The pathophysiology of high altitude pulmonary edema

Transcription

1 Wilderness and Environmental Medicine, 10,88-92 (1999) CLINICAL UPDATES IN WILDERNESS MEDICINE Introduction From time to time, we plan to include proceedings from the Wilderness Medical Society's educational conferences in this section. The conferences include state-of-the-art presentations by recognized experts in a particular content area, making them ideal for a section whose goal is to bring you up-to-date clinical information on core wilderness medicine topics. This issue's section includes proceedings from the "Altitude Update," which was held February 20, 1998, in Snowbird, UT, as a postconference workshop after the Wilderness Medical Society's winter meeting. It features three of the foremost authorities in highaltitude medicine. We think you will find this section and future ones like it quite worthwhile. As always, we invite your comments. Carol S. Federiuk, MD, PhD Section Editor The pathophysiology of high altitude pulmonary edema COLIN K. GRISSOM, MD, MARK R. ELSTAD, MD From the Pulmonary and Critical Care Division, Department ofintemul Medicine, LDS Hospital. Salt Lake City, UT (Dr Grissom), the Pulmonary Division and the Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah. Salt Lake City, UT (Dr Grissom, Dr Elstad), and the Department of Medicine, Veterans Affairs Medical Cellfer. Salt Lake City. UT (Dr Elstad). High-altitude pulmonary edema (HAPE) is a noncardiogenic pulmonary edema that afflicts susceptible persons who ascend to altitudes above 2500 m and remain there for hr or longer. The incidence, which varies with rate of ascent and ultimate altitude attained, has been reported to be as high as 15% in Indian troops airlifted from sea level to altitudes between 3500 and 5500 m [1], 2% in climbers making a more gradual ascent to 6150 m on Mt McKinley in Alaska [2], and 0.01 %-0.1 % in visitors to ski resorts in the Rocky Mountains at altitudes of m [3]. Factors contributing to the development of HAPE may include exertion, cold ambient temperature, or preexisting upper respiratory infections. Typical symptoms are fatigue, dyspnea at rest, decreased exercise tolerance, and a dry cough that progresses to a cough productive of white frothy sputum. Signs include cyanosis, tachycardia, tachypnea, low- Direct correspondence to Pulmonary Division. LDS Hospital, 8th Ave and CSt, Salt Lake City. UT, (Dr Grissom). grade fever, and crackles on lung auscultation. The chest radiograph shows a patchy bilateral, or unilateral in early HAPE, interstitial, with air space infiltrate more prominent in the lower lobes and a normal cardiac silhouette [4]. Treatment of HAPE consists of improving oxygenation and lowering pulmonary artery pressure, either with descent to a lower altitude or administration of supplemental oxygen. Nifedipine is a proven adjunct to therapy for HAPE [5] and may be used for prophylaxis in susceptible individuals [6]. Mild to moderate cases respond with resolution of symptoms within hours after a m descent in altitude. Untreated HAPE, however, may progress to death in less than 24 hr. Houston [7] was among the first to describe HAPE as a unique clinical syndrome in 1960, and Hultgren et al [8] showed that HAPE is a form of noncardiogenic pulmonary edema. Subsequent observations by Hultgren et al [9] implicated pulmonary hypertension at high altitude in the pathophysiology of HAPE. Persons susceptible to

2 Pathophysiology of high-altitude pulmonary edema 89 HAPE have an exaggerated hypoxic pulmonary vasoconstrictor response that leads to elevated pulmonary artery pressures at high altitudes. Hackett et al [10] reported four cases of HAPE at moderate altitudes in persons with congenital absence of the right pulmonary artery, suggesting that overperfusion of a constricted pulmonary vascular bed leads to lung leak in HAPE. The role of overperfusion and pulmonary hypertension in HAPE is supported by the efficacy of nifedipine in prevention [6] and treatment [5], where the presumed mechanism is the lowering of pulmonary artery pressure. Inhaled nitric oxide (NO) is also an effective treatment for HAPE because it vasodilates the pulmonary circulation in wellventilated areas and reduces the perfusion of areas in which "patchy" pulmonary edema occurs, thereby improving ventilation perfusion-matching [11]. Hypoxic pulmonary vasoconstriction, overperfusion, and increased pulmonary artery pressure are clearly associated with the pathophysiology of HAPE. However, it has been debated whether these events result in a highpressure (transudative) edema or a permeability edema due to injury of the endothelium. Schoene et al (12,13] performed fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) on