Clinics and Practice 2011; volume 1:e83

Metoclopramide-induced monitor patients and remain diligent in sur - veillance and reporting of bradydysrrhythmias Correspondence: Martha M. Rumore, Drug cardiac arrest and cardiac arrest in patients receiving meto - Information Center, New York-Presbyterian clopramide. Hospital, 622 West 168th St., New York, NY, Martha M. Rumore, 1,2 Spencer Evan Lee, 3 10032, USA. Attn: Pharmacy Dept., VC Basement. Steven Wang, 3 Brenna Farmer 4 Tel. +1.212.305.9992 - Fax: +1.212.342.5348. E-mail: [email protected] 1Drug Information, New York - Presbyterian Hospital; 2Pharmacy & Introduction Key words: metoclopramide, case report, adverse Health Outcomes, Touro College of drug reaction, cardiac arrest, bradycardia, Pharmacy, New York; 3St. John’s Metoclopramide, a dopamine antagonist supraventricular tachycardia. University, College of Pharmacy and structurally related to procainamide, has been widely used for its gastric prokinetic and anti- Received for publication: 6 October 2011. Allied Health Professions, Jamaica; emetic effects. The drug blocks dopamine (D2) Accepted for publication: 12 October 2011. 4Division of Emergency Medicine, receptors and may have anti-dysrrhythmic prop - Weill-Cornell Medical Center/New York This work is licensed under a Creative Commons erties. 1,2 In high doses, metoclopramide blocks Presbyterian Hospital, New York, NY, USA Attribution NonCommercial 3.0 License (CC BY- serotonin receptors in the chemoreceptor trigger NC 3.0). zone in the central nervous system (CNS). 1,3 In 1974, Shaklai first reported cardiovascu - ©Copyright M.M. Rumore et al., 2011 lar (CV) adverse effects associated with meto - Licensee PAGEPress, Italy Abstract clopramide. 4 We report a case of extreme Clinics and Practice 2011; 1:e83 doi:10.4081/cp.2011.e83 bradycardia and cardiac arrest following The authors report a case of cardiac arrest administration of metoclopramide as a preop - in a patient receiving intravenous (IV) meto - erative antiemetic. clopramide and review the pertinent literature. artery disease, hypertension, hyperlipidemia, A 62-year-old morbidly obese female admitted colon cancer and sigmoidectomy, cellulitis, and for a gastric sleeve procedure, developed car - polio. There was no previous history of chest diac arrest within one minute of receiving Case Report pain, dysrhythmia, and dyspnea on exertion, metoclopramide 10 mg via slow intravenous syncope or postural hypotension, renal or hepatic impairment. Outpatient medications (IV) injection. Bradycardia at 4 beats/min A 62-year-old woman was given metoclo - included lisinopril 10 mg daily, aspirin 81 mg immediately appeared, progressing rapidly to pramide 10 mg and glycopyrrolate 0.2 mg daily, rosuvastatin 5 mg daily, docusate 100 mg asystole. Chest compressions restored vital through an IV catheter preoperatively for twice daily, omeprazole 20 mg daily, calcitonin function. Electrocardiogram (ECG) revealed laparoscopic sleeve gastrectomy. Within a ST depression indicative of myocardial injury. minute, the patient reported dizziness and 200 IU nasal spray daily, and alendronate 70 Following intubation, the patient was trans - shortness of breath. Oxygen via nasal cannula mg weekly. Baseline HR and BP were not noted ferred to the intensive care unit. Various car - was administered (O saturation- 96%). The in the chart. She had no known prior drug 2 allergies or documented adverse drug reac - diac dysrrhythmias including supraventricular patient developed oxygen desaturation, tions (ADRs). tachycardia (SVT) associated with hyperten - became rapidly bradycardic (heart rate (HR)- 4 Upon follow-up that day, no pleural effusion sion and atrial fibrillation occurred. Following beats/min), and went into cardiac arrest. A or pulmonary edema was noted and lungs were IV esmolol and metoprolol, the patient reverted code was called and chest compressions were to normal sinus rhythm. Repeat ECGs revealed given, for about 15 s, until a pulse was palpat - grossly clear on chest x-ray and physical exam - ST depression resolution without pre-admis - ed. Her rapid response electrocardiogram ination. The patient was extubated without dif - sion