Abstract
BACKGROUND:
Ranitidine injection is not well-known to cause cardiac arrest except in few published case reports. The Eritrean Pharmacovigilance Centre received four cases of cardiac arrest associated with ranitidine injection.
OBJECTIVE:
To assess the causal relationship between cardiac arrest and ranitidine, and to identify possible risk factors.
METHODS:
This is a descriptive case series assessment of cardiac arrest associated with ranitidine and data was mined to supplement the cases from the WHO global database of individual case safety reports.
RESULTS:
In all cases, ranitidine injection was administered fast IV bolus without proper dilution and the outcome was fatal in three. All patients encountered cardiac arrest within 20 minutes of intravenous use. Causality was found to be probable in two cases and possible in the other two. Cardiac arrest could have been prevented in all cases. On top of this, from the WHO global database, 185 cases of cardiac arrest and cardio-pulmonary arrest associated with ranitidine were retrieved and 49.7% were fatal. In 40% of the cases, ranitidine was reported as a single suspect. In 36 cases, cardiac arrest resolved following withdrawal of ranitidine and reaction recurred in one case after re-introduction of the product.
CONCLUSION:
There appears a causal link between ranitidine and cardiac arrest, possibly related to medication errors that warrants immediate attention from healthcare professionals.
Keywords
Introduction
Ranitidine is a rapidly acting specific histamine H2 receptor antagonist that inhibits basal gastric acid secretion as well as gastric acid secretion stimulated by betazole and pentagastrin [1]. Although ranitidine reduces total pepsin output in proportion to the decrease in volume of gastric juice, it does not affect the secretion of pepsin or any other gastric juices. It is indicated for the treatment of conditions where reduction of gastric acid output is beneficial such as duodenal ulcer, benign gastric ulcer, post-operative ulcer, reflux esophagitis and Zollinger–Ellison syndrome [2].
According to the US Food and Drug Administration (FDA) prescription information and the summary of product characteristics (SPC) of Zantac®, ranitidine injection should be diluted prior to intravenous administration; i.e. 50 mg in 0.9% sodium chloride solution or other compatible intravenous solutions to a concentration no greater than 2.5 mg/ml (20 ml) and must be injected at a rate no greater than 4 ml/min [1,2].
The SPC of Zantac® injection reported adverse cardiovascular reactions that include arrhythmias tachycardia, bradycardia, asystole, atrioventricular block, and premature ventricular beats although they were rare. These types of adverse cardiac reactions have also been reported with other H2-blockers. That being said, there are only few published case reports on cardiac arrest associated with ranitidine injection [3–5].
Since the introduction of ranitidine injection in 2016, the Eritrean Pharmacovigilance Center has received four cases of cardiac arrest associated with intravenously injected ranitidine HCl (50 mg/2 ml). This study was conducted to assess the causal relationship between cardiac arrest and ranitidine and to identify other possible risk factors.
Methods
Study design and data source
This was a descriptive case series assessment of cases of cardiac arrest associated with intravenous ranitidine injection retrieved from the database of the Eritrean Pharmacovigilance Centre. To supplement this data, a descriptive analysis of previously reported cases of cardiac arrest associated with the use of ranitidine HCl to the WHO global database was carried out. Search on the WHO global database of individual case safety reports, VigiBase, was made on November 30, 2018. VigiBase is a databank developed and maintained by the Uppsala Monitoring Centre (UMC), Sweden which is the world’s largest database of its kind with around 19 million reports (as of November, 2018) submitted from 131-member states since the establishment of the WHO Program for International Drug Monitoring in 1968. “Ranitidine hydrochloride” as drug substance and the high-level MedDRA reaction terms “cardiac arrest” and “cardio-respiratory arrest” were used as search criteria. Potential duplicates were removed automatically with VigiMatch. Cases retrieved with VigiLyze, an analysis tool of the VigiBase, were exported to an Excel spreadsheet for further statistical descriptive analysis.
Exposure and outcome definition
Intravenous administration of ranitidine at varying doses was considered as exposure in the locally reported cases. In addition, all cases in the global database who had been exposed to all forms of ranitidine prior to developing reactions were considered. Medical Dictionary for Regulatory Activities (MedDRA) coded cases of cardiac arrest and cardio-respiratory arrest encountered following administration of ranitidine were included in this study. The cases could not be validated because of the retrospective nature of the study. According to the American Heart Association, cardiac or cardiorespiratory arrest is defined as a sudden, sometimes temporary, cessation of the heart’s functioning in a person who may or may not have been diagnosed with heart disease [6].
Case assessment
The causal relationship of the cases from Eritrea was assessed using the Naranjo Adverse Drug Reaction Probability Scale [7]. Further assessment of causality in the series of cases reported from Eritrea and beyond was assessed using Hill’s criteria [8]. Preventability of the locally reported cases was assessed with the P-method (preventability method) developed by the Moroccan Pharmacovigilance Centre in collaboration with the WHO [9]. The preventability criteria are those that are considered by the reviewer as critical for the occurrence of the specific adverse effect, cardiac arrest. The method constitutes 20 criteria that are used to assess the preventability of adverse drug reactions. If at least one critical criterion is identified, the case is considered as “preventable”. If none of the critical criteria is identified, the case is considered as “non-preventable”. The case is categorized as “not assessable” if any of the critical criteria is unknown. Labeledness of the adverse effect was checked through extensive literature review including the Summary of Product Characteristics (SPCs) of the product.
