Inappropriate Acetazolamide Use for a Hiker Who Developed Acute Kidney Injury

Abstract

Prophylactic use of acetazolamide (ACZ) to prevent acute mountain sickness (AMS) is a common practice among high altitude travelers and mountaineers. With its use comes a possible risk of acute kidney injury (AKI). We present a case in which a 56-year-old male hiker in Grand Canyon National Park developed acute exertional rhabdomyolysis and subsequent AKI while taking prophylactic ACZ to prevent AMS. This medication was prescribed despite the hiker encountering only moderate altitude at Grand Canyon with a planned descent within <24 h. The resulting AKI was determined to be the combined result of acute exertional rhabdomyolysis and dehydration/hypovolemia, with the ACZ, a diuretic, as a contributing factor. Medical providers need to recognize the risks/benefits with ACZ use for AMS prophylaxis and avoid prescribing it to individuals whose altitude exposure and activity fall outside the clinical practice guidelines recommended for use.

Introduction

Prophylactic acetazolamide (ACZ) for prevention of acute mountain sickness (AMS) is recommended for high altitude trekkers, especially the unacclimated, in environments generally above 2500 m with planned ascent to higher altitudes. Its use below this elevation is less common and usually unnecessary.^1–3 Additionally, AMS has not been identified as a medical condition among recreationists to Grand Canyon National Park by Emergency Medical Services. ⁴ Rather, the most common hazard confronting Grand Canyon hikers is exposure to excessive heat combined with limited accessibility to potable/nonpotable water. Consequently, hypovolemia and heat-related illness are common among Grand Canyon hikers.^4,5 Furthermore, development of acute exertional rhabdomyolysis (AER) is another potential risk when hiking in the Grand Canyon, especially with the sustained eccentric muscle contractions that occur when walking downhill.^6,7 In this case report, we present a patient who took ACZ prophylactically, which probably contributed to the development of AER and AKI.

Case Report

On March 6, 2018, a 56-year-old male with Class I obesity (body mass index of 33.50 kg/m²) and controlled hypertension arrived at Grand Canyon National Park's South Rim, elevation 2100 m. His trip plans included a 5-day backpacking trek into the inner canyon. Several years earlier, he had completed this same hike uneventfully. Prior to this second hike, he consulted his primary care physician, who 3 months earlier had done comprehensive laboratory tests that were normal other than a borderline creatinine of 1.31 mg⋅dL⁻¹ (normal range 0.76-1.27 mg⋅dL⁻¹). Because of previously experienced shortness of breath at elevations >2700 m while in Colorado, the patient expressed a desire to avoid any acute altitude symptoms while at Grand Canyon's rim country. In addition to his maintenance blood pressure medicine, omelsartan, his doctor then prescribed ACZ 250 mg to be taken twice daily starting 2 days before his hike.

After 1 night on the rim and after having taken a total of 1000 mg ACZ within the 48 h prior, the patient descended (∼13% inclination) 776 m in elevation and 12 km down the South Kaibab Trail, arriving at the canyon bottom by mid-day. Air temperature neared 26.6 °C. During his 6-h hike, the patient had taken several rest breaks and consumed an estimated 3 L of water.

Due to extreme calf and thigh muscle soreness, the patient spent the next day resting in his tent. Despite this, by day 3, his leg discomfort had worsened. Additionally, he had been anuric for 36 h. Physically unable to hike, he contacted the emergency services at the Phantom Ranch ranger station. On the morning of day 4, he was evacuated by helicopter to the South Rim's clinic, where he presented with normal vital signs and in no acute distress but was unable to ambulate due to extreme pain, swelling, and weakness in his calves and thighs. Laboratory testing revealed an elevated serum creatinine (CR) level of 7.5 mg⋅dL⁻¹, a creatine kinase (CK) level exceeding the maximum limit, 7000 U⋅L⁻¹, measurable by the device (normal range for males 55-170 U⋅L⁻¹), and an elevated potassium level of 5.2 mmol⋅L⁻¹ (normal range 3.5-5.0 mmol⋅L⁻¹). Pedal pulses, sensation, and motor function remained intact in his feet. After administration of 2 L of intravenous (IV) normal saline, he was able to provide a scant specimen of urine, brown in color. He was diagnosed with AER and AKI and was transported to Flagstaff Medical Center for further treatment.

