Carbonic anhydrase inhibitors, such as acetazolamide, are widely used in the treatment of open-angle glaucoma. Severe metabolic acidosis is a rare complication of acetazolamide use, and life-threatening acidosis occurs most commonly in elderly patients, in patients with advanced renal failure, and in patients with diabetes. We describe an unusual case of an elderly patient with diabetic nephropathy and chronic renal failure who presented to the emergency department with severe metabolic acidosis and coma after exposure to high doses of acetazolamide in the postoperative period of ophthalmic surgery. As symptoms of acetazolamide intoxication and uremia are similar, high suspicion is required to detect excessive plasma drug concentrations and intoxication in patients presenting with concomitant uremia. Clinical symptoms are potentially reversible with prompt diagnosis and treatment, including supportive treatment, bicarbonate therapy, and renal replacement therapy. Hemodialysis is particularly helpful in the management of acetazolamide overdose as the medication is dialyzable

Kerber, Juliana Maria

Mello, Juliana Dias de

Moura, Karolinny Borinelli de Aquino

Rech, Tatiana Helena

Silva, Gustavo Cardoso da

Wawrzeniak, Iuri Christmann

Case Reports in Critical Care

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HindawiCase Reports in Critical CareArticle ID 3764972Case ReportAcetazolamide Intoxication in an Elderly Patient with Diabetesand Chronic Renal Failure after Cataract SurgeryJuliana Maria Kerber,1 Juliana Dias de Mello,1 Karolinny Borinelli de Aquino Moura,2GustavoCardosodaSilva,3 IuriChristmannWawrzeniak ,2 andTatianaHelenaRech 2,41School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil2Intensive Care Unit, Hospital de Cĺınicas de Porto Alegre, Porto Alegre, RS, Brazil3Department of Neurology, Hospital de Cĺınicas de Porto Alegre, Porto Alegre, RS, Brazil4Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilCorrespondence should be addressed to Tatiana Helena Rech; threch@hcpa.edu.brReceived 19 July 2019; Revised 18 October 2019; Accepted 13 November 2019Academic Editor: Kenneth S. WaxmanCopyright © 2020 Juliana Maria Kerber et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.Carbonic anhydrase inhibitors, such as acetazolamide, are widely used in the treatment of open-angle glaucoma. Severe metabolicacidosis is a rare complication of acetazolamide use, and life-threatening acidosis occurs most commonly in elderly patients, inpatients with advanced renal failure, and in patients with diabetes. We describe an unusual case of an elderly patient with diabeticnephropathy and chronic renal failure who presented to the emergency department with severe metabolic acidosis and coma afterexposure to high doses of acetazolamide in the postoperative period of ophthalmic surgery. As symptoms of acetazolamideintoxication and uremia are similar, high suspicion is required to detect excessive plasma drug concentrations and intoxication inpatients presenting with concomitant uremia. Clinical symptoms are potentially reversible with prompt diagnosis and treatment,including supportive treatment, bicarbonate therapy, and renal replacement therapy. Hemodialysis is particularly helpful in themanagement of acetazolamide overdose as the medication is dialyzable.1. BackgroundAcetazolamide is a carbonic anhydrase inhibitor that acts byinhibiting the reversible reaction of hydration of carbondioxide and dehydration of carbonic acid. This medicationdecreases the production of aqueous humor within the eye,reducing intraocular pressure [1]. In the kidney, it stimulatesthe formation of bicarbonate-rich urine in the renal prox-imal tubular epithelium, producing a diuretic effect andmetabolic acidosis [2]. In the central nervous system, itretards abnormal excessive discharge of neurons and lowersintracranial pressure, been widely used for this purpose. Thismechanism of action is based on the reduction of cere-brospinal fluid (CSF) secretion by the choroid plexus, whereacetazolamide affects both ion transport and protein ex-pression [3]. Therefore, acetazolamide is commonly used totreat elevated intraocular pressure, fluid retention, andepilepsy, as well as other rare diseases such as high altitudesickness, hypokalemic periodic paralysis, hydrocephalus,and Meniere’s disease [4].Serious side effects are rare, but acetazolamide mayinduce adverse reactions in several organs and