To the Editor
We write to report a case highlighting the possible association between lisdexamfetamine (Vyvanse), a low-potency amphetamine commonly prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), and new-onset high altitude pulmonary edema (HAPE). The high-potency amphetamine fenfluramine has well-known side effects of both normobaric pulmonary hypertension and increased HAPE susceptibility. 1 In fact, fenfluramine displayed such devastatingly toxic cardiovascular effects that it was banned by the US Federal Drug Administration more than a decade ago. In contrast, lisdexamfetamine is one of a class of increasingly popular low-potency amphetamines (prescribed for pediatric and adult ADHD treatment) that have not yet been clearly implicated with increased HAPE susceptibility. From a public health perspective, the risk of significant side effects owing to the marked increase in prevalence of prescriptions for these low-potency amphetamines should not go unnoted.
Our patient was a previously healthy, physically active 49-year-old man with a history as a successful mountaineer who experienced marked dyspnea at rest after summiting Mt Rainier (4389 m [14 400 feet]). His medical history was significant only for chronic, asymptomatic ventricular arrhythmias with fully intact ejection fraction and functional capacity, and a recent diagnosis of ADHD for which he only recently was prescribed lisdexamfetamine 20 mg orally once daily. This patient had previously summited Mt Rainier 3 times and had 25 additional significant exposures higher than 3048 m (10 000 feet) with no significant altitude-related illness.
The patient left his home (<304.8 m [1000 feet] elevation) and arrived at the base of Mt Rainier 4 days before the onset of symptoms. At this time, he began a previously well-tolerated course of acetazolamide (125 mg, 3 times/d) for altitude prophylaxis in addition to his daily lisdexamfetamine. He was on no other medications. Three days later during his summit climb, at 4206 m (13 800 feet), our patient began to note markedly atypical and rapidly progressive dyspnea, first on exertion and then at rest. Despite climbs at similar altitudes and exertion levels in the recent past, our patient had never before experienced this dyspnea at rest. The patient then noted the onset of a dry raspy cough. Although he successfully reached the summit, his dyspnea continued to progress and required frequent prolonged rest stops on descent. Upon reaching Camp Muir (3072 m [10 080 feet]), an experienced National Park Service ranger noted him to be in marked respiratory distress. Given his worrisome appearance, the ranger initiated an immediate helicopter evacuation for a clinical diagnosis of acute HAPE. On arrival, the flight medics noted a regular heart rate at 116 beats/min, systolic blood pressure of 130 mm Hg, respiratory rate of 26 breaths/min, and oxygen saturation of 85% on 4 L/min nasal cannula. They documented the patient as being in respiratory distress, with regular rhythm with occasional premature ventricular contractions, and bilateral mild pulmonary rales to auscultation. His examination was otherwise unremarkable.
After the administration of oxygen and during helicopter descent, our patient noted a rapid improvement of his dyspnea. At no point did he experience chest pain, fever, lightheadedness, or palpitations. He was transferred to a ground ambulance at 1524 m (5000 feet) and taken to a sea level hospital, by which time he had been on oxygen more than 6 hours and his symptoms had fully resolved. Initial evaluation described a limited, asymptomatic ventricular ectopy, which had been previously noted at low altitude. His chest roentgenogram and electrocardiogram were read as unremarkable. During an admission to the hospital, he was evaluated for and subsequently exonerated of having acute coronary syndrome, pneumonia, pulmonary embolism, decreased ejection fraction, impaired cardiac wall motion, and valvular abnormalities. Despite the absence of radiopaque infiltrates on chest roentgenogram, he was ultimately diagnosed with HAPE at the time of discharge.
High altitude pulmonary edema typically develops at altitudes higher than 2438 m (8000 feet) within 2 to 3 days of exposure with an incidence of 0.1%–1.6%. 2 The diagnosis requires a combination of at least 2 symptoms: dyspnea at rest, cough, decreased exercise performance, chest tightness, or congestion; and at least 2 physical examination findings: tachycardia, tachypnea, crackles or wheezing heard in the lungs, or hypoxia. 3 High altitude pulmonary edema develops as a result of pulmonary hypertension, resulting in degeneration of the alveolar blood-gas barrier and the consequent development of interstitial edema. 2
The present data regarding prescription amphetamine effects on the pulmonary vasculature are limited to several case reports and retrospective studies, predominantly of the banned high-potency agent fenfluramine, including the aforementioned case report of fenfluramine-associated HAPE. Although scant, the current data point to an association between even low-potency amphetamines and pulmonary arterial hypertension, including several case reports of lisdexamfetamine inducing pulmonary arterial hypertension. 1 ,4,5 The mechanism of this relationship likely involves both direct and indirect sympathomimetic effects, ultimately leading to pulmonary vasculature vasoconstriction.
Limitations of this report are many. By the time he was evaluated at the sea level hospital, this patient had received more than 6 hours of oxygen therapy and greater than 3962 m (13 000 feet) of descent, and his symptoms had resolved in full. Despite documentation of audible rales on examination in the field, given the lack of a compelling chest roentgenogram suggestive of edema at the sea level hospital, it is possible he did not have HAPE. Several alternative diagnoses were entertained during our patient's evaluation, including medication side effect (dyspnea 2%), excessive acetazolamide-induced diuresis from inappropriate dosing (although our patient had taken the identical regimen previously), an interaction between acetazolamide and the metabolism or excretion of lisdexamfetamine, and ventricular trigeminy (a chronic diagnosis previously well tolerated). These competing diagnoses continue to appear much less likely than a new occurrence of HAPE.
Given the increasingly large numbers of pediatric and adolescent patients on low-potency oral amphetamines, close surveillance is indicated. Further investigations into low-potency oral amphetamine use and potential increased HAPE susceptibility will be required to establish an association.