Noncardiogenic pulmonary edema is a disease process that results in acute hypoxia secondary to a rapid deterioration in respiratory status. The disease process has multiple etiologies, all of which require prompt recognition and intervention. Increased capillary permeability and changes in pressure gradients within the pulmonary capillaries and vasculature are mechanisms for which noncardiogenic pulmonary edema occurs. To differentiate from cardiogenic pulmonary edema, pulmonary capillary wedge pressure is not elevated and remains less than 18 mmHg. This is important to differentiate as the management changes based on this distinction. Other findings during the initial evaluation of the patient may include a lack of acute cardiac disease or inappropriate fluid balance, flat neck veins, and the absence of peripheral edema. Chest imaging may reveal a peripheral distribution of bilateral infiltrates with no evidence of excessive pulmonary vasculature congestion or cardiomegaly. An echocardiogram may also be used to confirm a lack of acute systolic or diastolic dysfunction. These findings suggest a noncardiogenic source. Arguably the most recognized form of noncardiogenic pulmonary edema is acute respiratory distress syndrome (ARDS), which is a noncardiogenic pulmonary edema that has an acute onset secondary to an underlying inflammatory process such as sepsis, pneumonia, gastric aspiration, blood transfusion, pancreatitis, multisystem trauma or trauma to the chest wall, or drug overdose. Diagnosis of ARDS also requires bilateral infiltrates on chest radiograph with a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2) to be less than 300 mmHg with positive end-expiratory pressure (PEEP) of 5 cmH2O. Clinical context also necessitates no evidence of acute heart failure or hypervolemia in the setting of ARDS. The scope of noncardiogenic pulmonary edema is much broader than ARDS. It includes other etiologies, which include high altitude pulmonary edema, neurogenic pulmonary edema, opioid overdose, salicylate toxicity, pulmonary embolism, reexpansion pulmonary edema, reperfusion pulmonary edema, and transfusion-related acute lung injury (TRALI). Treatment is specific to the underlying etiology, and all require prompt recognition as clinical decline can be rapid and severe.
Most of the different etiologies of noncardiogenic pulmonary edema are rare but are essential to include on broad differential diagnosis in the appropriate clinical setting. ARDS affects roughly 200000 patients in the United States, 75000 of which are associated with mortality. ARDS is also responsible for 10% of intensive care unit (ICU) admissions globally. HAPE is a rare disease that does not have a systematic epidemiologic analysis; however, those who have risk factors for acute mountain sickness with assent to altitudes greater than 2250 meters are at risk for HAPE. TRALI is the leading cause of death from a blood transfusion and is more commonly seen in critically ill patients, as these patients often require more transfused blood products, and can be found in 1 of 5000 units of packed red blood cells. TRALI also has increased incidence in blood products with a higher ratio of plasma content, with 1 in 2000 plasma containing components and 1 in 400 whole blood products. Female donors have a higher incidence of TRALI; this was thought to be due to human leukocyte antigen (HLA) antibiotics found in parous female donors.
The underlying pathology is at the microvascular level due to the increase in pulmonary vascular pressure. In addition to this, the capillaries also become leaky, causing the formation of edema. The imbalance between the hydrostatic and oncotic forces, along with the enhanced permeability of the pulmonary capillaries results in pulmonary edema. The capillaries become permeable due to the underlying cause such as sepsis, pancreatitis, etc.
History will include a patient who has had progressive worsening of respiratory status and increasing dyspnea. Depending on the specific etiology, this could happen very rapidly. A thorough evaluation should take place as disease processes such as ARDS can occur in the setting of an increased inflammatory response in the body, such as sepsis, trauma, pneumonia, and pancreatitis. History should also include medication review, specifically opioid and salicylate use, as these can rarely cause noncardiogenic pulmonary edema. Recent or current blood transfusions, risk factors for pulmonary embolism, recent thoracic surgery should be a consideration. With appropriate geography, rapid ascent with increasing altitude may cause noncardiogenic pulmonary edema, and this should warrant further inquiry if suspected. The physical examination can rule out a cardiogenic source of pulmonary edema. Flat neck veins, appropriate fluid balance, lack of peripheral edema are findings in noncardiogenic pulmonary edema.
