Thirty Years of Personal Experience in Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State

Division of Endocrinology, Diabetes, and Metabolism, University of Tennessee Health Science Center, 920 Madison Avenue #909, Memphis, TN 38163, USA.
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.21). 06/2008; 93(5):1541-52. DOI: 10.1210/jc.2007-2577
Source: PubMed


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.
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.
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.
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.

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    • "Intravenous infusion is a preferred route of insulin delivery in patients with DKA.13 Insulin infusion without initial volume resuscitation is not advised as it may only worsen dehydration. Insulin treatment has evolved from the use of high-dose insulin, with doses up to 100 U/h by various routes of administration, to lower doses in the range of 5–10 U/h.14 We recommend an initial bolus of regular insulin of 0.1 U/kg followed by continuous insulin infusion. "
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    ABSTRACT: Diabetic ketoacidosis (DKA) is a rare yet potentially fatal hyperglycemic crisis that can occur in patients with both type 1 and 2 diabetes mellitus. Due to its increasing incidence and economic impact related to the treatment and associated morbidity, effective management and prevention is key. Elements of management include making the appropriate diagnosis using current laboratory tools and clinical criteria and coordinating fluid resuscitation, insulin therapy, and electrolyte replacement through feedback obtained from timely patient monitoring and knowledge of resolution criteria. In addition, awareness of special populations such as patients with renal disease presenting with DKA is important. During the DKA therapy, complications may arise and appropriate strategies to prevent these complications are required. DKA prevention strategies including patient and provider education are important. This review aims to provide a brief overview of DKA from its pathophysiology to clinical presentation with in depth focus on up-to-date therapeutic management.
    Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 06/2014; 7:255-64. DOI:10.2147/DMSO.S50516
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    • "Several guidelines are currently available for the management of DKA in both adults and children.[8–10] The mainstay in treatment of patients of DKA involves administration of low doses of regular insulin by continuous intravenous infusion or by frequent intramuscular or subcutaneous injections of regular insulinor rapid acting insulin analogs.[11] Although many reports have shown that low dose insulin therapy is effective regardless of the route of administration, it is preferable to give continuous intravenous infusion of regular insulin until resolution of ketoacidosis because of potential delay in onset of action and longer half-life of subcutaneously given regular insulin.[1213] "
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    ABSTRACT: To compare the efficacy and safety of rapid acting insulin analog lispro given subcutaneously with that of standard low-dose intravenous regular insulin infusion protocolin patients with mild to moderate diabetic ketoacidosis. In this prospective, randomized and open trial, 50 consecutive patients of mild to moderate diabetic ketoacidosis were randomly assigned to two groups. The patients in group 1 were treated with intravenous regular insulin infusion and admitted in intensive care unit. The patients in group 2 were treated with subcutaneous insulin lispro 2 hourly and managed in the emergency medical ward. Response to therapy was assessed by duration of treatment and amount of insulin administered until resolution of hyperglycemia and ketoacidosis, total length of hospital stay, and number of hypoglycemic events in the two study groups. The baseline clinical and biochemical parameters were similar between the two groups. There were no differences in the mean duration of treatment and amount of insulin required for correction of hyperglycemia and ketoacidosis. There was no mortality and no difference in the length of hospital stay between the two groups. The length of stay and amount of insulin required for correction of hyperglycemia was greater in patients who had infection as the precipitating cause than those with poor compliance. The hypoglycemic events were higher in the regular insulin group (2 vs1) than in the lispro group. Patients with uncomplicated diabetic ketoacidosis can be managed in the medical wards with appropriate supervision and careful monitoring. Rapid acting insulin analog lispro is a safe and effective alternative to intravenous regular insulin for this subset of patients.
    Indian Journal of Pharmacology 07/2011; 43(4):398-401. DOI:10.4103/0253-7613.83109 · 0.69 Impact Factor
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    • "Phosphate levels are usually low in DKA and may drop even further after insulin therapy is initiated; there is a theoretical reason for its replacement that is the decrease in tissue oxygenation due to a fall in 2,3 diphosphoglycerate (2,3 DPG) levels (phosphate depletion syndrome), however, the benefits of its replacement have not yet been proven, since it may induce hypocalcemia and hypomagnesemia [26,27]. "
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    ABSTRACT: DKA is a severe metabolic derangement characterized by dehydration, loss of electrolytes, hyperglycemia, hyperketonemia, acidosis and progressive loss of consciousness that results from severe insulin deficiency combined with the effects of increased levels of counterregulatory hormones (catecholamines, glucagon, cortisol, growth hormone). The biochemical criteria for diagnosis are: blood glucose > 200 mg/dl, venous pH <7.3 or bicarbonate <15 mEq/L, ketonemia >3 mmol/L and presence of ketonuria. A patient with DKA must be managed in an emergency ward by an experienced staff or in an intensive care unit (ICU), in order to provide an intensive monitoring of the vital and neurological signs, and of the patient's clinical and biochemical response to treatment. DKA treatment guidelines include: restoration of circulating volume and electrolyte replacement; correction of insulin deficiency aiming at the resolution of metabolic acidosis and ketosis; reduction of risk of cerebral edema; avoidance of other complications of therapy (hypoglycemia, hypokalemia, hyperkalemia, hyperchloremic acidosis); identification and treatment of precipitating events. In Brazil, there are few pediatric ICU beds in public hospitals, so an alternative protocol was designed to abbreviate the time on intravenous infusion lines in order to facilitate DKA management in general emergency wards. The main differences between this protocol and the international guidelines are: intravenous fluid will be stopped when oral fluids are well tolerated and total deficit will be replaced orally; if potassium analysis still indicate need for replacement, it will be given orally; subcutaneous rapid-acting insulin analog is administered at 0.15 U/kg dose every 2-3 hours until resolution of metabolic acidosis; approximately 12 hours after treatment initiation, intermediate-acting (NPH) insulin is initiated at the dose of 0.6-1 U/kg/day, and it will be lowered to 0.4-0.7 U/kg/day at discharge from hospital.
    Diabetology and Metabolic Syndrome 06/2010; 2(1):41. DOI:10.1186/1758-5996-2-41 · 2.17 Impact Factor
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