Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor.

Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor. JAMA 2002;287:2228–35.Swenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbaurl H, Bartsch P. Pulmonary and Critical Care Section, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, U.S.A. Comments: This study was designed to determine whether inflammation is a primary event high-altitude pulmonary edema (HAPE) and to define the temporal sequence of events in HAPE. The study group consisted of 10 subjects with susceptibility to HAPE and 6 subjects resistant to HAPE, all of whom were nonprofessional alpinists with previous mountaineering experience above 3,000 m. Study parameters included results of bronchoalveolar lavage (BAL) and pulmonary artery (PA) pressure measurements at low altitude (490 m) and shortly before or at the onset of HAPE at an altitude of 4,559 m. HAPE was suspected clinically and confirmed if the radiograph showed patchy opacities compatible with interstitial or alveolar edema in at least one quadrant and SaO2 less than 70%. PA pressure was assessed by echocardiography. Flexible bronchoscopy was performed under topical anesthesia and intravenous sedation, and supplemental oxygen was delivered by nasal cannula at 2 to 3 L/minute. One subject in Zurich and five subjects at high altitude were unable to undergo bronchoscopy because of unsuccessful upper airway anesthesia or severe headache with acute mountain sickness. Thus, BAL data at both altitudes were obtained in 10 HAPE-susceptible and 6 HAPE-resistant subjects. BAL effluent was obtained from a subsegment of the right middle lobe by instilling 5 aliquots of 30-mL sterile pyrogen-free normal saline. A mean of 55% of the instilled fluid was recovered. BAL effluent was subjected to immediate total cell counts. The BAL effluent was subsequently used to measure total protein, albumin, immunoglobulin G, interleukin 1β, interleukin 6, interleukin 8, tumor necrosis factor α, leukotriene B4, prostaglandin E2, thromboxane B2, Clara cell protein, surfactant protein A, and concentrations of nitrate and nitrite. The results showed that systolic PA pressures were not significantly different between the HAPE-resistant and HAPE-susceptible groups at low altitude. At high altitude, mean systolic PA pressures were higher in both groups. The HAPE-susceptible subjects, however, had significantly higher pressures. The mean systolic PA pressure in the HAPE-susceptible subjects was 66 mmHg vs. 37 mmHg (p = 0.004) in the HAPE-resistant group at 4,559 m. SaO2 and PaO2 in all subjects at low altitude were normal. At high altitude immediately before BAL, there were significant differences in SaO2 and PaO2 among the three groups, demonstrating a continuum of declining SaO2 and PaO2 from those well at high altitude to those with the earliest onset of HAPE. In HAPE-resistant subjects, the chest radiograph scores remained at 0 point at high altitude, indicating no evidence of interstitial or alveolar edema. The chest roentgenograph score was 12.7 points for the three HAPE-susceptible subjects who developed HAPE before BAL was performed; they were lavaged within 3 to 5 hours. The six HAPE-susceptible subjects who developed HAPE on the day after BAL had a mean score on bronchoscopy of 1.5 points, which rose the next day to 4.6 points, reflective of mild pulmonary edema. However, there were no differences in BAL fluid total leukocyte counts between HAPE-resistant and HAPE-susceptible subjects or between counts taken at low and high altitudes. Subjects who developed HAPE had high BAL concentrations of plasma-derived proteins and erythrocytes, but there was no increase in plasma concentrations of surfactant protein A and Clara cell protein. In HAPE cases, there were no elevations in a number of proinflammatory cytokines and eicosanoid and nitric oxide metabolites. The authors conclude that early HAPE is characterized by high PA pressures that lead to a protein-rich and mildly hemorrhagic edema, with normal levels of leukocytes, cytokines, and eicosanoids, and that HAPE is a form of hydrostatic pulmonary edema with altered alveolar–capillary permeability. As noted by Swenson et al., the central issue has been whether the alveolar–capillary leak in HAPE is caused by high microvascular pressures or inflammation. The common understanding is that acute PA hypertension is the main ingredient necessary for the development of HAPE. Several studies, based on results of BAL analysis, have indicated that inflammatory etiology may play a role in well-established HAPE. Giving credence to the latter hypothesis is the known development of HAPE in children after upper respiratory tract infection, and observation of BAL neutrophilia and elevated concentrations of plasma proteins, thromboxane metabolites, and proinflammatory cytokines in BAL effluent obtained at high altitudes in patients with established HAPE (JAMA 1986;256:63–6;J Appl Physiol 1988;64:2605–13). The key feature of the study by Swenson et al. is that early HAPE is characterized by high PA pressures that lead to a protein-rich and mildly hemorrhagic edema, with normal levels of leukocytes, cytokines, and eicosanoids. These findings suggest that HAPE is a form of hydrostatic pulmonary edema with altered alveolar–capillary permeability. This study also illustrates the important role for BAL in providing important material for detailed analysis of changes that take place at the alveolar level in subjects who develop HAPE.