The evaluation should exclude a cardiogenic source; this can be done by echocardiogram to assess any changes in left ventricular ejection fraction or acute changes in the systolic or diastolic function of the heart. If the etiology is unclear from physical examination or echocardiogram, definitive evaluation is possible by assessment of pulmonary capillary wedge pressure; wedge pressure of less than 18 mmHg will rule out a cardiogenic etiology. Chest imaging should be next, which, if ARDS is of concern, will show bilateral infiltrates. Arterial blood gas will reveal a PaO2/FiO2 ratio (P/F ratio) of less than 300 in ARDS. Reexpansion and reperfusion pulmonary edema may cause unilateral pulmonary edema. TRALI should be considered in a patient with respiratory decline and hypoxia within 6 hours of a blood transfusion.
Treatment of noncardiogenic pulmonary edema involves addressing the underlying cause of the event. There are currently no treatment options to address the vascular permeability in ARDS. Therefore management involves supportive care and treatment of the underlying disease process until there is the resolution of the acute lung injury. Inhaled nitric oxide, prostacyclin, anti-inflammatory therapy, and high-frequency ventilation has not shown consistent clinical benefit. The other causes of noncardiogenic pulmonary edema are also managed similarly with supportive care, including supplemental oxygen or mechanical ventilation, if needed as well as addressing the inciting cause.
Differential diagnosis should include cardiogenic pulmonary edema as this is a cause of pulmonary edema that needs to be ruled out. In the appropriate clinical context with systemic inflammation, sepsis, or severe injury, evaluation for ARDS is necessary. HAPE should be a diagnostic option if the history provides quick ascent in altitude. Medication and drug use should be reviewed to assess for salicylate toxicity and opioid overdose, as these often get overlooked as etiologies of pulmonary edema. Pulmonary embolism should always be considered if presenting with dyspnea, tachycardia, or signs of hemodynamic instability. Reexpansion and reperfusion pulmonary edema should also be a differential, and the provider should consider TRALI if pulmonary edema and hypoxia present within 6 hours of a blood transfusion. The following list of differentials should be reviewed:
Prognosis varies depending on the cause of noncardiogenic pulmonary edema. Severe ARDS carries a 40% mortality rate. HAPE recurs in 60% of patients who ascend above 4500 meters and have a previous diagnosis of HAPE. Prognosis is poor in neurogenic pulmonary edema as this condition is associated with an insult to the central nervous system (CNS), 71% of those with intracranial hemorrhage were documented to have NPE. However, there are no statistics concerning NPE in the context of other neurologic conditions such as epilepsy. Ischemia-reperfusion injury accounts for 25% of the mortality after lung transplantation. Mortality from TRALI is 5 to 10%; however, it can reach 47% in critically ill patients.
The main complication from noncardiogenic pulmonary edema is ventilator-dependent respiratory failure requiring intubation and possible prolonged requirement of the ventilator, which necessitates prompt diagnosis to prevent the severity of this complication.
In appropriate situations, noncardiogenic pulmonary edema is preventable. Patients should be educated about HAPE if they have been found to have pulmonary edema in the setting of a rapid increase in altitude, as these patients risk a 60% chance of recurrence with a rapid ascent to greater than 4500 meters. Salicylate toxicity is a consideration in those with chronic use, and opioid users should receive education about the adverse effects of chronic opioid use and the possible sequela of pulmonary edema.
A collaborative healthcare team is vital to the prompt recognition of noncardiogenic pulmonary edema. The nursing staff is critical for the recognition of reactions during a blood transfusion, which, if acted on, can prevent TRALI. Pharmacists can have an active role in those being prescribed opioids and salicylates and can recognize the rare adverse effects of these drugs as the development of pulmonary edema. ARDS can more promptly be diagnosed in the ICU with the care team cooperation between the intensive care physician, respiratory therapy, and nursing staff. Interprofessional communication at all levels plays a key role in case management and directing optimal outcomes.[Level V]
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