Acute hypoxemic respiratory failure (AHRF) is severe arterial hypoxemia that is refractory to supplemental O₂. It is caused by intrapulmonary shunting of blood secondary to airspace filling or collapse. Findings include dyspnea and tachypnea. Diagnosis is by ABGs and chest x-ray. Treatment usually requires mechanical ventilation.

Etiology

Airspace filling in AHRF may result from

• Elevated alveolar capillary hydrostatic pressure, as occurs in left ventricular failure or hypervolemia
• Increased alveolar capillary permeability, as occurs in any of the conditions predisposing to acute lung injury/acute respiratory distress syndrome (ALI/ARDS)
• Blood, as seen in diffuse alveolar hemorrhage

Pathophysiology

ALI/ARDS: ALI resulting in more severe hypoxemia is known as ARDS. However, differentiation between these 2 forms (see Table 1: Respiratory Failure and Mechanical Ventilation: Consensus Definition of ALI/ARDS) is arbitrary given that Pao₂ correlates poorly with lung pathology and clinical course.

Table 1
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Consensus Definition of ALI/ARDS Acute onset of respiratory failure Diffuse bilateral infiltrates on chest x-ray Absence of left atrial hypertension (PAOP* ≤ 18 mm Hg) or no clinical evidence of left atrial hypertension Hypoxemia, defined as Pao2/Fio2 ≤ 300 (ALI) or ≤ 200 (ARDS)† * If available (pulmonary artery catheter insertion has not been found to be beneficial in treating patients with ALI/ARDS). † Pao2 in mm Hg; Fio2 in decimal fraction (eg, 0.5). ALI/ARDS = acute lung injury/acute respiratory distress syndrome; Fio2 = fraction of inspired O2; PAOP = pulmonary artery occlusive pressure.

In ALI/ARDS, pulmonary or systemic inflammation leads to release of cytokines and other proinflammatory molecules. The cytokines activate alveolar macrophages and recruit neutrophils to the lungs, which in turn release leukotrienes, oxidants, platelet-activating factor, and proteases. These substances damage capillary endothelium and alveolar epithelium, disrupting the barriers between capillaries and airspaces. Edema fluid, protein, and cellular debris flood the airspaces and interstitium, causing disruption of surfactant, airspace collapse, ventilation-perfusion mismatch, shunting, and pulmonary hypertension. The injury is distributed heterogeneously but mainly affects dependent lung zones.

Causes of ALI/ARDS (see Table 2: Respiratory Failure and Mechanical Ventilation: Causes of ALI/ARDS) may involve direct lung injury (eg, pneumonia, acid aspiration) or indirect lung injury (eg, sepsis, pancreatitis, massive blood transfusion, nonthoracic trauma). Sepsis and pneumonia account for about 60% of cases.

Table 2
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Causes of ALI/ARDS Causes Direct Lung Injury Indirect Lung Injury Common Acid aspiration Sepsis Pneumonia Trauma with prolonged hypovolemic shock Less common Diffuse alveolar hemorrhage Bone marrow transplantation Fat embolism Burns Lung transplantation Cardiopulmonary bypass Near drowning Drug overdose (eg, aspirinSome Trade Names BUFFERIN ECOTRIN GENACOTE Click for Drug Monograph , cocaine, opioids, phenothiazines, tricyclics) Pulmonary contusion Massive blood transfusion (> 15 units) Toxic gas inhalation Neurogenic pulmonary edema due to stroke, seizure, head trauma, anoxia Pancreatitis Radiographic contrast (rare) ALI/ARDS = acute lung injury/acute respiratory distress syndrome.

Refractory hypoxemia: In both types of AHRF, flooded airspaces allow no inspired gas to enter, so the blood perfusing those alveoli remains at the mixed venous O₂ content no matter how high the fractional inspired O₂ (Fio₂). This effect ensures constant admixture of deoxygenated blood into the pulmonary vein and hence arterial hypoxemia. In contrast, hypoxemia that results from ventilating alveoli that have less ventilation than perfusion (ie, low ventilation-to-perfusion ratios as occurs in asthma or COPD and, to some extent, in ARDS/ALI) is readily corrected by supplemental O₂.

