Acute Respiratory Failure

Franco DAlessio, MD; Kent R. Nilsson, Jr., MD, MA; Lara Wittine, MD;
and Landon S. King, MD

FAST FACTS

18

Respiratory failure can be divided into hypoxic respiratory failure

(PaO2 < 60 mmHg) and hypercapnic ventilatory failure
(PaCO2 > 45 mmHg with concurrent acidemia).
Initial evaluation of a patient in respiratory distress includes a
focused history and physical exam, chest film, and arterial blood gas
analysis. The goals of this initial evaluation are to determine the risk
of impending respiratory failure, the type of respiratory failure (i.e.,
hypoxic or hypercarbic), and the specific cause.
For patients in extremis, ventilatory support should not be delayed.

Acute respiratory failure is one of the most time-sensitive situations

in medicine because delay in diagnosis and treatment can result in
significant morbidity and mortality. This chapter is meant to establish
a framework for evaluating patients with respiratory failure. Clinical
presentation, diagnosis, and management of the various disorders that
may cause respiratory failure are addressed in subsequent chapters.
Because of its prevalence and new insights into its management, adult
respiratory distress syndrome (ARDS) is discussed in detail at the end of
this chapter.
I. CLINICAL PRESENTATION
1. The presentation of respiratory distress varies widely and depends on
both the underlying cause and the rapidity of onset (e.g., minutes to
hours for a pulmonary embolism in contrast to days for a chronic
obstructive pulmonary disease exacerbation). Signs and symptoms can
be divided into those caused by hypoxemia or hypercarbia and those
caused by the underlying disease process.
2. Symptoms of hypoxemia and hypercarbia.
a. Symptoms of hypoxemia vary but typically involve the central nervous
system (confusion, agitation, and seizures), cardiovascular system
(arrhythmias, hypotension, or hypertension), and respiratory system
(dyspnea, tachypnea).
b. In contrast, hypercarbic respiratory failure presents predominantly with
symptoms of somnolence, lethargy, dysarthria, and change in mental
status. If respiratory acidosis is severe, myocardial depression can
occur, which may lead to hypotension. Progressive hypoxemia and
hypercarbia may blunt the sensation of dyspnea and can confound the
clinical assessment of its severity.
218

Acute Respiratory Failure 219

II. DIAGNOSTIC STUDIES

1. The arterial blood gas is the single most useful test to evaluate acidbase status and the degree of hypoxemia and hypercapnia. Hypoxemic
respiratory failure is characterized by a PO2 less than 60 mmHg;
hypercapnic respiratory failure exists when there is acidosis (pH less
than 7.34) and PCO2 greater than 45 mmHg.
2. Once the patient has been evaluated and stabilized, a portable chest
radiograph can provide insights into the cause of respiratory failure.
Abnormalities include consolidations, diffuse alveolar infiltrates,
effusions, and pneumothorax.
III. CAUSES OF RESPIRATORY FAILURE
A. HYPOXEMIC RESPIRATORY FAILURE
Hypoxemia (PaO2 < 60 mmHg) usually is caused by one of five
mechanisms: decreased FIO2, hypoventilation, diffusion impairment (low
DLCO), ventilation-perfusion mismatch, and shunt. Careful analysis of the
arterial blood gas and calculation of the A-a gradient (Box 18-1) can be
useful in assessing the cause of hypoxemia.1 See Fig. 18-1 for a
diagnostic algorithm and Table 18-1 for details regarding the diagnosis
and management of specific causes.
BOX 18-1
ALVEOLAR-ARTERIAL (A-a) OXYGEN GRADIENT EQUATION
A-a gradient = [FIO2% (PATM - PaH2O) - (PaCO2/R)] - PaO2.
At sea level on room air, this equation is:
A-a gradient = 150 - (1.25 PaCO2) - PaO2.
Age-adjusted A-a gradient = 2.5 + (0.21 age).
Atmospheric pressure (PATM) is 760 mmHg at sea level; partial pressure of water vapor (PaH2O)
is 47 mmHg at sea level. The respiratory quotient (R) is approximately 0.8. FIO2, fraction of
inspired oxygen; PaCO2, arterial carbon dioxide pressure, used to approximate alveolar carbon
dioxide pressure; PAO2, alveolar oxygen pressure, equals [FIO2 (PATM - PaH2O) (PaCO2/R)]; PaO2, arterial oxygen pressure.

