Clin Chest Med 24 (2003) 583–606 Critical issues in endocrinology Philip A. Goldberg, MD, Silvio E. Inzucchi, MD* Section of Endocrinology, Yale University School of Medicine, TMP 534, 333 Cedar Street, New Haven, CT 06520, USA Endocrine emergencies are commonly encountered The underlying mechanism for DKA and HHS is in the intensive care unit (ICU). This article focuses on the reduced net activity of circulating insulin, usually several important endocrine emergencies, including with concurrent stimulation of counter-regulatory hor- diabetic hyperglycemic states, adrenal insufficiency, mone activity (eg, glucagon, catecholamines, gluco- myxedema coma, thyroid storm, and pituitary apo- corticoids [GC]). As shown in Fig. 1, these hormonal plexy. Other endocrine issues that are related to inten- changes lead to increased glucose production and sive care, such as intensive insulin therapy, relative decreased peripheral glucose use. Hyperglycemia adrenal insufficiency, and thyroid function test abnor- ensues, which leads to a vigorous osmotic diuresis malities also are covered in detail. Because of space which precipitates volume contraction and severe limitations, additional endocrinologic emergencies in- electrolyte losses [12]. In the setting of absolute insulin cluding hypoglycemia, calcium disorders, and fluid deficiency (ie, DKA), accelerated lipolysis and fatty and electrolyte disorders are not included (for reviews acid oxidation also generate ketoacidosis [13].In see references [1–7]). general, DKA afflicts patients who have type 1 diabe- tes, whereas HHS occurs in patients who have type 2 diabetes; however, there is substantial overlap between Critical issues in metabolism these two clinical syndromes. In clinical practice, HHS can present with variable degrees of ketosis and Diabetic hyperglycemic crises: diabetic ketoacidosis acidosis. Conversely, DKA is being seen with increas- and hyperosmolar hyperglycemic states ing frequency in patients who have type 2 diabetes, with a predilection for obese African Americans [14]. Diabetic hyperglycemic crises are commonly en- Most hyperglycemic crises have an identifiable countered in the ICU. Diabetic ketoacidosis (DKA) precipitating event. Infections trigger up to 50% of occurs with an annual incidence of four to eight cases [10]. Pneumonia, urinary tract infections (UTIs), episodes per 1000 diabetic patients [8,9]. It accounts and sepsis are common precipitants, as are common for more than 100,000 yearly hospital admissions [10], viral triggers, such as gastroenteritis and upper respi- with total costs (at more than $13,000 per admission) ratory infections. Inadequate insulin treatment, includ- that exceed $1.3 billion per year [11]. The incidence ing medication noncompliance and insulin pump and economic impact of hyperosmolar hyperglycemic failure, accounts for an additional 20% to 40% of states (HHS) are more difficult to ascertain, because of cases [10]. Table 1 lists some of the more common a lack of population-based studies. Although hospital precipitants for diabetic hyperglycemic crises. admission rates for HHS are likely lower than those for DKA [10], the growing type 2 diabetes epidemic Diagnosis suggests that the incidence of HHS is increasing. The presence of DKA or HHS is suggested by a history of polyuria, polydipsia, nausea, vomiting, or dehydration in the setting of known diabetes. DKA/ * Corresponding author. HHS may also be the initial presentation of new E-mail address: [email protected] diabetes. Because of the discomfort that is induced (S.E. Inzucchi). by acidosis, DKA typically evolves within 24 hours, 0272-5231/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0272-5231(03)00091-1 584 P.A. Goldberg, S.E. Inzucchi / Clin Chest Med 24 (2003) 583–606 Fig. 1. Pathogenesis of diabetic hyperglycemic states. whereas HHS may progress over several days [15]. For variable degrees of lethargy, mental status changes, this reason, patients who have HHS typically present and dehydration; the latter is suggested by decreased with more severe dehydration and electrolyte distur- skin turgor, dry mucous membranes, tachycardia, and bances. Focal neurologic symptoms or seizures may be orthostatic hypotension. Abdominal pain is common seen in severe cases [16]. On physical examination, in DKA and may reflect delayed gastric emptying or patients who have hyperglycemic crises present with intestinal ileus [17]; this symptom is less commonly seen in HHS. The presence of ketoacidosis is sug- gested by the presence of ‘‘acetone breath’’ or rapid, deep Kussmaul respirations. Table 1 The diagnosis of hyperglycemic crises is usually Known precipitants of diabetic hyperglycemic crises straightforward. The presence of hyperglycemia in