The revised Surviving Sepsis Campaign (SSC) guidelines for the management of severe sepsis and septic shock have recently been published. These guidelines represent the end product of an intense process and provide a template approach to the early resuscitation and support of patients with sepsis, based on a synthesis of evidence that has been shown to improve the outcome of the septic patient. The SSC guidelines arose from a recognition that care of the septic patient was suboptimal for at least three reasons. First, the entity of sepsis was frequently not diagnosed in a timely fashion, allowing the process to evolve into a life-threatening syndrome of major physiologic organ system dysfunction. Secondly, even when sepsis was recognized, the urgency of treatment was underappreciated – and so haemodynamic resuscitation was tentative, and the administration of effective antibiotic therapy was
Dichloroacetate (DCA), an activator of the pyruvate dehydrogenase complex, has been shown to reduce blood lactate levels effectively in various conditions. DCA administration has also sometimes resulted in beneficial cardiovascular effects. To assess its potential value in the routine management of septic shock, we studied the effects of DCA on a canine endotoxic shock model associated with moderate lactic acidosis. Eighteen dogs were pentobarbitone anesthetized, intubated, and mechanically ventilated. Thirty minutes after the administration of 3 mg/kg of Escherichia coli endotoxin, 10 dogs received 100 mg/kg followed by 100 mg/kg/hr of DCA, and eight dogs served as control. In all animals, fluid administration was titrated according to the left-sided filling pressures. In the DCA-treated animals, lactate levels rapidly fell from 3.1 +/- 1.2 to 1.3 +/- 0.8 mEq/liter after 30 min. The bolus of DCA was usually followed by a very transient increase in arterial pressure, but no sustained hemodynamic change was noted. Oxygen consumption (measured from the exhaled gases) was not affected. Four dogs in the DCA group and one dog in the control group survived the next morning (difference not significant). The present study confirms that DCA can effectively reduce blood lactate levels in endotoxic shock and might therefore be useful in severe lactic acidosis related to septic shock. However, the routine use of DCA in septic shock to improve hemodynamic status is not supported by the present findings.
We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis.
