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.