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Management of High Altitude Pulmonary Edema in the Himalaya: A Review of 56 Cases Presenting at Pheriche Medical Aid Post (4240 m)

Published:October 11, 2012DOI:https://doi.org/10.1016/j.wem.2012.07.004

      Objective

      The purpose of this study was to review the patient characteristics and management of 56 cases of high altitude pulmonary edema at the Pheriche Himalayan Rescue Association Medical Aid Post, and to measure the use of medications in addition to descent and oxygen.

      Methods

      In a retrospective case series, we reviewed all patients diagnosed clinically with high altitude pulmonary edema during the 2010 Spring and Fall seasons. Nationality, altitude at onset of symptoms, physical examination findings, therapies administered, and evacuation methods were evaluated.

      Results

      Of all patients, 23% were Nepalese, with no difference in clinical features compared with non-Nepalese patients; 28% of all patients were also suspected of having high altitude cerebral edema. Symptoms developed in 91% of all patients at an altitude higher than the aid post (median altitude of onset of 4834 m); 83% received oxygen therapy, and 87% received nifedipine, 44% sildenafil, 32% dexamethasone, and 39% acetazolamide. Patients who were administered sildenafil, dexamethasone, or acetazolamide had presented with significantly lower initial oxygen saturations (P ≤ .05). After treatment, 93% of all patients descended; 38% descended on foot without a supply of oxygen.

      Conclusions

      A significant number of patients presenting to the Pheriche medical aid post with high altitude pulmonary edema were given dexamethasone, sildenafil, or acetazolamide in addition to oxygen, nifedipine, and descent. This finding may be related to perceived severity of illness and evacuation limitations. Although no adverse effects were observed, the use of multiple medications is not supported by current evidence and should not be widely adopted without further study.

      Key words

      Introduction

      High altitude pulmonary edema (HAPE) is a potentially fatal disease that occurs in otherwise healthy persons after ascent to altitudes of more than 2000 m. The incidence of HAPE among unacclimatized travelers to high altitude varies widely, ranging between 0.2% and 15%,
      • Hackett P.H.
      • Rennie D.
      The incidence, importance, and prophylaxis of acute mountain sickness.
      • Menon N.D.
      High-altitude pulmonary edema: a clinical study.
      • Hultgren H.N.
      • Marticorena E.A.
      High altitude pulmonary edema Epidemiologic observations in Peru.
      depending on the setting. The development of HAPE has been associated with young age, male gender, rapid rate of ascent, strenuous exercise, previous episodes of HAPE, and conditions resulting in exaggerated hypoxemia at high altitude, such as patent foramen ovale.
      • Schoene R.B.
      Illnesses at high altitude.
      Although outcome varies significantly depending on altitude, management, and access to medical care, the mortality rate has been reported to be as high as 11%.
      • Lobenhoffer H.P.
      • Zink R.A.
      • Brendel W.
      • et al.
      High altitude pulmonary edema: analysis of 166 cases.
      High altitude pulmonary edema is a noncardiogenic form of pulmonary edema characterized by increased capillary permeability and pulmonary edema fluid with high protein and red blood cells.
      • Swenson E.R.
      • Maggiorini M.
      • Mongovin S.
      • et al.
      Pathogenesis of high-altitude pulmonary edema inflammation is not an etiologic factor.
      Right-side heart catheterization studies of HAPE patients
      • Maggiorini M.
      • Melot C.
      • Pierre S.
      • et al.
      High-altitude pulmonary edema is initially caused by an increase in capillary pressure.
      as well as transthoracic echocardiogram studies of HAPE-susceptible patients
      • Kawashima A.
      • Kubo K.
      • Kobayashi T.
      • et al.
      Hemodynamic responses to acute hypoxia, hypobaria, and exercise in subjects susceptible to high-altitude pulmonary edema.
      have demonstrated a relationship between HAPE and high isolated pulmonary artery pressures. Exaggerated and nonuniform hypoxic pulmonary vasoconstriction is thought to lead to overperfusion and stress failure in portions of the pulmonary vascular bed.
      • West J.B.
      • Tsukimoto K.
      • Mathieu-Costello O.
      • et al.
      Stress failure in pulmonary capillaries.
      Impaired alveolar fluid clearance further impairs gas exchange,
      • Vivona M.L.
      • Matthay M.
      • Chabaud M.B.
      • et al.
      Hypoxia reduces alveolar epithelial sodium and fluid transport in rats: reversal by beta-adrenergic agonist treatment.
      which can result in respiratory failure. Although elevated pulmonary artery pressure is not the sole mechanism of the disease, pulmonary vasodilators are effective in preventing HAPE in susceptible persons.
      • Bartsch P.
      • Maggiorini M.
      • Ritter M.
      • et al.
      Prevention of high-altitude pulmonary edema by nifedipine.
      • Maggiorini M.
      • Brunner La-Rocca H.P.
      • Peth S.
      • et al.
      Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.
      Despite the well-documented effectiveness of gradual ascent, cases still commonly occur along trekking routes at high altitude. Recent consensus guidelines from the Wilderness Medical Society (WMS) for the management of HAPE emphasize descent and oxygen as the cornerstone of management;
      • Luks A.M.
      • McIntosh S.E.
      • Grissom C.K.
      • et al.
      Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness.
      however, our experience is that adjunctive medications, including nifedipine, dexamethasone, salmeterol, and acetazolamide, are also frequently used. We reviewed the characteristics and management of 56 patients with HAPE who presented at the Pheriche Himalayan Rescue Association Medical Aid Post during the Spring and Fall 2010 seasons, with an aim to quantify the use of medications in addition to descent and oxygen.