changes. Metoclopramide is a non-specif - (ECG) showed ST depression. The patient ficulty (O 2 sat 96%). She remained in normal ic dopamine receptor antagonist. Seven cases became tachycardic (HR- 210 beats/min), and sinus rhythm with HR ranging at 70-80 of cardiac arrest and one of sinus arrest with hypertensive (270/176 mmHg). This was beats/min, and normotensive without the use metoclopramide were found in the literature. thought to be a self-limiting SVT. Per hospital of vasoactive drugs. Her troponin levels were The metoclopramide prescribing information protocol, adenosine was prepped to be admin - trended immediately following the arrest: does not list precautions or adverse drug reac - istered, but the patient’s HR lowered to the 120 baseline- 0.01 ng/mL (30 min post-event), tions (ADRs) related to cardiac arrest. The s with the underlying rhythm of atrial fibrilla - peaking at 8 h- 0.66 ng/mL, 16 h- 0.39 ng/mL, reaction is not dose related but may relate to tion. The patient received two doses of midazo - and 72 h-0.03 ng/mL - all indicating occurrence the IV administration route. Coronary artery lam 1 mg, esmolol 10 mg x 2 and metoprolol 5 of initial myocardial injury had occurred. Post- disease was the sole risk factor identified. mg all IV push and was intubated. She reverted event ECG showed the ST depressions identi - According to Naranjo, the association was pos - to normal sinus rhythm with a HR in the 80 s, fied during her cardiac arrest had resolved, sible. Other reports of cardiac arrest, severe and her blood pressure (BP) stabilized at with no lasting ischemic damage, ECG bradycardia, and SVT were reviewed. In one 125/72 mmHg. The patient was transferred on unchanged from pre-admission. However, case, five separate IV doses of 10 mg metoclo - a ventilator to the intensive care unit for ongo - myocardial infarction/acute coronary syn - pramide were immediately followed by asystole ing management. The ST depressions normal - drome work up was not further pursued and repeatedly. The mechanism(s) underlying ized once the HR reached the 70 s – 80 s. the possibility of a myocardial infarction could metoclopramide’s cardiac arrest-inducing Relevant investigation revealed no electrolyte, not be completely excluded. The patient under - effects is unknown. Structural similarities to creatinine or bilirubin abnormalities with the went sleeve gastrectomy procedure, had no fol - procainamide may play a role. In view of eight exception of a 1.3 mEq/L magnesium level. low-up cardiac evaluation, and was discharged previous cases of cardiac arrest from metoclo - The patient is morbidly obese, weighing 247 the next day. pramide having been reported, further elucida - lbs., 5’2” tall, with a body surface area of 2.09 Two days following discharge, she presented tion of this ADR and patient monitoring is m2. Past medical history includes a gastric lap to the emergency room, complaining of light - needed. Our report should alert clinicians to band removed in the previous year, coronary headedness and nausea. Her HR was in the 70

[page 174 ] [Clinics and Practice 2011; 1:e83] Brief Report s, and a repeat ECG showed no changes. She patients. 5 Careful consideration of the risks would not supply any information regarding remained hemodynamically stable, was diag - and benefits of metoclopramide for preopera - whether or not they had received reports of nosed with presyncope, and discharged. tive nausea and vomiting prophylaxis is neces - cardiac arrest from metoclopramide sary. To identify pertinent literature describing [Personnel Communication- Rachel CV ADRs from metoclopramide, we conducted Ellerbroek, RN, Baxter Healthcare- Global a search using MEDLINE (1966- to September Pharmacovigilance (847) 948-4281]. A total of Discussion 2011), SCOPUS (1996-September 2011), and seven cases of cardiac arrest were retrieved, Google Scholar. Bibliographies of identified making this is the eighth reported case (Table Metoclopramide has various physiologic articles were reviewed for additional citations. 1). This ADR was submitted to the FDA effects with side effects occurring in 10-20% of The product manufacturer was contacted but MedWatch program.

