that provides full support, such as
volume-targeted assist-control ventilation, should initially
be chosen. In the absence of acute lung injury or severe
airflow obstruction, ventilator settings should be chosen to
aim for values of arterial pH and arterial PCO2 in the normal
range, and supplemental oxygen should be supplied (with

positive end-expiratory pressure [PEEP] if necessary) to maintain normal arterial PO2. Unless there are serious coexisting
pulmonary conditions, weaning should be carried out as
soon as there is evidence that ventilatory drive is restored
(see Chapter 101). Extubation is probably safe if the patient
has a spontaneous cough, does not require frequent suctioning, and is judged to be able to protect the airway, even
if alertness remains impaired.24

DUE TO NEURAL TRANSMISSION
IMPAIRMENT (see Chapter 97)
CERVICAL SPINAL CORD INJURY
Injury to the upper cervical spinal cord may interrupt
transmission of the stimulus to breathe from the respiratory
centers in the brain stem to the diaphragm and other ventilatory muscles, depending on the injury level. Because the
phrenic nerve roots that supply the diaphragm arise from
spinal segments C3 to C5, patients with acute injury at this
level or above usually require ventilatory assistance. Patients
with C1C2 spinal injury levels are permanently ventilator
dependent, whereas those with C3C4 injuries may eventually achieve at least partial ventilator independence. Lesions
below C4 are usually compatible with unassisted ventilation unless there are complicating processes such as intrinsic lung disease or impaired mental status.
Adverse physiologic effects can happen within the first
days or weeks after the injury, including loss of lung volumes
and inability to take deep breaths (which predisposes to atelectasis), inability to cough normally (which predisposes to
the development of pneumonia and complicates its management), and impaired hypoxic pulmonary vasoconstriction (which predisposes to severe and often refractory
hypoxemia after atelectasis or pneumonia).25 These physiologic effects depend on the level of injury, being more frequent with lesions above C4, and on the degree of injury,
being more frequent with complete, than with incomplete,
lesions.26
The short-term prognosis of spinal cord lesions is generally related to the level of the injury,25 even though some
retrospective studies have shown that both mortality27,28
and intensive care unit (ICU) length of stay25 are more
strongly influenced by the development of pneumonia and
other respiratory complications than by the specific cord
injury level.
Although there are reports of initial management of
patients with high cervical spinal cord injury (C3-4 or
higher) with NIV,29 great expertise is required to avoid aspiration and other complications. Decisions about NIV should
be made on a case-by-case basis26; in most centers, invasive
ventilatory support is preferable, at least initially. Phrenic
nerve30-32 or diaphragm pacing,33 permitting extubation or
removal of the tracheostomy tube (decannulation), has also
been reported in the later period following injury. The eventual ability to wean from ventilatory support and to undergo
decannulation from tracheostomy are major determinants
not only of survival but also of quality of life for patients
with cervical spinal cord injury.25,27
MOTOR NEURON DISEASE

Amyotrophic lateral sclerosis (ALS) and other motor neuron
diseases demonstrate a variable but progressive weakness
of the bulbar and ventilatory muscles. This progression
determines the course of ventilatory failure and pulmonary
complications, which represent the most common cause of
death in these patients.34,35 Typically, ventilatory muscle
weakness develops gradually after the diagnosis is already
well established; therefore repeated assessments during outpatient evaluation are useful to monitor the progression of
ventilatory muscle impairment.34-38 This permits intervention with NIV or, less often, tracheostomy before the onset
of acute ventilatory failure. However, some cases present
with acute ventilatory failure as the initial manifestation of
the disease.39
Elective initiation of noninvasive ventilation is becoming
a standard of care in motor neuron disease patients with
progressive ventilatory impairment because it improves
both quality of life and survival rate37,38,40 in patients without
significant bulbar involvement. NIV has been successful not
only in the chronic, slowly progressive setting, but also in
acute ventilatory failure complicating ALS.41 However,
bulbar weakness and a high risk of aspiration make invasive
mechanical ventilation a preferred choice for ALS patients
with acute ventilator failure, at least initially. With appropriate counseling about end-of-life planning, only a small proportion of patients with ALS receive invasive mechanical
ventilation, and presentation to an emergency department
with acute ventilatory failure should be unusual.42
INJURY OR DISEASE AFFECTING THE

PHRENIC NERVE
Loss of diaphragm function leading to ventilatory failure is
often due to spinal cord injury, immunologic diseases (such
as Guillain-Barr syndrome or multiple sclerosis), or neuropathy (ALS, Charcot Marie Tooth). Unilateral paralysis of
the diaphragm leading to ventilatory failure may be a result
of phrenic nerve injury or disease. Its presentation ranges
from an incidentally discovered radiographic abnormality
without clinical impact to acute ventilatory failure requiring long-term mechanical ventilation, although the latter
is quite unusual and generally due to multiple factors.31,43
In the past, unilateral diaphragmatic palsy following
phrenic nerve injury was most often caused by cold cardioplegia during open-heart surgery or direct injury during
internal mammary artery harvesting.44 Since routine use
of insulation for the phrenic nerves during cardiac surgery,
this complication is now rare, but unilateral or bilateral
phrenic nerve palsies are still seen as a consequence of
direct invasion by neoplasm, infectious diseases (such as
herpes zoster and Lyme disease), metabolic peripheral
neuropathy (diabetes or porphyria), and radiotherapy.45
Although acute ventilatory failure as a consequence of
bilateral diaphragmatic paralysis is unusual, these patients
are much more symptomatic than those with unilateral
paralysis and usually have severe orthopnea.
IMMUNOLOGIC NEUROPATHIES
Guillain-Barr syndrome, now known as acute idiopathic
demyelinating polyneuropathy (AIDP), is an autoimmune
polyneuropathy that accounts, together with myasthenia

gravis, for the majority of admissions for ventilatory
failure due to neuromuscular impairment.46-51 Therapy
with plasma exchange and intravenous immunoglobulin
improves outcomes in AIDP, although 2% to 10% still die,
and up to 20% of individuals who survive remain seriously
disabled.52 Theoretically, death should be preventable in the
vast majority of patients with this disease because mortality
is primarily from potentially avoidable respiratory complications (see the discussion in Chapter 97). It remains
unclear whether the need for mechanical ventilation can be
predicted before the onset of frank ventilatory failure in this
condition.53
NEUROMUSCULAR JUNCTION IMPAIRMENT

Immunologic Disease
Myasthenia gravis is less common than AIDP as a cause
of acute ventilatory failure, although up to 15% to 20%
of myasthenic patients experience a crisis during their
lifetime. These events usually happen in patients with an
established diagnosis of myasthenia gravis. With adequate
therapy (plasmapheresis and intravenous immunoglobulin)
and respiratory support through noninvasive or invasive
mechanical ventilation, the mortality rate is 5% to 10%.54,55
Isolated ventilatory muscle weakness requiring mechanical
ventilation has been reported as the initial manifestation of
the disorder.46
Infectious Disease
Botulism remains an infrequent but important cause of
acute ventilatory failure worldwide. In western countries,
the incidence of ventilator failure due to food-borne illness
has been unusual but steady in recent decades, with about
23 cases/year in the United States. On the other hand,
due to subcutaneous injection of black-tar heroin, the incidence of wound botulism has been rising since the 1990s
among injectable drug users.56-58 The vast majority of
patients with both forms of botulism manifest respiratory
symptoms and up to 75% of individuals develop clinically
significant respiratory failure due to progressive descending
flaccid paralysis, requiring mechanical ventilation, which is
usually more prolonged in wound botulism patients.59,60
Recovery may likewise be prolonged, with residual ventilatory muscle weakness detectable as long as 2 years after
presentation.61
Myopathies
Primary myopathies due to muscular dystrophies or other
congenital myopathies are an uncommon cause of acute
respiratory failure in most acute care hospitals but are more
common in the pediatric setting. These patients usually
develop ventilatory failure gradually and are begun on NIV
in an outpatient setting. When they present with acute ventilator failure, it is usually in the setting of a precipitating
factor such as pneumonia or bronchitis that causes problems with secretion retention. In such an event, they should
be placed in an intensive care unit and treated with an
aggressive regimen to assist with secretion clearance.62
Endotracheal intubation may be necessary to control secretions with weaning to NIV once the acute crisis subsides. Dermatomyositis may also cause respiratory muscle
weakness severe enough to lead to acute ventilatory

failure,63,64 although not as an initial manifestation in the
absence of other typical symptoms and signs of this condition. In these reported cases, ventilatory function recovered
as the disease was brought under control with immunosuppressive therapy.
Pharmacologic Causes
Neuromuscular blocking drugs are sometimes administered to ventilated patients, in conjunction with sedation,
to facilitate mechanical ventilation, reduce oxygen consumption, or control intracranial pressure. The clinical
kinetics of these agents have been determined mainly in
the context of short-term general anesthesia, and their
effects on ventilatory muscle function in critically ill
patients are much more variable. For example, most neuromuscular blocking drugs are cleared more slowly in the
presence of hepatic or renal insufficiency. This is particularly true for pancuronium and vecuronium; the effects of
these drugs can last days or even weeks in the presence of
renal failure.65 In contrast, atracurium and cisatracurium
are metabolized in plasma and do not depend on renal or
hepatic function for clearance; thus, they are not associated with prolonged muscle weakness as a result of delayed
clearance.66
Train-of-four stimulation can be used to monitor the
depth of neuromuscular blockade, avoiding excessive paralysis and reducing the quantity of drug used, as well as the
recovery time of neuromuscular function in critically ill
patients.67 Although these benefits may not be seen when
atracurium and cisatracurium are used,68 train-of-four
testing is sufficiently simple and inexpensive to perform that
many experts believe it should be employed routinely.69
Minimizing the use of neuromuscular blocking drugs in
ventilator management and using train-of-four stimulation
to monitor the degree of muscle relaxation, as well as
employing daily interruptions of paralysis, may reduce the
incidence of prolonged paralysis.70
NEUROMUSCULAR WEAKNESS ASSOCIATED

