Diabetic Emergencies
Diabetic ketoacidosis (DKA) is an acute complication of diabetes mellitus. It is characterized by the triad of hyperglycemia, ketosis, and metabolic acidosis.1 DKA complicates mainly patients with Type 1 diabetes mellitus, where it may be the first manifestation of the disease, and rarely people with Type 2 diabetes.1 A special heterogeneous syndrome of ”ketosis – prone diabetes (KPD),” in usually adult patients who may lack the typical clinical phenotype of autoimmune Type 1 diabetes, has recently been identified. While initially the condition was thought to be limited to persons of non-Caucasian ethnicity (African-Americans and Hispanics), its prevalence appears to be increasing worldwide.2 DKA is an emergency situation and hospitalization of the patient is necessary for immediate treatment. Its frequency is reported as 4.8 – 8.0 episodes per 1000 diabetic patients.3,4 The mortality rate is 2.5 – 9% and increases along with age, level of consciousness on admission, degree of hyperosmolality and acidosis, as well as severity of azotemia.5,6 In the US, hospitalizations due to DKA reach 100,000 and the cost of treatment has been reported as 1 billion dollars per year
DKA can be mild, moderate, or severe. It is considered severe when the arterial blood pH is less than 7.0, the concentration of plasma bicarbonate is less than 10 mEq/L, and the anion gap is greater than 12 mEq/L. In severe DKA, the patient is in stupor or in coma. Notably, the severity of DKA does not necessarily coincide with the degree of hyperglycemia.
DKA can rarely be seen without marked hyperglycemia (euglycemic DKA), and in one series of 722 consecutive episodes of DKA only 1.1% had blood glucose levels less than 180 mg/dl (10 mmol/L).10
Relatively euglycemic DKA has been reported in patients using subcutaneous insulin infusion pumps, which contain short – acting insulin. In these patients, interruption of insulin delivery results in rapid development of ketosis, as patients become insulin deficient within 2 – 4 hours of cessation of insulin delivery. Euglycemic DKA has also been reported during pregnancy and in subjects using conventional insulin regimens. In these cases, the secretion of large amounts of glucose in the urine or lower rates of hepatic glucose production may account for the relatively ”low” glucose concentrations.6 Moreover, prolonged fasting before the onset of DKA may result in a lower increase in blood glucose than non-fasting.10
Since the mid-1990s, increasing attention has been focused on a heterogeneous condition characterized by presentation with DKA in patients who do not necessarily fit the typical characteristics of autoimmune Type 1 diabetes. Earlier reports used the terms ”atypical diabetes,” ”Flatbush diabetes,” ”diabetes type 1B,” and ”ketosis-prone type 2 diabetes mellitus” to describe subsets of this condition.
It was noted that in some instances patients presented with DKA as the first manifestation of diabetes and subsequently evolved to insulin independence.2 This condition, now called ”ketosis–prone diabetes (KPD),” comprises a group of atypical diabetes syndromes characterized by severe β-cell dysfunction (manifested by presentation with DKA or unprovoked ketosis) and a variable clinical course. To date, the best attempt to differentiate patients with KPD into clinically distinct subgroups has resulted in the so-called A β classification, based on the presence (A +) or absence (A −) of pancreatic autoantibodies (anti-GAD65 [glutamic acid decarboxylase] and/or anti-IA-2 [islet-antigen autoantibody-2]) and the presence or absence of β-cell functional reserve, as measured by a fasting or glucagon-stimulated C-peptide level.11 Thus, the four subgroups are defined as follows:
• A + β − autoantibodies present, β-cell function absent
• A + β + autoantibodies present, β-cell function present
• A − β − autoantibodies absent, β-cell function absent
• A − β + autoantibodies absent, β-cell function present.
A + β − and A − β − patients are immunologically and genetically distinct from each other but share clinical characteristics of Type 1 diabetes, with decreased β-cell function, and both subgroups would be termed Type 1 diabetes (Type 1A and 1B) in the current American Diabetes Association (ADA) classification system. A + β + and A − β + patients are immunologically and genetically distinct from each other but share clinical characteristics of Type 2 diabetes, with preserved β-cell functional reserve, and would be termed Type 2 diabetes in the ADA scheme. A − β + patients comprise the largest KPD subgroup (approximately 50%)12 and are also the patients who most commonly come to the notice of physicians because they present with DKA yet have the clinical features and subsequent behavior of Type 2 diabetes. 13 Most A − β + subjects have new-onset diabetes and are obese, middle-aged males with a strong family history of Type 2 diabetes. In these patients, β-cell function is substantial when measured within 1-2 weeks of the index DKA and improves further when measured after 6-12 months.11
Predisposing factors for DKA
DKA can be the first manifestation of Type 1 diabetes in 10-30% of cases.4,5,14 With regard to the remaining cases, DKA is caused by factors associated with either increase in insulin needs (serious infections, trauma or surgery where insulin resistance suddenly and dramatically increases) or decrease of insulin availability (deliberate discontinuation of treatment, dysfunction of infusion systems, inappropriate changes of insulin doses, or mistakes in insulin delivery). In several series, infections were the commonest (28-43%) identifiable cause of DKA followed by errors in insulin delivery or non-diabetic ketoacidosis in adults5 compliance (18-26%).9 DKA may be precipitated in patients with Type 2 diabetes during the course of overwhelming infections and less commonly during acute myocardial infarction or trauma.14 The contributing factors to the development of DKA in patients with known diabetes are depicted in Box 1.1.9
Regarding KPD patients, approximately 50% of A − β + KPD patients have new-onset diabetes and develop DKA without a clinically evident precipitating factor (” unprovoked” A − β + KPD), while the remainder have long-standing diabetes prior to presentation with DKA, and develop ketoacidosis in association with an acute illness or non-compliance with antidiabetic treatment (”provoked” A − β + KPD). Unprovoked A − β + KPD patients display a striking male predominance (2.6:1 male:female) that is quite distinct from provoked A − β + KPD patients (0.7:1).15 Unprovoked A − β + KPD patients show a better prognosis regarding insulin independence compared to the provoked A − β + KPD group.
