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CARDIAC ARREST DUE TO ONDANSETRON?

Or SYNERGISTIC ACTION
WITH PREGABALIN? A CASE REPORT.
INTRODUCTION
Long QT syndrome (LQTs) is an abnormal feature of heart’s electrical system that can lead to
can lead to fatal dysrhythmia called Torsades de Pointes (TdP).1 Tdp is a polymorphic
ventricular tachycardia characterized by twisting of QRS complex morphology 2 with several
unique features of ventricular tachyarrhymias.3
The ventricular rate in TdP is often <200 beats per minute, and it frequently terminates
spontaneously, and it can degenerate into ventricular fibrillation and cardiac arrest. 4 LQTs is
described by prolonged QT interval on electrocardiography (ECG). LQTs is defined as a QT
interval >0.45 s in males and >0.47 s in females. 5 LQTs can be inherited (congenital) or
acquired by medications or condition (electrolyte imbalance) . Correction of electrolyte
imbalance or discontinuation of the medication brings QT interval within the normal range
(Moss, 2003)6. (Haverkamp et al., 2000).7
Acquired long QT syndrome is an important and preventable cause of cardiac arrest. Certain
medications when administered in combination can increase the risk of LQTs. One such drug
is Ondansetron, which is used inadvertently in the hospital for its antiemetic property. 8
Pregabalin is a widely used drug for management of neuropathic pain. This also has the
effect on prolongation QT interval.
CASE REPORT
A 33 year old female was admitted to the ward with complaints of fever, shortness of breath
and cough. After admission, she had an episode of vomiting in the ward after antibiotic
administration. She was administered IV ondansetron after which she became
unresponsive, on physical examination carotid was not felt and BP was not recordable.
CODE BLUE was activated and CPR was started as per ACLS guidelines. After 2 cycles of CPR
and Inj adrenaline, patient attained ROSC. Then patient was intubated and shifted to ICU
where she was kept on mechanical ventilation. Her ECG revealed features of LQTs.
Supportive vasopressor drug noradrenaline was required for a short period of time. ABG
revealed normal values. Serum samples were investigated for any evidence of
dyselectrolytemia and hypoglycemia. Blood sugars, Sodium, Potassium, Calcium and
Magnesium levels were within the normal range. As the hemodynamics were well
maintained and patient was conscious and oriented, she was extubated within 6 hours.
On detailed history taking, she was found to be a known case of rheumatoid arthritis and
interstitial lung disease for past 8 years. She was taking DMARDS and pregabalin for arthritic
pain and Azathioprine for Interstitial lung disease.
DISCUSSION
Torsades de pointes (TdP) is a potentially life-threatening arrhythmia. The incidence of TdP
in the general population is unknown but has been reported to range from 2.5 and 4.0 per 1
million person-years in men and women,9 respectively, to as high as 4.0 per 100 000
individuals annually.10 The incidence of TdP among patients in adult intensive care and
progressive care units over a 2-month period was 0.07%; 6% of cardiac arrests were caused
by TdP.11--- Circulation.
TdP is not only associated with antiarrhythmic drugs, but also noncardiac drugs of several
classes. All these drugs prolong the QT interval by blocking the potassium channel I(Kr), and
many are metabolized by the cytochrome P450 isoenzyme CYP3A4. Polypharmacy with
other drugs utilizing the same enzyme, or inhibiting CYP3A4, can lead to TdP. A consistent
finding of all the QT-prolonging drugs is predominance of TdP in women. Other risk factors
for QT prolongation and TdP include hypokalemia, congestive heart failure, and structural
heart disease. Knowledge of potential drug interactions and other risk factors for TdP can
help in reducing the number of adverse events associated with the use of QT-prolonging
drugs. 13
Ondansetron which is a 5-HT3 antagonists was used to treat vomiting in our case. And this
could be the cause for LQTs and TdP related cardiac arrest. A number of studies have
indicated that QT prolongation is a significant side effect of ondansetron which is probably
mediated by the blockade of cardiac sodium channels. 8 FDA is now adding a new warning to
avoid the use of ondansetron in patients with congenital long QT syndrome because these
patients are at particular risk for developing TdP. Additional recommendations for ECG
monitoring in patients with electrolyte abnormalities (e.g., hypokalemia or
hypomagnesemia), congestive heart failure, bradyarrhythmias, or in patients taking other
medications that can lead to QT prolongation, are being added to the ondansetron drug
labels.
Our patient was taking pregabalin for arthritic pain which may be considered the
contributory cause for LQTs and fatal TdP. For the first time Adar et al. reported in his case
that pregabalin can cause prolonged QT interval even in humans. 5 In an experimental
research on rats, Alp et al. (2008) demonstrated that pregabalin causes increases the heart
rate and prolongs QT interval on ECG. 14
The present case suggests that the administration of two drugs that has effect on QT
interval might have precipitated the fatal arrythmia due to TdP.
Etiology of TdP is usually multifactorial, 15 and the risk factors predisposing to LQT and Tdp
includes medications ( antidepressants, antipsychotics, antibiotics, Amiodarone), electrolyte
imbalances (hypocalcaemia, hypokalemia, hypomagnesemia) and clinical risk factors (older
age, female gender, alcohol abuse, sleep apnoea, complete AV block, bradycardia, dilated
cardiomyopathy). The QT intervals normalized with cessation of offending medications and
replacement of electrolytes.16
Digby et al17 in his case series on acquired LQT, highlights that there were ≥2 prominent risk
factors and polypharmacy for the development of LQT and Tdp.
It illustrates the multifactorial nature of acquired LQT and it is important to recognize the
risk factors and prevent the fatal consequences with early action.
Wei et al.18 in his case report and review of literature documented that QTc prolongation
and torsades de pointes occurred due to a coadministration of fluoxetine and amiodarone.
A potential drug-drug interaction (DDI) may lead to a life-threatening drug adverse reaction
(ADR) when QTc-prolonging agents are given to patients with cardiac abnormalities, and to
avoid combining 2 QTc-prolonging drugs. Perioperative incidence of prolonged QT interval
in noncardiac surgery and the interaction of drugs used and the procedure (thoracic
epidural) should be kept in mind.19
In the present case, we attributed that prolonged QT interval to pregabalin and precipitation
to polymorphic type of Tdp by coadministration of ondansetron. Women gender may also
be a contributory factor. Similar risk factors were also documented by Adar at al. 5 and
Wolbrette.13

CONCLUSION
The probability of QT prolongation with concomitant use of pregabalin and its augmented
effect with fatal polymorphic arrythmia of Tdp. This case highlights the importance of
checking concomitant drug use prior to prescribing routine drugs like ondansetron and
other drugs that prolong the QT interval that lead to fatal long QT syndrome. The clinical
condition of the patient with heart failure and bradycardia, electrolyte imbalance, female
gender and old age that contribute to the fatal Tdp should also be considered.

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