Brief Reports

Torsades de Pointes Associated With Intravenous Haloperidol in Critically Ill Patients

Many psychiatric medications have the potential to cause QT interval prolongation and increase the risk for torsades de pointes (TdP). While it is challenging to risk-stratify most agents, citalopram is thought to convey greater risk than most antidepressants, and thioridazine, chlorpromazine and ziprasidone are more strongly associated with QT interval prolongation and TdP than are other antipsychotics. Methadone also has the potential to cause significant QT interval prolongation and TdP, and should be used with caution, particularly in patients who may be at higher risk. Psychiatrists should be aware of the potential for medications to prolong the QT interval and TdP, and should think carefully about the need for monitoring and consultation with colleagues in cardiology in certain situations.

Risk factors are important for the development of torsades de pointes (TdP), and drug-induced TdP is extremely rare in the absence of risk factors. Traditional risk factors for QTc interval prolongation and TdP include acute myocardial infarction/ischemia, older age, anorexia/malnutrition, bradyarrhythmias, conversion from atrial fibrillation to sinus rhythm, elevated plasma concentrations of QT interval-prolonging drugs, female sex, heart failure with reduced ejection fraction, hepatic cirrhosis, electrolyte abnormalities (hypocalcemia, hypokalemia, and hypomagnesemia), hypothyroidism, history of TdP, possibly premature ventricular complexes, and prolongation of the QTc interval to ≥ 500 ms and/or > 60 ms from baseline (as a risk factor for TdP). Concomitant administration of multiple QT interval-prolonging drugs may be a risk factor for QTc prolongation and TdP, but not all studies support this concept, and whether a combination of QT interval-prolonging drugs increases the risk of QTc prolongation compared to that associated with individual QT-prolonging drugs alone likely depends on the specific drugs being combined. To minimize the risk of TdP, correctable risk factors should be ameliorated. In patients with non-modifiable risk factors who require therapy with a QT interval-prolonging medication, QTc interval-prolonging drugs should be used cautiously, and frequent QT interval monitoring should be implemented where feasible.

Significant advances in cancer treatment have resulted in decreased cancer related mortality for many malignancies with some cancer types now considered chronic diseases. Despite these improvements, there is increasing recognition that many cancer patients or cancer survivors can develop cardiovascular diseases, either due to the cancer itself or as a result of anticancer therapy. Much attention has focused on heart failure; however, other cardiotoxicities, notably cardiac rhythm disorders, can occur without underlying cardiomyopathy.

Supraventricular tachycardias occur in cancer patients treated with cytotoxic chemotherapy (anthracyclines, gemcitabine, cisplatin and alkylating-agents) or kinase-inhibitors (KIs) such as ibrutinib. Ventricular arrhythmias, with a subset of them being torsades-de-pointes (TdP) favored by QTc prolongation have been reported: this may be the result of direct hERG-channel inhibition or a more recently-described mechanism of phosphoinositide-3-kinase inhibition. The major anticancer drugs responsible for QTc prolongation in this context are KIs, arsenic trioxide, anthracyclines, histone deacetylase inhibitors, and selective estrogen receptor modulators.

Anticancer drug-induced cardiac rhythm disorders remain an underappreciated complication even by experienced clinicians. Moreover, the causal relationship of a particular anticancer drug with cardiac arrhythmia occurrence remains challenging due in part to patient comorbidities and complex treatment regimens. For example, any cancer patient may also be diagnosed with common diseases such as hypertension, diabetes or heart failure which increase an individual's arrhythmia susceptibility. Further, anticancer drugs are generally usually used in combination, increasing the challenge around establishing causation.

Thus, arrhythmias appear to be an underappreciated adverse effect of anticancer agents and the incidence, significance and underlying mechanisms are now being investigated.

Cardiac complications in cancer patients have been a significant medical problem in the last few years. Cardiosafety profile of most novel approved drugs, in cancer patients, is required by regulatory authorities. Risk of proarrhythmic effect associated with a new drug, in fact, is usually evaluated with specific studies conducted in agreement with ICHE14 guidelines. In this overview, we detailed the cardio safety profile of antiemetic drugs. In particular, we focused on data of 5HT3-RA drugs used for prevention of chemotherapy-induced nausea and vomiting in the oncology setting.

A literature search was conducted using the PubMed database to identify studies reporting arrhythmic complications of antiemetic drug used in oncology.

Most of the antiemetic drugs have been approved by regulatory authorities when ICHE14 guidelines were not issued, so the cardiotoxicity of those drugs has been defined with the post-marketing authorization pharmacovigilance activity. We reviewed the cardiotoxicity data of major antiemetic and adjuvant agents, providing a general overview and recommendations about their use in medical oncology.