WITH CRITICAL ILLNESS
Neuromuscular dysfunction associated with critical illness
commonly contributes to the subsequent inability to wean
such patients from mechanical ventilation.66 Several forms
of critical illnessassociated neuromuscular dysfunction
are recognized.
Intensive Care UnitAcquired Weakness

Unexpected acute weakness and prolonged ventilatory
failure were first reported in patients with status asthmaticus treated with corticosteroids and neuromuscular
blocking drugs.71,72 Subsequently, a similar syndrome was
recognized in other groups of ICU patients, especially those
with sepsis and systemic inflammation, even without corticosteroid administration or therapeutic paralysis.66 Either
muscle or nerve abnormalities can predominate, leading to
a confusing array of diagnostic terms, such as critical
illness myopathy, critical illness polyneuropathy, postparalytic myopathy, ICU-acquired paresis, acute quadriplegic myopathy, and the preferred term, ICU-acquired
weakness.
The pathophysiology of ICU-acquired weakness is poorly

understood but may involve elements of disuse and active
muscle catabolism sparked by systemic inflammation. Electromyography reveals reduced compound muscle action
potentials on motor nerve stimulation (with normal conduction velocity); increased action potential duration; and
spontaneous electrical activity on muscle needle recording
(e.g., fibrillation potentials, positive sharp waves).73 Biopsy
findings may include primary axonal degeneration, type II
muscle fiber atrophy, thick filament (myosin) loss, and
(occasionally) necrotizing myopathy.
One quarter to one half of all patients who require more
than 7 days of ICU care and the majority of patients who
develop the systemic inflammatory response syndrome can
be shown by neurophysiologic testing to have ICU-acquired
weakness.66 These neurophysiologic abnormalities arise
early, accumulate during the course of illness, and usually
affect both nerves and muscles.74 Prospective studies have
shown that about one third of critically ill patients exhibit
weakness on clinical evaluation.66,75 The typical patient
exhibits symmetrical extremity weakness in which proximal function is more impaired than distal function and
the facial muscles are spared. Clinically, this disorder can
produce severe neuromuscular weakness, often affects the
respiratory muscles, and may prolong the need for ventilatory support.75,76 This syndrome should be suspected in
patients who are weak (Medical Research Council score <
4875) in the context of critical illness, have the typical clinical examination, and in whom no better alternative cause
for weakness can be identified. Handgrip strength may
serve as a simple test to identify ICU-acquired weakness.77
Nerve conduction studies, electromyography, and muscle
biopsy generally are not necessary, but their role in diagnosis remains an area of active investigation. The prognosis
for recovery of strength is variable, with many patients
improving rapidly over days to weeks while others remain
weak for many months or longer. The incidence of ICUacquired weakness may be reduced by intensive insulin
therapy,76,78,79 avoiding neuromuscular blocking drugs
and corticosteroids where possible, and possibly by early
mobilization.80,80a Because ICU-acquired weakness is so
strongly associated with severity of illness, length of ICU
stay, and the presence of multiple organ system dysfunction, prevention focuses on scrupulous attention to good
general ICU care and avoidance of sepsis.66
Ventilator-Induced Diaphragmatic Dysfunction

Many critically ill patients develop muscle weakness that
impedes functional recovery and is associated with prolonged mechanical ventilation. Some component of this
represents ICU-acquired weakness,81 but mechanical ventilation itself (without systemic inflammation) can induce
respiratory muscle weakness.82-84 The lack of neural stimulation or associated contraction plays a role in the evolution
of weakness because measures to keep muscles contracting
can ameliorate weakness. The diaphragm, the muscle most
responsible for sustaining the work of breathing, may be
even more sensitive than other skeletal muscles to the
effects of critical illness. In animal models, the diaphragm
weakens during the first 1 to 3 days of mechanical ventilation. Using phrenic nerve stimulation, one study demonstrated weakness by measuring a reduction in maximal
transdiaphragmatic pressure in a group of continuously

ventilated patients in comparison with findings in normal
volunteers.85 As in studies of peripheral skeletal muscle,
stimulating the diaphragm attenuates the loss of strength.86
This suggests that partial rather than full ventilatory
support may serve to maintain diaphragmatic strength,
potentially reducing time on the ventilator.86
ASSESSMENT OF NEED FOR MECHANICAL

VENTILATION IN NEUROMUSCULAR WEAKNESS
Respiratory muscle weakness can be suspected when there
is obvious peripheral muscle weakness, but neuromuscular
abnormalities may not always be evident. Respiratory
muscle weakness should also be suspected when dyspnea is
out of proportion to radiographic and respiratory mechanical abnormalities seen during mechanical ventilation.
Orthopnea raises the possibility of diaphragmatic weakness
or paralysis. Further, suspicion is raised when maximal
inspiratory pressure is reduced or, in some instances, when
ultrasound examination of the diaphragms is abnormal.
Early clinical indicators of the need for mechanical ventilation in patients with neuromuscular weakness remain
controversial. In addition to subjective assessments of
symptoms of dyspnea and respiratory distress, objective
assessments of vital capacity and maximum inspiratory
and expiratory pressures have been used to evaluate ventilatory muscle capability.
In AIDP, rapid disease progression, bulbar and bilateral
facial weakness, and dysautonomia are highly correlated
with the need for intubation and mechanical ventilation.
Moreover, a reduced vital capacity (<20mL/kg), maximum
inspiratory pressure (less negative than 30cm H2O), and
maximum expiratory pressure (<40cm H2O) are associated
with the need for intubation.50 However, no prospective randomized studies have assessed these variables, and predictors of the need for intubation may merely reflect the criteria
in current use to determine when a patient should be
intubated.
One study on AIDP reported an association between electrophysiologic evidence of demyelination and the need for
intubation and mechanical ventilation.87 Another study on
44 AIDP patients who required mechanical ventilation
showed greater cranial nerve involvement and immunoglobulin G (IgG) anti-GQ1b antibody levels than 87 AIDP
patients not requiring intubation.88 These could also be
markers of greater disease severity, thus explaining the
higher intubation rates.
In myasthenia gravis (MG), the criteria to predict the need
for intubation are not as reliable as for AIDP, mostly due to
the fluctuating nature of MG.89 Nonetheless, serial assessments of vital capacity and the use of the same predictors
as for AIDP are still recommended in MG as long as the
patient is monitored closely in an ICU and caregivers are
prepared for emergent intubation if necessary.90,91
In ALS, as previously noted, serial ventilatory muscle
assessments during outpatient management are required
for the timely initiation of NIV to avoid respiratory crises
and the need for emergency intubation. Evaluation of clinical signs of respiratory muscle weakness (such as use of
accessory muscles and paradoxical or diminished excursion of the abdomen) and symptoms of diaphragm weak-
ness (such as orthopnea) are important to assess. We

recommend serial measurement of pulmonary function
tests, nocturnal oximetry, and sniff inspiratory pressure as
an index of diaphragm strength. Recommendations for
starting NIV in ALS patients vary widely from FVC less than
80% predicted, with the idea that deterioration in respiratory muscle function can be slowed, to less than 50% predicted in the United States as per the threshold for Medicare
reimbursement for NIV.92-94 The authors believe that data
are insufficient to make firm recommendations on any specific FVC threshold for NIV initiation but that, in association with pulmonary dysfunction, NIV should be started
when patients develop symptoms that are likely to respond
to NIV. For example, dyspnea at rest or orthopnea can
respond to NIV, as can symptoms attributable to poor sleep,
such as daytime fatigue, hypersomnolence, or morning
headaches.
Although the optimal means for monitoring respiratory
muscle function remain uncertain, it is clear that initiation
of NIV or, if that fails, intubation and mechanical ventilation (if patients desire it) should be undertaken before
the development of severe respiratory acidosis or respiratory arrest. For this reason, patients with acute neuromuscular disease who show signs of pulmonary compromise
should be monitored in an ICU. Although the rate of progression may fluctuate, serial measurements of vital capacity and maximal inspiratory pressure along with repeated
physical examinations focusing on bulbar function and
ability to cough are advisable to avoid emergent intubations
(Fig. 99-3).95
Progressive
tachypnea
Alternating
abdominal and
rib cage breathing
Paradoxical inward
abdominal motion
during inspiration
Hypercapnia
Bradypnea
Respiratory arrest
Figure 99-3 The sequence leading from ventilatory pump failure to
respiratory arrest. Individual patients proceed through the steps shown
at variable rates and may skip one or more stages. However, except for
sudden events affecting the central nervous system or the administration
of paralyzing drugs, respiratory arrest does not present abruptly without
preceding physical manifestations. (Adapted in part from Cohen CA, Zagelbaum G, Gross D, etal: Clinical manifestations of inspiratory muscle fatigue.
Am J Med 73:308316, 1982.)
PRINCIPLES OF VENTILATOR MANAGEMENT

