Page 31 - Journal of Special Operations Medicine - Summer 2015

perhaps due to the rate of administration, and may also Most recently, Freedman et al. performed an exten-
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be used along with IV ondansetron. 10 sive systematic analysis of the published literature, the
manufacturer’s database, the FDA Adverse Events Re-
It is important to note that all of the studies we cite porting System, and the World Health Organization
describing the use of oral ondansetron were specifically Individual Safety Case Reports Database (VigiBase),
evaluating the ODT formulation. 45–49 There is a nondis- looking for all cases of documented or perceived ar-
solving oral tablet form of ondansetron that, unlike the rhythmia within 24 hours of ondansetron administra-
ODT, relies on the gut for absorption and is, therefore, tion. They found no reports of arrhythmia occurring
not as useful in the combat trauma casualty. Also, the with a single dose of oral ondansetron (the primary
oral formulation has a much lower bioavailability than end point). Their secondary end point, arrhythmia af-
the ODT formulation—56% versus 90%. 14,49,50 ter parenteral administration, identified 49 cases of
arrhythmia, 48 of which occurred with IV administra-
Ondansetron has an excellent side effect profile and has tion. All of the cases involved patients being treated
been demonstrated to be safe in multiple patient popula- for PONV, having preexisting cardiac disease, con-
tions. It has been used safely and effectively by paramed- comitant administration of proarrhythmic agents, or
ics in the prehospital environment. There have been a combination of these. There were four cases of tors-
3
concerns raised regarding the possibility of it lowering ades de pointes: three involving significant contribut-
seizure thresholds, and there have been at least three re- ing history and one involving prolonged scheduled use
ports of seizure activity in otherwise healthy patients af- of oral ondansetron. There were no reports of torsades
ter ondansetron administration. This is a controversial in patients who approach our target patient popula-
51
concern, since data have demonstrated both proepilep- tion—the relatively young, previously healthy, acutely
togenic and antiepileptogenic potential in animal mod- injured trauma patient. 10
els, and its use in neurosurgical trauma patients has
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not been associated with either extrapyramidal symp- Torsades de pointes, specifically, is very rare and has
toms or increased seizure activity. 52 not been reported in trauma patients who have been
given IV ondansetron (PubMed search, June 2014). Un-
Most concerning of ondansetron’s known adverse effects like droperidol, which has an FDA black box warning
is a prolonged QT interval that could develop into tor- regarding QT prolongation at or below recommended
sades de pointes. This has been of particular concern in doses, ondansetron has no such warning and this side
patients with a preexisting long QT syndrome or with ex- effect is most likely of no concern in the acute trauma
isting or acutely developing cardiovascular disease (i.e., setting. Interestingly, promethazine has also been found
heart failure or acute coronary syndromes). The FDA to prolong QTc intervals but is not believed to be sig-
53
revised the Drug Safety Communication for ondansetron nificantly torsadogenic. 8
in September 2011 to reflect the dose-response effect of
IV ondansetron administration. GlaxoSmithKline plc Information gathered from the JTTS on medication ad-
54
similarly announced that it removed the 32mg single- ministration to combat casualties in Afghanistan from
dose option from the drug labeling. This high dose was 4 January 2013 to 8 May 2014 looked at 576 patients,
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specifically associated with episodes of prolonged QT 247 of whom received a total of 395 doses of a study
intervals, with an average increase of 20 milliseconds; drug (at least one dose of fentanyl, ketamine, morphine,
however, at single IV doses of 16mg or less, QT prolon- ondansetron, and/or promethazine). Twenty-seven per-
gation is minimal (approximately 6 milliseconds). 53 cent of patients received multiple doses of the analgesics
studied. Of these, 31 received one of the antiemetics; 23
Another retrospective review of the 5-HT receptor of those 31 patients (75%) received ondansetron. No
3
agonists ondansetron and dolasetron looked at a total patient received both antiemetic drugs, although one
of 1,429 patients given a study drug and 1,022 control patient received two doses of ondansetron and 39% re-
subjects. The researchers found that 17% of patients ceived an antiemetic simultaneously or within 1 minute
given 5-HT receptor antagonists (n = 242) and 22% of analgesic administration. Although the registry does
3
of controls (n = 220) had postoperative QTc exceeding not have data on the effectiveness of treatment or the
500 milliseconds, but that the average QTc prolonga- incidence of adverse events (E. Burrell, personal com-
tion was only 6%. They did not record torsades de munication, 17 June 2014), the simple demonstration
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pointes events or any other life-threatening dysrhyth- of the predominant use of ondansetron and the general
mias. Although the antiemetic dose was not reported in lack of repeated dosing or the need for rescue with pro-
the study, it is reasonable to expect that ondansetron methazine or another antiemetic indicate ondansetron’s
dosing was consistent with standard perioperative dos- wide acceptance by operational medical personnel and a
ing of 4mg to 8mg, and certainly not more than 16mg likely favorable experience with its use. This preference
per individual dose for ondansetron is not limited to US medical personnel.

Replacement of Antiemetics in TCCC 21