POSITION STATEMENT Hyperglycemic Crises in Patients With Diabetes Mellitus AMERICAN DIABETES ASSOCIATION and sympathomimetic agents (e.g., do- butamine and terbutaline), may precipi- tate the development of HHS or DKA. In young patients with type 1 diabetes, psy- etoacidosis and hyperosmolar hy- lation from adipose tissue (lipolysis) and chological problems complicated by eat- perglycemia are the two most seri- to unrestrained hepatic fatty acid oxida- ing disorders may be a contributing factor K ous acute metabolic complications tion to ketone bodies (␤-hydroxybutyrate in 20% of recurrent ketoacidosis. Factors of diabetes, even if managed properly. [␤-OHB] and acetoacetate), with result- that may lead to insulin omission in These disorders can occur in both type 1 ing ketonemia and metabolic acidosis. On younger patients include fear of weight and type 2 diabetes. The mortality rate in the other hand, HHS may be caused by gain with improved metabolic control, patients with diabetic ketoacidosis (DKA) plasma insulin concentrations that are in- fear of hypoglycemia, rebellion from au- is Ͻ5% in experienced centers, whereas adequate to facilitate glucose utilization thority, and stress of chronic disease (13). the mortality rate of patients with hyper- by insulin-sensitive tissues but adequate osmolar hyperglycemic state (HHS) still (as determined by residual C-peptide) to DIAGNOSIS remains high at ϳ15%. The prognosis of prevent lipolysis and subsequent keto- both conditions is substantially worsened genesis, although the evidence for this is History and physical examination at the extremes of age and in the presence weak (14). Both DKA and HHS are asso- The process of HHS usually evolves over of coma and hypotension (1–10). ciated with glycosuria, leading to osmotic several days to weeks, whereas the evolu- This position statement will outline diuresis, with loss of water, sodium, po- tion of the acute DKA episode in type 1 precipitating factors and recommenda- tassium, and other electrolytes (3,15–20). diabetes or even in type 2 diabetes tends tions for the diagnosis, treatment, and The laboratory and clinical characteristics to be much shorter. Although the symp- prevention of DKA and HHS. It is based of DKA and HHS are summarized in Ta- toms of poorly controlled diabetes may be on a previous technical review (11), bles 1 and 2. As can be seen, DKA and present for several days, the metabolic al- which should be consulted for further in- HHS differ in magnitude of dehydration terations typical of ketoacidosis usually formation. and degree of ketosis (and acidosis). evolve within a short time frame (typically Ͻ24 h). Occasionally, the entire symp- PATHOGENESIS — Although the PRECIPITATING tomatic presentation may evolve or de- pathogenesis of DKA is better understood FACTORS — The most common pre- velop more acutely, and the patient may than that of HHS, the basic underlying cipitating factor in the development of present in DKA with no prior clues or mechanism for both disorders is a reduc- DKA or HHS is infection. Other precipi- symptoms. For both DKA and HHS, the tion in the net effective action of circulat- tating factors include cerebrovascular ac- classical clinical picture includes a history ing insulin coupled with a concomitant cident, alcohol abuse, pancreatitis, of polyuria, polydipsia, polyphagia, elevation of counterregulatory hormones, myocardial infarction, trauma, and drugs. weight loss, vomiting, abdominal pain such as glucagon, catecholamines, corti- In addition, new-onset type 1 diabetes or (only in DKA), dehydration, weakness, sol, and growth hormone. These hor- discontinuation of or inadequate insulin clouding of sensoria, and finally coma. monal alterations in DKA and HHS lead in established type 1 diabetes commonly Physical findings may include poor skin to increased hepatic and renal glucose leads to the development of DKA. Elderly turgor, Kussmaul respirations (in DKA), production and impaired glucose utiliza- individuals with new-onset diabetes (par- tachycardia, hypotension, alteration in tion in peripheral tissues, which result ticularly residents of chronic care facili- mental status, shock, and ultimately coma in hyperglycemia and parallel changes ties) or individuals with known diabetes (more frequent in HHS). Up to 25% of in osmolality of the extracellular space who become hyperglycemic and are un- DKA patients have emesis, which may be (12,13). The combination of insulin de- aware of it or are unable to take fluids coffee-ground in appearance and guaiac ficiency and increased counterregula- when necessary are at risk for HHS (6). positive. Endoscopy has related this find- tory hormones in DKA also leads to the Drugs that affect carbohydrate metab- ing to the presence of hemorrhagic