systems. Inthe central nervous system, it causes drowsiness, depression,malaise, fatigue, and paresthesia, while in the kidney, itcauses polyuria, metabolic acidosis, and electrolyte imbal-ance [2, 5]. Advanced renal dysfunction is the most im-portant contraindication to its use, as acetazolamide iseliminated from the body exclusively by the kidneys and itsuse can induce bicarbonaturia and normal anion gaphyperchloremic metabolic acidosis. Other contraindicationsinclude hypersensitivity to the medication, hepatic dys-function, hypokalemia or hyponatremia, concomitant use ofhigh-dose aspirin, adrenal insufficiency, and hyperchloremicmetabolic acidosis [1].Severe metabolic acidosis is a rare complication, but life-threatening acidosis may occur particularly in elderly pa-tients, in patients with advanced renal failure, in patientswith diabetes, and in the presence of concomitant use ofnephrotoxic agents. These situations should be seen as riskfactors for prescribing acetazolamide.Altered mental status is common in elderly patients, butthe differential diagnosis is not always straightforward be-cause several diseases are possible and may occur con-comitantly with polypharmacy [6]. We present here the caseof an elderly patient with coma and severe metabolic acidosiswith risk factors for acetazolamide intoxication.2. Case ReportA 70-year-old woman with a history of systemic arterialhypertension and type 2 diabetes was admitted to theemergency department with inappetence, altered mentalstatus, hyperreflexia, and myoclonus lasting for 2 weeks.Despite the diabetic retinopathy and nephropathy withadvanced renal failure, the patient had been in her usual stateuntil 3 weeks before admission, when she underwent cat-aract surgery in the right eye at a private clinic, with nointraoperative complications. In the postoperative period,she was maintained on acetazolamide 500 mg 4 times a dayfor 5 days, and then the dosage was reduced to 250 mg 4times a day because of incipient neurologic symptoms.Acetazolamide was prescribed for a total of 20 days.On examination at the emergency department, thetemperature was 34.6°C, heart rate 112 beats per minute,blood pressure 98/61 mmHg, respiratory rate 28 breaths perminute, oxygen saturation 95% while breathing room air,and capillary blood glucose 161 mg/dL. Findings from thephysical examination were normal, and her pupils weremedium sized and reactive to light, with no focal neurologicdeficits or signs of meningeal irritation. The urinary outputat admission was 2.0 mL/kg/h. Her condition deterioratedwith respiratory insufficiency due to a declining mentalstatus, requiring intubation and mechanical ventilation.Together with the neurologic signs and symptoms, shepresented with severe metabolic acidosis. Arterial blood gasanalysis obtained during mechanical ventilation with FiO20.21 revealed the following values: pH 7.23; PaCO226 mmHg; bicarbonate 11 mmol/L; base excess 15 mmol/L;PaO2 118 mmHg; SaO2 96%; anion gap 18 mEq/L; andlactate 0.5 mmol/L. Diagnostic workup did not suggest thepresence of an infectious process: C-reactive protein0.3 mg/L and leukocytes 11.5×103/μL. The chest X-ray wasnormal. A computed tomography scan of the brain wasobtained, revealing small old ischemic defects, with no acuteabnormal findings. Cerebrospinal fluid analysis revealedclear fluid, with an opening pressure of 20 mmHg, glucose107 mg/dL, protein 86 mg/dL, and lactate 1 mmol/L.Eight hours after emergency department admission, thepatient was transferred to the intensive care unit (ICU) dueto coma and worsening renal function, with a serum cre-atinine of 4.8 mg/dL (more than twice as much as the valuebefore surgery), urea 275 mg/dL, bicarbonate 11 mEq/L,chloride 106 mEq/L, phosphate 4.3 mg/dL, and anion gap18.5 mEq/L. The results of blood tests for sodium, potassium,magnesium, calcium, and phosphate were normal (Table 1).Urinary density and sediment were also normal, as were theultrasound images of the urinary tract. The patient under-went an electroencephalogram, notable for a severe diffusemetabolic encephalopathy, without epileptiform paroxysms.In addition, aggressive intravenous fluids were administeredto treat hypovolemic shock, and sodium bicarbonate wasinfused to reverse severe metabolic acidosis (250 mEq ofsodium bicarbonate over 24 hours).Renal replacement therapy was prescribed because severemetabolic acidosis was resistant to sodium bicarbonate in-fusion and