- Email: [email protected]
High-altitude pulmonary edema: More lessons from the master
Wilderness and Environmental Medicine, 8,202-203 (1997)
EDITORIAL High-altitude pulmonary edema: More lessons from the master "We all labour against our own cure, for death is the cure of all diseases. " [Sir Thomas Browne, Religio Medici (1642)] Despite what pathologists say, death may be the cure; but it is not the answer. The article by Hultgren et al. in this issue is a perfect demonstration of this concept [1]. They have reported on 10 autopsy cases of high-altitude pulmonary edema (HAPE) and have left us with results that give insight into the terminal events of RAPE but do not help us understand the mechanism of the early events in its pathophysiology. Because almost all victims of HAPE recover completely, the factors that lead to death in the rare few may be little related to the cascade of events in the clinical entity itself. But given the paucity of information on necropsy data in HAPE, the article is still a valuable contribution to the field. Herb Hultgren was the leading investigator in the field of HAPE in the 1960s and 1970s and continued his interest and contribution to the field until his death this year. Herb observed that HAPE occurred in otherwise healthy young individuals who ascended rapidly to high altitude. With pulmonary artery catheterizations, Herb demonstrated that HAPE was not secondary to left ventricular dysfunction but was associated with accentuated pulmonary hypertension [2,3]. The present report also confirms his reports of some 30 years ago and shows that the left ventricles were normal, but the right atria and ventricles showed signs of hypertrophy and strain. Recent studies in the Italian Alps demonstrated that nifedipine lowered pulmonary artery pressures in HAPE-susceptible climbers who ascended to high altitude. This calcium channel blocker and vasodilator prevented HAPE, thus supporting the association of high pulmonary vascular pressures and HAPE [4]. Fiberoptic bronchoscopic examination of alveolar fluid by bronchoalveolar lavage (BAL) at high altitude on Mt. McKinley revealed remarkable findings in climbers with HAPE [5,6]. The consistent findings demonstrated very high protein concentrations including high molecular proteins as well as presence of chemotactic (LTB 4 ) and vasoactive (thromboxane B2 ) mediators in the alveolar fluid. Additionally, there was evidence of chemotaxis, primarily for macrophages rather than neutrophils. These BAL studies defined HAPE as a permeability leak with evidence of inflammation but could not clarify the sequence of events preceding the leak. The questions re1080-6032.© 1997 Chapman & Hall
mained: did the high pressures lead to insult of the microvascular endothelium and leak that subsequently incited an inflammatory response, or did some degree of inflammation make the endothelium vulnerable to the high pressures? A recent study of tourists at moderate altitude in Colorado found that there was a clinical history of a concomitant or preceding viral upper respiratory infection in almost 75% of their patients [7], which suggests that inflammation may play an important permissive role. Thus to date, HAPE is known to be a form of noncardiogenic pulmonary edema that is associated with individuals who have accentuated pulmonary vascular pressures when exposed to hypoxia and exercise and who many times have either clinical or biochemical markers of inflammation. The autopsy reports of 10 HAPE victims by Hultgren et al. support some of the above findings in patients who survived HAPE, yet some perplexing questions remain. Because the large majority of HAPE patients not only survive but recover fully and quickly, what differentiates the patients in this report from the usual victims? Did a concomitant infection lead to pneumonia, which pared away the margin of physiological safety between life and death at high altitude? Did the situation of each subject prevent rescue and thus allow the cascade of catastrophic events that lead to unsupportable hypoxemia? Do the postmortem specimens represent in any way the pre-mortem state that can help us to unravel the mechanism of disease? Blood-stained fluid was diffusely present in the heavy lungs at autopsy, which supports the impression of many clinical and radiographic studies, but ironically only one patient had the presence of hyaline membranes, the gold standard for the presence of organizing proteinaceous alveolar fluid. The predominance of neutrophils over macrophages contrasts with the lavage data but may give insight into the end of the spectrum of a process when the initial leak is faced with a continuing insult and avalanches into overwhelming inflammation. As in previous postmortem reports, thrombi were found in the microvasculature of many subjects; these are more likely a result of perimortem stasis of blood flow than an initial event. Several studies have looked into the role of hypercoagulability in the development of altitude illnesses and have not found a consistent relationship [8J. The suggestion of pneumonia in some subjects tracks the earlier postmortem studies. The manuscript by Hultgren and Wilson is a welcome addition to the field of maladaptation at high altitude, but more importantly it is a tribute to Herb Hultgren whose tireless pursuit of the understanding of human adaptation at
203
Editorial
high altitude is a standard that will be hard to match. We all will miss his humble, unquenchable curiosity. Herb, it is an honor for me and others to follow your lead.
