Respiratory Complications Associated With Acetazolamide Use in the Management of Idiopathic Intracranial Hypertension

Clinical Correspondence Respiratory Complications Associated With Acetazolamide Use in the Management of Idiopathic Intracranial Hypertension Fiona Costello, MD, FRCPC, Kate Skolnik, MD, FRCPC, Justyna Sarna, MD, PhD, FRCPC, Rhea Varughese, MD, FRCPC I diopathic intracranial hypertension (IIH) is characterized by manifestations of raised intracranial pressure and predominantly affects overweight young women (1). Although common symptoms of IIH include headaches, visual loss, and pulsatile tinnitus, the clinical presentation is highly variable (1). There is an emerging consensus that acetazolamide ameliorates the effects of IIH (1,2). By stopping the conversion of water and carbon dioxide to bicarbonate and hydrogen ions with carbonic anhydrase inhibition, acetazolamide reduces cerebrospinal fluid secretion with the consequent reduction of water and ions across the choroid plexus (1). In the 2014 IIH Treatment Trial, patients were treated with acetazolamide up to 4 g daily, with an average adherence of 89% in the treatment group (2,3). Seventeen treated IIH patients (20%) experienced 23 metabolic adverse effects, including metabolic acidosis (n = 6), decreased appetite (n = 6), hyperchloremia (n = 4), hypokalemia (n = 4), and dehydration (n = 2) (2,3). Although the metabolic acidosis associated with acetazolamide is typically mild, we present 2 IIH cases in which acetazolamide was associated with severe metabolic acidosis and respiratory compromise. CASE 1 A 52 -year old woman presented with a longstanding history of IIH (diagnosed by modified Dandy criteria), asthma/chronic obstructive pulmonary disease (COPD) overlap syndrome, and obesity (body mass index [BMI] = 37 kg/m2). Her baseline spirometry showed mixed obstruction from airway disease and restriction from obesity (forced expiratory volume 1 1.48 L [53%], forced vital capacity 2.30 L [65%], ratio 64%). Three years before, she successfully used acetazolamide 2,500 mg daily during an IIH exacerbation with severe visual compromise. She had tapered her daily acetazolamide dose to 500–750 mg when Departments of Clinical Neurosciences and Surgery (FC), Medicine– Respirology (KS, RV); and Clinical Neurosciences (JS), University of Calgary, Calgary, Canada. The authors report no conflicts of interest. Address correspondence to Fiona Costello, MD, FRCPC, Foothills Medical Centre, Clincial Neurosciences, 12th Floor, 1403-29th Street NW, Calgary, Alberta, Canada T2N 2T9; E-mail: fi[e-mail] Costello et al: J Neuro-Ophthalmol 2019; 39: 511-512 she developed dyspnea, cough, fever, and somnolence. Arterial blood gas (ABG) revealed hypercapnia and acute respiratory acidosis with metabolic acidosis (pH 7.02, pCO2 121 mm Hg, pO2 75 mm Hg on 6 L of oxygen, HCO3 31 mmol/L), requiring 2 days of mechanical ventilation. While in the intensive care unit, she demonstrated numerous obstructive hypopneas with sustained oxygen desaturations, suggesting hypoventilation. She was diagnosed with multifactorial hypercapnic respiratory failure caused by COPD exacerbation and community-acquired pneumonia, worsened by untreated sleep-disordered breathing and smoking. Because of her presentation and profound academia, acetazolamide was discontinued. Her symptoms of headache and optic disc edema were well controlled after initiating continuous positive airway pressure therapy (titrated by polysomnogram) for chronic nocturnal hypoventilation. CASE 2 A 32-year old obese woman (BMI = 38 kg/m2) with a 14year history of IIH (meeting modified Dandy criteria) and no known lung disease presented with severe headaches, vision loss, and papilledema. Her headaches were initially treated with twice daily acetazolamide 500 mg and topiramate 25 mg, without clinical improvement. After increasing acetazolamide to 1,500 mg per day, she developed painless dyspnea and tachypnea (without hypoxia). Primary pulmonary causes of dyspnea were excluded by chest x-ray, a computed tomography pulmonary angiogram, and ultrasound of the lower limbs. There was no wheeze, suggestive of asthma. ABG demonstrated normoxemia with an acute, partially compensated metabolic acidosis (low pH 7.35; low pCO2 24 mm Hg, high pO2 98 mm Hg, low HCO3 13 mmol/L, and high chloride 120 mmol/L). Contributions from renal disease, diabetes, and medication withdrawal were excluded. The hyperventilation was not due to anxiety, as this would be associated with respiratory alkalosis and hypophosphatemia. Her dyspnea resolved with cessation of acetazolamide and topiramate. The patient underwent lumbar drain insertion and ventriculoperitoneal shunt treatment to manage her condition, with complete clinical 511 