the % of Cases Precipitating event proper clinical setting should trigger the clinician to 30–50% Infections: Viral infections, test for serum and urine ketones and to obtain arterial pneumonia, UTI, sepsis blood gases. Follow-up serologic evaluation should 20–40% Inadequate insulin therapy include a complete blood count with differential, 3–6% Myocardial ischemia/infarction chemistries (including divalent cations), serum osmo- < 2% Cerebrovascular accident lality, liver and pancreatic function tests, and cardiac Intracranial bleeding enzymes. Bacterial cultures of blood, urine, and other Pulmonary embolus sources should be obtained, along with a urinalysis, Intestinal thrombosis or obstruction chest radiograph, and 12-lead ECG. A full septic work- Acute pancreatitis up should be considered in all patients, particularly Alcohol intoxication Acute renal failure, peritoneal dialysis infants. Recent laboratory criteria that are endorsed by Hyperthermia or hypothermia the American Diabetes Association (ADA) for the Severe burns diagnosis of DKA and HHS [18] are displayed in Endocrine disorders: thyroid Table 2. In general, DKA is diagnosed when plasma storm, Cushing’s syndrome glucose is greater than 250 mg/dL and arterial pH is Total parenteral nutrition less than 7.30 in the setting of detectable urine/serum Drugs: b-blockers, calcium channel ketones. DKA severity may be graded using pH, blockers, diuretics, corticosteroids, bicarbonate, and other clinical criteria (see Table 2). antipsychotics, phenytoin, cimetidine HHS is diagnosed when plasma glucose is greater P.A. Goldberg, S.E. Inzucchi / Clin Chest Med 24 (2003) 583–606 585 Table 2 Laboratory diagnosis and classification of DKA and HHS Mild DKA Moderate DKA Severe DKA HHS Plasma glucose (mg/dL) > 250 >250 >250 >600 Serum osm (mosm/kg) Variable Variable Variable >320 Urine/serum ketones Positive Positive Positive Weak/negative Arterial pH 7.25–7.30 7.00–7.24 < 7.00 >7.30 Serum HCO3 À (mEq/L) 15–18 10–15 < 10 >15 Anion gap (mEq/L) >10 >12 >12 < 12 From Kitabachi AE, et al. Technical review. Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001;24:131–55; with permission. than 600 mg/dL and serum osmolarity is greater than itate cerebral edema through accelerated fluid shifts 320 mosm/kg. The term ‘‘HHS’’ [15] is now preferred into the brain [12]. over ‘‘hyperglycemic hyperosmolar nonketotic coma’’ to emphasize two important clinical points: (1) mental Insulin. Insulin therapy is an essential component of status changes usually occur in the absence of frank therapy for DKA, and is useful in most cases of HHS. coma, and (2) some degree of ketosis may be present Although severe insulin resistance is present in both in HHS. conditions, supraphysiologic insulin doses are not recommended, because they can result in hypokale- mia, hypophosphatemia, or delayed hypoglycemia Management [21,22]. Standard insulin therapy for DKA uses an The clinical management of diabetic hyperglyce- IV bolus of 0.15 U/kg of regular insulin, followed by mic crises is complex, and requires frequent attention a continuous insulin infusion of 0.1 U/kg/hour [18]. to details regarding hydration, electrolyte repletion, Smaller insulin doses may be used for treating HHS. and acid-base status. For this reason, patients who have In some cases of HHS, insulin may not be required to DKA or HHS are best managed in an ICU setting. The lower BG levels, because tissue perfusion and insulin initial goals of therapy for both syndromes are to sensitivity may be restored by volume restoration replace volume and electrolyte deficits. Hyperglyce- alone. Ideally, BG levels should decrease by 50 to mia should be corrected slowly. A modification of the 75 mg/dL/hour [18]. To achieve this steady decline, ADA-endorsed treatment algorithm for DKA/HHS it is essential to monitor BG hourly during the early [18] is presented in Fig. 2. The five major components hours of therapy. After BG is less than 250 mg/dL of therapy are considered below. (and ketoacids have been cleared, in DKA), subcuta- neous (SQ) insulin therapy can be initiated. In Volume replacement. Restoration of intravascular patients who have DKA, it is best to overlap IV and volume is the first goal of therapy, to correct tissue SQ insulin therapy by 1 to 2 hours, to prevent recur- hypoperfusion, improve glomerular filtration (restor- rent ketonemia. Following the restoration of normo- ing renal glucose and ketone clearance), and reverse glycemia, long-term diabetes management may be insulin resistance. DKA and HHS may present with slowly (re)initiated. massive total-body water deficits, up to 10 to 12 L [15,19]. Although water losses generally exceed the Potassium. Aggressive potassium repletion is criti- loss of salts,