individuals with HAPE at 4200 m on Mt McKinley, AK, and found high concentrations of proteins in the lavage fluid, consistent with increased capillary permeability. In association with increased pulmonary artery pressure in HAPE, Hultgren [14] proposed that uneven hypoxic pulmonary vasoconstriction leads to recruitment and overdistension of some parts of the pulmonary vascular bed. Exercise and cold at high altitudes may redistribute blood volume to the central circulation because of sympathetic stimulation and further overperfuse an already-compromised pulmonary vascular bed. The importance of sympathetic tone in the pulmonary vascular bed in HAPE is supported by the finding of Hackett et al [15] that intravenous phentolamine, a short-acting alpha-adrenergic blocker, decreased pulmonary vascular resistance and improved gas exchange in persons with HAPE. Mechanical injury to pulmonary endothelial cells, in the setting of elevated pulmonary artery pressures and overperfusion, may be caused by several mechanisms, including stretching of endothelial cell intercellular junctions and pores, shear stress from increased velocity of blood flow as proposed by Staub [16], or stress failure secondary to increased capillary transmural pressure as proposed by West et al [17]. Any of these mechanical causes of endothelial cell injury could result in increased capillary permeability. Recently, the concept of HAPE as a form of permeability edema has been challenged. Kleger et al [18] studied systemic albumin escape in subjects at low altitudes and then after development of pulmonary edema at high altitudes. The transcapillary escape rate of albumin was only slightly higher in HAPE, suggesting that an extensive pulmonary capillary leak was not a dominant feature of HAPE. How can this be reconciled with the elevated alveolar fluid protein concentration observed in HAPE? This might be explained by an intact alveolar epithelium that actively pumps water out of flooded alveoli faster than protein via the Na+ - K+ ATPase. Matthay and Weiner-Kronish [19] showed that increased alveolar protein concentration was associated with a better outcome in both cardiogenic and noncardiogenic pulmonary edema, presumably because injury to the alveolar epithelium was limited. In HAPE, endothelial cell injury may be limited to isolated areas of overperfused pulmonary capillaries. Therefore, areas of capillary permeability are patchy rather than extensive, and the alveolar epithelium is relatively spared. This is consistent with the easy reversibility of HAPE with appropriate therapy as compared with the acute respiratory distress syndrome (ARDS) and the patchy distribution of infiltrates observed on the chest radiograph. Several studies suggest that inflammation may also play a role in the pathophysiology of HAPE. Schoene et al [12,13] reported increased leukocytes, primarily macrophages, and increased markers of inflammation including thromboxane B2, a mediator of pulmonary hypertension, and leukotriene B4, a potent chemotactic factor for leukocytes, in bronchoaveolar lavage (BAL) fluid from climbers with HAPE at 4200 m on Mt McKinley. Investigators in Japan reported increased leukocytes, macrophages and neutrophils, and increased concentrations of IL-1 beta, IL-6, and IL-8 in BAL fluid from climbers with HAPE [20]. Finally, Kaminsky et al [21] reported increased urinary leukotrienes in persons with HAPE at more moderate altitudes (2700 m and higher) in Summit County, Colorado. These findings suggest that an inflammatory response does occur in HAPE, either as a primary event or in response to mechanical endothelial cell injury. Studies of leukocyte adhesion molecules in plasma and BAL fluid of patients with HAPE suggest that endothelial cell activation, platelet activation, and neutrophil recruitment in the lung in HAPE is not as extensive as that in ARDS. E-selectin is a leukocyte adhesion molecule that is expressed on the surface of activated or injured endothelial cells and is released into the circulation in a soluble form. Plasma concentrations of soluble E-selectin are elevated in HAPE [22]. This suggests that endothelial cell injury and leukocyte recruitment occur in HAPE. Interestingly, patients with acute mountain sickness (AMS) who were hypoxemic but did not have