gastri- release of free fatty acids into the circu- olism, such as corticosteroids, thiazides, tis. Mental status can vary from full ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● alertness to profound lethargy or coma, with the latter more frequent in HHS. Al- The recommendations in this paper are based on the evidence reviewed in the following publication: Management of hyperglycemic crises in patients with diabetes (Technical Review). Diabetes Care 24:131– though infection is a common precipitat- 153, 2001. ing factor for both DKA and HHS, The initial draft of this position statement was prepared by Abbas E. Kitabchi, PhD, MD; Guillermo E. patients can be normothermic or even Umpierrez, MD; Mary Beth Murphy, RN, MS, CDE, MBA; Eugene J. Barrett, MD, PhD; Robert A. Kreisberg, hypothermic primarily because of pe- MD; John I. Malone, MD; and Barry M. Wall, MD. The paper was peer-reviewed, modified, and approved by the Professional Practice Committee and the Executive Committee, October 2000. Revised 2001. ripheral vasodilation. Hypothermia, if Abbreviations: ␤-OHB, ␤-hydroxybutyric acid; AKA, alcoholic ketoacidosis; DKA, diabetic ketoacidosis; present, is a poor prognostic sign (21). HHS, hyperosmolar hyperglycemic state. Caution needs to be taken with patients S100 DIABETES CARE, VOLUME 25, SUPPLEMENT 1, JANUARY 2002 Position Statement Table 1—Diagnostic criteria for DKA and HHS is usually not lower than 18 mEq/l. DKA must also be distinguished from other DKA causes of high–anion gap metabolic aci- dosis, including lactic acidosis, ingestion Mild Moderate Severe HHS of drugs such as salicylate, methanol, eth- Plasma glucose (mg/dl) Ͼ250 Ͼ250 Ͼ250 Ͼ600 ylene glycol, and paraldehyde, and Arterial pH 7.25–7.30 7.00–7.24 Ͻ7.00 Ͼ7.30 chronic renal failure (which is more typi- Serum bicarbonate (mEq/l) 15–18 10 to Ͻ15 Ͻ10 Ͼ15 cally hyperchloremic acidosis rather than Urine ketones* Positive Positive Positive Small high–anion gap acidosis). Clinical history Serum ketones* Positive Positive Positive Small of previous drug intoxications or met- Effective serum osmolality Variable Variable Variable Ͼ320 formin use should be sought. Measure- (mOsm/kg)† ment of blood lactate, serum salicylate, Anion gap‡ Ͼ10 Ͼ12 Ͼ12 Ͻ12 and blood methanol level can be helpful Alteration in sensoria or mental Alert Alert/drowsy Stupor/coma Stupor/coma in these situations. Ethylene glycol (anti- obtundation freeze) is suggested by the presence of cal- cium oxalate and hippurate crystals in the *Nitroprusside reaction method; †calculation: 2[measured Na (mEq/l)] ϩ glucose (mg/dl)/18; ‡calculation: ϩ Ϫ Ϫ ϩ Ϫ urine. (Na ) (Cl HCO3 ) (mEq/l). See text for details. Paraldehyde ingestion is indicated by its characteristic strong odor on the who complain of abdominal pain on pre- triglyceridemia. Serum potassium con- breath. Because these intoxicants are low– sentation, because the symptoms could centration may be elevated because of an molecular weight organic compounds, be either a result or an indication of a pre- extracellular shift of potassium caused by they can produce an osmolar gap in addi- cipitating cause (particularly in younger insulin deficiency, hypertonicity, and aci- tion to the anion gap acidosis (14–16). patients) of DKA. Further evaluation is demia. Patients with low-normal or low necessary if this complaint does not re- serum potassium concentration on ad- TREATMENT — Successful treatment solve with resolution of dehydration and mission have severe total-body potassium of DKA and HHS requires correction of metabolic acidosis. deficiency and require very careful car- dehydration, hyperglycemia, and electro- diac monitoring and more vigorous po- lyte imbalances; identification of comor- Laboratory findings tassium replacement, because treatment bid precipitating events; and above all, The initial laboratory evaluation of pa- lowers potassium further and can pro- frequent patient monitoring. Guidelines tients with suspected DKA or HHS should voke cardiac dysrhythmia. The occur- for the management of patients with DKA include determination of plasma glucose, rence of stupor or coma in diabetic and HHS follow and are summarized in blood urea nitrogen/creatinine, serum ke- patients in the absence of definitive eleva- Figs. 1, 2, and 3. Table 3 includes a sum- tones, electrolytes (with calculated anion tion of effective osmolality (>320 mOsm/ mary of major recommendations and ev- gap), osmolality, urinalysis, urine ketones kg) demands immediate consideration of idence gradings. by dipstick, as well as initial arterial blood other causes of mental status change. Ef- gases, complete blood count with differ- fective osmolality may be calculated by Fluid therapy ential, and electrocardiogram. Bacterial the following formula: 2[measured Na Adult