Acetazolamide induced noncardiogenic pulmonary edema, an underreported serious adverse event

Abstract

Purpose

To report a case of acute noncardiogenic pulmonary edema (NCPE) after administration of acetazolamide post routine cataract surgery.

Observations

30 minutes after administration of oral acetazolamide, the patient experienced abdominal pain, nausea, vomiting, diarrhea, and diaphoresis. The patient was taken to the emergency room where she was found to have pulmonary edema. After life threatening respiratory failure resulting in prolonged intubation, the patient was eventually discharged from the hospital.

Conclusions and importance

NCPE is a rare but severe adverse effect of acetazolamide and should be considered when prescribing such agents.

1. Introduction

Acetazolamide is a carbonic anhydrase inhibitor widely used in ophthalmology to control intraocular pressure in glaucoma patients and in the postoperative period after intraocular surgery, including cataract surgery.¹ The risk of serious adverse reactions following prescription of an oral or topical carbonic anhydrase inhibitor is reported as low. Rare and serious complications cited include Stevens-Johnsons syndrome, toxic epidermal necrolysis, and aplastic anemia.² In this article, we present the first reported case in the United States of acute NCPE occurring after one dose of oral acetazolamide, as well as providing a review of the existing literature on this rare but serious adverse event.

2. Case report

A 59-year-old white female of Mediterranean (Italian) descent underwent uncomplicated cataract surgery in her right eye for nuclear sclerotic and mild posterior subcapsular cataract with phacoemulsification and intraocular lens implantation under monitored anesthesia care with 2mg of midazolam and no other systemic analgesic agents. Her past medical history includes anemia, malignant essential hypertension, mixed hyperlipidemia, type 2 diabetes and personal history of mild COVID-19 infection four months prior to surgery, which was treated without complications with nirmatrelvir/ritonavir. There was no evidence of “Long Covid” or other sequelae. Her home medications included atorvastatin, ferrous sulfate, insulin lispro, insulin glargine, losartan-hydrochlorothiazide, metformin, omeprazole, liraglutide, and vitamin B2. Past surgical history included cholecystectomy, and gastric surgery for morbid obesity in 2010. Past ocular history includes ocular hypertension, narrow angles post bilateral peripheral iridotomies, and bilateral intermediate dry macular degeneration on eye vitamins and supplements. Family history was significant for glaucoma suspect in her mother. Most recent preoperative labs indicated no renal or electrolyte abnormalities (Bun 11mg/gL, Creatinine 0.8mg/dL, Sodium 143 mmol/L, Potassium 5.0mmol/L, Chloride 102mmol/L, Bicarbonate 30.0mmol/L).

After discharge from the surgical center, the patient was instructed to restart her preoperative drops: ofloxacin, ketorolac and prednisolone 1%, and was given one dose of acetazolamide 250 mg after discharge to be taken at home at 6pm. The decision to administer acetazolamide after surgery was made to prevent increased IOP given her history of ocular hypertension and narrow angles. Thirty minutes after taking the dose of acetazolamide, the patient's husband contacted the ophthalmologist reporting the patient was experiencing severe stomach pain, nausea, vomiting, diarrhea and sweating. Emergency medical services was called due to rapid worsening of symptoms.

Upon arrival at the hospital emergency department, the patient received 0.3mg epinephrine, 10mg IV dexamethasone, and inhaled ipratropium bromide/albuterol x 2 without significant improvement. The oxygen saturation upon arrival was 59% on room air, improving to 91% with oxygen delivered at 15L with a nonrebreather mask. Treatment for anaphylaxis with epinephrine and ipratropium bromide/albuterol was instituted despite the lack of urticaria on exam. Laboratory results included troponin of 467.3, lactate 4.9 mmol/L, and an arterial blood gas with a low PaO2 of 64.4 mmHg. Chest X-ray revealed diffuse airspace disease (Fig. 1) and CT angiography of the chest showed diffuse interstitial edema and pleural effusions consistent with acute pulmonary edema (Fig. 2).

Fig. 1.

Chest X-rays of a 59-year-old woman treated with acetazolamide. (A) Chest X-ray taken upon admission to the emergency department. It shows pleural effusion and diffuse bilateral opacities. (B) Chest X-ray taken 6 days after admission to the hospital. It shows a resolution of lung opacities and improvement in pleural effusions.

Fig. 2.