      Methods

      Setting

      The village of Pheriche is located in the Solo Khumbu region of the Nepal Himalaya at 4240 m, en route to Everest Base Camp. A medical aid post was established in Pheriche in 1973, with the aim to decrease morbidity and mortality from altitude-related illness in both the indigenous population and visiting tourists. It is equipped with solar power, piped nonpotable water, 2 oxygen concentrators, portable hyperbaric chambers, portable oxygen, and an extensive supply of medications. Diagnostic capabilities are limited to vital signs, pulse oximetry, physical examination, electrocardiography (with a limited supply of paper and probes) and 2-dimensional ultrasonography (with a limited supply of gel). During each 3-month trekking season (March to May and September to November), the facility is staffed by 2 licensed physicians and a medical assistant. Approximately 60% of patients seen are Nepalese, including local residents and traveling guides and porters. Services provided include outpatient consultation, overnight hospitalization, and assistance with arranging helicopter evacuation. Consultations are $50 USD per visit for foreigners and 50 Nepali rupees (approximately $0.75 USD) for Nepalese patients. During consultations and hospitalizations, patients' vital signs, including heart rate, blood pressure, respiratory rate, and oxygen saturation by pulse oximetry are monitored frequently.

      Data Collection

      We reviewed the records of all patients who presented to the Pheriche Himalayan Rescue Association Medical Aid Post during the Spring and Fall of 2010 with a clinical diagnosis of HAPE, defined as symptoms of shortness of breath, cough, or decreased exercise tolerance within 2 to 4 days of ascent to altitude, as well as physical examination findings of inspiratory crackles. Although oxygen saturations are notoriously variable and nondiagnostic in isolation, saturations below 80% increased suspicion of HAPE when other clinical signs and symptoms were present. The diagnosis of additional high altitude cerebral edema (HACE) was based on the presence of headache as well as physical examination findings of altered mental status or ataxia. Demographic and clinical features recorded included nationality, gender, self-reported history of HAPE, rate of ascent, altitude at onset of symptoms, Lake Louise Self-Report Score for acute mountain sickness (AMS), physical examination findings, and vital signs including pulse oximetry. Oxygen therapy, medication administered, and evacuation method were reviewed. All information was deidentified before analysis and was reviewed with permission from the Himalayan Rescue Association.
      The study was submitted for review by the Intermountain Health Care Institutional Review Board (Salt Lake City, UT) and granted an exemption.