Symptoms and Signs

Acute hypoxemia (see also Approach to the Critically Ill Patient: Oxygen Desaturation) may cause dyspnea, restlessness, and anxiety. Signs include confusion or alteration of consciousness, cyanosis, tachypnea, tachycardia, and diaphoresis. Cardiac arrhythmia and coma can result. Airway flooding or closure causes crackles, detected during chest auscultation; the crackles are typically diffuse but sometimes worse at the lung bases. Jugular venous distention occurs with high levels of PEEP or severe right ventricular failure.

Diagnosis

• Chest x-ray and ABGs
• Clinical definition (see Table 1: Respiratory Failure and Mechanical Ventilation: Consensus Definition of ALI/ARDS)

Hypoxemia is usually first recognized using pulse oximetry. Patients with low O₂ saturation should have a chest x-ray and ABGs. Symptomatic patients should be treated with supplemental O₂ while awaiting test results.

If supplemental O₂ does not improve the O₂ saturation to > 90%, right-to-left shunting of blood should be suspected. An obvious alveolar infiltrate on chest x-ray implicates alveolar flooding as the cause, rather than an intracardiac shunt. However, at the onset of illness, hypoxemia is often present before changes are seen on x-ray.

Once AHRF is diagnosed, the cause must be determined, considering both pulmonary and extrapulmonary causes. Sometimes a known ongoing disorder (eg, acute MI, pancreatitis, sepsis) is an obvious cause. In other cases, history is suggestive; pneumonia should be suspected in an immunocompromised patient, and alveolar hemorrhage is suspected after bone marrow transplant or in a patient with a connective tissue disease. Frequently, however, critically ill patients have received a large volume of IV fluids for resuscitation, and high-pressure AHRF (eg, caused by ventricular failure or fluid overload) resulting from treatment must be distinguished from an underlying low-pressure AHRF (eg, caused by sepsis or pneumonia).

High-pressure pulmonary edema is suggested by a 3rd heart sound, jugular venous distention, and peripheral edema on examination and by the presence of diffuse central infiltrates, cardiomegaly, and an abnormally wide vascular pedicle on chest x-ray. The diffuse, bilateral infiltrates of ALI/ARDS are generally more peripheral. Focal infiltrates are typically caused by lobar pneumonia, atelectasis, or lung contusion. Although echocardiography may show left ventricular dysfunction, implying a cardiac origin, this finding is not specific because sepsis can also reduce myocardial contractility.

Pulmonary Edema

Acute Respiratory Distress Syndrome

When ALI/ARDS is diagnosed but the cause is not obvious (eg, trauma, sepsis, severe pulmonary infection, pancreatitis), a review of drugs and recent diagnostic tests, procedures, and treatments may suggest an unrecognized cause, such as use of a radiographic contrast agent, air embolism, or transfusion. When no predisposing cause can be uncovered, some experts recommend doing bronchoscopy with bronchoalveolar lavage to exclude alveolar hemorrhage and eosinophilic pneumonia and, if this procedure is not revealing, a lung biopsy to exclude other disorders (eg, extrinsic allergic alveolitis, acute interstitial pneumonitis).

Prognosis

Prognosis is highly variable and depends on a variety of factors, including etiology of respiratory failure, severity of disease, age, and chronic health status. In particular, mortality in ALI/ARDS was very high (40 to 60%) but has declined in recent years to 25 to 40%, probably because of improvements in mechanical ventilation and in treatment of sepsis. Most often, death is not caused by respiratory dysfunction but by sepsis and multiorgan failure. Persistence of neutrophils and high cytokine levels in bronchoalveolar lavage fluid predict a poor prognosis. Mortality otherwise increases with age, presence of sepsis, and severity of preexisting organ insufficiency or coexisting organ dysfunction. Pulmonary function returns to close to normal in 6 to 12 mo in most ALI/ARDS patients who survive; however, patients with a protracted clinical course or severe disease may have residual pulmonary symptoms, and many have persistent neuromuscular weakness.

Treatment

• Mechanical ventilation if saturation is < 90% on high-flow O₂

Underlying conditions must be addressed as discussed elsewhere in The Manual. AHRF is initially treated with high flows of 70 to 100% O₂ by a nonrebreather face mask. If O₂ saturation > 90% is not obtained, mechanical ventilation probably should be instituted. Specific management varies by condition.