as the patient remained in coma, probably sec-ondary to uremia exacerbated by the use of acetazolamide.After 2 sessions of intermittent hemodialysis, her neurologicstatus progressively improved and she was successfullyextubated after 3 days in the ICU. On hospital day 6, she wasdischarged home with a normal neurologic examination andwithout the need for renal replacement therapy, as serumcreatinine levels and urine output returned to baseline.3. DiscussionWe described here a case of severe acetazolamide intoxicationin an elderly patient with diabetic nephropathy and chronicrenal failure. Because acetazolamide is eliminated solely by thekidneys, it accumulates in patients with renal impairment[5, 7]. Altered mental status, ranging from fatigue to deepcoma, occurs as a result of the direct effects of acetazolamideon the central nervous system, but hyperammonemia may alsocontribute to neurologic symptoms during acetazolamideintoxication [8]. Moreover, due to the similarity of symptomsof acetazolamide toxicity and hyperammonemia, drug toxicitymay go unnoticed in patients who subsequently develop renaldysfunction and uremia. Unfortunately, ammonia levels andtoxicological screen tests were not measured in our patient.However, a classic feature of acetazolamide intoxication, incontrast to uremic symptoms, is the rapid recovery and res-olution of the symptoms soon after the start of renal re-placement therapy, as the medication is easily dialyzable [4, 9].This was precisely the clinical course presented by our patient,with rapid clinical and neurologic improvement after only 2hemodialysis sessions.The usual dose of acetazolamide in patients with glau-coma ranges from 250 to 1000 mg per day [1]. Our patientreceived a dose of up to 2000 mg per day in the first 5 days oftreatment, which can be interpreted as overdose. Further-more, some important remarks can be made based on thetreatment of this patient: the off-label use of acetazolamidein cataract surgery; the prescription of the medication to apatient with renal dysfunction; and the iatrogenic use of themedication at higher than recommended doses. In addition,advanced age and diabetes are risk factors for acetazolamidetoxicity. Taken together, all these clinical features haveevolved with the development of acute neurologic impair-ment and worsening chronic renal disease leading to thesevere metabolic acidosis presented by the patient.The mechanism involved in acetazolamide intoxicationis the inhibition of carbonic anhydrase in the renal proximal2 Case Reports in Critical Caretubular epithelium, leading to bicarbonate-rich urine andhyperchloremic metabolic acidosis. This mechanism appearsto be more pronounced in elderly patients with diabetes orwith renal failure [2, 10]. Serum levels of acetazolamide werenot measured in our patient, because acetazolamide levelsare not commonly measured in clinical settings, which is alimitation of this report. However, the patient’s laboratoryworkup revealed increased acid production, with markedlyincreased anion gap in the absence of other sources ofplasma acidification, such as lactate or ketones. This fact,together with her clinical history of medication overdose,strongly suggests hyperchloremic metabolic acidosis causedby acetazolamide intoxication in combination with highanion gap acidosis due to tubular abnormalities associatedwith chronic renal failure secondary to diabetic nephropa-thy. Despite its high intraerythrocytic distribution andplasma binding properties (about 94%), acetazolamide canbe effectively removed by dialysis, especially if renal im-pairment coexists. It is estimated that the rate of acetazol-amide clearance in hemodialysis is about 150 mg in 4 hoursand the acetazolamide-to-urea nitrogen excretion ratio is0.16, which allows the prediction of the acetazolamidedialysance in several dialyzing conditions [4]. As expected,the drug was rapidly eliminated in our patient, with rapidand full neurologic recovery.4. ConclusionAltered mental status is common in elderly patients pre-senting to the emergency department. However, differentialdiagnosis is often difficult. The present case provides a rarereport of acetazolamide overdose, an uncommon entity thatrequires high suspicion because of the similarity of symp-toms with those of more frequent causes of metabolic en-cephalopathy. Elderly patients, patients with diabetes, andpatients with chronic kidney disease are at the highest risk ofacetazolamide intoxication. The deleterious neurologic ef-fects are caused by the direct action of the drug on the centralnervous system, together with hyperammonemia and severemetabolic acidosis, since acetazolamide leads to renal ex-cretion of bicarbonate. Renal replacement therapy is rec-ommended early, especially when renal failure is present,leading to rapid resolution of symptoms.Conflicts of InterestThe authors declare that they have no conflicts of interest.References[1] Taro Pharmaceuticals, Acetazolamide Tablets, Taro Pharma-ceuticals, Hawthorne, NY, USA 1, 2013.