Association of early ondansetron use with 30-day mortality in patients with acute respiratory distress syndrome: a retrospective cohort study

Introduction

Acute respiratory distress syndrome (ARDS), a result of non-cardiogenic pulmonary edema (1), is one of the most prevalent diseases encountered in the intensive care unit (ICU). The prevalence of ARDS on ICU admission has been reported to be 10.4% with in-hospital mortality of as high as 24–46% (2,3). Although mechanical ventilation (MV) has saved many lives as an important supportive treatment for ICU patients, the mortality rate of ARDS patients on MV can reach 45% (2,4). Consequently, it is immediately urgent to identify viable strategies to enhance the clinical outcome of patients with ARDS.

The role of inflammation in the pathogenesis of ARDS and MV-induced lung injury is of central importance (5-7). 5-hydroxytryptamine (5-HT) is released within the lung as an inflammatory mediator (8) and is considered an immune modulator (9). The 5-HT type 3 (5-HT₃) receptor antagonist can reduce the excessive production of inflammatory cytokines and has protective effects on lung (10), heart (11), liver (12,13), and nervous system (14). As a 5-HT₃ receptor antagonist, ondansetron (OND) is a commonly employed antiemetic with a high degree of safety (15-17). Previous studies reported that OND treatment was associated with a decreased risk of mortality in hospitalized patients with coronavirus disease 2019 (COVID-19) and acute kidney injury (AKI) (18-20). Boshen et al. (21) found that early OND use in myocardial infarction (MI) patients may have protective effects on lower odds of in-hospital, 28- and 90-day mortality. And the beneficial effect of OND on MI patients was brought upon by an anti-inflammatory effect (21). Tao et al. (22) also found a significant association of early use of OND with a reduced mortality risk in ICU patients on MV. To our knowledge, however, whether the early OND use has a benefit in ARDS patients on MV is unknown.

The current study aimed to investigate the relationship between the early use of OND and 30-day mortality risk in ARDS patients who received MV support, which may bring survival benefits to critically ill patients. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1082/rc).

Methods

Study design and population

This cohort study retrospectively identified ARDS patients treated in the ICU with and without OND treatment from the Medical Information Mart for Intensive Care (MIMIC)-IV database. MIMIC-IV database, a comprehensive and public database, covers comprehensive records for each patient admitted to the Tertiary Academic Medical Center in Boston, MA, USA from 2008 to 2019. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

The following individuals were included: (I) patients aged ≥18 years; (II) patients diagnosed with ARDS (23-25).

Excluded criteria were as follows: (I) patients admitted to ICU <24 hours; (II) patients without MV use; (III) missing the information of death time.

Data extraction

The following variable information was extracted in this study: age, gender, weight, race, ventilator-associated pneumonia (VAP), malignant cancer, AKI, congestive heart failure (CHF), mean arterial pressure (MAP), diastolic blood pressure (DBP), systolic blood pressure (SBP), temperature, heart rate (HR), respiratory rate, oxygen saturation (SpO₂), fraction of inspired oxygen (FiO₂), pressure of arterial oxygen (PaO₂), pressure of alveolar carbon dioxide (PaCO₂), pressure of arterial oxygen/fraction of inspired oxygen (PaO₂/FiO₂), positive end-expiratory pressure (PEEP), hemoglobin, blood urea nitrogen (BUN), platelet, white blood cells (WBC), hematocrit, lactate, glucose, creatinine, international normalized ratio (INR), anion gap, red cell distribution width (RDW), sequential organ failure assessment score (SOFA), Charlson comorbidity index (CCI), ventilation time, chemotherapy (CT), radiotherapy (RT), surgery, extracorporeal membrane oxygenation (ECOM) support, length of stay (LOS), follow time, and 30 days survival status.

Definitions and outcomes

Early OND use referred to the OND use from ICU admission to MV intervention during ICU admission. The OND dose was stratified by low-dose (>0 and ≤8 mg), moderate-dose (>8 and ≤16 mg), and high-dose (>16 mg) OND. The primary outcome measure was 30-day mortality. The start time of follow-up was the time of first ICU admissions, and the end time was the time of 30-day death or discharge. In the case of patients who were admitted to ICU multiple times, only the data from the initial admission were analyzed. The time of median follow-up was 30.00 (30.00, 30.00) days.

Statistical analysis

Data exhibiting a normally continuous distribution were presented as the mean ± standard deviation (SD), and inter-group comparisons were conducted using the Student’s t-test.

Data failing to exhibit a normally continuous distribution were presented as medians and quartiles [M (Q1, Q3)], and comparisons were conducted using Mann-Whitney U-test. Categorical variables were presented as numbers (n) and percentages, and inter-group comparisons were conducted using either chi-squared test or Fisher’s exact test.