Mechanical ventilation in cardiogenic pulmonary edema: Mechanical ventilation benefits the failing left ventricle in several ways. Positive inspiratory pressure reduces left and right ventricular preload and left ventricular afterload and unloads the respiratory muscles, reducing the work of breathing. Reducing the work of breathing may allow redistribution of a limited cardiac output away from overworked respiratory muscles. Expiratory pressure (expiratory positive airway pressure [EPAP] or positive end-expiratory pressure [PEEP]) redistributes pulmonary edema from alveoli to the interstitium, allowing more alveoli to participate in gas exchange.

Noninvasive positive pressure ventilation (NIPPV) is useful in averting endotracheal intubation in many patients because drug therapy often leads to rapid improvement. Typical settings are inspiratory positive airway pressure (IPAP) of 10 to 15 cm H₂O and EPAP of 5 to 8 cm H₂O.

Conventional mechanical ventilation can use several ventilator modes. Most often, assist-control (A/C) is used in the acute setting, when full ventilatory support is desired. Initial settings are tidal volume of 6 mL/kg ideal body weight (see Respiratory Failure and Mechanical Ventilation: Initial Ventilator Management in ALI/ARDS), respiratory rate of 25/min, Fio₂ of 1.0, and PEEP of 5 to 8 cm H₂O. PEEP may then be titrated upward in 2.5-cm H₂O increments while the Fio₂ is decreased to nontoxic levels. Pressure support ventilation can also be used (with similar levels of PEEP). The initial pressure delivered should be sufficient to fully rest the respiratory muscles as judged by subjective patient assessment, respiratory rate, and accessory muscle use. Typically, a pressure support level of 10 to 20 cm H₂O over PEEP is required.

Mechanical ventilation in ALI/ARDS: Nearly all patients require mechanical ventilation, which, in addition to improving oxygenation, reduces O₂ demand by resting respiratory muscles. Targets include

• Plateau transpulmonary pressures < 30 cm H₂O (estimated from plateau alveolar pressures and a consideration of factors that potentially decrease chest wall and abdominal compliance)
• Tidal volume 6 mL/kg predicted body weight to minimize further lung injury
• Fio₂ as low as is allowed to maintain adequate SaO₂ to minimize possible O₂ toxicity

NIPPV is occasionally useful with ALI/ARDS. However, compared with treatment of cardiogenic pulmonary edema, higher levels of support for a longer duration are often required, and EPAP of 8 to 12 cm H₂O is often necessary to maintain adequate oxygenation. Achieving this expiratory pressure requires inspiratory pressures > 18 to 20 cm H₂O, which are poorly tolerated; maintaining an adequate seal becomes difficult, the mask becomes more uncomfortable, and skin necrosis and gastric insufflation may occur. Also, NIPPV-treated patients who subsequently need intubation have generally progressed to a more advanced condition than if they had been intubated earlier; thus, critical desaturation is possible at the time of intubation. Intensive monitoring and careful selection of patients (see Respiratory Failure and Mechanical Ventilation: Noninvasive positive pressure ventilation (NIPPV)) are required.

Conventional mechanical ventilation in ALI/ARDS previously focused on normalizing ABG values. It is now clear that ventilating with lower tidal volumes reduces mortality. Accordingly, in most patients, tidal volume should be set at 6 mL/kg ideal body weight (see Respiratory Failure and Mechanical Ventilation: Initial Ventilator Management in ALI/ARDS for Equation). This necessitates an increase in respiratory rate, even up to 35/min, to produce sufficient alveolar ventilation to allow for adequate CO₂ removal. On occasion, however, respiratory acidosis develops, some degree of which is accepted for the greater good of limiting ventilator-associated lung injury and is generally well tolerated, particularly when pH is ≥ 7.15. If pH drops below 7.15, bicarbonate infusion may be helpful. Because hypercapnia may cause dyspnea and cause the patient to breathe in a fashion that is not coordinated with the ventilator, analgesics (fentanylSome Trade Names
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) and sedatives may be needed (eg, propofolSome Trade Names
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initiated at 5 μg/kg/min and increasing to effect up to 50 μg/kg/min; because of the risk of hypertriglyceridemia, triglyceride levels should be checked every 48 h). Sedation is preferred to neuromuscular blockade because blockade still requires sedation and may cause residual weakness.