18
ACUTE RESPIRATORY FAILURE

c. Because hypoxemia and hypercarbia often coexist, clinical presentation

may reflect a combination of these symptoms.
3. Physical examination findings are nonspecific as to whether the primary
derangement is hypoxia or hypercarbia. However, examination findings
are extremely helpful in determining the underlying pathologic process
(e.g., elevated jugular venous pressure and rales suggests congestive
heart failure; prolonged expiration and wheezing suggest airway
obstruction) and the degree of the patients distress.
a. Findings may include tachypnea, accessory muscle use, and
paradoxical respirations.
b. Inadequate cough, inability to protect the airway, use of accessory
muscles, and pulsus paradoxus are all findings suggestive of impending
respiratory failure. Often the simple question Are you tiring out? can
be an astute diagnostic test for impending respiratory failure.

Hypoventilation
plus another
mechanism

Yes

No

Low FiO2

V/Q mismatch
Pulmonary embolism
Airway disease (e.g.,
asthma)
Intraalveolar filling

Yes

A-a gradient?

Interstitial lung disease

(e.g., IPF)

Yes

DLCO

Yes

Is PaO2 correctable
with oxygen?

No

No

Normal or decreased

Determination of the mechanism for hypoxia. A-a gradient, alveolar-arterial gradient; ARDS, adult respiratory distress
syndrome; AVM, arteriovenous malformation; COPD, chronic obstructive pulmonary disease; DLCO, carbon monoxide
diffusing capacity; FIO2, fraction of inspired oxygen; IPF, interstitial pulmonary fibrosis; L, left; PaCO2, arterial carbon dioxide
pressure; PaO2, arterial oxygen pressure; PFO, patent foramen ovale; R, right; V/Q, ventilation-perfusion. (Modified from
Fauci AS et al: Harrisons principles of internal medicine, 14th ed, New York, 1997, McGraw-Hill.)

FIG. 18-1

PaCO2

Shunt physiology
Intraalveolar filling (e.g., ARDS, pneumonia)
Atelectasis
R L intracardiac shunt (e.g., PFO)
Intrapulmonary shunt (e.g., AVM)

Hypoventilation
Respiratory drive (e.g., opioids)
Neuromuscular disease
Other causes of hypercarbic failure

No

A-a gradient?

Hypoventilation

Increased

Hypoxemia (PaO2 < 60)

220 Critical Care Medicine

Mixed venous blood bypasses functional lung

and lowers systemic O2 tension.

Airway disease (asthma, chronic

obstructive pulmonary disease,
bronchitis, pneumonia)
Interstitial lung disease
Pulmonary vascular disease
(pulmonary embolus, pulmonary
hypertension)
Intrapulmonary alveolar disease (adult
respiratory distress syndrome,
atelectasis, pulmonary edema,
pneumonia)
Vascular disease (arteriovenous
malformation, hepatopulmonary
syndrome)
Intracardiac (septal defects)

Interstitial lung diseases

See Box 19-2

Associated Diseases

Increased A-a gradient

Normal or mildly elevated PCO2
PO2 does not correct with
supplemental O2

Increased A-a gradient

Normal or low PCO2
PaO2 corrects with supplemental O2

Should correct with a small

amount of supplemental O2
Desaturation with minimal exertion
DLCO

Comments
Seldom clinically significant

ACUTE RESPIRATORY FAILURE

A-a gradient, alveolar-arterial gradient; DLCO, carbon monoxide diffusing capacity; FIO2, fraction of inspired oxygen; PaO2, arterial oxygen pressure; PCO2, partial pressure of carbon
dioxide; PO2, partial pressure of oxygen.

Shunt

TABLE 18-1
DIFFERENTIAL DIAGNOSIS OF HYPOXEMIA
Cause of Hypoxemia
Mechanism of Hypoxemia
Atmospheric pressure at high altitude or
Decreased FIO2
on airplanes.
Alveolar O2 tension.
Hypoventilation
Alveolar CO2 decreases alveolar O2
concentration.
Diffusion impairment
Time for O2 to cross the alveolarcapillary membrane or loss of total
alveolar-capillary surface area decreases
O2 delivery to hemoglobin.
Ventilation-perfusion
Altered ratio of ventilation to perfusion reduces
mismatch
efficiency of gas exchange and decreases O2
delivery to hemoglobin.