Variables with more than 20% missing were deleted, and variables with less than 20% missing were imputed by random forest imputation (Python version 3.9.12, Python Software Foundation, Delaware, USA). The sensitivity analyses on comparison of variables before and after data interpolation are shown in Table S1. The multicollinearity assessment for covariates is presented in Table S2. The results showed that there is no collinearity among covariates. All potential covariates were incorporated in the univariate and multivariable Cox proportional hazard models with a two-way stepwise regression analysis and the smallest value of Akaike information criterion, and those with a P<0.05 were identified as the covariates (Table S3). Univariate and multivariable Cox proportional hazard models were used to evaluate the association of early OND use with 30-day mortality before or after the propensity score matching (PSM), with hazard ratios (HRs) and 95% confidence intervals (CIs). The Kaplan-Meier curves of 30-day survival were performed between the groups with or without early OND use. Subgroup analysis was performed stratified by age, gender, ARDS grades, VAP, AKI, ventilation time, and vasopressor. The multiple comparisons were carried out using false discovery rate (FDR) correction. Statistical analyses in this study were performed by SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R software version 4.2.2 (Institute for Statistics and Mathematics, Vienna, Austria). A P value of less than 0.05 was deemed to be statistically significant.

Results

Patients’ characteristics

Figure 1 shows the selection process of participants. A total of 6,457 ARDS patients were analyzed, including 1,855 treated with OND at an early stage. Table 1 presents the characteristics of ARDS patients using OND or not. The results showed the statistical differences in age, gender, race, vasopressor, steroid, VAP, SpO₂, SBP, DBP, MAP, temperature, HR, respiratory rate, weight, FiO₂, PaO₂, PaO₂/FiO₂, PEEP, hemoglobin, BUN, platelet, WBC, hematocrit, lactate, glucose, creatinine, INR, anion gap, RDW, SOFA, ventilation time, chemotherapy, radiotherapy, surgery, and LOS (all P<0.05).

Figure 1 The selection process of ARDS patients. ARDS, acute respiratory distress syndrome; ICU, intensive care unit; MIMIC IV, Medical Information Mart for Intensive Care-IV; MV, mechanical ventilation.

Association of early OND use with 30-day mortality in ARDS patients on MV

Figure 2 presents the 30-day survival between ARDS patients who received or did not receive OND intervention before MV. The 30-day survival of early OND use was higher than those without. Table 2 shows the association between early OND use and 30-day mortality in ARDS patients. Patients who received OND intervention before MV had lower odds of 30-day mortality compared with those who did not receive OND intervention (HR =0.66, 95% CI: 0.57–0.78). The low dose of early OND use was associated with a decreased risk of 30-day mortality (HR =0.56, 95% CI: 0.46–0.67) (patients who did not receive OND intervention as reference).

Figure 2 The 30-day survival between ARDS patients who received or did not receive OND intervention before MV. ARDS, acute respiratory distress syndrome; MV, mechanical ventilation; OND, ondansetron.

Association of early OND use with 30-day mortality in ARDS patients on MV after PSM

After PSM, patients who received early OND use had lower odds of 30-day mortality compared with those who did not (HR =0.77, 95% CI: 0.63–0.94). The low dose of early OND use was associated with a decreased risk of 30-day mortality (HR =0.67, 95% CI: 0.54–0.83) (Table 3).

Subgroup analyses

To further explore the associations, subgroup analyses were performed with results shown in Figure 3. Early OND use was related to lower odds of 30-day mortality of ARDS patients aged ≥65 years (HR =0.54, 95% CI: 0.43–0.67), with females (HR =0.77, 95% CI: 0.61–0.97) or males (HR =0.58, 95% CI: 0.47–0.72), with ARDS grades of mild (HR =0.57, 95% CI: 0.44–0.74), moderate (HR =0.76, 95% CI: 0.60–0.97) or severe (HR =0.69, 95% CI: 0.49–0.98), without VAP (HR =0.64, 95% CI: 0.55–0.76), with AKI (HR =0.62, 95% CI: 0.52–0.74), with short (<43.87 h, HR =0.65, 95% CI: 0.50–0.83) or long (≥43.87 h, HR =0.71, 95% CI: 0.58–0.87) ventilation time, and those who received vasopressor (HR =0.67, 95% CI: 0.56–0.80) or not (HR =0.65, 95% CI: 0.46–0.90). The age (P_interaction<0.001) or VAP (P_interaction=0.01) and early OND use had an interaction effect on 30-day mortality risk.