On arrival there, the patient was given another 2 L of IV normal saline. Repeat laboratory testing confirmed AKI and AER, with a serum CR level of 7.5 mg⋅dL⁻¹, a blood urea nitrogen (BUN) level of 81 mg⋅dL⁻¹ (normal range 7-20 mg⋅dL⁻¹), and a CK level of 73,767 U⋅L⁻¹. Elevated alanine aminotransferase (ALT; normal range 7-60 U⋅L⁻¹) and aspartate aminotransferase (AST; normal range 9-40 U⋅L⁻¹) levels at 392 and 1254 U⋅L⁻¹, respectively, also reflected muscle cell injury, not liver injury. Urinalysis was positive for blood but negative on microscopy for red blood cells, a finding consistent with rhabdomyolysis and myoglobinuria. The patient was admitted for AER and AKI and treated with IV lactated Ringers (LR). Despite this intervention, laboratory values several hours later indicated worsening renal function by an increase in CR to 8.5 mg⋅dL⁻¹ and BUN to 86 mg⋅dL⁻¹, although the CK level dropped slightly to 64,404 U⋅L⁻¹.

Nephrology consultation was obtained the following day. The patient was diagnosed with Stage 3 AKI due to a combination of AER, dehydration, and hypovolemia. Acute hemodialysis was not indicated due to his slowly improving urine output. Repeat urinalysis remained positive for blood, but no red blood cells were found on microscopy. Serum CR peaked at 9.0 mg⋅dL⁻¹, and CK decreased to 56,792 U⋅L⁻¹. The patient continued to receive IV LR at a slower rate because minor edema was present. He was also administered 5000 IU of low-molecular-weight heparin subcutaneously for deep vein thrombosis prophylaxis.

On March 11, 5 days after his evacuation, the patient’s laboratory values showed improvement in serum CR since injury onset at 8.3 mg⋅dL⁻¹, and CK dropped to 24,509 U⋅L⁻¹, but BUN remained elevated at 85 mg⋅dL⁻¹. Subsequent laboratory values showed continued improvement over the following week. The patient received physical therapy to improve his leg muscle strength and mobility. Final laboratory values on March 16, 10 days after admission, showed a CR level of 2.9 mg⋅dL⁻¹, a CK level of 682 U⋅L⁻¹, and BUN level of 29 mg⋅dL⁻¹.

Discussion

Altitude Illness

Using the Lake Louis AMS score, AMS is defined as a total of 3 or more points from 4 rated symptoms (headache, gastrointestinal symptoms, dizziness/light-headedness, and fatigue/generalized weakness) occurring in the setting of recent ascent or gain in altitude, with at least 1 point from headache.^3,8 AMS occurs at altitudes generally >2500 m but may occur as low as 2000 m.^1–3,8 High altitude cerebral edema is a progression of AMS with neurologic signs such as ataxia, altered mental status, confusion, and seizure. ¹ High altitude pulmonary edema is another potentially life-threatening condition that can develop independently of AMS. It is defined by the presence of significant dyspnea (exertional and nonexertional), cyanosis, coughing, and chest pressure/tightness. ¹ Importantly, the current recommendation for ACZ use is in the prevention and treatment of AMS and high altitude cerebral edema, but not high altitude pulmonary edema. ¹

Acetazolamide Use for AMS Prevention & Treatment

ACZ, a sulfonamide derivative, is a carbonic anhydrase inhibitor and diuretic. It is the first-line medication for treatment and prevention of AMS.^1–3 When ascending to higher altitudes, the lower partial pressure of oxygen is sensed by peripheral hypoxia-sensitive chemoreceptors, which increases respiratory drive. Hyperventilation ensues, inducing a respiratory alkalosis. By inhibiting carbonic anhydrase, ACZ induces urinary wasting of bicarbonate, thus allowing earlier compensation for the respiratory alkalosis. The resulting metabolic acidosis from bicarbonate excretion will decrease cerebrospinal fluid bicarbonate level, which allows the central chemoreceptors to respond more effectively to hypoxic stimuli.^2,3 Taking ACZ prophylactically can result in an increase in arterial oxygenation and assist in normalization of respiratory pattern, which aids in altitude acclimatization.^1,2

Several studies indicate that the effective prophylactic dose of ACZ is 250 mg per day given in divided doses of 125 mg.^1–3 Furthermore, a 2019 randomized, controlled trail conducted on trekkers to the Everest Base Camp found that 2 daily ACZ doses of 62.5 mg was just as effective for prophylactic AMS treatment as 125 mg bid. ³

Most common side effects of ACZ include paresthesia, nausea, vomiting, myopia, and increased micturesis. ⁹ Although AKI is not typically discussed as a complication of ACZ use, in rare cases (dating back to the 1970s) it has been reported as a cause of AKI and anuria.^10,11 A 2014 case report described renal failure in a patient following prophylactic ACZ use for AMS prevention. ¹¹ The patient took 1250 mg in 48 h and experienced bilateral flank pain along with anuria without radiographic evidence of an obstructive uropathy. The AKI was attributed to an ACZ-induced sulfonamide crystalluria causing an intratubular obstruction leading to retrograde urine flow.