      Statistics

      Data were analyzed using STATA Version 11.2 statistical software (StataCorp, College Station, TX). Statistical associations were tested by comparing subgroups. For categorical variables, a χ2 test or Fisher's exact test, as appropriate, was used. For continuous variables, an independent sample t test was used.

      Results

      Fifty six patients were treated for HAPE, representing 5.4% of all patients seen at the aid post during the study period (total n = 1045). Of those patients with HAPE, 23% were Nepalese, and 73% were male. Characteristics of Nepalese versus non-Nepalese patients were similar except for gender (Table 1). Seven percent of all patients (n = 4) reported a history of HAPE. Symptoms developed in 91% of patients at an altitude higher than the aid post, with a median altitude of onset of 4834 m (SD 378 m). Twenty-eight percent of patients (n = 16) were also managed for suspected concurrent HACE.
      Table 1Demographics and clinical features of patients by nationality
      DemographicsNepalese (n = 13)Non-Nepalese (n = 43)P value
      Female, n (%)1 (7)14 (32)<.05
      Altitude at onset, m, mean ± SD4846 ± 3594800 ± 381.22
      Oxygen saturation, mean ± SD65 ± 14%67 ± 9%.55
      Lake Louise Score (±SD)4.1 ± 2.75.4 ± 4.0.35
      Evacuated by foot, n (%)11 (85)10 (23)<.01
      In all, 83% (n = 46) of patients were given oxygen; those not given oxygen were considered to have resolving HAPE, and the majority of those patients (80%; n = 8) continued to descend while being treated with nifedipine sustained-release 20 mg or 30 mg twice daily. The majority of patients were given medications in addition to oxygen and descent; only 3 patients were given oxygen alone; 87% (n = 49) were given nifedipine, 44% (n = 25) sildenafil 50 mg every 6 to 8 hours, 32% (n = 18) dexamethasone 4 mg every 6 hours, and 39% (n = 22) acetazolamide 250 mg twice daily. Overall, 30% were given at least 3 medications, 25% were given 2 medications, and 43% were given only 1 medication. All but 3 patients descended. Patients administered sildenafil, dexamethasone, and acetazolamide presented with significantly lower initial oxygen saturations (Table 2), suggesting that perceived severity of presentation resulted in more aggressive pharmacologic management. Patients with suspected HACE were more likely to receive dexamethasone (88% versus 10%, or RR = 8.75, P < .001). No patient had a medication discontinued because of the development of hypotension or other adverse effects.
      Table 2Pretreatment oxygen saturation of patients and medications administered
      MedicationGivenNot givenP value
      Independent samples t test.
      Sildenafil63 ± 11%69 ± 8%.02
      n = 25
      Summing samples sizes across medications produces a sample size greater than total population owing to the use of multiple medications.
      n = 31
      Dexamethasone60 ± 11.6%69 ± 8%<.001
      n = 18n = 38
      Acetazolamide63 ± 12%69 ± 9%.05
      n = 22n = 34
      Nifedipine66 ± 10%68 ± 11%.70
      n = 49n = 7
      Data shown as mean ± SD.
      a Independent samples t test.
      b Summing samples sizes across medications produces a sample size greater than total population owing to the use of multiple medications.
      The only fatality in this case series was that of a 28-year-old Nepalese trekking guide who had a history of HAPE during a prior season, as well as a vague history of cardiac disease as a child. His initial examination was notable for oxygen saturation of 50% on room air, a regular heart rate with 2/6 systolic murmur but no right ventricular heave or thrill, and initially no ataxia or altered mental status. A point-of-care echocardiogram by a noncertified technician (B.E.J.) was suspicious for mitral regurgitation, although only 2-dimensional echocardiography was available, and there was no color Doppler to confirm that or assess the severity. His left ventricular function appeared normal with no wall motion abnormalities. The right ventricle was enlarged, although we were not able to estimate right ventricular systolic pressure. No electrocardiography was performed, as this was not customary unless ischemia was suspected owing to the short supply of electrocardiography paper and probes. The patient received high-flow oxygen at our maximum capacity of 10 L/min and all adjunctive medications (nifedipine, sildenafil, dexamethasone, and acetazolamide as well as nebulized salbutamol), but his status deteriorated rapidly despite our interventions, including intubation and resuscitation, and he died after cardiopulmonary arrest 6 hours after his presentation. His death was thought to be due to respiratory failure, possibly secondary to a combination of HAPE and an underlying cardiac disease.
      The modes of evacuation are described in the Figure. Due to prohibitive cost, no Nepalese patients were evacuated by helicopter. Of the patients who descended on foot, all were accompanied, and none had a supply of oxygen.

