Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state

Abstract

Context: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) cause major morbidity and significant mortality in patients with diabetes mellitus. For more than 30 yr, 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, and 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 (ADA) 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 to do the following: 1) establish the efficacy of bicarbonate therapy in DKA for a pH less than 6.9; 2) establish the need for a bolus insulin dose in the initial therapy of DKA; 3) determine the pathophysiological mechanisms for the absence of ketosis in HHS; 4) investigate the reasons for elevated proinflammatory cytokines and cardiovascular risk factors; and 5) evaluate the efficacy and cost benefit of using sc regular insulin vs. more expensive insulin analogs on the general ward for the treatment of DKA.

Figure 1

Treatment protocols for DKA studies (14).

Figure 2

The efficacy of low-dose vs. conventional therapy of insulin for treatment of DKA. Reproduced from Kitabchi et al. (1) with permission of the Annals of Internal Medicine.

Figure 3

Comparison of high-insulin dosage (A) with low-insulin dosage group (B) as well as low-dose insulin dosage by the sc (C), iv (D), and im (E) routes in plasma. IRI and its glucose-lowering effect in DKA patients previously untreated with insulin. B. Wt., Body weight. Reproduced, with permission, from Kitabchi et al. (15).

Figure 4

Comparison of the effects of iv, sc, and im low-dose insulin regimens on changes of plasma glucose and total ketone bodies in patients with DKA. Reprinted from Fisher et al. (17), with permission of the New England Journal of Medicine.

Figure 5

Calculated serum osmolarity in 122 ketoacidotic patients with relation to mental status at time of admission. Data from Kitabchi et al. (1); Fisher et al. (17); and Sacks et al. (18). Reproduced by permission from Kitabchi and Fisher (19) in Handbook of Diabetes Mellitus (Brownlee M, ed.) and Garland ATPM Press. UTCHS, University of Tennessee Center for Health Sciences.

Figure 6

Protocol for management of adult patients with DKA or HHS (modified from Ref. 58).