3 90 HAPE also had elevated E-selectin. This suggests that endothelial cell injury and lung interstitial edema occur in the setting of AMS before development of frank HAPE. This is supported by studies showing an elevated alveolar to arterial oxygen pressure difference [23], a decreased forced vital capacity [24], or a decreased diffusing capacity for carbon monoxide [25] in patients with AMS. P-selectin, another adhesion molecule expressed on endothelial cells and activated platelets and released into the circulation in a soluble form, is not elevated in plasma [22] or BAL fluid [20] in patients with HAPE but is markedly elevated in patients with ARDS [26], again suggesting that endothelial cell injury and platelet activation in HAPE are not as extensive as in ARDS. An inflammatory response in the lung may cause increased capillary permeability and allow leakage of fluid into alveoli at lower hydrostatic pressures. Animal studies suggest that inflammation may predispose the lung to increased capillary permeability at high altitudes. Rats injected with endotoxin have increased lung edema after exposure to high altitudes [27], and rats pretreated with dexamethasone are protected from lung leak on exposure to high altitudes [28]. A preexisting respiratory infection during ascent to high altitudes is known to increase susceptibility to HAPE in humans [29]. Inflammation, therefore, may "prime" the pulmonary endothelium to mechanical injury and increase susceptibility to HAPE on ascent to high altitudes. Autopsy studies clearly show inflammation associated with terminal HAPE. Autopsy specimens from persons dying of HAPE show diffuse lung edema, neutrophil alveolitis, focal alveolar hemorrhages, thrombi in small pulmonary arteries, and alveolar hyaline membranes [30]. Right ventricular and atrial dilation with a normal left ventricle and atrium were also observed. Histologically, these findings are consistent with diffuse alveolar damage, the hallmark of ARDS. Terminal HAPE, therefore, has much in common with ARDS, and two cases of HAPE progressing to ARDS are reported in the literature [31]. In early HAPE, as compared with ARDS, the initial process appears to be patchy rather than diffuse, the initial inflammatory response consists of predominantly macrophages rather than neutrophils, and there is little evidence for fibrosis or collagen turnover, such as that seen in the later stages of ARDS. The focal areas of alveolar hemorrhage noted at autopsy, however, may begin very early in the pathophysiology [32] and may result from pressure-induced pulmonary capillary damage in selected overperfused regions. Theories describing the mechanism of HAPE must account for 1) high pulmonary artery pressures, presumably caused by an exaggerated hypoxic pulmonary va- Grissom and Elstad soconstrictor response; 2) increased permeability edema and alveolar hemorrhage; 3) a patchy distribution ofedema, as seen on the chest radiograph and at autopsy; and 4) easy reversibility with appropriate treatment. A possible mechanism may include overperfusion of selected areas of the pulmonary vascular bed secondary to uneven hypoxic pulmonary vasoconstriction, leading to mechanical injury to endothelial cells with an ensuing permeability edema and alveolar hemorrhage. Inflammation may be a predisposing event, or it may occur concomitantly with mechanical endothelial cell injury. Discussion Question: Would anti-inflammatory agents, and specifically the new leukotriene antagonists, be useful in preventing HAPE? Dr Grissom: That is very interesting; we are doing a study on Denali this spring to evaluate zileuton, a 5 lipoxygenase inhibitor, in prevention of AMS and correlate AMS symptoms with urinary leukotriene levels. Experience with a complicated disease like ARDS, however, would suggest that the inflammatory pathways are complicated and interrelated, and blocking one may not have a desired therapeutic effect. Question: Free radicals have been suggested to participate in the pathophysiology of high altitude cerebral edema (HACE), and it seems to me that the effect of free radicals on membranes and permeability might be something involved in HAPE, but I have seen very little evidence that this is a factor. Do you have any information? Dr Elstad: I think that the effect of free radicals is hard to measure. We tried to look for evidence of free radical generation in ARDS patients by measuring superoxide anion, and were not able to measure it using standard techniques. So, I think that free radicals are a possibility, but unfortunately when you are interested in the lungs, blood measurements are probably worthless and lavage measurements have not been forthcoming. Question: You said that with the rat model of endotoxin you could predispose a rat to high-altitude pulmonary edema with endotoxin. In that same rat model, if you prime with endotoxin, you can reduce the likelihood of pulmonary edema from endotoxin, which is thought to be related to production of oxygen scavengers. So the study would be, if you prime with endotoxin, can you then further reduce the likelihood of pulmonary edema with altitude in rats?