      Discussion

      Our findings of significant use of adjunctive medications are consistent with a previous review of 10 patients treated for HAPE at Pheriche,
      • Fagenholz P.J.
      • Gutman J.A.
      • Murray A.F.
      • Harris N.S.
      Treatment of high altitude pulmonary edema at 4240 m in Nepal.
      which reported the use of nifedipine in all 10, acetazolamide in all 10, and sildenafil in 7 of 10 patients. The reviewers reported continued descent and severity of disease as factors influencing use of adjunctive therapy.
      Recent WMS guidelines for the management of HAPE emphasize descent and oxygen as the cornerstones of management.
      • Luks A.M.
      • McIntosh S.E.
      • Grissom C.K.
      • et al.
      Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness.
      Indeed, previous studies have demonstrated that patients with HAPE can clinically improve with bed rest alone, although treatment with oxygen results in more rapid recovery.
      • Marticorena E.
      • Hultgren H.N.
      Evaluation of therapeutic methods in high altitude pulmonary edema.
      • Zafren K.
      • Reeves J.T.
      • Schoene R.
      Treatment of high-altitude pulmonary edema by bed rest and supplemental oxygen.
      In a nonrandomized trial, nifedipine, a calcium channel blocker, was shown to decrease pulmonary hypertension and reduce hypoxemia in patients with HAPE in the absence of oxygen or descent.
      • Oelz O.
      • Maggiorini M.
      • Ritter M.
      • et al.
      Nifedipine for high altitude pulmonary edema.
      Although phosphodiesterase inhibitors, dexamethasone, salmeterol, and acetazolamide have also been proposed as potentially beneficial medications for preventing HAPE, no studies have established the efficacy of these medications for treating HAPE. A recent study found no additional benefit of nifedipine when oxygen and descent are available.
      • Deshwal R.
      • Iqbal M.
      • Basnet S.
      Nifedipine for the treatment of high altitude pulmonary edema.
      Because of its extensive use as adjunctive therapy, nifedipine has been deemed reasonable by current management guidelines, but additional medications are discouraged by the WMS.
      • Luks A.M.
      • McIntosh S.E.
      • Grissom C.K.
      • et al.
      Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness.
      In contrast, the Union Internationale des Associations d'Alpinisme (UIAA) emphasizes a low threshold for administering the combination of dexamethasone, nifedipine, and acetazolamide for patients at high altitude with unclear diagnoses.
      UIAA medical recommendations: AMS, HAPE, and HACE emergency field management.
      It has been argued that requiring a first responder to distinguish between altitude illnesses may be asking too much, especially for mountain guides at high altitudes;
      • Hillebrandt D.
      Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness—a view from the other side of the Atlantic [Letter].
      however, the WMS guideline is designed for medical professionals at moderate altitudes.
      • Luks A.M.
      • McIntosh S.E.
      • Grissom C.K.
      • et al.
      In reply to Dr Hillebrandt.
      This discrepancy highlights the importance of considering clinical setting and specific limitations when applying recommendations to one's practice.
      There are several theoretical risks to the administration of nifedipine, dexamethasone, or acetazolamide for treatment of HAPE. Sildenafil, a potent vasodilator, has the potential to cause systemic hypotension, especially when coadministered with nifedipine. However, this potential adverse effect was not observed in any of the 56 cases reviewed. Acetazolamide, a carbonic anhydrase inhibitor, causes a metabolic acidosis, which could theoretically exacerbate acid-base disturbance in decompensated HAPE, although acidemia is not a clear life-threatening complication of severe HAPE. Dexamethasone, a corticosteroid, has fewer hemodynamic effects and is clearly indicated for HACE and possibly indicated for severe AMS. Despite the possibility that HACE may be initially diagnosed in a patient with acute hypoxic encephalopathy, the negligible side effects of a single dose of dexamethasone are outweighed by the significant potential benefit of early initiation of dexamethasone for HACE. Therefore, a low threshold for initiating dexamethasone in patients with severe HAPE and any change in mental status, or for those with any suspicion of HACE or severe AMS, seems reasonable.
      The patients diagnosed with HAPE at the Pheriche aid post represent a unique clinical scenario. The majority of patients seek medical care after partial descent, are treated with oxygen for several hours, then resume a slow descent on foot without oxygen the next day. Unlike at high altitude ski resorts or mountain ranges with direct road access, definitive therapy with rapid descent and oxygen are not available to the majority of patients at Pheriche. The nature of descent combined with the abundance of adjunctive medications, the severity of the disease, and lack of life support capabilities likely encourages a more aggressive pharmacologic approach to treatment. Although we did not observe any deleterious effects of this approach, the use of multiple adjunctive medications for the treatment of HAPE is not supported by the medical literature. While the application of any guideline should be tailored to local resources, evacuation potential, and patient characteristics, a polypharmacological approach to treating HAPE should not be widely adopted before its safety and efficacy are further studied.

