3124 Diabetes Care Volume 37, November 2014 Francisco J. Pasquel and Hyperosmolar Hyperglycemic Guillermo E. Umpierrez State: A Historic Review of the Clinical Presentation, Diagnosis, and Treatment Diabetes Care 2014;37:3124–3131 | DOI: 10.2337/dc14-0984 The hyperosmolar hyperglycemic state (HHS) is the most serious acute hypergly- cemic emergency in patients with type 2 diabetes. von Frerichs and Dreschfeld described the first cases of HHS in the 1880s in patients with an “unusual diabetic coma” characterized by severe hyperglycemia and glycosuria in the absence of Kussmaul breathing, with a fruity breath odor or positive acetone test in the urine. Current diagnostic HHS criteria include a plasma glucose level >600 mg/dL and increased effective plasma osmolality >320 mOsm/kg in the absence of ketoacidosis. The incidence of HHS is estimated to be <1% of hospital admissions of patients with diabetes. The reported mortality is between 10 and 20%, which is about 10 times higher than the mortality rate in patients with diabetic ketoacidosis (DKA). Despite the severity of this condition, no prospective, randomized studies have determined best REVIEW treatment strategies in patients with HHS, and its management has largely been extrapolated from studies of patients with DKA. There are many unresolved questions that need to be addressed in prospective clinical trials regarding the pathogenesis and treatment of pediatric and adult patients with HHS. The hyperosmolar hyperglycemic state (HHS) is a syndrome characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of ketoacidosis. The exact incidence of HHS is not known, but it is estimated to account for ,1% of hospital admissions in patients with diabetes (1). Most cases of HHS are seen in elderly patients with type 2 diabetes; however, it has also been reported in children and young adults (2). The overall mortality rate is estimated to be as high as 20%, which is about 10 times higher than the mortality in patients with diabetic keto- acidosis (DKA) (3–5). The prognosis is determined by the severity of dehydration, presence of comorbidities, and advanced age (4,6,7). Treatment of HHS is directed at replacing volume deficit and correcting hyperosmolality, hyperglycemia, and electrolyte disturbances, as well as management of the underlying illness that pre- cipitated the metabolic decompensation. Low-dose insulin infusion protocols de- signed for treating DKA appear to be effective; however, no prospective randomized Division of Endocrinology, Department of Med- studies have determined best treatment strategies for the management of patients icine, Emory University School of Medicine, Atlanta, GA with HHS. Herein, we present an extensive review of the literature on diabetic coma Corresponding author: Guillermo E. Umpierrez, and HHS to provide a historical perspective on the clinical presentation, diagnosis, [email protected]. and management of this serious complication of diabetes. Received 18 April 2014 and accepted 6 July 2014. © 2014 by the American Diabetes Association. History of Diabetic Coma and HHS Readers may use this article as long as the work In 1828, in the textbook Versuch einer Pathologie und Therapie des Diabetes Mellitus, is properly cited, the use is educational and not August W. von Stosch gave the first detailed clinical description of diabetic coma in an for profit, and the work is not altered. care.diabetesjournals.org Pasquel and Umpierrez 3125 adult patient with severe polydipsia, of patients with diabetic coma, noting (glycogenolysis) and by inadequate use polyuria, and a large amount of glucose that not all cases presented with the char- of glucose by peripheral tissues, pri- in the urine followed by progressive acteristic Kussmaul respiration or positive marily muscle. From the quantitative decline in mental status and death (8). urine acetone or diacetic acid (22–26). standpoint, increased hepatic glucose Several case reports followed this publi- These reports created confusion and production represents the major patho- cation, describing patients with newly di- weretakenwithskepticism,asthe genic disturbance responsible for hyper- agnosed or previously known diabetes source of ketone bodies and the role of glycemia in DKA (34). As the glucose presenting with drowsiness or coma, acetoacetic acid in the pathogenesis of concentration and osmolality of extra- most of them with a peculiar breath diabetic coma were not known at the cellular fluid increase, an osmolar gra- odor resembling acetone (9). In 1857, time. Many physicians were against ac- dient is created that draws water out of Petters (10) detected a substance in cepting that adult patients could prog- the cells. Glomerular filtration is ini- the urine of a fatal case of diabetic