References 1. Hultgren H.N., Wilson, R Lung pathology in high-altitude pulmonary edema. J Wilderness and Environ Med 1998; 8, 000000. 2. Hultgren, H.N., Lopez, C.E., Lundberg, E., Miller, H. Physiologic studies of pulmonary edema at high altitude. Circulation 1964; 29, 393-408. 3. Hultgren, H.N., Grover, R.F., Hartley, L.H. Abnormal circulatory responses to high altitude in subjects with a previous history of high-altitude pulmonary edema. Circulation 1971; 44, 759-770. 4. Bartsch P., Maggiorini, M., Ritter, M., et al. Prevention of high
5.
6.
7.
8.
altitude pulmonary edema by nifedipine. N Engl J Med 1991; 1284-1289. Schoene, R.B., Hackett, P.H., Henderson, W.R., et al. Highaltitude pulmonary edema: Characteristics of lung lavage fluid. JAMA 1986; 256, 63-69. Schoene, RB., Swenson, E.R, Pizzo, c.J., et al. The lung at high altitude: Bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol 1988; 64, 26052613. Kaminsky, D.A., Jones, K., Schoene, RB., Voelkel, N.F. Urinary leukotriene E 4 in high-altitude pulmonary edema: A possible role for inflammation. Chest 1996; 110, 939-945. Bartsch, P., Waber, U., Haeberli, A., et al. Enhanced fibrin formation in high-altitude pulmonary oedema. J Appl Physiol 1987; 63, 752-757. ROBERT B. SCHOENE, MD
Seattle, Washington, USA
EDITORIAL High-altitude pulmonary edema: More lessons from the master "We all labour against our own cure, for death is the cure of all diseases. " [Sir Thomas Browne, Religio Medici (1642)] Despite what pathologists say, death may be the cure; but it is not the answer. The article by Hultgren et al. in this issue is a perfect demonstration of this concept [1]. They have reported on 10 autopsy cases of high-altitude pulmonary edema (HAPE) and have left us with results that give insight into the terminal events of RAPE but do not help us understand the mechanism of the early events in its pathophysiology. Because almost all victims of HAPE recover completely, the factors that lead to death in the rare few may be little related to the cascade of events in the clinical entity itself. But given the paucity of information on necropsy data in HAPE, the article is still a valuable contribution to the field. Herb Hultgren was the leading investigator in the field of HAPE in the 1960s and 1970s and continued his interest and contribution to the field until his death this year. Herb observed that HAPE occurred in otherwise healthy young individuals who ascended rapidly to high altitude. With pulmonary artery catheterizations, Herb demonstrated that HAPE was not secondary to left ventricular dysfunction but was associated with accentuated pulmonary hypertension [2,3]. The present report also confirms his reports of some 30 years ago and shows that the left ventricles were normal, but the right atria and ventricles showed signs of hypertrophy and strain. Recent studies in the Italian Alps demonstrated that nifedipine lowered pulmonary artery pressures in HAPE-susceptible climbers who ascended to high altitude. This calcium channel blocker and vasodilator prevented HAPE, thus supporting the association of high pulmonary vascular pressures and HAPE [4]. Fiberoptic bronchoscopic examination of alveolar fluid by bronchoalveolar lavage (BAL) at high altitude on Mt. McKinley revealed remarkable findings in climbers with HAPE [5,6]. The consistent findings demonstrated very high protein concentrations including high molecular proteins as well as presence of chemotactic (LTB 4 ) and vasoactive (thromboxane B2 ) mediators in the alveolar fluid. Additionally, there was evidence of chemotaxis, primarily for macrophages rather than neutrophils. These BAL studies defined HAPE as a permeability leak with evidence of inflammation but could not clarify the sequence of events preceding the leak. The questions re1080-6032.© 1997 Chapman & Hall
