Prashanth Anamthathmakula, PhD: No relevant financial relationship(s) to disclose.
Introduction: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. While conventional antibiotic treatment is still one of the mainstays in sepsis management, antibiotic resistance of bacteria poses serious concerns. Currently, there are no drugs approved by FDA for treating sepsis since previous clinical trials proved unsuccessful. In this study, we tested the efficacy of small molecule drugs: dimethyl sulfoxide (DMSO), dexamethasone and ciclesonide to attenuate sepsis and improve the survival rate in rats.
Methods: We developed cecal ligation and laceration (CLL) procedure to induce lethal sepsis in adult male and female Sprague-Dawley rats. Briefly, the cecum was ligated beneath the ileocecal junction followed by a laceration (0.5 cm) and returned to the abdominal cavity. The abdomen and skin were closed and 30 minutes later rats (N=8 per group) received intraperitoneal resuscitation as a single bolus of fluid volume equal to 8% body weight. The experimental groups received either DMSO (35 mM), dexamethasone or ciclesonide (116 uM dissolved in 35 mM DMSO) in an isotonic aqueous solution, while the control group received the aqueous solution only. Source control or use of antibiotics was not prescribed. Sepsis scores were recorded daily, and survival was monitored for 30 days. The Kaplan-Meier method was used for survival analysis, and statistical analysis was carried out using the log-rank (Mantel-Cox) test.
Results: The control rats died within 24 hr. We found an improvement in the sepsis score of rats treated with either DMSO, DMSO containing dexamethasone or ciclesonide. DMSO was effective in mitigating sepsis and improved survival in 62.5% of rats (survival range 36 hr to >30 days; p< 0.05). Single intraperitoneal bolus of synthetic glucocorticoids (dexamethasone or ciclesonide) increased the survival in 87.5% of sepsis induced rats beyond 24 hr (survival range 36 hr to >30 days; p< 0.0001) compared to the control group.
Conclusions: This is the first study to report the efficacy of DMSO in surviving a lethal model of sepsis. Further, dexamethasone and ciclesonide provided maximum increase in survival rate and combating sepsis. Studies are ongoing to delineate the role of these drugs as modulators of sepsis-induced inflammatory factors and pathways.