[2] I. Heller, J. Halevy, S. Cohen et al., “Significant metabolicacidosis induced by acetazolamide: not a rare complication,”Archives of Internal Medicine, vol. 145, no. 10, pp. 1815–1817,1985.[3] M. Uldall, H. Botfield, I. Jansen-Olesen, A. Sinclair, andR. Jensen, “Acetazolamide lowers intracranial pressure andmodulates the cerebrospinal fluid secretion pathway inhealthy rats,” Neuroscience Letters, vol. 645, pp. 33–39, 2017.[4] N. D. Vaziri, J. Saiki, C. H. Barton, M. Rajudin, and R. L. Ness,“Hemodialyzability of acetazolamide,” Southern MedicalJournal, vol. 73, no. 4, pp. 422-423, 1980.[5] I. Yano, A. Takayama, M. Takano et al., “Pharmacokineticsand pharmacodynamics of acetazolamide in patients withtransient intraocular pressure elevation,” European Journal ofClinical Pharmacology, vol. 54, no. 1, pp. 63–68, 1998.[6] A. T. Smith and J. H. Han, “Altered mental status in theemergency department,” Seminars in Neurology, vol. 39,no. 01, pp. 005–019, 2019.[7] M. H. Schwenk, D. A. Blaustein, and J. D. Wagner, “Thepharmacokinetics of acetazolamide during CAPD,” Advancesin Peritoneal Dialysis, vol. 10, pp. 44–46, 1994.[8] J.-M. Kim, W.-S. Ryu, Y.-H. Hwang, and J. S. Kim, “Ag-gravation of ataxia due to acetazolamide induced hyper-ammonaemia in episodic ataxia,” Journal of Neurology,Neurosurgery & Psychiatry, vol. 78, no. 7, pp. 771-772, 2006.[9] M. H. Schwenk, W. L. Peter, M. G. Meese et al., “Acetazol-amide toxicity and pharmacokinetics in patients receivinghemodialysis,” Pharmacotherapy, vol. 15, no. 4, pp. 522–527,1995.[10] E. Elinav, Z. Ackerman, N. P. Gottehrer et al., “Recurrent life-threatening acidosis induced by acetazolamide in a patientwith diabetic type IV renal tubular acidosis,” Annals ofEmergency Medicine, vol. 40, no. 20, pp. 259-260, 2002.Table 1: Laboratory values at baseline (before surgery) and at ICUadmission.Variable Baseline ICU admission Normal rangeSodium (mmol/L) 137 137 135–145Potassium (mmol/L) 4.9 5.1 3.5–5.5Calcium (mg/dL) 9.4 8.3 8.5–10.2Chloride (mEq/L) — 106 98–107Phosphate (mg/dL) 4.2 4.3 2.5–4.5Creatinine (mg/dL) 2.1 4.8 0.5–1.1Urea (mg/mL) 111 275 16–48pH — 7.23 7.35–7.45Bicarbonate (mmol/L) — 10.9 22–26Total CO2 (mmol/L) — 11.8 23–27Anion gap (mEq/L) — 18.5 10–20Case Reports in Critical Care 3Composition Comments1. Please check whether Reference [1] is displayed correctly.4 Case Reports in Critical CareIt is very important to confirm the author(s) last and first names in order to be displayed correctlyon our website as well as in the indexing databases:Author 1Given Names: JulianaLast Name: Maria KerberAuthor 2Given Names: JulianaLast Name: Dias de MelloAuthor 3Given Names: KarolinnyLast Name: Borinelli de Aquino MouraAuthor 4Given Names: GustavoLast Name: Cardoso da SilvaAuthor 5Given Names: Iuri ChristmannLast Name: WawrzeniakAuthor 6Given Names: TatianaLast Name: Helena RechIt is also very important for each author to provide an ORCID (Open Researcher and Contributor ID). ORCIDaims to solve the name ambiguity problem in scholarly communications by creating a registry of persistent uniqueidentifiers for individual researchers.To register an ORCID, please go to the Account Update page (http://mts.hindawi.com/update/) in our ManuscriptTracking System and after you have logged in click on the ORCID link at the top of the page. This link will take youto the ORCID website where you will be able to create an account for yourself. Once you have done so, your newORCID will be saved in our Manuscript Tracking System automatically.Author(s) Name(s)

Acetazolamide intoxication in an elderly patient with diabetes and chronic renal failure after cataract surgery

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Acetazolamide intoxication in an elderly patient with diabetes and chronic renal failure after cataract surgery

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