ress to diabetic coma in the absence of tially increased, which leads to glucosu- coma that resembled acetone in its reac- ketonuria. For example, in the 1930s, ria and osmotic diuresis. The initial tion with sulfuric acid and caustic alkalis Elliot P. Joslin (17) and others (27) glucosuria prevents the development and was later recognized as acetoacetic stated that the presence of acetone or of severe hyperglycemia as long as the acid, also called diacetic acid (11,12). Ac- diacetic acid in the urine was requisite glomerular filtration rate is normal. etone was then recognized as an impor- for the diagnosis of diabetic coma. It However, with continued osmotic di- tant outcome marker warning physicians was later hypothesized that diabetic uresis, hypovolemia eventually occurs, about serious diseases, including diabe- coma with negative urinary ketones which leads to a progressive decline in tes (13,14). In 1874, Kussmaul reported was the result of impaired renal excre- glomerular filtration rate and worsen- several fatal cases of diabetic coma pre- tion, liver dysfunction, and the presence ing hyperglycemia. ceded and accompanied by severe dys- of other acids, such as b-hydroxybutyric Higher hepatic and circulating insulin pnea (15,16). Kussmaul breathing, as this acid, rather than diacetic acid or ace- concentration as well as lower glucagon condition came to be known, quickly be- tone (25,26,28). are present in HHS compared with pa- came one of the hallmarks in the diagno- HHS syndrome received little atten- tients with ketoacidosis (32,33). The sis of diabetic coma, along with the tion and remained poorly understood higher circulating ratio of insulin/glu- presence of positive urine ketones until the reports by de Graeff and Lips cagoninpatientswithHHSprevents (14,17). In the 1880s, Stadelmann (18), (29) and Sament and Schwartz (30) in ketogenesis and the development of Kulz¨ (19), and Minkowski (20) reported 1957. They reported that severe hyper- ketoacidosis. This concept is supported that the urine of most patients with di- glycemia resulted in osmotic diuresis, by clinical studies both in animals and in abetic coma contained, in addition to polyuria, and progressive water deficit. humans, which have shown that the acetoacetic or diacetic acid, the pres- They discussed the relevance of measur- half-maximal concentration of insulin ence of considerable quantities of ing sodium and chloride levels to esti- for antilipolysis is lower than for glucose b-oxybutyric acid (Table 1). The discov- mate extracellular hypertonicity and use by peripheral tissues (35). Finally, a ery of high concentrations of acetoace- cellular dehydration, and they proposed direct role of hyperosmolarity by inhib- tic acid and b-hydroxybutyric acid led that patients with severe hyperglycemia iting lipolysis and free fatty acid release clinicians and researchers in the late and diabetic coma should be treated from adipose tissue has been shown in 1890s to conclude that diabetic coma with large quantities of water (29). experimental animals (36). was a “self-intoxication” due to an ex- Sament and Schwartz (30) suggested Severe hyperglycemia is associated cess of acids in the body (12,13). that some comatose patients with se- with a severe inflammatory state char- The first reports of HHS are attributed vere hyperglycemia and negative or acterized by an elevation of proinflam- to von Frerichs (21) and Dreschfeld (14). trace ketonuria could be treated suc- matory cytokines (tumor necrosis In the 1880s, they reported patients pre- cessfully with the administration of flu- factor-a, interleukin (IL)b,IL6,andIL8) senting with an unusual type of diabetic ids and lower amounts of insulin and reactive oxygen species, with insulin coma characterized by severe hyper- compared with regular acidotic patients secretion and action. Hyperglycemia glycemia and glycosuria but without with diabetic coma. causes an increase in oxidative stress Kussmaul breathing, fruity breath markers such as membrane lipid perox- odor, or a positive urine acetone test. Pathophysiology idation (37). The degree of lipid perox- Dreschfeld (14) described a case series HHS is characterized by extreme eleva- idation is directly proportional to the of patients with “diabetic collapse” pre- tions in serum glucose concentrations glucose concentrations in diabetic pa- senting after age 40 years, who were and hyperosmolality without significant tients. This is thought to occur via several well nourished at the time of the attack, ketosis (Fig. 1). These metabolic de- well-studied mechanisms, including in- andwithfattyinfiltration of the liver rangements result from synergistic fac- creased polyol pathway flux, increased and the heart. Shortly after these re- tors including