DCMS99-Box1.1
dcms99-CG-Boxb
Pathogenesis
The combined effect of reduced insulin concentrations (absolute or relative, but always serious) and elevated concentrations of the counter-regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone) leads to hyperglycemia, ketosis, dehydration, and electrolyte disturbances.6,10 It is of note that, in the absence of insulin deficiency, elevated levels of the counter-regulatory hormones per se do not cause ketosis.6 The fundamental difference between DKA and hyperosmolar hyperglycemic state (HHS) is that small residual amounts of insulin in HHS can prevent significant ketosis and, therefore, acidosis. The pathogenesis of DKA and of HHS is depicted
References
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Umpierrez GE, Smiley D , Kitabchi AE . Narrative review: ketosis – prone type 2 diabetes mellitus . Ann Intern Med 2006 ; 144 : 350 – 7.
Faich GA , Fishbein HA , Ellis SE . The epidemiology of diabetic acidosis: a population – based study Am J Epidemiol 1983 ; 117 : 551 – 8.
Katsilambros N. Epidemiology of acute manifestations and complications . In: Williams R , Papoz L , Fuller J (ed), Diabetes in Europe, A Monograph on Diabetes Epidemiology in Europe produced as part of the ’ Eurodiab ’ Concerted Action Programme of the European Community , London, UK : John Libbey & Company Ltd , 1994 : 39 – 209.
Ellemann K , Soerensen JN , Pedersen L , Edsberg B , Andersen O . Epidemiology and treatment of diabetic ketoacidosis in a community population . Diabetes Care 1984 ; 7 : 528 – 32.
Wyckoff J, Abrahamson MJ . Diabetic ketoacidosis and hyperosmolar hyperglycemic state . In: Kahn R , King GL , Moses AC , Weir GC , Jacobson AM , Smith RJ (ed), Joslin ’ s Diabetes Mellitus , 14 th edn , Philadelphia, USA : Lippincott Williams & Wilkins , 2005 : 887 – 99
Javor KA, Kotsanos JG , McDonald RC , Baron AD , Kesterson JG , Tierney WM . Diabetic ketoacidosis charges relative to medical charges of adult patients with Type I diabetes . Diabetes Care 1997 ; 20 : 349 – 54.
Kitabchi AE , Umpierrez GE , Murphy MB , Barrett EJ , Kreisberg RA , Malone JI , Wall BM . Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001: 24 : 131 – 53.
Kitabchi AE , Umpierrez GE , Miles JM , et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association . Diabetes Care 2009; 32: 1335 –43.
Krentz AJ , Nattrass M . Acute metabolic complications of diabetes: diabetic ketoacidosis, hyperosmolar non – ketotic hyperglycemia and lacticacidosis . In: Pickup JC , Williams G (ed), Textbook of Diabetes Mellitus , 3 rd edn , Oxford, UK : Blackwell Publishing , 2003 : 32 . 1 – 24.
Maldonado M , Hampe CS , Gaur LK , et al. Ketosis – prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta – cell functional classifi cation, prospective analysis, and clinical outcomes . J Clin Endocrinol Metab 2003 ; 88 : 5090 – 8.
Balasubramanyam A , Nalini R , Hampe CS , Maldonado M . Syndromes of ketosis – prone diabetes mellitus . Endocr Rev 2008 ; 29 : 292 – 302.
Umpierrez , GE . Ketosis – prone type 2 diabetes: time to revise the classify cation of diabetes . Diabetes Care 2006 ; 29 : 2755 – 7.
Newton CA , Raskin P . Diabetic ketoacidosis in Type 1 and Type 2 diabetes mellitus . Arch Intern Med 2004 ; 164 : 1925 – 31.
Pinero – Pilona A , Raskin P . Idiopathic Type 1 diabetes . J Diabetes Complications 2001 ; 15 : 328 – 35 .
Nikolaos Katsilambros, MD, PhD, FACP
SCOPE Founding Fellow
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ’Christeas Hall’
Athens, Greece
From diabetesincontrol.com
Nyhetsinfo
www red DiabetologNytt
Christina Kanaka-Gantenbein, MD, PhD
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Athens, Greece
Stavros Liatis, MD
Consultant in Internal Medicine and Diabetology
Laiko General Hospital
Konstantinos Makrilakis, MD, MPH, PhD
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Athens, Greece
Nikolaos Tentolouris, MD, PhD
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital
Athens, Greece
A John Wiley & Sons, Ltd., Publication This edition first published 2011 © 2011 by John Wiley & Sons, Ltd.
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Diabetic Emergencies: Diagnosis and Clinical Management provides emergency room staff, diabetes specialists and endocrinologists with highly practical, clear-cut clinical guidance on both the presentation of serious diabetic emergencies like ketoacidosis, hyperosmolar coma and severe hyper- and hypoglycemia, and the best methods of both managing the emergencies and administering appropriate follow-up care.