Patients with acute ventilatory failure due to neuromuscular disease usually have normal underlying lung parenchyma. Although NIV is often used successfully in these
patients, significant bulbar involvement is associated with
a high likelihood of NIV failure and patients with these
deficits should be intubated if the goal is prolongation of
life. Intubated patients are usually supported with volumetargeted ventilators using tidal volumes of 6 to 8mL/kg,
rates slightly below spontaneous, and 5 to 10cm H2O PEEP
to prevent atelectasis. These targets can also be achieved
using portable pressure-limited ventilators with the pressure difference between inspiratory and expiratory pressure adjusted to achieve similar tidal volumes (pressure
difference usually at least 8 to 10cm H2O) while avoiding
respiratory alkalosis. In patients requiring continuous ventilatory assistance, settings should aim not only to maintain gas exchange but also comfort, considering that there
is no convincing evidence that exercising respiratory
muscles in neuromuscular disease speeds recovery. Some
advocate a new protocol using prophylactic NIV and
mechanical cough assistance to facilitate extubation and
avert the need for reintubation in patients with neuromuscular disease who are weaning from invasive mechanical
ventilation.62,96

DUE TO CHEST WALL DEFECTS
(see Chapter 98)
Many restrictive diseases of the lungs or chest wall progress insidiously over months or years. Critical illness may
represent the natural history of the underlying condition
but may also signal an acutely superimposed, potentially
reversible crisis such as infection, pneumothorax, or
thromboembolism.
CHEST WALL SKELETAL ABNORMALITIES

Thoracic restriction and ventilatory muscle dysfunction
due to severe kyphoscoliosis typically lead to gradually progressive ventilatory insufficiency. Such patients can present
with acute or acute-on-chronic ventilatory failure and
require intensive care. Physiologic studies have shown that
both lung and chest wall mechanics are impaired during
acute respiratory failure in patients with kyphoscoliosis.97
Chest trauma, especially when leading to flail chest due to
rib fractures, may also cause the development of acute
hypercapnic respiratory failure. In either case, the ventilator pump fails because of inability to sustain ventilatory
work due to abnormalities that compromise ventilatory
function, such as increased chest wall stiffness in kyphoscoliosis and decreased ventilator efficiency due to paradoxical
chest wall motion and pain in flail chest.
PLEURAL DISEASE
Primary disease of the pleura, such as asbestos-related
diffuse pleural thickening or postinflammatory fibrothorax,
could potentially present in a similar way as skeletal deformities, but dyspnea and hyperventilation are more common
with these chronic pleural diseases. Respiratory acidosis
develops late in the course of the disorder unless ventilatory
drive is depressed or there is concomitant lung involvement.
Pleural effusion or pneumothorax can likewise precipitate
acute ventilatory failure, usually in the presence of underlying obstructive or restrictive pulmonary parenchymal
disease.
PRINCIPLES OF MANAGEMENT
Long-term NIV appears to be beneficial in selected patients
with kyphoscoliosis and other chest wall diseases98 and has
been reported to be successful in acute-on-chronic ventilatory failure.99-102 Some recent studies report that NIV
reduces the need for intubation and leads to a shortened
hospital stay in patients with chest trauma.103,104
Parenchymal Lung Disease

Idiopathic pulmonary fibrosis and other pulmonary parenchymal restrictive diseases are usually associated with
hyperventilation rather than hypoventilation. However,
acute ventilatory failure can arise in the late stages of these
conditions, either as a manifestation of the primary disease
process105,106 or, more often, in conjunction with pneumonia, surgery, or other intercurrent illness.107-109 Physiologic
assessment has demonstrated marked increases in lung
stiffness and airway resistance in patients with end-stage
idiopathic pulmonary fibrosis requiring mechanical ventilation,109 explaining the development of hypercapnia and
acute ventilatory failure.
Several case series have documented the poor prognosis
of patients who present with acute respiratory failure in the
setting of advanced interstitial fibrosis.106,108,109 In one retrospective report, all 14 consecutive patients with acute
respiratory failure and idiopathic pulmonary fibrosis admitted to the ICU died despite aggressive ventilatory support.107
In another report of 23 similar patients, 22 patients died;
the single survivor received a lung transplant shortly after
admission.108 In a third series of 19 patients with idiopathic
pulmonary fibrosis and ARF, 13 died.109 Outcomes appear
equally poor regardless of whether ventilation is invasive or
noninvasive.110
Principles of Ventilator Management
Due to increased lung stiffness, NIV for restrictive disease
usually requires higher airway pressures than are used for
COPD. Thus, avoiding gastric insufflation and air leaks
around the mask is more challenging. Furthermore, considering that a superimposed condition such as a respiratory
infection often precipitates the acute bout of respiratory
failure, accompanied by increased work of breathing and
secretion retention, invasive ventilatory support is often
warranted. The best way to ventilate patients with acute
respiratory failure in the setting of underlying restrictive
thoracic or lung disease has not been determined by clinical
trials. The potential for hemodynamic compromise, barotrauma, and ventilator-induced lung injury with the use of
high pressures and the physiologic similarity to ARDS in
patients with deteriorating pulmonary fibrosis make it reasonable to apply similar lung-protective ventilator strategies
and management targets (see Chapter 101). Low tidal

volumes (e.g., 6mL/kg predicted body weight) should be
applied, attempting to keep the end-inspiratory plateau
pressure below 30cm H2O if possible. Patients with restrictive lung disease typically breathe rapidly and shallowly,
so tachypnea may not be avoidable during the weaning
process and should not be used as the sole reason for delaying extubation if gas exchange and other assessments are
acceptable.

DUE TO AIRWAY OBSTRUCTION
UPPER AIRWAY OBSTRUCTION
Upper airway obstruction is an occasional cause of acute
ventilatory failure. The onset can be precipitous, as with
occlusion of the glottis by an aspirated foreign body (i.e.,
caf coronary) or a swollen and edematous epiglottis due
to acute epiglottitis.111 The onset can also be insidious, progressing over months, as with a tracheal tumor. The severity and length of narrowing and air flow determine the
airway resistance and thus the additional work of breathing imposed by the obstruction. Gradually progressive
upper airway narrowing may be well tolerated, at least
while breathing at rest, until a critical limit is reached, often
when the airway diameter drops to the range of 5 to 6mm.
The location and variability of the narrowing are also
important in determining the clinical manifestations. Extrathoracic variable upper airway narrowing affects mainly
inspiratory flow because the negative intraluminal pressure
exacerbates the narrowing during inspiration. During expiration, the positive intraluminal pressure widens extrathoracic airways. Vocal cord paralysis is an excellent example
of a variable extrathoracic upper airway obstruction, producing stridor and severe airway obstruction during inspiration but no significant obstruction during expiration. The
opposite pertains to variable intrathoracic obstructions,
with narrowing becoming less severe during inspiration
because pressure gradients favor airway widening. During
expiration, the airways narrow and the severity of the
obstruction worsens. Tracheomalacia can cause variable
intrathoracic airway obstruction. Fixed obstructions
affect both inspiration and expiration regardless of their
location.
Upper airway obstruction causes ventilatory failure by
increasing airway resistance to the point where respiratory
muscles can no longer sustain minute volume at a level
adequate to maintain CO2 homeostasis. Negative-pressure
pulmonary edema can also contribute to the gas-exchange
impairment.112 Ideally, the therapeutic aim is to relieve the
obstruction. This may be achieved by removal of a foreign
body, laser therapy of an endotracheal tumor, placement of
a stent in an area of tracheomalacia or stenosis, or tracheostomy to bypass an area of obstruction. Inhalation of
heliox (to reduce airway resistance), continuous positive
airway pressure (CPAP), or noninvasive ventilation using
pressure support and PEEP can help to reduce the work of
breathing and avoid intubation in patients who have reversible causes of their upper airway obstruction, such as
postextubation stridor, or who are awaiting tracheostomy

or surgical repair of an obstruction. However, these temporizing measures require close monitoring with the recognition that the patient can deteriorate abruptly.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE

