Association between early ondansetron administration and in-hospital mortality in critically ill patients: analysis of the MIMIC-IV database

Ondansetron (OND) is the earliest used serotonin 5-hydroxytryptamine (5-HT₃) receptor antagonist as an antiemetic drug with widespread applications. Early use of OND would effectively prevent and alleviate nausea and vomiting for critically ill patients to reduce complications and the mortality rate in ICU [1‐3]. Interestingly, the latest study found that OND could be used to decrease mortality in the coronavirus disease 2019(COVID-19) inpatients [4]. In addition, OND has been illustrated the potentially pleiotropic effect, including neuroprotection [5], renal protection [6, 7], and anticoagulation [8, 9]. However, research on the survival benefit of initial use of OND, particularly in the critically ill, is lacking. Therefore, this study aimed to evaluate the association between early treatment of OND and in-hospital mortality in ICU patients and whether this association differed according to OND dose.

This study showed that early OND use was significantly associated with lower in-hospital mortality in ICU patients, and there was probably a remarkable association between daily low to moderate dose of OND and in-hospital mortality. Early OND usage would be strongly connected to in-hospital mortality in critically ill patients with cardiovascular diseases.

Similar to our study, the present study demonstrated that OND may promote mortality in critically ill patients. First, a latest study found that OND use would reduce 30-day all-cause mortality in COVID-19 inpatients [4]. Recent studies explained that 5-HT₃ receptor antagonists could prevent the rotavirus-induced release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting [12, 13]. A similar study illustrated that the impaired 5-HT-dependent signalling would delay the intracellular transport of incoming virions by altering the distribution of early endosomes in disassembly kinetics, resulting in decreased infectivity and impaired cell killing by diverse viruses including reovirus, chikungunya virus (CHIKV), mouse hepatitis virus (MHV) and two unrelated RNA viruses [14, 15]. In addition, OND would be neuroprotective. A recent animal study indicated that OND penetrates into the central nervous system (CNS), which may depend on the expression level of efflux transporters at the capillaries of the blood–brain barrier (BBB), such as P-glycoprotein (Pgp) encoded by the ABCB1 gene [16]. OND treatment significantly attenuated BBB breakdown, edema formation, glial fibrillary acidic protein (GFAP) and heat shock protein (HSP 72 kDa) expression and neuronal injuries [5]. Importantly, potentially favourable effects of OND on reduced in-hospital mortality in acute kidney injury (AKI) patients in the ICU were reported depending on the MIMIC-III database, the eICU database and the MIMIC-IV database. Based on the comparison of gene expression signatures, the latest study illustrated that the advantageous effect of OND might be elicited through the NF-KB pathway and JAK-STAT pathway [6, 7]. A recent pharmacoepidemiology study reported that OND was also associated with a significant decrease in 90-day mortality on the High-Density Intensive Care (HiDenIC-15) database containing intensive care data for 13 hospitals across Western Pennsylvania [17]. Last but not least, OND would inhibit agonist-induced platelet aggregation. And the negative effect of OND on platelet aggregation might manifest through the attenuation of agonist-induced IP3 production and MAPK phosphorylation resulting in suppressed intracellular Ca (2+) mobilization, TXB2 formation, and ATP release [8]. Thus, OND would become a promising drug for improving prognosis in critically ill patient with common conditions in the ICU.

The results of the subgroup analysis are also notable in this study. The relationship between the worse outcome and early OND use was more evident in ICU patients suffering from cardiovascular diseases. This might be the result of the following mechanisms. Importantly, OND therapy exerts its lower effect on in-hospital mortality may involve the prevention of cardiac inhibitory and the improvement of hemodynamics and cardiovascular collapse [18‐20]. Additionally, the effect of OND therapy on reducing mortality could differ according to age or comorbidities.

In the medical ICU population, the association between early OND use and the outcome was more remarkable than in the surgical ICU population. For one thing, patients in the medical ICU have relatively more severe illnesses than patients in the surgical ICU, where the main purpose of early OND application is to prevent postoperative nausea and vomiting (PONV). In contrast with antiemetic prophylaxis, the early OND administration in the majority of patients is to relieve nausea and vomiting caused by critical illness in the medical ICU. For another thing, the pleiotropic effect of OND on in-hospital mortality could differ according to diverse disease types, comorbidities as well as different sample sizes.

In our study, the daily low- and moderate-dose of OND were probably related to the reduced in-hospital mortality in ICU patients. On the one hand, the latest research mentioned that there was no significant difference among diverse doses of OND to reduce emesis. A recent study established a dose–response relationship for OND in patients and showed that a single 8 mg OND was equivalent to a single 32 mg OND in terms of the antiemetic effect [21]. Some researchers hypothesized there could be a plateau in the therapeutic efficacy of OND which further dose escalation does not improve outcome rather than potently increasing the adverse cardiovascular events [21, 22]. On the other hand, the FDA has issued multiple safety announcements regarding potential risks for dysrhythmias secondary to QTc prolongation following application of OND at doses higher than that which are typically utilized in the ICU. In response, drug manufacturers currently recommended that a daily dose of OND should not be more than 16 mg [23]. The dose recommendation (< 16 mg per day) is compatible with the range of low- and moderate-OND doses in our study. Last but not least, the risk of significant QTc prolongation and arrhythmia is more remarkable in ICU patients receiving multiple medications, especially in poor metabolizers when combined with other medications which are metabolized through the cytochrome P450 (CYP) 2D6 pathway [23]. Thus, further experiments in vivo and in vitro are necessary to confirm the optimal daily dose of OND in the early stage in ICU patients.

Our study had several limitations. First, given its retrospective observational design, many confounders needed to be controlled by PSM, IPTW or multivariable adjustment. Second, although we performed PSM to adjust for confounders in this study, there might be unmeasured confounders and selection bias. For example, the severity of disease was insufficiently measured or included in the PSM and thus might affect OND use in this study. Moreover, patients who applied with OND, despite having similar comorbidities after PSM, might be a different quality of outpatient care or other macro-level health care. Therefore, adherence to OND use in OND users was also unclear during hospitalization among patients in this study. Finally, this was a single-centre study. The results need to be validated by multicenter trials.

Early OND use is significantly associated with lower in-hospital mortality among critically ill patients. Daily low-to-moderate OND dose is valuable related to in-hospital mortality in ICU. This association might be greater in those with cardiovascular diseases. Our results may be beneficial for the rational use of OND in critically ill patients, especially with cardiovascular diseases.