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence recovery. Her diagnosis was hyperventilation in response to metabolic acidosis, caused by combined topiramate and acetazolamide. Interestingly, in previous years, this patient had tolerated acetazolamide monotherapy of 2000 mg daily in divided doses. Six years before, she had used acetazolamide 500 mg 3 times daily with topiramate 75 mg twice daily without complications. Metabolic acidosis is the excessive accumulation of nonvolatile acid, leading to a reduction in serum bicarbonate concentration and low plasma pH (4). Clinical manifestations of metabolic acidosis in IIH are highly variable (5,6) and may include hyperventilation, fatigue, anorexia, cardiac arrhythmias, and coma (4,6). Both acetazolamide and topiramate cause metabolic acidosis, by inhibiting carbonic anhydrase enzymes required for effective bicarbonate reabsorption in the kidneys (4). Acetazolamide causes bicarbonaturia and mild hyperchloremic metabolic acidosis, whereas topiramate generates a hyperchloremic metabolic acidosis (4). In Case 1, the patient had significant comorbidities. Thus, the extent acetazolamide contributed to her clinical decline is unclear. She was using a relatively low dose of acetazolamide when she developed respiratory failure, despite tolerating much higher doses previously. Regrettably, the complexity of her airway disease and obstructive sleep apnea with mild hypoventilation was unknown to her treating physicians because of her earlier noncompliance with pulmonary follow-up. Carbonic anhydrase inhibition may lead to impaired ventilation perfusion matching and reduction in hypoxic drive, worsening hypercapnia in the acutely unwell patient. This case illustrates the importance of communication between multidisciplinary team members regarding the potential deleterious effects of drugs that have the potential to exacerbate coexisting medical conditions. In Case 2, the topiramate and acetazolamide combination caused the patient’s risk of metabolic acidosis, prompting a compensatory increase in the respiratory rate to reduce arterial carbon dioxide to normalize the pH. Excluding other causes of dyspnea, including primary pulmonary pathology, hyperventilation secondary to other causes of metabolic acidosis, and anxiety-induced hyperventilation (characterized by respiratory alkalosis and hypophosphatemia), was essential. This patient demonstrated good tolerability for these agents in combination 512 previously. Her respiratory manifestations of metabolic acidosis seemed to be dose-dependent with the amount of daily acetazolamide she received. The lessons learned from this case include avoiding dual therapy with agents having carbonic anhydrase inhibitor activity when possible. Moreover, recognizing clinical manifestations of metabolic acidosis is critical because it has been linked to cerebral edema and coning in the setting of IIH in extreme circumstances (6). In summary, acetazolamide may result in adverse respiratory symptoms among individuals with or without lung disease, particularly when used at high doses and/or combined with topiramate. Individuals using acetazolamide for IIH should be monitored for electrolyte imbalances and tachypnea because these uncommon but potentially severe side effects may have insidious onset. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: F. Costello, K. Skolnik, J. Sarna, and R. Varughese; b. Acquisition of data: F. Costello; c. Analysis and interpretation of data: F. Costello, K. Skolnik, J. Sarna, and R. Varughese. Category 2: a. Drafting the manuscript: F. Costello, K. Skolnik, J. Sarna, and R. Varughese; b. Revising it for intellectual content: F. Costello, K. Skolnik, J. Sarna, and R. Varughese. Category 3: a. Final approval of the completed manuscript: F. Costello, K. Skolnik, J. Sarna, and R. Varughese. REFERENCES 1. Markey KA, Mollan SP, Jensen RH, Sinclair AJ. Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions. Lancet Neurol. 2016;15:78–91. 2. Wall M, McDermott MP, Kieburtz KD, et al; for the NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA. 2014;311:1641–1651. 3. Quick S, Linn D. Chapter 18 diuretics. Side Eff Drugs Annu. 2017;39:189–195. 4. Pham AQ, Xu LH, Moe OW. Drug-induced metabolic acidosis. F1000Res. 2015;4:F1000 Faculty Rev-1460. 5. Strohmaier M, Baum RA, Bailey AM, Bronner J. Development of acute metabolic acidosis in a pediatric patient with idiopathic intracranial hypertension treated with acetazolamide: a case report. Ann Clin Case Rep Pediatr. 2018;3:1530. 6. Borire AA, Hughes AR, Lueck CJ. Tonsillar herniation after lumbar puncture in idiopathic intracranial hypertension. J Neuroophthalmol. 2015;35:293–295. Costello et al: J Neuro-Ophthalmol 2019; 39: 511-512 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.