mained: did the high pressures lead to insult of the microvascular endothelium and leak that subsequently incited an inflammatory response, or did some degree of inflammation make the endothelium vulnerable to the high pressures? A recent study of tourists at moderate altitude in Colorado found that there was a clinical history of a concomitant or preceding viral upper respiratory infection in almost 75% of their patients [7], which suggests that inflammation may play an important permissive role. Thus to date, HAPE is known to be a form of noncardiogenic pulmonary edema that is associated with individuals who have accentuated pulmonary vascular pressures when exposed to hypoxia and exercise and who many times have either clinical or biochemical markers of inflammation. The autopsy reports of 10 HAPE victims by Hultgren et al. support some of the above findings in patients who survived HAPE, yet some perplexing questions remain. Because the large majority of HAPE patients not only survive but recover fully and quickly, what differentiates the patients in this report from the usual victims? Did a concomitant infection lead to pneumonia, which pared away the margin of physiological safety between life and death at high altitude? Did the situation of each subject prevent rescue and thus allow the cascade of catastrophic events that lead to unsupportable hypoxemia? Do the postmortem specimens represent in any way the pre-mortem state that can help us to unravel the mechanism of disease? Blood-stained fluid was diffusely present in the heavy lungs at autopsy, which supports the impression of many clinical and radiographic studies, but ironically only one patient had the presence of hyaline membranes, the gold standard for the presence of organizing proteinaceous alveolar fluid. The predominance of neutrophils over macrophages contrasts with the lavage data but may give insight into the end of the spectrum of a process when the initial leak is faced with a continuing insult and avalanches into overwhelming inflammation. As in previous postmortem reports, thrombi were found in the microvasculature of many subjects; these are more likely a result of perimortem stasis of blood flow than an initial event. Several studies have looked into the role of hypercoagulability in the development of altitude illnesses and have not found a consistent relationship [8J. The suggestion of pneumonia in some subjects tracks the earlier postmortem studies. The manuscript by Hultgren and Wilson is a welcome addition to the field of maladaptation at high altitude, but more importantly it is a tribute to Herb Hultgren whose tireless pursuit of the understanding of human adaptation at
203
Editorial
high altitude is a standard that will be hard to match. We all will miss his humble, unquenchable curiosity. Herb, it is an honor for me and others to follow your lead.
References 1. Hultgren H.N., Wilson, R Lung pathology in high-altitude pulmonary edema. J Wilderness and Environ Med 1998; 8, 000000. 2. Hultgren, H.N., Lopez, C.E., Lundberg, E., Miller, H. Physiologic studies of pulmonary edema at high altitude. Circulation 1964; 29, 393-408. 3. Hultgren, H.N., Grover, R.F., Hartley, L.H. Abnormal circulatory responses to high altitude in subjects with a previous history of high-altitude pulmonary edema. Circulation 1971; 44, 759-770. 4. Bartsch P., Maggiorini, M., Ritter, M., et al. Prevention of high
5.
6.
7.
8.
altitude pulmonary edema by nifedipine. N Engl J Med 1991; 1284-1289. Schoene, R.B., Hackett, P.H., Henderson, W.R., et al. Highaltitude pulmonary edema: Characteristics of lung lavage fluid. JAMA 1986; 256, 63-69. Schoene, RB., Swenson, E.R, Pizzo, c.J., et al. The lung at high altitude: Bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol 1988; 64, 26052613. Kaminsky, D.A., Jones, K., Schoene, RB., Voelkel, N.F. Urinary leukotriene E 4 in high-altitude pulmonary edema: A possible role for inflammation. Chest 1996; 110, 939-945. Bartsch, P., Waber, U., Haeberli, A., et al. Enhanced fibrin formation in high-altitude pulmonary oedema. J Appl Physiol 1987; 63, 752-757. ROBERT B. SCHOENE, MD
Seattle, Washington, USA