Rhabdomyolysis

Rhabdomyolysis may result from physical, chemical, biological, or hypoxic injury to muscle cells.^7,12–15 Certain medications, including diuretics, have been associated with the development of rhabdomyolysis. ¹⁴ It is a potentially life-threatening clinical condition due to the disintegration of muscle fibers and the release of toxic intracellular components into the bloodstream. Rhabdomyolysis that arises from prolonged muscular effort is termed acute exertional rhabdomyolysis.^7,12,13 Exertional rhabdomyolysis can be diagnosed when there are severe muscle symptoms such as pain, weakness, or stiffness and evidence of myocyte injury, and CK is >5 times the upper limit of normal. ¹³

The damaged myocytes release intracellular components into the circulation, including electrolytes, myoglobin, and the enzymes (eg, CK, AST, ALT, aldolase, and lactate dehydrogenase). When a significant amount of myoglobin enters the bloodstream, it is filtered by the glomerulus and can cause AKI by damaging the glomerular structure and renal tubules through direct toxicity and generation of free radicals. Myoglobin can further exacerbate AKI by causing local renal vasoconstriction, proximal tubular necrosis, and distal tubular obstruction. ¹⁵

Although the clinical presentation of AER can vary widely, the common triad of symptoms present includes muscle pain and weakness combined with dark-brown urine. Liver dysfunction is found in roughly 25% of patients with AER. ¹⁵ AKI and disseminated intravascular coagulation typically present 12-72 h after injury onset. ¹⁵

Serum CK levels are the most specific marker of myocyte destruction, having a direct relationship with the amount of muscle damage. Although CK levels have limited reliability when used to predict the development of AKI, increasing CK levels or failure to return to normal levels despite treatment has been associated with AKI. The treatment for rhabdomyolysis includes aggressive fluid therapy because early IV fluid hydration is paramount to prevent or decrease the severity of the AKI.^12–15

Case Patient's ACZ Dosing

Despite the facts that the Grand Canyon's South Rim is only moderate in elevation and that the patient’s an itinerary included plans for rapid descent within 24 h of arrival, the patient was given ACZ 250 mg bid for prophylaxis. This dose is double what is currently recommended for AMS prophylaxis and is consistent with the currently recommended treatment dose.^1,2

While the altitude at which AMS develops in individuals can vary, the medical literature suggests that it is uncommon at <2500 m; however, prophylactic ACZ can be considered for individuals traveling to 2000 m with a prior history of performance difficulties at high altitude, plans to ascend, and limited time for acclimatization. ¹ Although this patient did have a prior history of mild altitude intolerance, it presented at an altitude of >2700 m, more than 600 m higher than the Grand Canyon's South Rim. Further, his plans included descending to lower elevation within <24 h. Given these factors, prophylactic ACZ was not indicated and certainly not at treatment dosage.

Unfortunately, the diuretic properties and potentially direct nephrotoxic effects of the 1000 mg of ACZ the patient took, combined with possible suboptimal physical conditioning and downhill eccentric muscle contraction in a warm and arid environment, likely contributed to the AKI and AER. The extent to which the ACZ contributed, however, is impossible to determine.

Summary

The use of prophylactic ACZ to prevent AMS is a common practice for high altitude travelers, and current dosing guidelines are for 125 mg bid for those ascending to altitudes >2500 m. Although rare, ACZ use comes with the risk of nephrotoxicity, the AKI in this patient was due to the combination of AER, dehydration, hypovolemia, and ACZ use. This case illustrates that medical providers need to understand the risks/benefits of ACZ use for AMS prophylaxis. Its use should be avoided in individuals whose altitude exposure and activity fall outside the recommended clinical guidelines. Again, this case illustrates that caution needs to be taken when administering ACZ for AMS prevention and that exceeding the recommended dosage guidelines for ACZ prophylactic use should be avoided.