Computed tomography angiogram of a 59-year-old woman treated with acetazolamide. It shows extensive bilateral airspace disease with air bronchogram and interstitial components bilaterally.

The following morning, the patient experienced worsening respiratory failure despite the use of bilevel positive airway pressure (BiPAP), furosemide, antibiotics, and high dose steroids, thus necessitating intubation. Despite high positive end-expiratory pressure, oxygenation was at critical levels, and metabolic acidosis required dialysis. Due to the absence of myocardial infarction or congestive heart failure, noncardiogenic pulmonary edema was diagnosed. Oxygen saturation slowly improved over several days, and the patient was extubated on postoperative day 7. The patient has since recovered back to normal activity. To help her pulmonary function in the months after her hospital admission, she was treated with oral prednisone and developed a mild steroid response. Vision is 20/20.

3. Discussion

Increased intraocular pressure after cataract surgery is a well known occurrence and the oral carbonic anhydrase inhibitor acetazolamide is used prophylactically to decrease intraocular pressure.¹ The mechanism of action of acetazolamide is a reduction of carbonic anhydrase, an enzyme necessary to create aqueous humor in the eye. Reduction of aqueous humor production subsequently causes a decrease in intraocular pressure. It is generally considered a safe medication.² There are however previously reported cases of serious adverse events associated with its administration. Recognized adverse effects of acetazolamide include metabolic acidosis, hyponatremia, and hypokalemia, and thus the medication is avoided in those with impaired renal or hepatic function.³

After exhaustive literature review, we describe possibly the first reported case in the United States of a rare and serious adverse event of noncardiogenic pulmonary edema, most likely related to the oral administration of acetazolamide. Similar reports from nine additional cases in the worldwide literature from outside the US that support the association between acetazolamide and pulmonary edema were compiled and analyzed4, 5, 6, 7, 8, 9, 10, 11 (Table 1). From 1987 to 2017 our data showed that 5/9 cases had the indication of administration related to cataract surgery. All cases had rapid onset of symptoms within 1 hour of administration. There was a heavy skew towards people of Mediterranean descent. Some patients had prior usage of hydrochlorothiazide diuretics. Most patients received the same dose as our case, which was 250 mg orally. Most patients had similar initial symptoms of nausea, dizziness, hypoxia, and cyanosis. In all cases the chest X-ray showed pulmonary edema. 2 of the 9 cases resulted in death.

Table 1.

This is a table summarizing reported cases of acetazolamide associated NCPE from 1987 to 2022.

Case Demographics of All Known Cases of Pulmonary Edema Due to Administration of Acetazolamide
Date	Sex	Age	Ethnicity/Race	Medical Indication for Acetazolamide	Comorbidities	Home Medications	Acetazolamide Dose	Onset to Symptoms	Presenting Symptoms	Imaging Results	Outcome
2022	F	59	Mediterranean	Cataract surgery	Anemia, Malignant essential hypertension, Mixed hyperlipidemia, Type 2 diabetes, COVID-19	atorvastatin, Iron, insulin lispro, insulin glargine, losartan-hydrochlorothiazide, metformin, omeprazole, liraglutide, and vitamin B2	250mg PO	30 Minutes	Severe stomach pain, Nausea, Vomiting, Diarrhea and sweating	Pulmonary edema	Resolution within 12 days
2017	M	61	Asian	Metabolic Acidosis	Cardiomyopathy, Chest wall instability, Intrahepatic hematoma	(not provided)	500mg IV	1 Hour	Hypertension, Tachycardia, Hypoxia, Wheezing	Bilateral butterfly shadow	Resolution within 8 hours
2016	M	81	Middle Eastern	Cataract surgery	Chronic renal insufficiency	(not provided)	250mg PO	45 minutes	Dyspnea, Cyanosis, Hypertension	Pulmonary edema	Spontaneous recovery
2014	M	76	White	Cataract surgery	Hypertension	clopidogrel, aspirin, metoprolol, ramipril, simvastatin	250mg PO	30 Minutes	Dyspnea, Nausea, Syncope, Hypotension, Hypoxemia	Pulmonary edema	Resolution within 12 hours
2013	F	80	Mediterranean	Cataract surgery	Hypertension, Diabetes mellitus, Hyperuricemia, Obesity, Dyslipidemia, Hypothyroidism	(not provided)	250mg PO	30 Minutes	Nausea, Cyanosis, Respiratory Failure, Hypotension	Pulmonary edema	Resolution within 3 days
2002	F	79	Mediterranean	Cataract surgery	Hypertension	fosinopril, hydrochlorothiazide	250mg PO	20 Minutes	Hypotension, Syncope	Pulmonary edema	Resolution after 24 Hours
2000	F	65	Dutch	Glaucoma	Hypertension, COPD	hydrochlorothiazide, metoprolol	250mg PO	10 Minutes	Nausea, Dyspnea, Cyanosis	Pulmonary edema	Death within 2 hours due to respiratory failure
1998	M	70	Mediterranean	Cataract surgery	(not provided)	(not provided)	250mg PO	30 Minutes	Nausea, Dyspnea, Cyanosis, Hypotension	(not provided)	Improvement within 12 hours
1992	F	66	Mediterranean	Glaucoma	(not provided)	timolol, dipivefrin	(not provided)	(not provided)	Laryngeal edema, Respiratory distress	(not provided)	Death

