(See also Overview of Mechanical Ventilation Overview of Mechanical Ventilation Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more .)
Etiology of Acute Hypoxemic Respiratory Failure
Airspace filling in acute hypoxemic respiratory failure (AHRF) may result from
Elevated alveolar capillary hydrostatic pressure, as occurs in left ventricular failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular failure causes shortness of breath and fatigue, and right ventricular failure causes peripheral and abdominal fluid... read more (causing pulmonary edema Pulmonary Edema Pulmonary edema is acute, severe left ventricular failure with pulmonary venous hypertension and alveolar flooding. Findings are severe dyspnea, diaphoresis, wheezing, and sometimes blood-tinged... read more ) or hypervolemia
Increased alveolar capillary permeability, as occurs in any of the conditions predisposing to acute respiratory distress syndrome (ARDS)
Blood (as occurs in diffuse alveolar hemorrhage Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage is persistent or recurrent pulmonary hemorrhage. There are numerous causes, but autoimmune disorders are most common. Most patients present with dyspnea, cough, hemoptysis... read more ) or inflammatory exudates (as occur in pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more or other inflammatory lung conditions)
Right-to-left intracardiac shunts, in which deoxygenated venous blood bypasses the lungs and enters the systemic circulation, usually occur as a long-term complication of large, untreated left-to-right shunts (eg, from patent foramen ovale, atrial septal defect). This phenomenon is termed Eisenmenger syndrome Eisenmenger Syndrome Eisenmenger syndrome is a complication of uncorrected large intracardiac or aortic to pulmonary artery left-to-right shunts. Increased pulmonary resistance may develop over time, eventually... read more . This discussion focuses on refractory hypoxemia due to pulmonary causes.
Pathophysiology of Acute Hypoxemic Respiratory Failure
ARDS is divided into 3 categories of severity: mild, moderate, and severe based on oxygenation defects and clinical criteria (see table Berlin Definition of ARDS Berlin Definition of ARDS Acute hypoxemic respiratory failure is severe arterial hypoxemia that is refractory to supplemental oxygen. It is caused by intrapulmonary shunting of blood resulting from airspace filling or... read more ). The mild category corresponds to the previous category termed acute lung injury (ALI).
In 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 Pulmonary Hypertension Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels become constricted... read more . The airspace collapse more commonly occurs in dependent lung zones. This early phase of ARDS is termed exudative. Later, there is proliferation of alveolar epithelium and fibrosis, constituting the fibro-proliferative phase.
Causes of ARDS may involve direct or indirect lung injury.
Common causes of direct lung injury are
Less common causes of direct lung injury are
Common causes of indirect lung injury include
Trauma with prolonged hypovolemic shock
Less common causes of indirect lung injury include
Drug overdose (eg, aspirin, cocaine, opioids, phenothiazines, tricyclics)
Neurogenic pulmonary edema due to stroke, seizure, head trauma, anoxia
Radiographic contrast (rare)
Sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more and pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more account for about 60% of cases.
Whatever the cause of airspace filling in AHRF, flooded or collapsed airspaces allow no inspired gas to enter, so the blood perfusing those alveoli remains at the mixed venous oxygen content no matter how high the fractional inspired oxygen (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 occur in asthma Asthma Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more or chronic obstructive pulmonary disease Chronic Obstructive Pulmonary Disease (COPD) Chronic obstructive pulmonary disease (COPD) is airflow limitation caused by an inflammatory response to inhaled toxins, often cigarette smoke. Alpha-1 antitrypsin deficiency and various occupational... read more and, to some extent, in ARDS) is readily corrected by supplemental oxygen.
Symptoms and Signs of Acute Hypoxemic Respiratory Failure
Acute hypoxemia (see also Oxygen Desaturation Oxygen Desaturation Patients without respiratory disorders who are in the intensive care unit (ICU)—and other patients—may develop hypoxia (oxygen saturation read more ) may cause dyspnea, restlessness, and anxiety. Signs include confusion or alteration of consciousness, cyanosis, tachypnea, tachycardia, and diaphoresis. Cardiac arrhythmia Overview of Arrhythmias The normal heart beats in a regular, coordinated way because electrical impulses generated and spread by myocytes with unique electrical properties trigger a sequence of organized myocardial... read more and coma can result.
Inspiratory opening of closed airways causes crackles, detected during chest auscultation; the crackles are typically diffuse but sometimes worse at the lung bases, particularly in the left lower lobe. Jugular venous distention occurs with high levels of positive end-expiratory pressure (PEEP) or right ventricular failure.
Diagnosis of Acute Hypoxemic Respiratory Failure
Chest x-ray and arterial blood gas (ABG) measurement
Hypoxemia is usually first recognized using pulse oximetry. Patients with low oxygen saturation should have a chest x-ray and ABGs and be treated with supplemental oxygen while awaiting test results.