      Study Limitations

      Our study was limited by an inability to confirm the diagnosis of HAPE with chest radiography. Even though the diagnosis seemed clear for the majority of patients, alternative diagnoses, including pneumonia, cardiogenic pulmonary edema, or altitude-related pulmonary hypertension, were difficult to rule out owing to lack of diagnostic capabilities, and our population likely includes a number of false positive cases. Using accepted diagnostic criteria such as the Lake Louise criteria for HAPE would have aided more accurate case definitions and minimized interphysician variability of diagnosis. For example, neither inspiratory crackles
      • Vock P.
      • Fretz C.
      • Franciolli M.
      • Bartch P.
      High altitude pulmonary edema: findings at high altitude chest radiography and physical examination.
      nor hypoxemia is specific for HAPE, so these findings are not diagnostic for HAPE in the absence of symptoms of fatigue, shortness of breath, or signs of hypoxemia, tachycardia, or tachypnea. Although this is a significant limitation against studying clinical features of HAPE in our population, the lack of radiographic confirmation is likely similar to many other austere high-altitude settings that require providers to make diagnoses on clinical grounds, and our findings of management patterns should not be affected by this limitation.
      We did not compare variation between physicians or trekking season, and that also may have affected diagnosis and management. Future observational studies should further characterize differences in physician practice strategies and evaluate for trends in outcomes.

      Conclusions

      In this review of 56 cases of HAPE presenting to the Pheriche medical aid post at 4240 m, a significant number of patients with HAPE were given dexamethasone, sildenafil, or acetazolamide in addition to nifedipine, oxygen, and descent. Patients who presented with lower oxygen saturations were more likely to receive more aggressive medical management. A significant number of patients continued to descend from the aid post on foot, without a supply of oxygen.

      Acknowledgments

      The authors would like to thank Colin Grissom, MD, and Buddha Basnyat, MD, for critical review of the manuscript; and the University of Utah REDCap team for database management. Database management and statistical analysis were funded in part by grants from the National Institutes of Heath (CTSA 5UL1RR025764-02 and 8UL1TR000105, formerly UL1RR025764). Dr. Jones is also supported by a grant from the National Institute of Health (5T32HL105321-02).

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