Note: Data is missing regarding the 1987 Case Report.

Two cases had an acetazolamide re-challenge with recrudescence of symptoms. One patient had recurrent shock and noncardiogenic pulmonary edema within two months, each after a single dose of acetazolamide post cataract surgery. Despite no clearly delineated pathophysiology for this reaction, the reproducibility and shared presentation suggests that acetazolamide is the trigger for the symptoms.⁵ Several previous case reports suggested an allergic etiology, as there is a theoretical allergic cross reactivity between acetazolamide and sulfa drugs. Multiple patients were negative for a specific allergy testing for acetazolamide, and none of the patients experienced overt signs of anaphylaxis such as urticaria, airway swelling, or obstruction. None of the patients had myocardial infarction or congestive heart failure, thus the diagnosis of NCPE.

NCPE is a disease process that results in acute hypoxemia secondary to a rapid deterioration in respiratory status without evidence of congestive heart failure.¹² The pathophysiology of NCPE is not well understood. Although there are multiple etiologies, the number of pharmaceutical agents linked to the diagnosis is limited. These include narcotic overdose, chemotherapeutic agents, salicylate intoxication, calcium antagonist overdose, contrast fluids and hydrochlorothiazide.¹³ The cases herein presented show common features with cases associated with hydrochlorothiazide exposure. Structurally, both drugs are sulfonamides. A study of 17 cases of NCPE associated with hydrochlorothiazide¹⁴ also showed dramatic acute onset with an average of 50 minutes from drug ingestion to onset of symptoms, and similar systemic findings of fever (6/17), chills and gastrointestinal symptoms (8/17). Many of the cases also presented at first exposure.

The common findings between the hydrochlorothiazide induced NCPE cases and the acetazolamide suspected cases strengthens the assertion that the acetazolamide is the etiologic agent and supports acetazolamide to be added to the short list of etiologic pharmaceutical culprits.

Although the onset of symptoms in close temporal association to the ingestion of acetazolamide suggests a causal link, the lack of awareness of this event may cause this association to be overlooked. This occurred in two of the cases reviewed leading to re-exposure and harm. This suggests that there could be other cases of postoperative pulmonary failure due to acetazolamide not atributed to the drug. . A recent publication on acetazolamide concludes that it is safe and that the reluctance towards prescribing oral carbonic anhydrase inhibitors should perhaps be reconsidered.² Our case and analysis of the case report literature brings to light the rare but potentially fatal event of pulmonary edema occurring shortly after the administration of acetazolamide. This reaction is important to consider for ophthalmologists who frequently prescribe acetazolamide in their practice as well as for staff in surgical centers where postoperative doses may be routinely dispensed. An observation period of at least 1 hour before discharge might be prudent given the rapid onset of symptoms consistent among the reported cases.

4. Conclusion

We report a rare case of NCPE resulting from acetazolamide administration after routine cataract surgery and compiled the first side by side comparison of all similar case reports throughout the world. Although rare, this adverse effect is life-threatening, unpredictable, and warrants further study. The unusual nature of the reaction and a previous lack of recognition in the current literature and texts suggests the possibility that this reaction has been under reported and should be included with hydrochlorothiazide as a cause of drug induced NCPE. We propose a 1 hour observation period after oral acetazolamide dosing to maximize safety.

Funding

No funding was provided to do this project.

Authorship

All authors attest that they meet the current ICMJE criteria for Authorship.

Patient consent

Written consent to publish this case has not been obtained. This report does not contain any personal identifying information.

Declaration of competing interest

All authors have no financial disclosures.