COPD is the third leading cause of death among adults aged
65 to 84 in the United States, being the primary contributor
to mortality caused by lower respiratory disease, and poses
enormous costs to the U.S. health care system, mostly due
to hospitalization.113 The vast majority of hospitalizations
are due to acute exacerbations of COPD, but other causes
such as acute pneumonia, congestive heart failure, pulmonary embolism, and pneumothorax may contribute to the
deterioration.
PATHOPHYSIOLOGY
Hyperinflation associated with severe COPD places the
respiratory muscles at a mechanical disadvantage (Fig.
99-4). The loss of elastic structures is responsible for an
increase in lung compliance leading to hyperinflation (with
an increase in total lung capacity and functional residual
capacity) and the collapse of small airways during expiration that contributes to an increase of residual volume,
often referred to as air trapping. The flattening of the
diaphragm increases the radius of curvature, which,
according to the Law of Laplace, also increases muscle
tension and impedance to blood flow. In addition, ventilatory efficiency is reduced because the shortened diaphragm
operates at a disadvantageous position on its length-tension
curve and the horizontal orientation of the flattened diaphragm causes the lower rib cage to move paradoxically
during inhalation, inward rather than outward (Hoover
sign).
Normal
COPD
Accessory
muscles
Reduced lung and
chest wall recoil
+
Auto PEEP
Horizontal ribs
Flattened
diaphragm
Decreased zone
of apposition
Figure 99-4 Schema depicting the chest wall configuration at functional residual capacity of a normal individual (left) and a patient with
severe COPD (right). The COPD patient has a flattened diaphragm, which
increases its radius of curvature and increases the tension for a given pressure. The COPD patients ribs are horizontal, and the zone of apposition
between the diaphragm and chest wall is reduced, greatly reducing the
diaphragms efficiency in expanding the chest wall. Also, intrinsic positive
end-expiratory pressure (auto PEEP) poses an inspiratory load, adding
further to the inspiratory work. Exhalation is slowed by airway collapse and
the loss of elastic recoil. (Redrawn from Hill NS: Current concepts in mechanical ventilation for chronic obstructive pulmonary disease. Semin Respir Crit
Care Med 20:375395, 1999.)
The hyperinflation and impairment in diaphragm function necessitate the recruitment of accessory muscles to
maintain ventilation at higher lung volumes, contributing
to the already increased oxygen cost of breathing. Finally,
the collapse of small airways predisposes to incomplete
emptying and positive intrathoracic pressure at endexpiration (intrinsic or auto-PEEP). Auto-PEEP poses an
inspiratory threshold load requiring that inspiratory
muscles lower the elevated alveolar pressure to subatmospheric in order to initiate airflow for the next breath.114,115
During an exacerbation of COPD, the combination of
airway swelling, secretions, and bronchospasm caused by
acute inflammation increases airway resistance, further
worsening the expiratory flow-limitation and increasing
end-expiratory lung volume. As depicted in Figure 99-5,
COPD patients adapt by attempting to maintain airflow by
breathing at even higher lung volumes. In addition, they
adopt a rapid, shallow breathing pattern that further limits
the time available for expiration, aggravating intrinsic PEEP
and adding further to the work of breathing. The diaphragm
flattens more and develops increased tension, further
impeding diaphragmatic blood flow. The resulting limitation in substrate delivery to muscle is aggravated by progressive hypoxemia, caused by worsening hypoventilation
imbalance related to secretion retention. Thus, as
and V/Q
the demand for breathing increases, the capacity to supply
breathing work diminishes. As respiratory drive increases
in a futile attempt to reverse the worsening alveolar
Flow
Exacerbation
COPD
RV
RV
Volume
Increased
volume
Figure 99-5 Flow-volume loops for a patient with a normal lung (blue
line on right) and one with COPD (brown line on left) along with their
respective tidal volume loops (inner black loops with arrows). Note that
the expiratory flow during tidal breathing in the COPD patient reaches
maximal expiratory flow. During an exacerbation (dashed lines), expiratory
flow drops; because the flow during tidal breathing is already maximal, the
only mechanism available for maintaining flow is to increase lung volume
during tidal breathing (leftward shift of tidal breathing loop, shown by red
arrow). Although this strategy maintains expiratory flow, it increases the
work of breathing and oxygen consumption, predisposing to inspiratory
muscle fatigue and eventual respiratory failure. RV, residual volume.
(Redrawn from Hill NS: Current concepts in mechanical ventilation for chronic
obstructive pulmonary disease. Semin Respir Crit Care Med 20:375393, 1999.)
hypoventilation, muscular performance deteriorates and

the diaphragm fatigues.116 A vicious cycle ensues, leading
inexorably to worsening respiratory muscle fatigue, ventilatory failure, and death unless therapeutic interventions
interrupt the cycle.
Clinical Assessment
Patients with exacerbations of COPD must be carefully
evaluated to identify those at risk of developing respiratory
failure and to exclude other causes of respiratory failure.
History and physical examination are useful. Although the
Borg or visual analogue scales help gauge the level of
dyspnea in clinical studies, a subjective assessment that
dyspnea is worse than at baseline and of at least moderate
severity suffices to identify patients who may be at risk for
respiratory failure. Physical findings seen with severe exacerbations include tachypnea; accessory muscle use; abdominal paradox; Hoover sign (inspiratory inward motion of
the lower, lateral rib cage); cyanosis; and mental status
alterations.
In addition to a sputum examination for purulence, a
white blood cell count, electrocardiogram, chest radiograph, and arterial blood gas should be obtained to assess
the severity of an exacerbation. The widespread use of continuous pulse oximetry and of venous blood gases has
decreased, but not eliminated, the need for arterial blood
gases. Whereas venous pH values generally agree with arterial values, venous PCO2 poorly reflects arterial PCO2; nonetheless, a normal venous PCO2 may be useful in excluding
hypercapnia.117 Arterial blood gases provide a rapid assessment of arterial PCO2 and pH, information that is critical
when deciding to place patients in critical care units or to
initiate mechanical ventilation and to assess response to
therapy. During severe exacerbations, patients with chronic
CO2 retention develop acute-on-chronic hypercapnia, manifested by a drop in pH indicative of retained CO2 uncompensated by bicarbonate, an important indicator of
ventilatory failure that can be detected only by measurement of arterial blood gases.
Medical Therapy
Medical therapy, consisting of bronchodilators, corticosteroids, and antibiotics, should be promptly started in patients
with severe exacerbations. Additional therapies, including
diuretics, nitrates, or anticoagulation, should be started
whenever comorbidities such as congestive heart failure or
pulmonary embolism are suspected.
Oxygen should be supplemented routinely to improve
hypoxemia, but it should be carefully titrated in patients
with CO2 retention to maintain a target SpO2 of 88% to
92%. Overzealous oxygen supplementation in such patients
has long been known to aggravate CO2 retention, by either
blunting the hypoxic ventilatory drive, increasing physiologic dead space (perhaps due to oxygen-induced bronchodilation in poorly perfused lung regions), or both. Because
hypoxemia in COPD patients is usually due mainly to
hypoventilation and is easily reversed, initial supplementation with nasal oxygen at 2L/min is often adequate.118 In
patients with severe exacerbations, arterial blood gases
should be repeated periodically to assess the effect of oxygen
supplementation on arterial PCO2.
Noninvasive Ventilation
Although medical therapy alone is usually effective in mild
COPD exacerbation, it is often not sufficient in severe exacerbations. In severe exacerbations, tachypnea, dyspnea,
and CO2 retention may persist or worsen despite initial
medical therapy. Before 10 years ago, patients in such a
predicament would usually be intubated and mechanically
ventilated. If they declined intubation, they were kept
comfortable while medical therapy was continued, but they
often died. Invasive mechanical ventilation was successful
in the majority of cases, but hospital mortality rates were
substantial, averaging 30% in several studies.119 Complications of invasive mechanical ventilation were common,
including upper airway trauma, pneumothorax, and nosocomial infection, all contributing to patient mortality.120
In 1990 Brochard and coworkers121 demonstrated that
the noninvasive delivery of pressurized air into the lungs
via a face mask was effective in providing partial ventilatory
assistance during COPD exacerbations. These workers used
a device designed to provide pressure support that reduced
diaphragmatic work of breathing by increasing airway
pressure with each inhalation. Later, Appendini and colleagues122 demonstrated that combining extrinsic PEEP (to
counterbalance the effects of intrinsic PEEP) with pressure
support even more effectively reduced the work of breathing in COPD patients than either CPAP or pressure support
alone. By reducing the work of breathing, NIV restores the
balance between supply and demand for the work of breathing, thereby serving as a crutch during COPD exacerbations and halting the progression of respiratory muscle
fatigue while medical therapies are given time to work.
Since Brochards groundbreaking study, multiple randomized controlled studies and meta-analyses have demonstrated the efficacy of NIV to treat exacerbations of COPD.120
When compared with conventional therapy alone, NIV for
severe exacerbations of COPD more rapidly improves
dyspnea, respiratory and heart rates, arterial PCO2, and
encephalopathy scores.123-125 In addition, intubation and
mortality rates drop precipitously (from roughly 75% and
30% in controls to 25% and 10%, respectively, in NIVtreated patients).123,124,126 NIV also lowers complication
rates and hospital lengths of stay compared with
controls.123-125 One study has reported that NIV failed to
lower intubation or mortality rates or hospital lengths of
stay in patients with COPD exacerbations, but it is notable
that blood gases were only mildly deranged and there were
no intubations or mortality in the control group. This result
suggests that patients with relatively mild COPD exacerbations are unlikely to derive benefit from NIV, and the modality should usually be reserved for those with mild to severe
symptoms.127,128
Several meta-analyses129,130 have concluded that NIV is
effective in avoiding intubation (relative risk 0.42 and absolute risk reduction 28%, respectively), reducing mortality
(relative risk 0.41 and absolute risk reduction 10%, respectively), and shortening hospital length of stay (by 4 days).
A recent study on a large cohort of patients (25,628) with
COPD exacerbations requiring mechanical ventilation
showed reduced mortality, length of stay, and cost with NIV
compared to invasive ventilation.130a On the basis of this
evidence, the authors of these meta-analyses, reviews, and