Acute Respiratory Failure 221

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222 Critical Care Medicine

B. HYPERCAPNIC RESPIRATORY FAILURE

1. Hypercapnia (PaCO2 > 45 mmHg and pH < 7.34) reflects either
excessive CO2 production or inadequate CO2 elimination. Exercise,
overfeeding, hyperthyroidism, burns, fever, and sepsis all increase CO2
production by increasing the metabolic rate but rarely cause ventilatory
failure. In contrast, decreased elimination of CO2 reflects lack of
ventilatory drive, a neuromuscular disorder, or conditions of increased
respiratory compliance (Box 18-2).
2. Acute hypercapnic failure occurs only when the patient has concurrent
acidemia, implying that the change in CO2 was too rapid or too extreme
for renal (metabolic) compensation. The pH indicates whether the
hypercarbia is acute or chronic (see Chapter 71).
IV. MANAGEMENT
1. Acute management is aimed at providing respiratory support and
correcting life-threatening gas exchange abnormalities in order to ensure
adequate oxygenation and ventilation. Ultimately, treatment must be
focused on managing the underlying cause of the respiratory failure.
2. For hypoxic respiratory failure, the mainstay of therapy is to provide
supplemental O2 using the simplest delivery system that maintains
oxygenation with PaO2 greater than 60 and O2 saturation greater than
90%:
a. Nasal prongs usually increase FIO2 by 3% to 4% for each 1 L of O2
delivered.
b. Venturi masks allow more precise titration and delivery of supplemental
oxygen than can be achieved with nasal cannula.
c. A properly fitting nonrebreather mask provides FIO2 of about 80% to
90% through the use of a one-way valve that allows exhaled gases to
exit the mask but prevents the entrainment of room air. If the valve is
removed, the concentration of delivered O2 is lower.
d. If these options are inadequate to improve oxygenation, then ventilatory
support in the form of noninvasive positive-pressure ventilation or
intubation with mechanical ventilation must be considered.
3. Management of hypercarbic respiratory failure depends on the
underlying disorder. Noninvasive positive-pressure ventilation or
intubation with mechanical ventilation can be used to correct lifethreatening acidemia.
4. Ventilatory support.
a. Noninvasive positive-pressure ventilation is first-line therapy for
hypercapnic respiratory failure in patients who can protect their
airways, can handle their own secretions, and are hemodynamically
stable. It can also be used in patients with hypoxic respiratory failure
that is expected to be rapidly reversible with medical intervention (e.g.,
congestive heart failure) (see Chapter 19).
b. Indications for intubation and mechanical ventilation include
noninvasive positive-pressure ventilation failure, apnea, hypoxemia

Acute Respiratory Failure 223

despite maximum supplementary O2, upper airway obstruction, inability

to clear secretions or protect the airway, severe respiratory acidosis, and
progressive decline of the respiratory effort (see Chapter 19).

V. SPECIAL CASE: ADULT RESPIRATORY DISTRESS SYNDROME

A. EPIDEMIOLOGY AND ETIOLOGY
1. The cited incidence of ARDS (about 150,000 cases/year) probably is
an underestimate in light of recent observations that about 20% of
mechanically ventilated patients meet criteria for ARDS.2
2. Mortality from ARDS has improved but remains high despite lung
protective strategies (36% to 40%). Most deaths are due either to the
underlying cause (first 3 days) or to nosocomial infections or multiorgan
dysfunction (more than 3 days), not simply progressive respiratory
failure.3
3. The most common underlying causes associated with ARDS are sepsis
(40%), severe trauma, aspiration, and massive transfusions (Box 18-3).

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ACUTE RESPIRATORY FAILURE

BOX 18-2
DIFFERENTIAL DIAGNOSIS OF HYPERCAPNIC RESPIRATORY FAILURE
Disorders of Muscle
VENTILATORY DRIVE
Muscular dystrophy
Myxedema
Periodic paralysis
Severe metabolic alkalosis
Inflammatory (polymyositis,
Multiple sclerosis
dermatomyositis)
Sleep apnea, obstructive or central
Neuromuscular Junction
Narcotic or benzodiazepine overdose
Myasthenia gravis
Central nervous system: medullary
Cholinergic crisis
tumor, infarction, or other lesion
Botulism
Encephalitis and postviral syndromes
Aminoglycoside toxicity
(e.g., Reyes syndrome)
Tick paralysis
NEUROMUSCULAR DISORDERS
Metabolic Disorders
Corticospinal Tracts and Anterior
Hypercalcemia
Horn Cells
Hypophosphatemia
Poliomyelitis
CONDITIONS OF INCREASED COMPLIANCE
Amyotrophic lateral sclerosis
Obstructive lung disease
Tetanus
Massive obesity
Trauma
Massive ascites
Peripheral Nerve
Kyphoscoliosis
Guillain-Barr syndrome
Pneumothorax or pleural effusion
Diphtheria
Idiopathic or postzoster phrenic
neuropathy
Porphyria