If supplemental oxygen does not improve the oxygen 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 can occur 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 myocardial infarction Acute Myocardial Infarction (MI) Acute myocardial infarction is myocardial necrosis resulting from acute obstruction of a coronary artery. Symptoms include chest discomfort with or without dyspnea, nausea, and diaphoresis.... read more , pancreatitis Overview of Pancreatitis Pancreatitis is classified as either acute or chronic. Acute pancreatitis is inflammation that resolves both clinically and histologically. Chronic pancreatitis is characterized by histologic... read more , sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more ) is an obvious cause. In other cases, history is suggestive; pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more should be suspected in an immunocompromised patient, and alveolar hemorrhage is suspected after bone marrow transplantation 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 due to left ventricular failure 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 ARDS are generally more peripheral. Focal infiltrates are typically caused by lobar pneumonia, atelectasis Atelectasis Atelectasis is collapse of lung tissue with loss of volume. Patients may have dyspnea or respiratory failure if atelectasis is extensive. They may also develop pneumonia. Atelectasis is usually... read more , or lung contusion Pulmonary Contusion Pulmonary contusion is trauma-induced lung hemorrhage and edema without laceration. (See also Overview of Thoracic Trauma.) Pulmonary contusion is a common and potentially lethal chest injury... read more . Although echocardiography may show left ventricular dysfunction, implying a cardiac origin, this finding is not specific because sepsis can also reduce myocardial contractility.
When 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 Air embolism Nonthrombotic sources of pulmonary embolism include air, fat, amniotic fluid, infected material, foreign bodies, and tumors. Pulmonary embolism (PE) can arise from nonthrombotic sources. PE... read more , or transfusion Transfusion-related acute lung injury (TRALI) The most common complications of transfusion are Febrile nonhemolytic reactions Chill-rigor reactions The most serious complications, which have very high mortality rates, are Acute hemolytic... read more . When no predisposing cause can be uncovered, some experts recommend doing bronchoscopy with bronchoalveolar lavage to exclude alveolar hemorrhage and eosinophilic pneumonia Overview of Eosinophilic Pulmonary Diseases Eosinophilic pulmonary diseases are a heterogeneous group of disorders characterized by the accumulation of eosinophils in alveolar spaces, the interstitium, or both. Peripheral blood eosinophilia... read more and, if this procedure is not revealing, a lung biopsy to exclude other disorders (eg, hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis is a syndrome of cough, dyspnea, and fatigue caused by sensitization and subsequent hypersensitivity to environmental (frequently occupational or domestic) antigens... read more , acute interstitial pneumonitis).
Prognosis for Acute Hypoxemic Respiratory Failure
Prognosis is highly variable and depends on a variety of factors, including etiology of respiratory failure, severity of disease, age, and chronic health status. Overall, mortality in 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. However, mortality remains very high (> 40%) for patients with severe ARDS (ie, those with a PaO2:FIO2 < 100 mm Hg). 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 months in most 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 of Acute Hypoxemic Respiratory Failure
Mechanical ventilation if oxygen saturation is < 90% on high-flow oxygen
Underlying conditions must be addressed as discussed elsewhere. AHRF is initially treated with high flows of 70 to 100% oxygen by a nonrebreather face mask. If oxygen saturation > 90% is not obtained, mechanical ventilation probably should be instituted. Specific management varies by condition.
Mechanical ventilation in cardiogenic pulmonary edema
Mechanical ventilation (see also Overview of Mechanical Ventilation Overview of Mechanical Ventilation Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more ) benefits the failing left ventricle in several ways. Positive inspiratory pressure reduces left and right ventricular preload and left ventricular afterload and reduces 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 Respiratory Mechanics Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more [EPAP] or PEEP) redistributes pulmonary edema from alveoli to the interstitium, allowing more alveoli to participate in gas exchange.
Noninvasive positive pressure ventilation (NIPPV) Noninvasive positive pressure ventilation (NIPPV) Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more , whether continuous positive pressure ventilation or bilevel ventilation, 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 Means and Modes of Mechanical Ventilation Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more . 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 to 8 mL/kg ideal body weight, respiratory rate of 25/minute, 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 inspiratory airway 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 ARDS
Nearly all patients with ARDS require mechanical ventilation, which, in addition to improving oxygenation, reduces oxygen demand by resting respiratory muscles. Targets include
Plateau alveolar pressures < 30 cm H2O (factors that potentially decrease chest wall and abdominal compliance considered)
Tidal volume 6 mL/kg predicted body weight to minimize further lung injury
FIO2 as low as is allowed to maintain adequate oxygen saturation to minimize possible oxygen toxicity
PEEP Ventilator settings Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more should be high enough to maintain open alveoli and minimize FIO2 until a plateau pressure of 28 to 30 cm H2O is reached. Patients with moderate to severe ARDS are the most likely to have mortality reduced by use of higher PEEP.
NIPPV Noninvasive positive pressure ventilation (NIPPV) Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more is occasionally useful with 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 for NIPPV are required.