guidelines129-135 have advised that NIV should be the ventilatory modality of first choice and should be started early
in the course of moderate to severe COPD exacerbations.
Heliox Combined with Noninvasive Ventilation. By
virtue of its lower density than nitrogen, helium can be
combined with oxygen to lower the airway resistance attributable to turbulent flow. The oxygen concentration can be
increased to about 40% in the helium-oxygen mixture but
not higher without losing the density advantage of the
added helium. Heliox has been combined with NIV to treat
patients with COPD exacerbations, with beneficial physiologic responses including reduced airway resistance and
more rapid improvements in gas exchange.136 However,
subsequent randomized, prospective trials on patients with
COPD in respiratory failure found that the addition of heliox
to NIV offered no significant advantages over NIV alone in
terms of intubation or mortality rates or hospital lengths of
stay.137,138
COPD Complicated by Pneumonia

COPD patients may develop acute or acute-on-chronic
respiratory failure due to an exacerbation complicated
by pneumonia. When evaluating a COPD patient with
worsening of baseline symptoms, concomitant pneumonia
should be considered as a contributing factor. By virtue
of impairment in cellular and molecular defense mechanisms and the common use of inhaled corticosteroids,
which have been associated with increased pneumonia
rates, COPD patients are at risk for pneumonia.139 In addition, pneumonia is related to a more severe presentation of
community-acquired pneumonia in hospitalized patients,
without being a risk factor for mortality.140
Pneumonia has been associated with a poor outcome in
patients treated with NIV.141 However, in one trial on severe
community-acquired pneumonia, NIV reduced intubation
(21% vs. 50%, P = 0.03) and mortality rates, and shortened
ICU length of stay (1.8 vs. 6.0 days, P = 0.04) compared
with standard oxygen therapy. Benefit, however, was confined to the subgroup of patients with underlying COPD.142
Thus, although the presence of pneumonia is a risk factor
for poorer outcome with NIV, COPD patients with pneumonia can still benefit.
Postoperative Patients
Postoperative pulmonary complications are defined as pulmonary abnormalities (such as atelectasis, pulmonary
embolism, ALI/ARDS) that arise frequently in the postoperative period, particularly in COPD patients. These complications, due to general anesthesia, postoperative immobility,
or to the surgery itself, increase morbidity, mortality, and
length of stay.
NIV has been reported to be effective in reducing the need
for intubation, ICU length of stay, and mortality rate in
postlung resection patients with acute respiratory insufficiency.143,144 Although only a portion of these patients had
COPD, accumulating evidence now supports the use of NIV
in selected postoperative (including COPD) patients to
maintain improved gas exchange and avoid reintubation
and its attendant complications. NIV techniques are also
being used prophylactically to reduce secretion problems,

atelectasis, and hypoxemia after thoraco-abdominal and
major abdominal surgery.145-147
Postextubation in COPD
Between 10% and 15% of patients develop respiratory
failure after a standard extubation, increasing the length of
stay on mechanical ventilation and in the ICU and therefore
the risk of related complications including mortality.148-150
In this context, NIV can be used in several ways: (1) to
permit earlier removal of the endotracheal tube by assisting
ventilation postextubation, (2) to prevent the onset of respiratory failure and need for reintubation in patients at risk
for respiratory failure postextubation, and (3) to avoid the
need for reintubation in patients who develop frank respiratory failure postextubation.151
Using NIV to allow earlier removal of the endotracheal
tube is supported by randomized controlled trials. One trial
demonstrated that extubation to NIV after 48 hours of intubation increased overall weaning rate after 60 days (88%
vs. 68%), shortened the duration of mechanical ventilation
(10.2 vs. 16.6 days), shortened the stay in the ICU (15 vs.
24 days), and improved 60-day survival (92% vs. 72%) (all
P < 0.05) compared with patients left intubated.152 A second
randomized, controlled trial in patients with persistent
weaning failure (failure of spontaneous weaning trials
on 3 consecutive days) showed that early extubation to
NIV significantly reduced ICU and hospital length of stay,
incidence of nosocomial pneumonia (from 59% to 24%,
P < 0.05), complication rate, and hospital and 90-day
mortality (odds ratio 3.5).153
These randomized studies support use of NIV to facilitate
early extubation of invasively ventilated COPD patients.
However, if early extubation is contemplated, it should be
reserved for carefully selected patients.151 Patients should be
recovering from COPD exacerbations, be on 15cm H2O or
less of pressure support, be able to sustain 5 to 10 minutes
of unassisted breathing, have an adequate cough without
excessive secretions, be easy to intubate, and have few if any
comorbidities.
Using NIV in patients who develop respiratory failure
postextubation to avoid reintubation has less support in the
literature. Two randomized trials of patients at high risk for
extubation failure used NIV prophylactically to prevent
reintubation but failed to show the anticipated benefit. In
one,154 NIV provided no reduction in the need for intubation, duration of mechanical ventilation, length of hospital
stay, or mortality. In the other, NIV failed to show benefit in
these variables and was associated with increased ICU mortality.155 In the latter study, the increased mortality was
thought to be related to a 10-hour longer delay before proceeding with reintubation compared with controls. Furthermore, only 10% of patients in both of these studies
had COPD, leading to the speculation that results might
have been favorable if more patients with COPD had been
enrolled.
This speculation has been borne out by two subsequent
randomized, controlled trials, one showing dramatic reductions in respiratory failure, need for reintubation, and mortality in a subgroup of hypercapnic patients,156 and the
other demonstrating that patients with hypercapnia postextubation have a significant reduction in acute ventilatory
failure if treated prophylactically with NIV compared with