224 Critical Care Medicine

BOX 18-3
CAUSES OF INCREASED PERMEABILITY PULMONARY EDEMA
(ADULT RESPIRATORY DISTRESS SYNDROME)
DIRECT PULMONARY INSULTS
Miscellaneous
Inhalation or Aspiration
Fat emboli
Smoke
Amniotic fluid emboli
Toxic chemicals
Air emboli
Chlorine
Pulmonary contusion
Cocaine inhalation
Radiologic contrast media
Gastric acid
INDIRECT PULMONARY INSULTS
Oxygen toxicity
Sepsis
Water (near-drowning)
Shock
Numerous community or industrial
Multiple transfusions
chemical gas exposures
Disseminated intravascular coagulation
Drugs and Chemicals
Sickle cell crisis
Heroin and morphine
Hyperthermia or hypothermia
Salicylates
Eclampsia
Bleomycin
Bone marrow transplantation
Amiodarone
Anaphylaxis
Methadone
Diabetic ketoacidosis
Cocaine and amphetamines
Cardiopulmonary bypass
Gemcitabine antineoplastic therapy
High altitude
Tocolytic therapy
Rapid lung reexpansion
Numerous drugs and poisons
Multisystem trauma
Infection
Neurogenic
Viral (e.g., influenza)
Pancreatitis
Rickettsial
Extreme physical exertion
Bacterial (e.g., Pneumococcus)
Tumor lysis syndrome
Fungal
Tuberculosis
Protozoal (Pneumocystis, malaria)
Modified from Fraser RS: Fraser and Pares diagnosis of diseases of the chest, 4th ed,
Philadelphia, 1999, WB Saunders.

BOX 18-4
DEFINITION OF ADULT RESPIRATORY DISTRESS SYNDROME
Acute onset
PaO2/FIO2 ratio 200 (regardless of positive end-expiratory pressure levels)
Bilateral infiltrates seen on chest film
No clinical evidence of left atrial hypertension or pulmonary artery wedge pressure
18
Note: Acute lung injury is defined similarly except that the PaO2/FIO2 ratio is 300.
FIO2, fraction of inspired oxygen; PaO2, arterial oxygen pressure.
From Bernard GR, Artigas A, Brigham KL, et al: Am J Respir Crit Care Med 149:818-824,
1994.

Acute Respiratory Failure 225

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ACUTE RESPIRATORY FAILURE

B. DIAGNOSIS (Box 18-4)

C. MANAGEMENT
1. Specific therapy. The underlying cause of ARDS should be determined
and treated aggressively (e.g., antibiotics for sepsis, corticosteroids for
diffuse alveolar hemorrhage).
2. Supportive therapy.
a. General measures. If there is no contraindication, all patients should
receive both deep vein thrombosis prophylaxis and stress ulcer
prophylaxis (see Chapter 17). Patients should be adequately sedated
because this facilitates ventilation and oxygenation.
b. Fluid management. The ARDS-net trial group is attempting to define
optimal fluid management in patients with ARDS. Until these data are
available, current recommendations are to attempt to maintain
intravascular euvolemia. An empiric trial of diuretics can be attempted
to improve oxygenation as long as it does not result in hypotension or
renal compromise.
c. Prone positioning. Although prone positioning improves ventilationperfusion matching both by increasing blood flow to better ventilated
areas and by promoting reexpansion of collapsed lung units, it has not
been shown to improve survival.4
d. Ventilatory support. The goal of mechanical ventilation in patients with
ARDS is to provide adequate oxygenation without causing complications
(e.g., ventilator-associated lung injury, barotrauma, oxygen toxicity, or
hemodynamic instability). Several different ventilation strategies have
been investigated, the most important of which are the following:
(1) Low tidal volume strategy. In patients with acute lung injury and
ARDS, mechanical ventilation with low tidal volumes (6 ml/kg of
predicted ideal body weight adjusted to maintain a plateau pressure
of <30 cm of water) results in lower mortality than traditional
ventilation (10 to 15 ml/kg).5
(2) High positive end-expiratory pressure strategy. In patients with
acute lung injury and ARDS who receive mechanical ventilation
with the low tidal volume strategy, clinical outcomes are similar
regardless of whether low or high levels of positive end-expiratory
pressure are used.6
(3) High-frequency oscillatory ventilation (HFOV). Recently, a
randomized, controlled trial comparing HFOV with conventional
ventilation (pressure control mode with a delivered tidal volume
of 6 to 10 ml/kg) demonstrated that the use of HFOV leads to
nonsustained improvements in the PaO2/FIO2 ratio and a trend
toward lower mortality. HFOV is a safe and effective rescue therapy
for patients with severe hypoxemic respiratory failure.7
e. Inhaled vasodilators. Inhaled nitric oxide (5 ppm) in patients with
acute lung injury not caused by sepsis has been shown to improve
oxygenation in the short term, but it has no significant impact on the
duration of ventilatory support or mortality.8

