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Question: Why do we worry about giving Ondansetron to patients with prolonged QT? What is the risk of cardiac arrhythmias in the average patient with long QT? Follow me down the rabbit hole of my first tweetorial! @tony_breu @thecurbsiders #MedEd #FOAMed
Case: You are the night float resident, and get called by the nurse for an 84 y/o patient with gastritis, having intractable vomiting. She asks you for an antiemetic. You go to order ondansetron, but stop b/c you notice the patient's EKG--the QTc is 495! What do you do?!!
Before we answer this question, lets review some cardiac physiology. Cardiac myoctes have a negatively charged resting membrane potential that is maintained by the active movement of charged ions, primarily via Na+/K+ ATPase, and Na+/Ca2+ exchange, across the cellular membrane.
During depolarization, there is a rapid flow of positive sodium ions into the cardiac myocyte. The cell then re-polarizes through the removal of positive ions, and the selected opening and closing of multiple ion channels to regain its resting potential.
The QT interval represents the elapsed time between ventricular depolarization and re-polarization. On EKG, this is the measured interval from the beginning of the Q wave to the end of the T wave. Normal QT is <470 ms in men and <480 in women.
Prolonged QT is an independent risk factor for development of Torsade Des Pointes (TdP). There is thought to be an increased risk for TdP whenever Qtc is >500 and whenever a drug increases QTc by >60-70 ms.
Prolonged QT results from congenital or iatrogenic causes (or a mix of both). There are over 17 known genes associated with cLQT syndrome, and seven genotypes. Iatrogenic causes include drugs that electrolyte abnormalities, myocardial injury, and many others.
In fact, much of our understanding of prolonged QT comes from similarities between the affected ion channels in cLQTS and the actions of the medications that increase QT. IKr, a major cardiac potassium current, is blocked by many meds.
Drug induced QT prolongation is common. Up until the 1990s, TdP was thought to be rare, confined to drugs like quinidine. It was later discovered that non cardiac drugs could also prolong QT. Since then 14 drugs have been removed from the market due to risk of TdP.
How does prolonged QT cause cardiac arrhythmias? That answer is complicated. Among people who have prolonged QT, only a small subset will get symptomatic arrhythmias. QT is a good surrogate marker for those who are at risk, it is not the sole determinant of risk for TdP.
Transmural dispersion of repolarization (TDR) might be a better indicator of TdP risk. This is difference in electrical properties between the epi- and endocardium. This can be measured on the EKG by measuring from the peak to the end of of the T wave.
To understand TDR, think anatomically; If you were to take a cross section of normal myocardium, you would see three different populations of cells—epicardial, endocardial and mid-myocardial (M cells), with a different mix of ion channels and electrophysiological properties.
In the lab, researchers have demonstrated that each cell line responds differently to drugs and other QT prolonging conditions. For example, M cells seem to be the most sensitive to medications.
If this difference is large enough, some myocytes will be in the refractory period, while others re-polarize more quickly. This results in a unidirectional block, setting the myocardium up for early after depolarizations (EAD), and reentrant arrhythmia, leading to TdP
Here's the rub: agents that do not increase transmural dispersion of repolarization have limited potential to induce TdP despite their affect on QT interval. Amiodarone, for example, can cause large QT prolongations but does not affect TDR.
That brings us to Ondansetron. Will you cause an arrythmia if you give it to a patient with prolonged QT? Unfortunately, the risk is not well quantified.
Ondansetron is a 5-HT3 receptor antagonist that works by blocking the action of serotonin, and was intended to treat nausea and vomiting in cancer patients. It. In 2011, the FDA issued a safety warning that the medication could cause TdP, and should be avoided in prolonged QT
This recommendation was based off of two studies of surgical patients. One looked at EKG changes, specifically QT prolongation, in 16 patients undergoing general anesthesia, who received either droperidol or ondansetron for post operative nausea and vomiting.
They demonstrated a clear dose dependent QT prolongation. Based on this study, the FDA initiated a safety review, and the company removed the 32 mg single intravenous dose from the market, and included a warning about QT prolongation.
Since then, there has been some pushback on whether we need to worry about ondansetron and other medications that prolong QT. Instead, some have argued that it's better to use transmural dispersion of repolarization to assess risk.
Complicating things further, this is really difficult to study TdP. We don't know what the incidence of TdP in people with prolonged QT, b/c the arrhythmia is transient and accurate diagnosis requires that an ECG be taken during an episode.
Until we have a better way to assess the risk of QT prolonging medications, and better means risk stratify, we are stuck with using QT in clinical practice. For our patient above, it involves weighing the risks and benefits, and using shared decision making with our patients.
Take Aways:
QT prolongation is an independent risk factor for torsade des pointes, and sudden cardiac death.
Drug induced TdP is multifactorial, and additive based on other pt risk factors
Ondansetron has a dose dependent effect on QT, that can last for hours after admin.
There is an increased risk for TdP whenever Qtc is >500 and whenever a drug increases QTc by >60-70 ms.
Get EKG to evaluate QT, and assess whether the patient is on other medications, or has other conditions that that prolong QT, and make informed decision with the patient.
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