standard oxygen supplementation.157 Thus, the best current
recommendation is to use NIV selectively in patients with
extubation failure, mainly for COPD or other hypercapnic
patients, and to avoid delays in intubation should NIV fail.
Do-Not-Intubate Patients
The use of NIV to treat respiratory failure in patients who
have declined intubation accounted for 10% of acute applications in one survey.158 This application has been controversial, with some arguing that there is little to lose because
it may reverse the acute deterioration or, at least, provide
relief of dyspnea and a few extra hours to finalize affairs.159
Others have argued that this merely prolongs the dying
process, consumes resources inappropriately, and may add
to discomfort or counter patients wishes about avoiding
life-prolonging measures.160 In prospective observational
studies of 113158 and 131161 do-not-intubate (DNI) patients
treated with NIV, survival to hospital discharge was greater
than 50% for COPD and congestive heart failure patients,
whereas it was lower (14% to 25%) for those with a diagnosis of hypoxemic respiratory failure (pneumonia) or
advanced cancer. Thus, NIV can be used to treat respiratory
failure for DNI patients with acutely reversible processes
such as COPD exacerbations. Alternatively, it can be used to
palliate DNI patients, by alleviating dyspnea or providing
temporary support. The patient or family should be informed
that NIV is being used as a form of life support that may be
uncomfortable and can be removed at any time.
Practical Application of Noninvasive Ventilation
A thorough discussion of the application of NIV is beyond
the scope of this chapter, and the reader is referred to
Chapter 102 and elsewhere for more complete descriptions.132,162 The following sections focus on aspects relevant
to applications in COPD patients with acute respiratory
failure.
Patient Selection. Selection of appropriate patients is key
to the successful application of NIV. The selection process
should take into account the patients clinical characteristics and risk of failure on NIV (Table 99-2). Predictors of
success of NIV have been identified139,163 (Table 99-3) and
include a good neurologic status (and hence more cooperativeness), ability to protect the airway, and only mildmoderate acid-base or gas-exchange derangement. Several
studies have also found that improvements in pH, arterial
PCO2, and level of consciousness within the first hour or two
of NIV initiation are strong predictors of success.139,163
These studies indicate that there is a window of opportunity when initiating NIV that opens when patients need
ventilatory assistance but closes if they progress too far and
become severely acidemic. Ultimately, it becomes a clinical
judgment that takes into account the patients diagnosis
that led to the respiratory failure, the need for ventilator
assistance, and the absence of contraindications (see
Table 99-2).164
Mask Selection. Tolerance of the mask is key to the
success of NIV. Thus, the mask must be a good fit and
strapped on sufficiently to control air leaks while avoiding
excessive strap tension. For acute applications, the standard
Table 99-2 Selection Criteria for Noninvasive PositivePressure Ventilation in Acute Exacerbations of Chronic
Obstructive Pulmonary Disease
ESTABLISH NEED FOR VENTILATORY ASSISTANCE
Moderate to severe respiratory distress
Tachypnea (RR > 24 breaths/min)
Accessory muscle use or abdominal paradox
pH < 7.35, arterial PCO2 > 45mmHg or
Arterial PO2/FIO2 < 200
EXCLUDE PATIENTS WITH CONTRAINDICATIONS TO
NONINVASIVE VENTILATION
Respiratory arrest
Medically unstable (septic or cardiogenic shock, uncontrolled upper
gastrointestinal bleeding, acute myocardial infarction with planned
intervention, uncontrolled arrhythmias)
Unable to protect airway
Excessive secretions
Uncooperative or agitated
Unable to fit mask
Recent upper airway or upper gastrointestinal surgery
FIO2, fractional concentration of oxygen in inspired gas; NIV, noninvasive
ventilation; PCO2; partial pressure of carbon dioxide; PO2, partial pressure
of oxygen; RR, respiratory rate.
Adapted from Liesching T, Kwok H, Hill NS: Acute applications of
noninvasive positive pressure ventilation. Chest 124:699713, 2003.
Table 99-3 Predictors of Success for Noninvasive PositivePressure Ventilation in the Acute Setting
EFFECTIVE SYNCHRONY OF PATIENT WITH VENTILATOR
Able to cooperate
Good neurologic status
Younger age
Minimal air leaks
Dentate
Compliance*
ABLE TO PROTECT AIRWAY
Low volume of secretions
Low aspiration risk
NOT TOO ACUTELY ILL
No pneumonia
Lower APACHE II score (<34)
Initial arterial PCO2 < 92mmHg
Initial pH > 7.10
GOOD INITIAL RESPONSE (WITHIN FIRST HOUR OR TWO)
Improvement in pH
Reduction in respiratory rate
Reduction in arterial PCO2
Improved level of consciousness
*Compliance refers to the clinicians assessment of the patients
acceptance of the technique.
APACHE, Acute Physiology, Age, and Chronic Health Evaluation; NIV,
noninvasive ventilation; PCO2, partial pressure of carbon dioxide.
Adapted from Ambrosino N, Foglio K, Rubini F, etal: Non-invasive
mechanical ventilation in acute respiratory failure due to chronic
obstructive pulmonary disease: correlates for success. Thorax 50:755757,
1995; and SooHoo GW, Santiago S, Williams AJ: Nasal mechanical
ventilation for hypercapnic respiratory failure in chronic obstructive
pulmonary disease: determinants of success and failure. Crit Care Med
22:12531261, 1994.
full-face (oronasal) mask is usually preferred because it is

better tolerated and avoids the leaking of air through the
mouth that can limit the efficacy of nasal masks.165 Nasal
masks, however, may be more comfortable for long-term
applications,166,167 so transitioning from a full face mask to
a nasal mask should be contemplated after the first few days
if NIV is to be continued. The helmet, consisting of a plastic
cylinder that seals over the neck and shoulders, offers an
alternative interface. It is effective for delivery of CPAP in
particular. Although difficulty achieving patient-ventilator
synchrony has been reported when it is used to deliver pressure support ventilation, increasing the PEEP level to render
the mask less compliant seems to help.166 Within each mask
category, many types of masks are available. Practitioners
should have a current knowledge of available masks and
their proper application in order to maximize the likelihood
of NIV success.
Ventilator Selection. In the acute setting, both critical
care and bilevel ventilators (portable pressure-limited
devices designed especially for the administration of noninvasive positive pressure ventilation) have been used with
similar success rates. A bilevel device designed for use in the
acute care setting that includes an oxygen blender and displays waveforms has gained popularity. In addition, many
ventilators designed primarily for invasive mechanical ventilation now offer noninvasive modes that are programmed
to improve leak compensation, silence nuisance alarms
that are triggered by air leaks, and permit limitation of
inspiratory time to enhance patient-ventilator synchrony.168
The capabilities of these modes differ considerably, however,
and may require additional adjustment if there are mask
leaks.169
NIV Initiation. At the start of NIV, the properly sized
mask is placed on the patients face and attached to the
ventilator. Patients often feel more comfortable if they can
hold the mask themselves. Pressure-limited modes may be
better tolerated than volume-limited modes.170 Initial ventilator pressures are usually low, to enhance patient comfort
and acceptance, but adjusted upward as tolerated to provide
adequate ventilatory assistance. Typical initial settings on
pressure-limited ventilators are 8 to 12cm H2O for inspiratory pressures and 4 to 5cm H2O for expiratory pressures
(e.g., PEEP), with subsequent adjustments as needed to alleviate respiratory distress or counterbalance intrinsic PEEP
or treat hypoxemia. The difference between inspiratory and
expiratory pressure is the level of pressure support and
should be adequate to alleviate inspiratory effort while
avoiding excessive discomfort.
Some ventilators permit adjustments in airflow to
enhance synchrony, such as the rise time, which determines the time to reach the target inspiratory pressure and
the adjustable inspiratory time. These may be helpful in
optimizing comfort in COPD patients who tend to prefer
relatively high inspiratory flows171 (and hence short rise
times, often 0.1sec) and short inspiratory times (usually <
1sec) to avoid prolongation of delivered inspiratory pressures during expiration.
Oxygenation and Humidification. Most patients with
COPD exacerbations do not have severe oxygenation defects
and can be managed successfully with pressure-limited

bilevel ventilators. With these ventilators, oxygen is administered at rates up to 15L/min into ports in the mask or via
a T-connector at the proximal end of the ventilator tubing,
adjusted to maintain the desired level of oxygenation
(usually to an arterial oxygen saturation [SaO2] > 90% to
92%). Because FIO2 using this arrangement cannot be generated at more than 45% to 50%, ventilators with oxygen
blenders are necessary when a higher FIO2 is needed, such
as for patients with COPD complicated by pneumonia.
Humidification should be used routinely because it may
reduce the work of breathing and enhance comfort and
tolerance during NIV.166,172,173
Adaptation and Monitoring. Coaching and encouragement, especially during the first few hours, are critical in
achieving adaptation. Judicious administration of low doses
of sedatives may enhance patient acceptance. Close bedside
monitoring is essential until the patients respiratory status
stabilizes. Although NIV can easily be administered on
general medical wards, the acuteness of the patients illness
and need for close monitoring should dictate the site of
administration. Acutely ill patients should be treated in an
ICU or step-down unit until their condition stabilizes.125,174
As shown in Table 99-4, patient comfort and tolerance
are key initial goals, together with a reduction in work
of breathing and respiratory distress and optimization
of patient-ventilator synchrony. Arterial SO2 is monitored
continuously, and blood gases are obtained as is clinically
indicated, at baseline and at least once during the first hour
or two.
Commonly Encountered Problems and Possible Remedies. Noninvasive ventilation is safe and well tolerated in
most properly selected patients. The most commonly
encountered problems in COPD patients are similar to those
in other patients and are related to the mask, air pressure,
or airflow (see Table 99-4). Minimizing air leaks is also an
important aim.
Table 99-4 Monitoring Noninvasive Positive-Pressure
Ventilation in Chronic Obstructive Pulmonary Disease
ACUTE SETTING
Patient comfort
Mask fit and leak
Patient-ventilator synchrony
Sternocleidomastoid muscle activity
Vital signs (heart and respiratory rate; systemic blood pressure)
Continuous oximetry (until stabilized)
Occasional blood gases (initial and after 30120 minutes, then as
clinically indicated)
CHRONIC SETTING
Patient comfort
Mask fit and leak
Hours of use
Problems with adaptation (e.g., nasal congestion, dryness, gastric
insufflation, conjunctival irritation, inability to sleep)
Symptoms (e.g., dyspnea, fatigue, morning headache,
hypersomnolence)
Gas exchange (daytime, nocturnal oximetry, blood gases periodically
to assess arterial PCO2)
Polysomnography (if symptoms of sleep disturbance persist or
nocturnal desaturation persists without clear explanation)
PCO2, partial pressure of carbon dioxide.
Increasing Use of NIV for COPD

