Thiamine and High Dose Insulin Treatment for Sepsis

Abstract

Sepsis is a major health problem and accounts for 20% of deaths worldwide. It is the most expensive condition treated in United States hospitals at $62 billion per year or about $46,000 per patient. Treatment consisting largely of fluid resuscitation and antibiotics has only a marginal impact. Mortality is about 27% for hospitalised patients and about 42% for patients in intensive care. There are two phases of sepsis – a hyperinflammatory phase and a subsequent hypoinflammatory phase. During the hyperinflammatory phase, the metabolic rate increases, and this is associated with an increase in body temperature and a rapid escalation of immune system functioning including increased numbers of leucocytes and their migration to infected and damaged tissues and increased supply and consumption of glucose to fuel this immune system. During the subsequent hypoinflammatory phase, the metabolic rate decreases, and this is associated with a decrease in body temperature and a generalised decrease in the physiological activity of many organs including the immune system akin to hibernation. The activated immune system has priority for the available glucose over most other organs and physiological functions during such potentially life-threatening circumstances. Thus, adenosine triphosphate (ATP) production by mitochondria (the source of energy at the cellular level for the organism as a whole) also has a lower priority for the available glucose relative to the activated immune system. If glucose availability is threatened, then the mitochondrial production of ATP is partially or substantially suppressed in favour of glycolysis because glycolysis can rapidly produce large quantities of ATP that are necessary for immune cell function in infected, anaerobic, ischaemic, or damaged tissues. However, glycolysis is only a temporary fix as it cannot produce the quantities of ATP necessary on an ongoing basis for the normal functioning of the healthy animal. Mitochondrial production of ATP must be recommenced for full recovery. It appears that the partial or substantial suppression of mitochondrial production of ATP by activation of the immune response becomes relatively fixated in some patients, leading to a substantial ATP deficit. This is the fundamental issue of sepsis. This paper reviews the metabolism of glucose and insulin during sepsis and concludes that high dose insulin with mild hyperglycaemia in conjunction with the intravenous administration of thiamine, an inhibitor of the pyruvate dehydrogenase kinase enzymes, to re-establish physiological ATP production by mitochondria, administered early in the hypometabolic (hypoinflammatory) phase of sepsis, may enhance survival relative to thiamine alone.