Patchy Vasoconstriction Versus Inflammation: A Debate in the Pathogenesis of High Altitude Pulmonary Edema

Abstract

High altitude pulmonary edema (HAPE) occurs in individuals rapidly ascending at altitudes greater than 2,500 m within one week of arrival. HAPE is characterized by orthopnea, breathlessness at rest, cough, and pink frothy sputum. Several mechanisms to describe the pathophysiology of HAPE have been proposed in different kinds of literature where most of the mechanisms are reported to be activated before a drop in oxygen saturation levels. The majority of the current studies favor diffuse hypoxic pulmonary vasoconstriction (HPV) as a pathophysiological basis for HAPE. However, some of the studies described inflammation in the lungs and genetic basis as the pathophysiology of HAPE. So, there is a major disagreement regarding the exact pathophysiology of HAPE in the current literature, which raises a question as to what is the exact pathophysiology of HAPE. So, we reviewed 23 different articles which include clinical trials, review articles, randomized controlled trials (RCTs), and original research published from 2010 to 2020 to find out widely accepted pathophysiology of HAPE. In our study, we found out sympathetic stimulation, reduced nitric oxide (NO) bioavailability, increased endothelin, increased pulmonary artery systolic pressure (PASP) resulting in diffuse HPV, and reduced reabsorption of interstitial fluid to be the most important determinants for the development of HAPE. Similarly, with the evaluation of the role of inflammatory mediators like C-reactive protein (CRP) and interleukin (IL-6), we found out that inflammation in the lungs seems to modulate but not cause the process of development of HAPE. Genetic basis as evidenced by increased transcription of certain gene products seems to be another promising hypoxic change leading to HAPE. However, comprehensive studies are still needed to decipher the pathophysiology of HAPE in greater detail.

Research Progress on the Mechanism of Right Heart-Related Pulmonary Edema

“…The reduction of the total volume of pulmonary capillaries, pulmonary perfusion, and the increase in pulmonary capillary filtration pressure after pneumonectomy are the key factors leading to its occurrence. Ischemia or reperfusion injury, inflammatory response, endothelial injury, lung overexpansion, and impaired lymphatic drainage are also involved in the pathophysiological process [ 46 , 47 ]. Intraoperative volume overload, preoperative radiation therapy, infusion of fresh frozen plasma, and intraoperative high-pressure mechanical ventilation are the independent risk factors for PPE [ 48 ].…”

Extravascular lung water and cardiac function assessed by echocardiography in healthy lowlanders during repeated very high-altitude exposure

“…It has been speculated that initially elevated hydrostatic pressure causes capillary leakage followed by extravasation of large-molecular-weight proteins and erythrocytes in the interstitial space, creating an increased osmotic gradient and increasing pulmonary edema [51]. Other potential modulating factors in HAPE could include the degree of inflammation or a susceptible genetic background [48,[51][52][53][54]. On the other hand, our findings of sustained elevated EVLW contrast results from a study at 4350 m, in which B-lines progressively dwindled during 3 days at altitude [17].…”

A Case for Hydrogen Sulfide Metabolism as an Oxygen Sensing Mechanism

“…High altitude pulmonary edema (HAPE) occurs in un-acclimatized individuals upon rapid ascent to altitudes over 2500 m. HAPE is noncardiogenic and generally attributed to pulmonary vasoconstriction-mediated exudate as a result of sympathetic stimulation, reduced nitric oxide (NO) bioavailability or increased endothelin; inflammatory mediators such as C-reactive protein (CRP) and interleukin (IL-6) may further modulate the disease but do not appear to be the cause [ 252 , 253 ].…”