The use of NIV in a French ICU increased from 20% of
initial ventilator starts to 80% during the 1980s. Concomitantly, the rate of ICU-acquired pneumonia dropped from
approximately 20% in 1994 to 8% in 2001.175 More recent
studies using nationwide hospital databases have shown
similar trends in the United States, with use of NIV increasing approximately 2.5- to 4.5-fold during the decade from
2000 to 2010, especially in patients older than 85 years,175a
accompanied by a drop in the use of invasive mechanical
ventilation and a gradual decline in mortality. The mortality rate for patients failing NIV and having to transition to
invasive ventilation has crept up over the same time period,
raising the concern that NIV may be used occasionally in
excessively ill patients who should have been intubated
initially.176
Invasive Mechanical Ventilation
Indications and Patient Selection. Although invasive
mechanical ventilation is being used less often for acute
exacerbations, it still has an important role in supporting
patients who want aggressive support and those who are
not eligible or who fail NIV. These and other indications for
the use of invasive mechanical ventilation for COPD are
listed in Table 99-5.
Invasive mechanical ventilation in COPD must be administered with care to minimize the risk of complications.
Excessive tidal volumes and rates must be avoided, and the
urge to normalize arterial PCO2 must be repressed in an
effort to minimize intrinsic PEEP and excessive hyperinflation. Excessive respiratory rates reduce the respiratory
cycle, shorten expiratory time, and prevent complete exhalation. This problem is aggravated by large tidal volumes.
The potential adverse consequence is air trapping and
intrinsic PEEP. With intrinsic PEEP, increased intrathoracic
pressure reduces venous return and lowers cardiac output.
Patients with severe intrinsic PEEP may be hypotensive with
Table 99-5 Indications for Invasive Mechanical Ventilation
in Chronic Obstructive Pulmonary Disease
Severe dyspnea with the use of accessory muscles and paradoxical
abdominal motion
Respiratory frequency > 35 breaths/min
Life-threatening hypoxemia (arterial PO2 < 40mmHg or arterial PO2/
FIO2 < 200)
Severe acidosis (pH < 7.25) and hypercapnia (arterial PCO2 >
60mmHg)
Respiratory arrest
Somnolence; impaired mental status
Cardiovascular complications (hypotension; shock; heart failure)
Other complications (metabolic abnormalities; sepsis; pneumonia;
pulmonary embolism; barotrauma; massive pleural effusion)
Failure of noninvasive positive-pressure ventilation
FIO2, fractional concentration of oxygen in inspired gas; PCO2, partial pressure
of carbon dioxide; PO2, partial pressure of oxygen.
From Pauwels RA, Buist AS, Calverley PM, etal: Global strategy for the
diagnosis, management, and prevention of chronic obstructive
pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive
Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med
163:12561276, 2001.
low cardiac output and elevated pulmonary artery wedge

pressure due to transmission of the intrathoracic pressure.
Their clinical presentation may therefore mimic that of cardiogenic shock. Temporary disconnection from the ventilator can differentiate hemodynamic compromise due to
intrinsic PEEP from true cardiogenic shock because the
release of intrathoracic pressure permits rapid resolution of
the former but not the latter. Intrinsic PEEP may also cause
patient-ventilator asynchrony if ventilator triggering is
missed when patients cannot reach the triggering threshold
due to the inspiratory threshold load.
Recommended Ventilator Settings. Volume-limited or
pressure-limited modes can be used, but volume-limited
assist-control is the most frequent choice initially and provides control over the tidal volume, which is important in
avoiding dynamic hyperinflation. A small tidal volume (e.g.,
5 to 7mL/kg predicted body weight) should be used. Care
should be taken to avoid overventilation and alkalemia. The
backup respiratory rate for COPD patients receiving invasive mechanical ventilation should be set between 10 and
14/min. Given an inspiratory time of 1 second, if the respiratory rate is 20/min, the expiratory time is only 2 seconds;
at a respiratory rate of 15/min, expiratory time increases
to 3 seconds. Thus, relatively small changes in rate have
large effects on expiratory time. Another way to increase
expiratory time is to shorten the inspiratory time by increasing the inspiratory flow rate. However, this strategy is not
as fruitful because substantial increases in flow rate result
in only minor decreases in inspiratory time. For example, if
the inspiratory time is 1 second and inspiratory flow is 60L/
min, an increase in the inspiratory flow rate to 100L/min
decreases the inspiratory time to 0.6 second (if tidal volume
is held constant); thus, expiratory time increases only from
2.0 to 2.4 seconds. Furthermore, rapid flow rates may
increase the spontaneous respiratory rate177 and sensation
of respiratory distress. COPD patients prefer flow rates in
the 60L/min range and tend to sense faster or slower rates
as less comfortable.171
ASTHMA
Acute ventilatory failure due to acute asthma should be
unusual if patients adhere to a medical regimen including
inhaled corticosteroids, monitor their peak flows, and alter
their medical regimen (with the addition of oral steroids)
when peak flow declines. Unfortunately, some patients are
not treated with optimal regimens: some do not adhere to
the regimen, and others have severe exacerbations even
with optimal regimens. Although less commonly encountered than in the past, acute ventilatory failure in asthmatics remains a problem. Studies on near-fatal asthma have
identified several risk factors for exacerbation, including
poor access to health care, substance abuse, nonadherence
with therapy, underuse of corticosteroids, and underestimation of the severity of attacks.178
Medical Management of Acute Asthma

Patients presenting with severe asthma should be promptly
treated with systemic, as well as inhaled, corticosteroids
and bronchodilators. Rapidly acting 2-agonists are administered by inhalation, although no optimal route of admin-
istration or dose has been established. Metered-dose inhalers

with spacers or nebulizers may be used, usually every 20
minutes for the first hour. Some centers use continuous
nebulization for severe acute asthma. Magnesium, either
intravenous or inhaled, has been administered, with some
evidence to suggest that it aids aggressive 2-agonist therapy,
especially in the most severely ill asthmatics.179
Heliox has been used since the 1930s to lower resistance
to flow related to turbulence in the airways of asthma
patients, just as in COPD patients. Several randomized, controlled trials of heliox have been performed with patients
with acute asthma, but the results are inconclusive. Two
demonstrated more rapid improvements in dyspnea and
airflow with heliox than with oxygen alone,180,181 but
another showed no improvement in airflow rates (although
dyspnea was reduced more by heliox).182 The study showing
little or no improvement with heliox enrolled less severely
obstructed patients than the favorable studies, but a subgroup analysis of sicker patients in the negative study
showed no benefit in that subgroup either. A Cochrane
analysis concluded that there is no defined role for heliox in
treating severe acute asthma.183
Ventilatory Management
Assessment of Ventilatory Status. In patients with
acute asthma exacerbations, frank ventilatory failure is
unusual. Signs of severe respiratory distress, such as excessive use of accessory muscles, extreme tachypnea, or
abdominal paradox, warrant the initiation of ventilatory
assistance. Arterial blood gases showing normocapnia in a
patient with severe respiratory distress should also cause
alarm because patients reach a crossover point as they
fail, when they can no longer sustain hyperventilation but
have not become sufficiently fatigued to retain CO2. These
patients should be monitored closely so that noninvasive
ventilatory aids can be initiated promptly in order to avert
the need for invasive ventilation with its attendant potential
complications.
Continuous Positive Airway Pressure. CPAP alone or
NIV may ameliorate respiratory distress in asthmatics by
reducing the work of breathing via a direct bronchodilator
effect of positive pressure,184 enhancing the effect of inhaled
albuterol and offsetting intrinsic PEEP. However, the
unequal distribution of airway resistance in asthma, in
contrast to the more simultaneous closure of airways in
COPD, creates areas with different expiratory time constants. In this setting, CPAP can promote overdistention of
some lung regions. Thus, caution should be exercised when
applying CPAP to these patients, at least at levels exceeding
5cm H2O, and CPAP should be reduced to 5cm H2O if there
is no further amelioration of respiratory distress at higher
levels.
Noninvasive Ventilation. The role of NIV in the management of asthma exacerbations has not been clearly defined.
An early cohort study observed substantial improvements
in blood gases (arterial PCO2 dropping from 65 to 52mmHg
in the first 2 hours) in 17 patients treated with NIV, only
2 of whom required intubation.185 More recent studies
have shown more rapid improvement in airflow186 or equivalent improvement with less -agonist medication.187 In a
study assessing the effects of bilevel ventilation on airflow