Results
Case presentation
Case 1
A 72-year-old female patient arrived at the emergency department complaining of epigastric pain, dyspepsia and vomiting. In addition, the patient also felt dizzy and generally weak when she got up. She had no previous history of any chronic illnesses. Physical examination showed that she was very weak and her blood pressure was unrecordable. On further cardiovascular examination, the patient was found to have irregular beats (arrhythmia). Moreover, she had a scaphoid abdomen with severe epigastric tenderness. With these findings, the patient was clinically diagnosed as a case of severe peptic ulcer disease and cardiogenic shock. Thus, patient was admitted to the emergency department and immediately was started on DNS 500 ml (slowly), antacid 20 ml stat orally and ranitidine 50 mg diluted in 10 ml IV push. As the patient’s condition started to deteriorate after 20 minutes, CPR with ambubag was started and adrenaline 1 ml was given IV. However, resuscitation failed and the patient passed away.
Summary of the four cases of cardiac arrest following administration of intravenous ranitidine reported from Eritrea
Summary of the four cases of cardiac arrest following administration of intravenous ranitidine reported from Eritrea
F: Female; M: Male; MI: Myocardial infarction; DNS: Dextrose in normal saline; Min: Minutes. Note: All patients came to the health facilities with complains of peptic ulcer disease.
A 52-year-old male patient admitted to the emergency department with the suspected diagnosis of acute myocardial infarction (MI) and severe peptic ulcer disease. To relieve the stress caused by the peptic ulcer, undiluted ranitidine 50 mg IV push was given. Just three minutes later, the patient suddenly died. ECG was not performed. In fact, the patient had not received any other treatment as the emergency team was still in preparation to manage the condition.
Case 3
A 68-year-old female patient was brought to the emergency department because of peptic ulcer disease. The patient suddenly collapsed 20 minutes after administration of undiluted ranitidine 50 mg IV push. Her vital signs became unrecordable and the patient passed away. The patient had no known history of cardiac problems or other chronic diseases.
Case 4
A 37-year-old female patient was admitted to the emergency department with the impression of peptic ulcer disease. She was a known HIV patient on anti-retroviral therapy. The patient was given a stat dose of ranitidine injection, 50 mg diluted in 10 ml pushed IV. Immediately, the patient developed cardiac arrest and was successfully resuscitated with cardiopulmonary resuscitation (CPR) and IV fluids without administration of other medications. She survived and was kept for monitoring. About 12 hours later, the patient started to complain of dyspeptic symptoms again and was given another dose of ranitidine, 50 mg diluted in 10 ml of sterile water for injection pushed IV. Again, the patient developed cardiac arrest and was successfully resuscitated with CPR and IV fluids. The patient was stabilized and once again placed for 24 hours observation. After 24 hours, the patient was discharged with oral medications and follow-up appointments. The oral medications prescribed were not mentioned in the report. The cases are summarized in Table 1.
Reports in the WHO global database of individual case safety reports
A total of 185 cases of cardiac arrest (135) and cardio-respiratory arrest (50) associated with ranitidine use were retrieved from the WHO global database. The cases were reported from 26 countries in five WHO regions: Africa (2.7%), Americas (49.7%), Asia (10.8%), Europe (34.6%) and Oceania (2.2%). The cases comprised 97 (52.4%) females, 84 (45.4%) males and in four cases sex was unknown. About 38% of the cases were aged less than or equals to 44 years.
Of the total cases submitted to WHO global database, 49.7% were reported as ‘fatal’. In 40% of the cases, ranitidine was reported as a single suspect and in 10.8% it was solely administered. Reaction resolved in 36 cases following discontinuation of ranitidine and in one case cardiac arrest recurred with re-administration of ranitidine. The information component or IC value was −0.54. More than half of the cases (57.3%) were reported by physicians. Levothyroxine (14.8%), clonazepam (13.7%) and simvastatin (13.1%) were the most commonly co-reported substances.
Discussion
Investigation of the cases from Eritrea showed that ranitidine injection was a possible cause of cardiac arrest and all cases were found to be possibly preventable. When the first fatal case of cardiac arrest was reported in January 2018, it was assessed as part of the weekly case-by-case assessment session carried out by the Eritrean Pharmacovigilance Centre. During the assessment, it was revealed that ranitidine injection (50 mg∕2 ml) was administered fast IV bolus without dilution, though it is required to be diluted in 20 ml of compatible solution and administered slowly over five minutes as per the manufacturer’s recommendation [1,2]. The second death case was received few days after the first case with the same administration error.
The pharmacovigilance team communicated a number of professionals from different hospitals and inquired about the way ranitidine injection was administered. The administration error was found to be widespread in many of the hospitals. Though the appropriate administration of ranitidine injection was clearly specified in the product information leaflet, it was not strictly followed by many healthcare professionals. The National Medicines and Food Administration of Eritrea issued a circular letter, as a corrective action, to all health facilities to properly administer ranitidine injection.