Conventional mechanical ventilation in ARDS previously focused on normalizing arterial blood gas values. It is 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 sidebar Initial Ventilator Management in ARDS Initial Ventilator Management in ARDS Acute hypoxemic respiratory failure is severe arterial hypoxemia that is refractory to supplemental oxygen. It is caused by intrapulmonary shunting of blood resulting from airspace filling or... read more ). This setting necessitates an increase in respiratory rate, even up to 35/minute, to produce sufficient alveolar ventilation to allow for adequate carbon dioxide removal. On occasion, however, respiratory acidosis Respiratory Acidosis Respiratory acidosis is primary increase in carbon dioxide partial pressure (Pco2) with or without compensatory increase in bicarbonate (HCO3−); pH is usually low but may be near normal. Cause... read more 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 or tromethamine may be helpful. Similarly, oxygen saturation below "normal" levels may be accepted; target saturation of 88 to 95% limits exposure to excessive toxic levels of FiO2 and still has survival benefit.
Because hypercapnia may cause dyspnea and cause the patient to breathe in a fashion that is not coordinated with the ventilator, analgesics (fentanyl or morphine) and sedatives (eg, propofol initiated at 5 mcg/kg/minute and increasing to effect up to 50 mcg/kg/minute; because of the risk of hypertriglyceridemia, triglyceride levels should be checked every 48 hours) may be needed. Sedation is preferred to neuromuscular blockade because blockade still requires sedation and may cause residual weakness.
PEEP Ventilator settings Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more improves oxygenation in 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. Routine use of recruitment maneuvers (eg, titration of PEEP to maximal pressure of 35 to 40 cm H2O and held for 1 minute) followed by decremental PEEP titration was found to be associated with an increased 28-day mortality (1 Treatment references Acute hypoxemic respiratory failure is severe arterial hypoxemia that is refractory to supplemental oxygen. It is caused by intrapulmonary shunting of blood resulting from airspace filling or... read more ). Therefore, many clinicians simply use the least amount of PEEP that results in an adequate arterial oxygen 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 oxygen delivery and minimizing oxygen consumption.
The best indicator of alveolar overdistention is measurement of a plateau pressure through an end-inspiratory hold maneuver Respiratory Mechanics Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more ; it should be checked every 4 hours 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 Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more , pleural effusion Pleural Effusion Pleural effusions are accumulations of fluid within the pleural space. They have multiple causes and usually are classified as transudates or exudates. Detection is by physical examination and... read more , acute abdomen, chest trauma Overview of Thoracic Trauma Thoracic trauma causes about 25% of traumatic deaths in the US. Many chest injuries cause death during the first minutes or hours after trauma; they can frequently be treated at the bedside... read more ), 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/minute 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, but supportive data are lacking, and it is the peak pressure rather than the plateau pressure that is being controlled. With pressure control ventilation, because the tidal volume will vary as the patient's lung compliance evolves, it is necessary to continually monitor the tidal volume and adjust the inspiratory pressure to ensure that the patient is not receiving too high or too low a tidal volume.
Prone positioning Patient positioning Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more improves oxygenation in some patients by allowing recruitment of nonventilating lung regions. One study suggests this positioning substantially improves survival (2, 3 Treatment references Acute hypoxemic respiratory failure is severe arterial hypoxemia that is refractory to supplemental oxygen. It is caused by intrapulmonary shunting of blood resulting from airspace filling or... read more ). Interestingly, the mortality benefit from prone positioning is not related to the degree of hypoxemia or the extent of gas exchange abnormality but possibly to mitigating ventilator-induced lung injury (VILI).
Optimal fluid management in patients with 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. 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 length of stay in the intensive care unit 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 (4 Treatment references Acute hypoxemic respiratory failure is severe arterial hypoxemia that is refractory to supplemental oxygen. It is caused by intrapulmonary shunting of blood resulting from airspace filling or... read more ). Patients not in shock Shock Shock is a state of organ hypoperfusion with resultant cellular dysfunction and death. Mechanisms may involve decreased circulating volume, decreased cardiac output, and vasodilation, sometimes... read more 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.
A definitive pharmacologic treatment for ARDS that reduces morbidity and mortality remains elusive. Inhaled nitric oxide, surfactant replacement, activated protein C (drotrecogin alfa), 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 (fibroproliferative) 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.
1. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura ÉA, et al: Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: A randomized clinical trial. JAMA 318(14):1335–1345, 2017. doi: 10.1001/jama.2017.14171
2. Guérin C, Reignier J, Richard JC, et al: Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 368(23):2159–2168, 2013. doi: 10.1056/NEJMoa1214103
3. Scholten EL, Beitler JR, Prisk GK, et al: Treatment of ARDS with prone positioning. Chest 151:215–224, 2017. doi: 10.1016/j.chest.2016.06.032. Epub 2016 Jul 8
4. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354(24):2564–2575, 2006. doi: 10.1056/NEJMoa062200