in asthmatics, bronchodilators were withheld for the first
hour of therapy and the higher bilevel setting was associated with greater improvement in FEV1 than oxygen therapy
alone.188 These results suggest that positive airway pressure
might exert a bronchodilator effect; however, in the absence
of evidence of favorable effects on other outcomes like intubation, mortality rate, or ICU or hospital lengths of stay, the
benefits of NIV have not been adequately established.
Nonetheless, considering that cohort studies suggest that
some patients with severe asthma treated with NIV can
avert intubation, a trial of NIV may be considered when
patients fail to respond promptly to initial bronchodilator
therapy, particularly if they manifest signs of respiratory
muscle fatigue, including a respiratory rate of more than
30 breaths/min, accessory muscle use, abdominal paradox,
normocapnia in patients with respiratory distress, hypercapnia or hypoxemia. Such patients should be monitored
closely in an ICU and intubated if they fail to improve
promptly.
Invasive Mechanical Ventilation. Invasive mechanical
ventilation in patients with acute ventilatory failure due to
asthma should be used as a last resort but is necessary
when patents present with coma or delirium or with hemodynamic instability. Another clear indication is failure of
medical therapy that may include NIV. Of patients admitted
to the ICU with acute severe asthma, about one third have
been reported to require invasive mechanical ventilation.178,189 Invasive mechanical ventilation is best avoided
because of the frequency and severity of the potential complications but, if needed, it should be initiated before a respiratory arrest intervenes. Complications of mechanical
ventilation in asthmatics include barotrauma such as pneumothorax and pneumomediastinum, reported in 6.5% of
patients in one series,190 and the need for sedation and
paralysis, which should be avoided because of the risk of
postparalysis myopathy, ventilator-associated pneumonia,
and mortality rates in the 5% to 10% range.191
If invasive mechanical ventilation is necessary, great care
must be exercised to minimize the risk of complications,
using an approach similar to that used for COPD patients.
Excessive respiratory rates and tidal volumes should be
avoided, with the ultimate goal of keeping plateau pressures
under 30 to 35cm H2O. Permissive hypercapnia,192 first
described in invasively ventilated asthma patients,193
remains a sensible approach in severely obstructed patients.
With permissive hypercapnia, plateau pressures are maintained in a relatively safe range (<30cm H2O) as the first
priority while allowing the CO2 to rise, in some reports up
to 70 to 100mmHg. Using this strategy, the major risks of
positive-pressure ventilation can be minimized while providing time for the medical therapy to take effect. Bicarbonate or other buffers such as tris-hydroxymethyl aminomethane
(THAM) can be administered if the pH drops too low, but
this is probably not necessary and may not even be effective
in raising the pH, a situation also described in patients with
acute lung injury.194 Because of the variability of resistance
between airways, some of which may be entirely obstructed,
measurement of intrinsic PEEP using the expiratory hold
technique may underestimate the severity of regional
hyperinflation.195 When ventilation remains difficult, even
with use of lung-protective ventilation and permissive

hypercapnia, the addition of heliox to the ventilator circuit
may help (although heliox may alter ventilator performance
and not all ventilators can accommodate heliox). As a last
resort, extreme measures such as general anesthesia with
bronchodilator anesthetics (e.g., halothane)196 or induced
hypothermia may be helpful.

DUE TO VASCULAR IMPAIRMENT
An increase in physiologic dead space by disorders affecting
the pulmonary vasculature reduces alveolar ventilation in
relation to overall minute ventilation. Although hypercapnia might be expected in such a circumstance, it is typically
prevented by a modest increase in overall ventilation. Thus,
acute ventilatory failure is seldom seen in primary pulmonary vascular disease. In pulmonary thromboembolism, for
example, hypercapnia is unusual. Hypercapnia following
pulmonary embolism can be seen, however, in patients with
a comorbid condition such as severe COPD or a depression
of the ventilatory drive by drugs that impair the function of
the ventilatory pump. Indeed, acute respiratory acidosis,
with or without concomitant worsening in oxygenation,
may be the initial manifestation of pulmonary thromboembolism in a patient on controlled mechanical ventilation or
with a high cervical spinal cord injury or pharmacologic
paralysis who cannot increase minute ventilation.
Another rare circumstance in which acute ventilatory
failure may develop as a result of a disorder of the pulmonary circulation is venous air embolism, in which hypercapnia and a marked discrepancy between arterial and
end-tidal exhaled CO2 levels may be observed.197 Hypercapnia may also complicate the acute chest syndrome in
patients with sickle cell disease; one series documented
respiratory acidosis in 42% of patients who developed this
syndrome.198
ACKNOWLEDGMENT
The author wishes to thank Dr. Giulia Spoletini for her assistance in revising this chapter.
Key Points
Ventilatory failure is the consequence of inadequate
alveolar ventilation, generally due to poor central
drive, neuromuscular disease, profound mechanical
derangement of lung parenchyma or chest wall, or
some combination of these factors. Depression of
central drive is infrequently a major contributor to the
development of acute ventilatory failure, except for
depression due to drugs.
Respiratory muscle weakness, regardless of the origin
of the impairment (e.g., immunologic, motor neuron
disease, myopathic), may either precipitate ICU admission or be acquired in the ICU.
Clinical assessment including physical examination,
measurement of maximal inspiratory and expiratory
pressures, or bedside ultrasound to visualize the diaphragm can be helpful in identifying respiratory
muscle weakness.
COPD exacerbation is the most common cause of
acute ventilatory failure seen in acute care hospitals.
COPD patients may develop acute or acute-on-chronic
ventilatory failure due not only to bronchitis but also
to complicating pneumonia, congestive heart failure,
pulmonary embolism, or pneumothorax.
Noninvasive positive-pressure ventilation reduces
work of breathing by applying extrinsic positive endexpiratory pressure (PEEP) to counterbalance intrinsic
PEEP and pressure support to assist inspiration. It is
especially useful in exacerbations of COPD but may
also play a role in other forms of acute ventilatory
failure due to COPD, such as in facilitating extubation
of those who fail a trial of spontaneous breathing
or in avoiding reintubation in those who fail
extubation.
Invasive mechanical ventilation can generally be
accomplished using small tidal volumes of roughly
6mL/kg, which limits intrinsic PEEP in COPD, reduces
the risk of ventilator-induced lung injury in those with
parenchymal lung disease, and minimizes the circulatory compromise that can complicate restrictive chest
wall conditions.
When initiating noninvasive ventilation, there is a
window of opportunity that opens when patients
need ventilatory assistance but closes if they progress
too far and become severely acidemic. Improvements
in pH, arterial PCO2, and level of consciousness within
the first hour or two of noninvasive ventilation are
strong predictors of success.
In patients with respiratory failure due to asthma

or COPD, attempts to normalize arterial PCO2 generally lead to dynamic hyperinflation, thereby risking
hypotension and pneumothorax; instead, permissive
hypercapnia is used to limit minute ventilation and
maintain airway pressures in a safe range while allowing the arterial PCO2 to rise.
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Acute Ventilatory Failure

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SECTION

ACUTE VENTILATORY FAILURE

ACUTE VENTILATORY FAILURE DUE

ACUTE VENTILATORY FAILURE DUE

1724 PART 3 Clinical Respiratory Medicine

Figure 99-1 The physiologic mechanisms of acute ventilatory failure.

determined accurately by physical examination, pulse

where arterial PCO2 is assumed to be nearly the same as

PAO2 = PIO2 (PaCO2 /R)

PaO2 (mm Hg)

PaCO2 (mm Hg)

(ARDS) and can increase dead spacetotidal volume ratios

ACUTE VENTILATORY FAILURE

99 Acute Ventilatory Failure 1725

Table 99-1 Clinical Classification of Ventilatory Failure by Site

Primary alveolar ventilation (Ondines Curse)

Cervical spinal cord injury

Kyphoscoliosis; tight casts or bandages; ankylosing spondylitis; flail chest

Epiglottitis, foreign body, tumor, vocal cord paralysis, tracheomalacia

Pneumothorax; pleural effusion; pleural thickening; malignancy

Hypovolemic or cardiogenic shock, CPR, pulmonary hyperinflation

typically not the sole mechanism for acute ventilatory

identifying the specific agent or agents involved and the use

OTHER ACQUIRED CAUSES

1726 PART 3 Clinical Respiratory Medicine

acute ventilatory failure compared with individuals without

range, and supplemental oxygen should be supplied (with

ACUTE VENTILATORY FAILURE

99 Acute Ventilatory Failure 1727

MOTOR NEURON DISEASE

INJURY OR DISEASE AFFECTING THE

polyneuropathy that accounts, together with myasthenia

NEUROMUSCULAR JUNCTION IMPAIRMENT

1728 PART 3 Clinical Respiratory Medicine

weakness severe enough to lead to acute ventilatory

NEUROMUSCULAR WEAKNESS ASSOCIATED

Intensive Care UnitAcquired Weakness

The pathophysiology of ICU-acquired weakness is poorly

Ventilator-Induced Diaphragmatic Dysfunction

99 Acute Ventilatory Failure 1729

transdiaphragmatic pressure in a group of continuously

ASSESSMENT OF NEED FOR MECHANICAL

ness (such as orthopnea) are important to assess. We

1730 PART 3 Clinical Respiratory Medicine

PRINCIPLES OF VENTILATOR MANAGEMENT

ACUTE VENTILATORY FAILURE

CHEST WALL SKELETAL ABNORMALITIES

Parenchymal Lung Disease

99 Acute Ventilatory Failure 1731

and management targets (see Chapter 101). Low tidal

ACUTE VENTILATORY FAILURE

postextubation stridor, or who are awaiting tracheostomy

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

1732 PART 3 Clinical Respiratory Medicine

hypoventilation, muscular performance deteriorates and

99 Acute Ventilatory Failure 1733

evidence, the authors of these meta-analyses, reviews, and

COPD Complicated by Pneumonia

1734 PART 3 Clinical Respiratory Medicine

being used prophylactically to reduce secretion problems,

failure if treated prophylactically with NIV compared with

99 Acute Ventilatory Failure 1735

full-face (oronasal) mask is usually preferred because it is

1736 PART 3 Clinical Respiratory Medicine