Context: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) cause major morbidity and significant mortality in patients with diabetes mellitus. For more than 30 years our group, in a series of prospective randomized clinical studies, has investigated the pathogenesis and evolving strategies of the treatment of hyperglycemic crises. This paper summarizes the results of these prospective studies on the management and pathophysiology of DKA.

Setting: Our earliest studies evaluated the comparative efficacy of low dose vs pharmacological amounts of insulin, and the use of low dose therapy by various routes in adults and later in children. Subsequent studies evaluated phosphate and bicarbonate therapy, lipid metabolism, ketosis-prone type 2 patients, use of rapid-acting insulin analogs, as well as leptin status, cardiac risk factors, proinflammatory cytokines, and the mechanism of activation of T-lymphocytes in hyperglycemic crises.

Main Outcome: The information garnered from these studies resulted in the creation of the 2001 American Diabetes Association technical review on DKA and HHS as well as the ADA Position and Consensus Paper on the therapy for hyperglycemic crises.

Conclusions: Areas of future research include prospective randomized studies: (a) to establish the efficacy of bicarbonate therapy in DKA for a pH < 6.9; (b) to establish the need for a bolus insulin dose in the initial therapy of DKA; (c) to determine the pathophysiologic mechanisms for the absence of ketosis in HHS; (d) to investigate the reason for elevated pro-inflammatory cytokines and cardiovascular risk factors; and (e) to evaluate the efficacy and cost benefit of using subcutaneous regular insulin versus a more expensive insulin analog on the general ward for the treatment of DKA.