PEEP improves oxygenation in ALI/ARDS by increasing the volume of aerated lung through alveolar recruitment, permitting the use of a lower Fio₂. The optimal level of PEEP and the way to identify it have been debated. Many clinicians simply use the least amount of PEEP that results in an adequate arterial O₂ saturation on a nontoxic Fio₂. In most patients, this level is a PEEP of 8 to 15 cm H₂O, although occasionally, patients with severe ARDS require levels > 20 cm H₂O. In these cases, close attention must be paid to other means of optimizing O₂ delivery and minimizing O₂ consumption (see Respiratory Failure and Mechanical Ventilation: Ventilator settings).

The best indicator of alveolar overdistention is measurement of a plateau pressure through an end-inspiratory hold maneuver (see Respiratory Failure and Mechanical Ventilation: Mechanical ventilation in ALI/ARDS); it should be checked every 4 h and after each change in PEEP or tidal volume. The target plateau pressure is < 30 cm H₂O. If the plateau pressure exceeds this value and there is no problem with the chest wall that could be contributing (eg, ascites, pleural effusion, acute abdomen, chest trauma), the physician should reduce the tidal volume in 0.5– to 1.0-mL/kg increments as tolerated to a minimum of 4 mL/kg, raising the respiratory rate to compensate for the reduction in minute ventilation and inspecting the ventilator waveform display to ensure that full exhalation occurs. The respiratory rate may often be raised as high as 35/min before overt gas trapping due to incomplete exhalation results. If plateau pressure is < 25 cm H₂O and tidal volume is < 6 mL/kg, tidal volume may be increased to 6 mL/kg or until plateau pressure is > 25 cm H₂O. Some investigators believe pressure control ventilation protects the lungs better, although supportive data are lacking and it is the peak pressure rather than the plateau pressure that is being controlled.

Sidebar 1
Initial Ventilator Management in ALI/ARDS
Generally, the following approach is recommended for ventilator management in ALI/ARDS: Assist-control mode is used initially with a tidal volume 6 mL/kg ideal body weight, respiratory rate 25/min, flow rate 60 L/min, Fio2 1.0, and PEEP 15 cm H2O. Once O2 saturation is > 90%, Fio2 is decreased. Then, PEEP is decreased in 2.5-cm H2O increments as tolerated to find the least PEEP associated with an arterial O2 saturation of 90% on an Fio2 of ≤ 0.6. The respiratory rate is increased up to 35/min to achieve a pH of > 7.15, or until the expiratory flow tracing shows end-expiratory flow. Ideal body weight (IBW) rather than actual body weight is used to determine the appropriate tidal volume for patients with lung disease receiving mechanical ventilation:

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Prone positioning (see Respiratory Failure and Mechanical Ventilation: Patient positioning) improves oxygenation in some patients by allowing recruitment of nonventilating lung regions. However, there is no evidence of improved survival.

Optimal fluid management of patients with ALI/ARDS balances the requirement for an adequate circulating volume to preserve end-organ perfusion with the goal of lowering preload and thereby limiting transudation of fluid in the lungs. Recently, a large multicenter trial has shown that a conservative approach to fluid management, in which less fluid is given, shortens the duration of mechanical ventilation and ICU length of stay when compared with a more liberal strategy. However, there was no difference in survival between the 2 approaches, and use of a pulmonary artery catheter also did not improve outcome. Patients not in shock are candidates for such an approach but should be monitored closely for evidence of decreased end-organ perfusion, such as hypotension, oliguria, thready pulses, or cool extremities (see Shock and Fluid Resuscitation: Shock).

A definitive pharmacologic treatment for ALI/ARDS that reduces morbidity and mortality remains elusive. Inhaled nitric oxide, surfactant replacement, and many other agents directed at modulating the inflammatory response have been studied and found not to reduce morbidity or mortality. Some small studies suggest that systemic corticosteroids may be beneficial in late-stage ALI/ARDS, but a larger, prospective randomized trial found no reduction in mortality. Corticosteroids may be deleterious when given early in the course of the condition.

Last full review/revision August 2007 by Brian K. Gehlbach, MD; Jesse B. Hall, MD

Content last modified April 2012