226 Critical Care Medicine

f. Exogenous surfactant. Two multicenter, randomized, double-blind trials

involving 448 patients with ARDS from various causes failed to show a
mortality benefit for intratracheal doses of a recombinant surfactant
protein C. Patients who received surfactant had a greater improvement
in gas exchange during the 24-hour treatment period than patients who
received standard therapy alone.9
g. Corticosteroids. Several prospective, placebo-controlled trials have
shown no benefit from the use of high-dose corticosteroids early in the
course of ARDS. However, one small study showed a possible role of
steroids in the fibroproliferative phase of ARDS.10 Larger randomized
trials are ongoing.
PEARLS AND PITFALLS
Cyanosis is not a reliable physical examination sign because it is
observer dependent and requires more than 5 g/dl of desaturated
hemoglobin.
The sensation of dyspnea correlates poorly with the severity of
respiratory failure.11
Pulse oximetry depends on pulse-coordinated receipt of the light
wavelengths of oxyhemoglobin transilluminated through the tissues.
Readings may be inaccurate in the absence of an observed arterial
waveform (e.g., with peripheral vascular disease, vasoconstriction, or
interference from nail polish).
Low SaO out of proportion to PaO suggests methemoglobinemia. Low
2
2
PaO2 out of proportion to high SaO2 suggests carboxyhemoglobinemia.
Four-channel co-oximetry confirms these diagnoses.
Low central venous oxygen saturation caused by decreased cardiac
output, sepsis, decreased oxygen carrying capacity, and
hypermetabolism may contribute to hypoxemia.
Insufficient delivery of oxygen to meet the metabolic demands of tissues
can occur despite oxyhemoglobin saturations (SaO2) greater than 90%.
Arterial oxygen content depends on total hemoglobin, the percent
hemoglobin saturation, and the amount of dissolved oxygen (arterial
oxygen content = [1.39 SaO2 Hb] + [0.0031 PaO2]).
REFERENCES
1. Mellemgaard K: The alveolar-arterial oxygen difference: size and components of
normal man, Acta Physiol Scand 67:10, 1966. B
2. Goss CH, Brower RG, Hudson LD, Rubenfeld GD: ARDS Network. Incidence
of acute lung injury in the United States, Crit Care Med 31(6):1607-1611,
2003. B
3. Montgomery AB, Stager MA, Carrico CJ, et al: Causes of mortality in patients
with the adult respiratory distress syndrome, Am Rev Respir Dis 132:485,
1985. B
4. Gattinoni L, Tognoni G, Pesenti A, et al: Effect of prone positioning on the
survival of patients with acute respiratory failure, N Engl J Med 345:568,
2001. A

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ACUTE RESPIRATORY FAILURE

5. The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal
volumes as compared with traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome, N Engl J Med 342:1301, 2000. A
6. The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network:
Higher versus lower positive end-expiratory pressures in patients with the acute
respiratory distress syndrome, N Engl J Med 351:327-336, 2004. A
7. Mehta S, Lapinsky SE, Hallet DC, et al: Prospective trial of high-frequency
oscillation in adults with acute respiratory distress syndrome, Crit Care Med
29:1360, 2001. B
8. Taylor RW, Zimmerman JL, Dellinger RP, et al: Low-dose inhaled nitric oxide in
patients with acute lung injury: a randomized controlled trial, JAMA
291(13):1603-1609, 2004. A
9. Spragg RG et al: Effect of recombinant surfactant protein C-based surfactant
on the acute respiratory distress syndrome, N Engl J Med 351(9):884-892,
2004. A
10. Meduri GU, Headley S, Golden E, et al: Effect of prolonged methyl-prednisolone
therapy in unresolving acute respiratory distress syndrome, JAMA 280:159,
1998. A
11. Wasserman K: Exercise testing in the dyspneic patient. The chairmans
postconference reflections, Am Rev Respir Dis 129(Suppl):1-2, 1984.