Discussion
Ondansetron is considered as a first-line agent in the ED to manage nausea and vomiting, with a relatively low risk of side effects compared to other antiemetics(12, 13). Despite the high safety profile of ondansetron, emerging literature on ondansetron toxicity has reported hypersensitivity reactions leading to skin rashes and urticaria(14) . It is entirely possible that with a combination of bronchospasms, hypotension, and urticaria-like rash at the site of injection, this patient had an allergic reaction to ondansetron prompting hydrocortisone administration. Allergic reactions to drug administration can be classified into two categories: Anaphylaxis (IgE-immune mediated) or Anaphylactoid reactions (non-IgE-immune mediated)(15). Anaphylaxis is often caused by a hypersensitivity reaction to drugs in hospital settings(16). Pre-sensitized individuals exposed to an allergen prompt an immunological response involving IgE antibodies initially binding to mast cells and basophils, and later cross-linking with other IgE antibodies to initiate the signal transduction cascade of preformed mediators (17). On the other hand, anaphylactoid reaction is independent of antigen-specific immune responses and mimics symptoms of anaphylaxis. Also known as a pseudo allergy, this phenomenon often occurs from the first dose of medication and can attribute to around two-thirds of hypersensitivity reactions(18). Typically, they are induced by opioid (i.e. codeine), complement activation-related drugs, non-steroidal anti-inflammatory drugs (i.e. aspirin), or traditional Chinese medicine injections(19). However, pseudo allergies are well underreported in the literature and can come with lethal complications due to its unpredictability. Though IgE levels were not determined, the absence of prior exposure to ondansetron nor any history of adverse allergic reaction to drugs makes it likely that this patient experienced an anaphylactoid reaction to ondansetron. Mehra et. al reported a similar case of hypersensitivity to intravenous ondansetron which was concluded to be an anaphylactoid reaction due to the absence of prior administration in the patient’s history(14).
Acute coronary syndrome was first reported in 1992 as an adverse effect of ondansetron(20). Since then, there have been 9 documented cases of coronary vasospasms and dysrhythmia after ondansetron administration to date(21). When the occurrence of cardiac symptoms arise in the context of anaphylactoid reactions to drugs, the condition can be coined as “Kounis Syndrome (KS)”. Despite KS being underreported, its pathophysiology is well discerned and can be attributed by an immune response generated from an anaphylactoid reaction, causing myocardial injury. Mast cell activation caused by an allergic reaction to a drug can cause the release of interrelated inflammatory cells such as T-lymphocytes through mast cell activation(22). The heart is a target of these chemical mediators during anaphylactoid reactions and can cause localized effects on the myocardium, leading to acute myocardial injury (non-ischaemic changes), ACS such as myocardial infarctions, and vasoconstriction of coronary vasculature(22). The investigations that would support KS include troponin levels, ECG, and ECHO. The only other case study reporting KS after ondansetron administration described a pregnant women experiencing a possible allergic reaction to ondansetron, leading to acute coronary syndrome. In the aforementioned case, a coronary angiography was indicated in to confirm the hypothesis of a coronary vasospasm and an ECG exhibited ST-segment elevations(23). In our study, though there was an absence of ischaemic changes and non-abnormal ECG changes, there were very high elevations of cardiac troponin levels. In a previously reported clinical study, 31 patients with anaphylaxis and urticaria was found with significantly increased cardiac troponin I levels compared to healthy controls(24). This was further confirmed by Cha et. al, where myocardial injury and elevated troponin levels was observed in 300 anaphylaxis cases(25). Given the patient’s medical history, an angiography was not ordered since his symptoms subsided after immediate administration of aspirin. On the echocardiogram, left ventricular hypertrophy was noted, an occurrence that has been reported once in a case series on KS by Forlani et. al(26). Due to the variety of cardiac manifestations and presentations, it can be difficult to interpret the exact pathophysiology. However, it is reasonable to suggest that the non-ischaemic nature of the patient’s cardiac symptoms were attributed by the acute nature of injury inflicted by anaphylactoid reactions, causing a rise in troponin and leading to hypertrophy as compensation. In accordance with the results of previous investigations, cardiac troponin levels may serve as an important marker in patients with acute allergic reactions(25).
To our best knowledge, this was one of the first cases of KS characterized by non-ischaemic myocardial injury and elevated troponin due to an anaphylactoid reaction to ondansetron. As a result, we bring awareness to the multi-faceted nature of KS and the importance of taking detailed history. If left untreated or misdiagnosed, the consequences can be detrimental to the patient’s health(22). A high index of clinical suspicion must be exercised when a patient is suspected to have a combination of allergic reactions and cardiac symptoms. However, the timing of hypersensitivity symptoms superimposed with non-ischaemic cardiac changes in our case made it difficult to diagnose KS. Future studies are warranted to further study how anaphylactoid reactions play a role in non-ischaemic changes as opposed to ACS and whether the time of presentation is important in the diagnosis. Moreover, further investigations should ascertain the association of pseudo allergies or anaphylactoid reactions with an increase in cardiac troponin levels. This case prompts a need to better distinguish anaphylactoid reaction from anaphylaxis when administering ondansetron and brings to light the multi-factorial presentation of Kounis syndrome.
There were several limitations to the case report. We did not obtain an angiogram, which would definitively diagnose a spontaneous coronary vasospasm that ensued after ondansetron administration. However, the results from the investigations raised our suspicions of spontaneous and acute myocardial injury that could have been caused by vasospasms given the lack of previous cardiovascular co-morbidities. Additionally, we did not determine the IgE levels of the patient, which would have strengthened our confidence that the patient has a pseudo allergy to ondansetron.