Rare serious side effect of low dose Ondansetron: Supraventricular tachycardia, hypertension, angina.

Author Information

Harde M, Dave S**, Bhadange R***, Bhadade R****.
(* Associate Professor, ** Professor, *** Resident Doctor, Department Of Anesthesiplpgy; **** Assistant Professor, Department of Medicine. Topiwala National Medical College & B.Y L. Nair Ch. Hospital, Mumbai, India.)

Abstract

Ondansetron is the most widely used drug for management of postoperative nausea, vomiting. Although it has been established as a safe drug its rare adverse events such as chest pain, acute myocardial ischemia and arrhythmias have been mentioned.

We present a case of total abdominal hysterectomy (TAH) under spinal anaesthesia developing supraventricular tachycardia (SVT), hypertension and ST changes after administration of ondansetron. This is a rare serious side effect of ondansetron where prompt diagnosis and specific management saved the patient from fatality.  It is prudent to use ondansetron judiciously and cautiously with extreme vigilance especially in presence of hypokalemia.

Introduction

Ondansetron is the prototypical drug in the class of 5-HT₃-receptor antagonist. 5-HT₃-receptor antagonists are the most widely used drugs for management of postoperative nausea, vomiting (PONV) and chemotherapy-induced nausea, vomiting (CINV). Most common adverse effects are constipation or diarrhea, headache, light-headedness but extra-pyramidal reactions and cardiovascular (CVS) effects are very rare. Studies have established its clinical safety, but few studies have reported serious adverse effects like myocardial infarction and arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia and atrial fibrillation.^[1-3] We present a case of total abdominal hysterectomy (TAH) under spinal anesthesia developing SVT, hypertension and ST changes after administration of ondansetron.

Case Report

A 40 year old female patient with American Society of Anesthesia (ASA) class I physical status posted for TAH was given subarachnoid block using 3.5 cc of 0.5% Bupivacaine and surgery commenced after achieving adequate (T6) level of block. Patient was comfortable and vitals were maintained within normal limits. After 45 minutes patient complained of nausea for which intravenous (IV) Ondansetron 4 mg diluted to 10 milliliters was given slowly. Immediately on injection patient complained of palpitations and cardioscope showed SVT with a rate of 180/minute. On examination, patient was conscious with a rapid pulse and blood pressure (BP) was 180/110 mm Hg. IV Lignocaine (preservative free) 50 mg was given followed by IV Metoprolol 1+1 mg (cardioselective β blocker) following which pulse rate reverted to normal but BP reading was still 170/100 mm Hg. Patient now complained of mild chest pain and discomfort and cardioscope showed ST depression and for which IV Nitroglycerine was given in 2 aliquots of 20 μicrograms (μg) each followed by infusion of 0.5 μg /min and ST changes reverted to normal in 10 minutes and BP returned to 110/80 mm Hg. Arterial blood gases were normal but serum potassium (K⁺) was 3.0 miliEquivalents/litre(mEq/l), other electrolytes and 12 lead ECG were within normal limits. For hypokalemia K⁺ infusion was started at the rate 0.1 mEq/kg/hr till K⁺ returned to 4 mEq/l. After this episode patient was stable throughout the surgery and postoperatively.

Discussion

The 5-HT3 receptor antagonists are the primary drugs used to treat PONV, CINV and post radiation induced emesis. Ondansetron is a valuable drug in treatment of above because of safety and cost effectiveness. Higher doses 32 milligrams(mg) of ondansetron have known risk of QTc prolongation but there are only a few reports of dysarrythmia and chest pain reported after administration of 4 mg ondansetron.^{[1, 4-7]}

The exact mechanisms by which ondansetron might precipitate myocardial ischaemia and arrhythmias is not clear however several ways have been postulated.  It blocks rapidly acting potassium channels and prolongs repolarization resulting in cardiac disturbances. 5-Hydroxytryptamine (HT₃) receptors mediate Bezold-Jarisch reflex which is an autonomic reflex consisting of bradycardia, hypotension and apnea. 5-HT₃ receptor blockade by ondansetron suppresses this reflex leading to tachycardia and also unopposed action of 5HT2 and 5HT4 receptors resulting in tachyarrhythmia and hypertension and a complex pattern of coronary vasoconstriction.^[5-8]   

With high doses of ondansetron used for the management of CINV there is risk of QTc prolongation leading to Torsade de Pointes (TdP). Hence FDA has cautioned that the risk of QT interval prolongation and cardiac arrhythmias with ondansetron is dose-related and recommends avoiding the drug in patients with congenital long QT syndrome. Recommended guidelines for the new maximum single intravenous dose of ondansetron in adults is 16 mg (infused over at least 15 minutes). To be used with caution in patients with risk factors for QT interval prolongation or cardiac arrhythmias and to be given with ECG monitoring in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and those taking other medications that prolong the QT interval.^{[9, 10]} The maximum recommended intravenous dose of ondansetron for the prevention and treatment of post-operative nausea and vomiting in adult patients is a single dose of 4 mg.^{[9, 10]}

Few reports have mentioned ondansetron induced chest pain and myocardial ischemia.^{[11, 12]}  The packaging insert for ondansetron lists “chest pain with or without ST depression” and hence should be used with caution in patients of suspected acute coronary syndromes.