Table 1. Published case reports of metoclopramide-associated cardiac adverse drug events. Reference Patient Information Metoclopramide (M) Description of event Probability of causation dose and concomitant medications Pollera (1984) 6 49-year-old woman given Stage III ovarian cancer, Patient had several dystonic Concomitant administration of M high-dose M (1 mg/kg) receiving 3 rd course of episodes and was treated with hexamethylmelamine may for four doses. intraperitoneal cisplatin; with diazepam and have contributed to CNS toxicity. hexamethylmelamine orphenadrine. Six hours (200 mg/day) was added after the first dose of M; on later. went into cardiac arrest and died. Withington (1986) 7 54-year-old male. Given M 10 mg IV as an Within 30 s of M Rechallenged with a smaller dose anti-emetic. Patient administration, developed (5 mg) of M developed sinus underwent total sinus bradycardia, asystole bradycardia with a slight pancreatectomy; post for 25 s, progressing to decrease in BP, both resolving surgical complications complete heart block and within 45 s. include DVT, PE, chest cardiac arrest. Heart rate infection; given dopamine and BP spontaneously for pressor support. returned to normal. Midtunn (1994) 8 62-year-old male with lung Patient given M 2.5 mg IV; Within seconds, developed Rechallenged with M 5 mg IV, emboli and atrial fibrillation. concomitant digoxin. extreme bradycardia, again developing bradycardia and followed by total heart block. total heart block. Concomitant digoxin may have contributed to heart block. Del Campo (2001) 9 30-year-old male trauma patient. Given M 10 mg IV when Within seconds, became Temporal relationship enteral nutrition was started. bradycardic and went into established. ECG taken during a sinus arrest. subsequent dose, and heart rate decreased to 40 beats/min. Bentsen (2002) 10 41-year-old male, with Previously weaned off Following administration, Temporal relationship intracerebral and subarachnoidal pressors 2 days prior to patient had a severe episode established. bleeding. being given M 10 mg IV. of asystole, with 5 Dopamine infusion rate was M was given IV through a subsequent episodes in the being tapered when M was central venous catheter next 48 h. Cardiac arrests started, possibly predisposing directly into the heart. lasted 15-30 s, one lasting patient to bradyarrhythmias. 2 min. Tung (2002) 11 38-year-old woman undergoing Given M 10 mg IV post- Within 5 min of M Temporal relationship sympatholysis of left index finger operatively. Given labetalol administration, developed established. Concomitant due to gangrene. 10 mg IV 15 min prior. junctional bradycardia administration of labetalol and Past medical history includes without a pulse. Eventually M may have contributed to hypertension, pulmonary stabilized and required bradyarrhythmia. hypertension, restrictive lung pressor support, but had disease, scleroderma. another episode of bradycardia, could not be resuscitated, and expired. Grenier (2003) 12 66-year-old female with no Given two separate doses One and eight min after Temporal relationship history of cardiac disease. of M 10 mg IV postoperatively. each respective dose of M, established. Same symptoms patient experienced developed when rechallenged. episodes of asystole. Schwartz (2010) 13 56-year-old male burn patient Patient treated with digoxin. After a month of concomitant After excluding other being treated for atrial Concomitantly treated for igoxin and M, patient had 7 possibilities, digoxin and M were fibrillation. a month with M 20 mg IV episodes of bradycardia and suspected and discontinued; every 6 h. 15 episodes of asystole hours later the bradyarrhythmias within 48 h. resolved.

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Assessed using the Naranjo scale, 14 our case Table 2. Naranjo adverse drug reactions probability scale evaluation for case report. highlights a possible association between Yes No Don’t know Score metoclopramide and cardiac arrest based on: i) occurrence of the effect immediately following 1. Are there previous conclusive reports of this metoclopramide injection, ii) the number of reaction? Yes +1 previous conclusive reports of bradycardia and 2. Did the adverse event appear after the cardiac arrest associated with metoclo - suspected drug was administered? Yes +2 pramide, iii) use of glycopyrrolate which could 3. Did the adverse reaction improve when the have caused the reaction, and iv) the ADR was drug was discontinued, or a specific antagonist confirmed by objective evidence (Table 2). was administered? Yes +1 Differential diagnosis of cardiac arrest 4. Did the adverse reaction reappear when the included: acute ischemic events, atypical ana - drug was readministered? N/A 0 phylaxis, flash pulmonary edema or pulmonary 5. Are there alternative causes embolism. Anaphylaxis was ruled out because (other than the drug) that could on their own of an absence of allergies or anaphylaxis symp - have caused the reaction? Yes -1 tomotology, e.g. pruritis, urticaria, flushing, 6. Did the reaction reappear when a placebo respiratory distress, nausea, or vomiting. was given? N/A 0 Similarly, myocardial infarction or flash pul - 7. Was the drug detected in the blood monary edema was unlikely based on the ECG (or other fluids) in concentrations known to be toxic? N/A 0 and symptomology. 