Granisetron Therapy In Patients With Sepsis

BackgroundSepsis,as a clinical syndrome with high incidence,mortality and cost,is a major challenge for critical care medicine.Granisetron and other 5-HT3 receptor antagonists,as a kind of anti-inflammatory drugs,have potential therapeutic value for sepsis.Our previous studies have demonstrated that gut microbes can produce granisetron to protect multiple organs during sepsis.In addition,our previous retrospective cohort study have provided preliminary evidence of the efficacy of ondansetron(a similar drug to granisetron)in reducing in-hospital mortality in patients with sepsis.Granisetron is a clinically widely used antiemetic,which is safe,inexpensive,and reliable.However,there are no randomized controlled trials to validate the therapeutic value of granisetron in sepsis.Therefore,this randomized controlled trial was designed to validate the efficacy and safety of granisetron in the treatment of sepsis.ObjectiveTo determine whether granisetron reduces 28-day all-cause mortality compared to placebo and to determine the safety of granisetron in patient with sepsis.MethodsIn this single-center,single-blind,randomized controlled trial,we would enroll 154 patients who meet sepsis 3.0 diagnostic criteria and with PCT≥2ng/ml.Subjects would be randomly assigned to the treatment group or control group in a 1:1 ratio.In addition to conventional treatment,patients in the treatment group would receive granisetron(3mg at 8-hour intervals)for 4 days or until ICU discharge or death,whichever occurs first.Patients assigned to the control group would receive normal saline at the same dose,frequency,and for the same duration.The primary outcomes was 28-day all-cause mortality.Secondary outcome include the duration of use of various organ function support devices,the improvement of SOFA score,the clearance rate of PCT,the incidence of new organ dysfunction and the changes of laboratory indicators such as interleukin-6.The safety outcome was the incidence of adverse events.ResultA total of 154 patients were enrolled from April 2019 to November 2020,and 150 patients(76 in the treatment group and 74 in the control group)were included in the intention analysis.For primary outcome,the 28-day all-cause mortality in the treatment group and the control group was 34.7%and 35.6%,respectively(RR 0.97,95%CI 0.63-1.51;OR 0.96,95%CI 0.49-1.89;p=0.90).In the analysis of secondary outcome,there showed no difference in the length of ICU stay,the duration of vasoactive drugs or CRRT or mechanical ventilation,the improvement of SOFA score,the clearance rate of PCT,the incidence of new organ dysfunction and the changes of laboratory indicators.But in the subgroup analysis of patients without abdominal or digestive tract infections,patients in the granisetron group had a 10.9%lower mortality than those in the control group,which showed a tendency to improve the risk of 28-day mortality(OR 0.63,95%CI 0.29--1.34).There was no significant difference in the incidence of adverse events between the two groups.ConclusionAccording to the results of this study,granisetron is safe for use in patients with sepsis,but granisetron fails to improves 28-day mortality and related outcomes in patients with sepsis.Combined with the results of the subgroup analysis,a larger-sample,multicenter,double-blind randomized trial is still needed to validate the efficacy of granisetron in septic patients without abdominal or digestive tract infections.