Our patient was ASA 1 without any comorbid conditions, hemodynamically stable with adequate (T6) level of spinal block, developed SVT, hypertension and angina immediately after ondansetron administration. Occurrence of SVT coincided with the IV administration of ondensetron and that time there was no other precipitating factor (noxious surgical stimuli). We could not find any other reason for above other than ondansetron. Also hypokalemia which was detected later can be precipitating reason for arrhythmia after ondansetron. Patient’s preoperative investigations showed normal potassium levels but they were of 3 days prior. Patient received bowel preparation a day prior to surgery in the form of oral Bisacodyl and enema which may cause loss of electrolytes and could be the possible reason for hypokalemia.  

Chandrakala R et al reported ondansetron induced fatal SVT in a 14-year-old girl.^[1] Immediate diagnosis of arrhythmia and ST changes and prompt management saved our patient from fatality.  Ondansetron definitely has a superior safety profile than many other antiemetics. However these reported CVS complications although rare are serious enough to use the drug very carefully in patients of suspected acute coronary syndromes, electrolyte abnormalities, congestive heart failure, in patients with risk factors for QT interval prolongation and cardiac arrhythmias. Also any electrolyte abnormality mainly hypokalemia and hypomagnesemia should be corrected prior to ondansetron administration.^{[9, 10]}

A systematic review by Freedman SB in 2014 mentions that current evidence does not support routine ECG and electrolyte screening before ondansetron administration and should be targeted to high-risk patients receiving IV ondansetron.^[3]

This case report is a rare side effect of ondansetron in a patient under spinal anaesthesia. Patient developed SVT, hypertension and ST changes after administration of ondansetron which was treated successfully. We highlight the importance of vigilance for unexpected arrhythmias and angina due to ondansetron especially in presence of hypokalemia. However further studies are warranted to establish clinical safety of ondansetron regarding cardiovascular side effects. Hence for patient’s safety, ondansetron should be used with caution and extreme vigilance.

References

1. Chandrakala RC, Vijayashankara N,  Kumar KK,  Sarala N. Ondansetron induced fatal SVT. Indian J Pharmacol. 2008; 40(4): 186–187. 
2. Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D. A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med. 2002;39:397–403.
3. Freedman SB, Uleryk E, Rumantir M, Finkelstein Y. Ondansetron and the Risk of      
4. Cardiac Arrhythmias: A Systematic Review and Postmarketing Analysis. Annals of Emergency Medicine 2014;64(1):19–25.e6 
5. C. Baguley WA, Hay WT, Mackie KP, Cheney FW, Cullen BF. Cardiac dysrhythmias   associated with the intravenous administration of ondansetron and metoclopramide. Anesth Analg. 1997;84:1380–1.
6. Saxena, A, Chand, T, Arya SK, Puri R, Mittal A, Shukla V. Ondansetron-induced SVT in a patient of caesarian section. J Obstet Anaesth Crit Care. 2012; 2: 103–104
7. Afonso N, Dang A, Namshikar V, Kamat S, Rataboli PV. Intravenous ondansetron causing severe bradycardia: Two cases. Ann Card Anaesth 2009;12:170-1
8. Kasinath N, Malak O, Tetzlaff J. Atrial fibrillation after ondansetron for prevention of postoperative nausea and vomiting. Can J Anaesth 2003;50:215–20. 
9. Kuryshev YA, Brown AM, Wang L, Benedict CR, Rampe D. Interactions of the 5-hydroxytryptamine 3 antagonists class of antiemetic drugs with human cardiac ion channels. J Pharmacol Exp Ther. 2000;295:614–20. 
10. Ondansetron (Zofran): risk of QTc prolongation – important new intravenous dose restriction . Drug Safety Update Aug 2012 vol 6, issue 1: A2.
11. Food and Drug Administration. FDA drug safety communication: abnormal heart rhythms may be associated with use of Zofran (ondansetron). Available at: http://www.fda.gov/Drugs/DrugSafety/ucm271913.htm. 
12. J Lee Ondansetron and chest pain. Letter Emerg Med J 2005;22:78
13. Bosek V, Hu P, Robinson L. Acute myocardial ischaemia after administration of ondansetron hydrochloride. Anesthesiology 2000;92:885–7.

Citation

Harde M, Dave S, Bhadange R, Bhadade R.Rare serious side effect of low dose Ondansetron: Supraventricular tachycardia, hypertension, angina. JPGO 2015. Volume 2 No. 6. Available from: http://www.jpgo.org/2015/06/rare-serious-side-effect-of-low-dose.html