8. Was the reaction more severe when the dose Our patient concurrently received glycopy - was increased, or less severe when the dose rrolate 0.2 mg IV. Glycopyrrolate is a nonselec - was decreased? N/A 0 tive anticholinergic drug, which blocks periph - 9. Did the patient have a similar reaction to the eral muscarinic receptors used preoperatively same or similar drug in any previous exposure? No 0 as an antisialogogue. While structurally simi - lar to atropine, glycopyrrolate is a quaternary 10. Was the adverse event confirmed by any objective evidence? Yes +1 amine with poor penetration through biologic membranes. Glycopyrrolate has parasympath - TOTAL 4 omimetic effects similar to placebo and, com - Scale: >8 = highly probable; 5-8 = probable; 1-4 = possible; 0 = doubtful pared to atropine, has fewer CV adverse events and dysrrhythmias. 15 Additionally, glycopyrro - both cases involved postanesthesia asystole. via a central venous catheter. Cases of conges - late via both the inhalation and IV routes Also, unlike our case, in both cases the patient tive heart failure following chronic metoclo - demonstrates bronchodilating effects. Thus, had serious underlying CV disease. In our pramide at doses of 40 mg daily are most like - one would not expect to see the respiratory case, the Naranjo probability scale for glycopy - ly due to a different mechanism of action as depression as observed with our patient. rrolate showed that causality was possible. dopaminergic inhibition may increase plasma A literature search for cardiac arrest from While there is a possibility of an association of aldosterone, thereby producing sodium reten - glycopyrrolate revealed only two cases, only cardiac arrest with glycopyrrolate, the associa - tion. 28 one of which was attributed to glycopyrro - tion with metoclopramide is stronger in view Our patient’s extreme bradycardia and car - late. 16,17 The first case describes asystole in a of the large amount of literature supporting diac arrest are similar to previous cases in the heart transplant patient who received concur - metoclopramide-induced cardiac arrest as well literature. 7-9,11,13 SVT, AV block, bradycardia, rent glycopyrrolate 0.8 mg and neostigmine 4 as the number of rechallenge cases that have heart failure, and hypertension/hypotension mg IV postoperatively for reversal of neuro - been reported. 12,8 but not cardiac arrest are listed in the package muscular blockade. The authors attributed the Cases of sinus or cardiac arrest, 6,7,9-13,18 as insert. 29 In our case, SVT was associated with ADR to neostigmine and did not mention gly - well as bradycardia followed by total heart hypertension (BP 270/176 mmHg) and copyrrolate. 16 The second case describes ven - block 13,8 have been reported. Other reports resolved after esmolol and metoprolol adminis - tricular fibrillation and cardiac arrest in a include cardiac dysrrhythmias such as tration with conversion to sinus tachycardia. patient with undiagnosed congenital QT pro - SVT, 4,19,20 QT prolongation, Torsade de There was no mention of the patient having longation who also concurrently received gly - Pointes, 21,22 ST depression, 19,20 acute hypoten - received epinephrine in accordance with ACLS copyrrolate 0.5 mg and neostigmine 2.5 mg IV sion, 23-26 circulatory collapse, 27 and congestive Guidelines. The duration of the reported car - postoperatively for reversal of neuromuscular heart failure. 28 In several of the cases, resolu - diac arrests is between 15-30 s, but on one blockade. The authors acknowledge that con - tion occurred within 10 min or less. 19 Although occasion lasted two min. 16 genital QT prolongation, in and of itself, may there was no re-challenge, in a number of the Suggested underlying predisposing or con - result in sudden cardiac arrest and cases have published cardiac arrest cases, inadvertent tributory factors for development of cardiac been reported in the literature. Nevertheless, metoclopramide rechallenge occurred, con - ADRs with metoclopamide include previous they attributed the cardiac arrest to the QT firming a cause-and-effect relationship. 8,10,12,27 cardiovascular disease, atrial fibrillation, 8 prolongation effects of glycopyrrolate. 17 The Bentsen reported five repeated episodes of car - autonomic dysfunction, 18 hyperbilirubinemia, 7 two cases reported in the literature differ from diac arrest following five separate metoclo - halothane anesthesia, 25,26 and pericardial our case in many aspects. First, we note that pramide injections over 48 h. 10 Asystolic drainage tube. 8 However, no clear association the doses of glycopyrrolate were 0.5 and 0.8 episodes stopped upon drug discontinuation. with any risk factors exists. Cardiac arrest mg, which is 2-4 times higher than the dose in Other cases have reported repeated circulatory occurred in patients without cardiac disease. 12 our case. Unlike the present case, in both collapse following metoclopramide administra - In at least some some of the previous cases cases the glycopyrrolate was given concurrent - tion. 27 Unlike our case where metoclopramide reports, the patients did have a history of coro - ly with neostigmine and to reverse neuromus - was administered IV over 1-2 min, metoclo - nary artery disease (CAD). Our patient had cular blockade postoperatively. Additionally, pramide was administered over a few seconds morbid obesity and CAD; two risk factors for