4 Pathophysiology of high-altitude pulmonary edema Dr Elstad: I think that that would be a good experiment. They have a couple of problems, though; one is the dose responses, and the timing has to be very carefully controlled. The second problem, at least from my point of view, is how close is that model to what we are really interested in with HAPE? There is not a lot of evidence, for example, that gram-negative infection occurs in HAPE. Question: The big issue regarding inflammation vs pressure is a chicken vs egg phenomenon, which comes first? Even in HAPE-susceptible subjects, there is nothing about acute exposure to hypobaric hypoxic that produces inflammation or capillary leak by itself. Although the stress failure hypothesis is intellectually appealing, it has not been proved or really even demonstrated in humans. Is it possible that there is simply a wide individual variability in how much pulmonary capillary pressure you need to overdistend a pore and cause a capillary leak? Dr Grissom: I agree that individual susceptibility is key, and maybe we didn't stress that enough. The strongest predictors of HAPE are, first, a prior history of HAPE and, second, rate of ascent and eventual altitude attained. So future studies should concentrate on the unique aspects of those HAPE- susceptible persons, perhaps as Dr Elstad suggested, by taking a step further beyond BAL and obtaining transbronchial biopsies of the lung during ascent in a controlled environment such as an altitude chamber. References 1. Singh I, Khanna PK, Srivastava MC, et al. Acute mountain sickness. N Engl J Med. 1969;280: Hackett PH, Roach RC, Schoene RB, et al. The Denali medical research project, Am Alpine J. 1986; 28: Sophocles AM. High-altitude pulmonary edema in Vail, Colorado, West J Med. 1986;144: Schoene RB, Hackett PH, Hombein TF. High altitude. In: Murray JF, Nadel JA, eds. Textbook of Respiratory Medicine. 2nd ed. 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5 Ono S, Wesctcott IY, Chang SW, et al. Endotoxin priming followed by high altitude causes pulmonary edema in rats. J Appl Physiol. 1993;74: Stelzner TJ, O'Brien RF, Sato K, et al. Hypoxia-induced increases in pulmonary transvascular protein escape in rats. J Clin Invest. 1988;82: Durmowicz AZ, Noordeweir E, Nicholas R, et al. Inflammatory processes may predispose children to high-altitude pulmonary edema. J Pediatr. 1997;130: Grissom and Elstad 30. Hultgren HN, Wilson R, Kosek IC. Lung pathology in high-altitude pulmonary edema. Wild Environ Med. 1997; 8: Zimmerman GA, Crapo RO. Adult respiratory distress syndrome secondary to high altitude pulmonary edema. West J Med. 1980;133: Grissom CK, Albertine KH, Elstad MR. Alveolar haemorrhage in a case of high altitude pulmonary oedema. Thorax. In press.