ObjectiveDravet syndrome (DS) is a severe developmental and epileptic encephalopathy with early childhood onset. Patients with DS do not respond well to antiepileptic drugs and have only a few treatment options available. Here, we evaluated the effect of medium chain triglyceride (MCT) diet therapy in a mouse model of DS.MethodsScn1aR1407X/+ DS mice were given diets supplemented with MCTs with varying ratios of decanoic (C10) and octanoic (C8) acid or a control diet for 4 weeks. Video monitoring was performed to evaluate spontaneous convulsive seizure frequency. Susceptibility to hyperthermia‐induced seizures was also examined. Medium chain fatty acids, and mitochondrial and antioxidant markers were assessed in brain homogenate.ResultsDietary intervention with MCTs significantly prolonged survival and reduced convulsive seizure frequency during the critical period of highest seizure occurrence in the Scn1aR1407X/+ DS mice. Moreover, MCT diet therapy showed protective effects against hyperthermia‐induced seizures. We demonstrated that coadministration of C10/C8 was effective at reducing both seizures and mortality, whereas C10 alone only reduced mortality, suggesting that the ratio of C10 to C8 in the MCT is an important factor for efficacy. When C10 and C8 are supplemented at an 80:20 ratio in the diet, C10 accumulates in the brain in high enough concentrations to enhance brain energy metabolism by both stimulating mitochondrial enrichment and increasing its antioxidant status.SignificanceThe results from this study indicate that MCT diet therapy may provide therapeutic benefits in DS. Future clinical studies would elucidate whether these positive effects are mirrored in human patients.

Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known. Twenty-nine mechanically ventilated adults with multi-organ failure were randomised into a two-centre safety and feasibility trial of ketogenic versus standard enteral feeding. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis. Patients receiving ketogenic feeding had fewer hypoglycaemic events (0% vs. 1.58%), required less exogenous insulin (0.0 IU (IQR 0-16) vs.78 IU (IQR 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Untargeted metabophenotyping revealed altered Cahill cycle flux and bioenergetic states, suggesting an advantageous metabolic profile. Ketogenic feeding is feasible and may be a novel intervention for addressing bioenergetic failure in critically ill patients.