[page 176 ] [Clinics and Practice 2011; 1:e83] Brief Report sudden cardiac arrest. However, the usual chronology for CAD is angina progressing to a myocardial injury/infarction triggering ventric - ular fibrillation, not bradycardia. Past medical history did not reveal angina. While any drug-drug interaction was ruled out, our patient was on lisinopril 10 mg daily prior to admission. Chronic use of angiotensin- converting enzyme (ACE) inhibitors has been associated with reduced adrenergic responsive - ness and hypotension during anesthesia. 11 Whether this possible interaction was contribu - tory to the cardiac arrest is unknown. However, in one cardiac arrest case the patient received an ACE inhibitor. 11 Neither age nor dose appears contributory. While the patients in most cases were elderly, cardiac arrest also occurred in middle-aged individuals. 10 Moreover, this ADR is not dose- related as it occurred after single 2.5-10 mg doses. 8,12,18 The route and rate of administra - tion may be causative. In all cases, metoclo - pramide was given IV either peripherally or via central venous lines. In several cases metoclopramide was administered over sec - onds, not slowly over 1-2 min. 24 In a 16 patient series, 10 mg IV produced average decreases in systolic and diastolic BP of 22% and 20%, respectively, occurring on average 44s after administration over 10 s. 25 However, the pack - age insert states slow injection avoids a tran - Figure 1. Structural comparison of 3 different agents: A) Metoclopramide; B) sient but intense feeling of anxiety and rest - Procainamide; C) Cisapride. lessness, followed by drowsiness , not rapid BP decreases. 29 Metoclopramide has potent central anti- choline producing cholinergic-induced brady - ly cause bradyarrhythmias progressing to cardiac dopaminergic and peripheral cholinergic dysrrhythmias. The effect on the heart may be arrest and paroxysmal SVT in patients without effects. 1,3 The mechanism(s) for metoclo - the result of changes in cholinergic tone mim - evidence of underlying cardiac abnormalities. pramide-induced extreme bradycardia, SVT, icking vagal stimulation. 36 and cardiac arrest are unknown but may be In studies, metoclopramide has been shown multifactorial involving: i) a direct cardiac to have quinidine-like antidysrrhythmic effect; ii) presynaptic autoreceptor blockade effects, increase atrial and AV nodal refractory Conclusions and enhanced catecholamine release, 13,30 iii) periods, 38 decrease systolic and diastolic blood other actions caused by enhanced cholinergic pressure, left ventricular systolic pressure, and Cardiac arrest is a rare but serious CV 31 total peripheral resistance. 2,39-42 neurotransmission, or iv) 5-HT 3 receptor adverse effect of metoclopramide. It would 31 Another potential mechanism is 5-HT 3 blockade or 5-HT 4 receptor agonism. appear to be prudent to monitor patients Support for a mechanism involving a direct receptor blockade or 5-HT 4 receptor agonism. receiving metoclopramide IV immediately after effect of metoclopramide on the heart may be 5-HT 4 receptors are also located in the heart injection for CV adverse effects. We believe it found in the structural similarity of metoclo - and the vasculature where they exert a posi - is also appropriate to warn against rapid IV pramide with procainamide. Figure 1 shows tive chronotropic effect and tachycardia by an injection, especially via the central venous that metoclopramide differs from pro - action on the atrium. As can be noted in route. In view of the number of reported cases, cainamide by only a 2,5 aryl substitution. 1 Figure 1, metoclopramide is structurally relat - we recommend addition of this ADR to the Procainamide and cholinergic stimulation, in ed to cisapride, both being gastric prokinetic metoclopramide Prescribing Information. This general, have long been known to cause sinus substituted benzamides. Cisapride was case should prompt a critical re-evaluation of arrest. 18 A direct effect is likely to appear known for its cardiotoxic QT prolongation and the risk/benefit of metoclopramide and consid - immediately; in most cases, the heart stopped torsades de pointes. Metoclopramide has eration of therapeutic alternatives, in concert within 30 s. 7-10 been shown to undergo CYP2D6 metabolism. with a search for underlying predisposing fac - Support for a mechanism involving presy - Elimination may be slowed in patients taking tors or mechanisms of action involved. naptic autoreceptor blocking and cate - inhibitors of this isoform, such as omepra - cholamine release is found in metoclo - zole. 32,43-45 Although our patient was receiving pramide’s ability to release catecholamines in omeprazole, a metabolic effect is deemed pheochromocytoma and hypertension. 30,31 One unlikely since the cardiac arrest occurred References cardiac arrest case occurred upon dopamine immediately in both our case and those discontinuation. 16 The effect may be the result reported in the literature. 1. Schulze-Delrieu K. Metoclopramide. N of increased release and levels 32-37 of acetyl - In summary, metoclopramide may occasional - Engl J Med 1981;305:28-33.

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