Another two cases of cardiac arrest were received after the information was issued in circular letter and medicine information bulletin. In these cases, ranitidine was diluted in only 10 ml instead of 20 ml compatible solution due to, as per their report, the unavailability of 20 ml syringes. In one case, ranitidine was reintroduced with the same administration error in the next day and cardiac arrest recurred. These two cases might have been prevented had the provided information was strictly followed. Ranitidine injection should be diluted prior to intravenous administration; i.e. 50 mg in 0.9% sodium chloride or other compatible IV solutions to a concentration no greater than 2.5 mg/ml (50 mg in 20 ml) and must be injected at a rate no greater than 4 ml/min [1,2]. Besides, patients developed cardiac arrest with ranitidine injection should not be rechallenged with the same drug.
The case reports of cardiac arrest published in medical literature were also linked to inappropriate administration of ranitidine injection (fast IV bolus) [3–5]. This shows that inappropriate use of ranitidine injection not only occurred in Eritrea and warrants immediate risk minimization plans.
In addition to the locally reported cases, several cases of cardiac arrest associated with ranitidine were submitted to the global database; about half of which had fatal outcome. The submission of cases from five WHO regions indicates consistency of the association. The fact that ranitidine was reported as the only suspected drug in about 40% of the cases and the solely administered drug in 10.8% shows some specificity and supports the causal association. Moreover, the positive dechallenge in several cases and positive rechallenge in one provides further evidence on the causal link between ranitidine and cardiac arrest. The plausible time to onset and the unavailability of other possible explanation in three cases reported from Eritrea as well as the consistency of the association in literature and in the global database also strengthens the causality.
Even though the association of ranitidine with cardiac arrest is not well established, drugs of the same class such as famotidine and cimetidine have been previously associated [10,11]. A possible mechanism by which ranitidine causes cardiac arrest could be explained by the effect of H2 receptor antagonism in the coronary smooth muscle via vasoconstriction [12]. Blockade of H2 receptor could increase the H1-receptor stimulation effect of histamine on the heart, which could result in atrioventricular block. Another possible mechanism is that H2-receptor blockade could terminate the H2-receptor-mediated dilatation of the coronary arteries leading to ischemia in the territory of the atrioventricular conduction bundle and may also ultimately result in atrioventricular block [10].
The IC value of ranitidine and cardiac arrest relationship was found to be negative. A negative IC value indicates that the drug-reaction combination was not frequently reported than expected. This is not in favor of the causal association and may suggest that the strength of association is weak; thought it could be masked with other frequently reported adverse effects of ranitidine. In some cases, the effect of other concurrently used drugs, old age and underlying causes like history of cardiac problems could not be ruled out.
The main limitation of this study is that the risk of cardiac arrest associated with ranitidine injection might be underestimated due to underreporting and cannot be quantified as the denominator in spontaneous reporting is unknown. Besides, the diagnosis of cardiac arrest could not be validated and the nature of the study could help us to measure the effect of other potential confounders which on their own might have caused the reaction. Preventability assessment of the cases retrieved from VigiBase was not possible as the global database does not capture such information.
Conclusion
The plausible temporal association, consistency and specificity of the association, the analogy with other drugs of the same class, the positive dechallenge and rechallenge reported in some cases and the possible biological mechanism suggest a causal link between ranitidine and cardiac arrest; possibly related to medication errors. The problem might have easily been averted by preparing and administering the product as per the manufacturer’s recommendation. To mitigate the risk, it warrants deployment of additional risk management plans including educational initiatives, direct healthcare professional communication and boxed warning to aware healthcare providers on the inappropriate use of ranitidine and its consequences. Healthcare professionals in other countries should also take this incident as a lesson to detect medication errors earlier and prevent further harm. Further studies are also required to substantiate this safety signal.
Footnotes
Acknowledgements
The authors would like to thank the reporters Eden Hailemariam, BSN, Simon Woldu, MD and Issac Gebreberhan, BSN, for their vigilance.
Author contributions
MR conceived the idea and all authors designed and conducted the study. Data was retrieved and analyzed by MR and all authors participated in the interpretation of the results. The manuscript was drafted by DT and reviewed by all authors. All authors gave their consent to be submit the manuscript for publication in an international journal.
Availability of data
The datasets generated and analyzed during the current study are not publicly available due to agreements between contributors of data to the database used (VigiBase) and the custodian of the database. National Centres (mainly drug regulatory authorities) constituting the WHO Programme for International Drug Monitoring (PIDM) contribute data to VigiBase and the Uppsala Monitoring Centre is the custodian in its capacity as WHO collaborating centre for international drug monitoring. Some subsets of the data may be available from the corresponding author on reasonable request.
Ethics approval
All cases were retrieved from databases. The databases contained de-identified patient information and thus ethical approval was not required for the study.
Conflict of interest
The authors declare that they have no competing interests.
Disclaimer
The conclusion reported in this article is that of the authors and does not represent the opinion of the WHO or the Uppsala Monitoring Centre, Sweden.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.