Figure 3 Associations of early OND use with 30-day mortality in ARDS patients in different groups. AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; CI, confidence interval; HR, hazard ratio; OND, ondansetron; VAP, ventilator-associated pneumonia.

Discussion

In the present study, we explored the associations of early OND use and dose of OND with the risk of 30-day mortality in ARDS patients who received MV support in the ICU. Our findings showed that patients who received early OND use had lower odds of 30-day mortality. Similar results were shown in ARDS patients aged ≥65 years, with females or males, with different ARDS grades (mild, moderate or severe), without VAP, with AKI, with short or long ventilation time, and those who received vasopressor or not. The low dose of early OND use was associated with a decreased risk of 30-day mortality.

Several studies have demonstrated that the use of OND helps reduce mortality in patients with critical illness (18-20). Bayat et al. found that an administration of OND ≥8 mg within 48 hours admission was linked to a lower risk of mortality within 30 days for all patients admitted to the hospital and ICU after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (18). Gray et al. revealed that OND administration within 24-hour admission to ICU was linked to a 5.48% reduction of 90-day mortality (26). Recently, early OND use has been demonstrated to be correlated with a reduction in mortality among patients in the ICU. A retrospective cohort study (n= 51,342) showed that early daily low- and moderate-dose OND treatment was negatively related to the in-hospital mortality (19). In Tao’s study, administration of OND in ICU, irrespective of the dosage prior to MV, was associated with a 38% and 31% reduction in the risk of in-hospital mortality and 60-day mortality (22). The current study similarly demonstrated that early use of OND (OND administration before MV) was linked to a decrease in mortality within 30 days in ARDS patients.

Older patients are predisposed to experience severe ARDS and have a significant deterioration (27,28), which is consistent with our findings that OND has some benefit in ARDS patients older than 65 years. Given that VAP can lead to bilateral pulmonary infiltrates and severe respiratory failure (23,29), there may be no discernible benefits of OND on disease development and mortality in ARDS patients with VAP. Tao et al. (22) consistently indicated that the use of OND in AKI patients was linked to a notable decline in risk-adjusted in-hospital death.

The mechanism by which early OND use mediates improved outcomes in ARDS patients on MV may be related to inflammation regulation. First, inflammation is a crucial factor in the decision-making process to initiate MV, prolong MV (30,31), and cause ventilator-induced lung injury (5-7). Studies have shown an elevated mortality in ICU patients on MV (32,33). The OND may result in a reduction in mortality among patients on MV by reducing excessive inflammatory response in the lungs (34). Second, 5-HT is released from the lung and functions as an inflammatory mediator (8). The type 3 receptor for 5-HT is expressed by neuroepithelial bodies in the mammalian lung (35). 5-HT is implicated in the aetiopathogenesis of bronchial constriction and airway edema (8,36). Inhibiting 5-HT synthesis has been shown to alleviate inflammation, fibrosis, and metabolic disorders, which may account for OND’s anti-inflammatory properties (9). Third, 5-HT may play a role in neutrophil polarization, neutrophil recruitment, and T-cell activation (37,38). 5-HT₃ receptor antagonists have been shown to significantly mitigate lung injury by inhibiting neutrophil recruitment in septic mice (10). In addition, the reduction in mortality in ICU patients with OND was explained to a large extent by the variation in neutrophil-lymphocyte ratio (35).

This is the first study to explore the association of early use of OND with 30-day mortality in ARDS patients who received MV support in the ICU, which may provide a new perspective and opportunity to develop therapeutic strategies for the prevention of ARDS in the ICU. OND, a common drug, is used for the prevention and treatment of nausea and vomiting in critical care settings. However, more studies are focusing on the effect of OND on the prognosis of critically ill patients, suggesting that OND may be a potential and valuable candidate evaluation indicator, which is conducive to the survival benefit of critically ill patients.

Several limitations should be acknowledged. First, due to the retrospective nature of the study, although PAM was performed, there may be some unmeasured confounders and selection bias. Second, the enrollment of critically ill patients from ICU needs external validation to determine the generalizability of OND-guided protocols for being applied to patients in general ward settings. Third, the anti-inflammatory effects of OND rely on preclinical studies (39-42), and more human studies are needed to verify the anti-inflammatory mechanism of OND. Further multicenter, randomized controlled trials are required to prove the reliability of the results.

Conclusions

Early OND use and daily low-dose OND use before MV support were associated with a decreased risk of 30-day mortality, indicating that the rational use of OND in ARDS patients may be beneficial. Multicenter and prospective trials are needed to validate the findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1082/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1082/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1082/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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