Diabetic Ketoacidosis and the Hyperglycemic Hyperosmolar Syndrome Elizabeth D. Ennis Robert A.

Kreisberg Diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar syndrome (HHS) are life-threatening forms of decompensated diabetes mellitus (DM). Although DKA and HHS often are discussed as distinct entities, they appear to represent two extremes in a spectrum of diabetic decompensation (1) (Fig. 40.1). DKA and HHS differ from each other by the magnitude of hyperglycemia, the severity of acidosis/ketonemia, and the degree of dehydration. Although DKA classically occurs in young patients with type 1 DM, many are older and have type 2 DM. In one epidemiologic survey, 45% of patients with DKA were over 44 years and 26% over 65 years of age (2). In another survey, 11% of patients with DKA were over 60 years of age (3). HHS typically develops in patients with type 2 DM; however, some patients have features of HHS and DKA. Clearly, metabolic abnormalities can vary on a continuum from one extreme to the other (Fig. 40.1). Episodes of DKA have occurred on some occasions and HHS on other occasions in the same patient. A comprehensive review of a large number of patients with decompensated DM revealed that 22% had DKA, 45% had HHS, and 33% had features of both disorders (3) (Fig. 40.2). Decompensated DM is an important cause of morbidity and mortality among diabetic patients. Three percent to four percent of all discharges among patients with DM are due to DKA (4). In 1996, there were 100,000 hospital discharges with the primary diagnosis of DKA (5). However, this underestimates the prevalence of DKA because mild DKA is often managed in an ambulatory setting. DKA occurs equally in female and male patients with DM, but minorities and those at the extremes of age are disproportionately affected. Although the death rate for DKA has declined from 24.3 per 100,000 people with DM in 1987 to 20.4 per 100,000 individuals in 1997 (1,766 deaths in 1997), age and ethnicity affect the risk of death from DKA (4). Those individuals under 45 years of age or over 75 years of age are at highest risk; 38.0 deaths per 100,000 individuals 0 to 44 years of age and 30.4 deaths per 100,000 individuals at least 75 years of age (4). African Americans are disproportionally affected. The rate of hospitalization for DKA in African Americans with DM was 24.0 per 1,000 diabetics in 1996, more than twice that of whites, the last year for which data are available (4,5). In 1996 African-American men had a DKA death rate of 36.8 per 100,000 diabetics as compared with 22.7 deaths per 100,000 white male diabetics, 24.6 deaths per 100,000 episodes in African-American women, and 16.8 deaths per 100,000 episodes in white women (4). One study showed that individuals with Medicaid or no health insurance have admissions for DKA two to three times more frequently than patients with commercial health insurance (6). In the past, women have been more likely than men to develop DKA, but increasing numbers of men have been hospitalized for DKA in the United States, while admissions for women have declined over the 1990s (4,7). In a British study, recurrent DKA, defined as at least three episodes in 4 years, was noted in 31 female and 12 male patients (199 episodes total) (8). Because female patients constitute less than half of patients with type 1 DM (0.8595:1, F:M), this suggests an excess of recurrent DKA among female patients (8). Lack of education, hindered access to specialty care and teaching, limited personal support, and increased numbers of emergency room visits, among others, have been identified as factors that may predict a high likelihood of recidivism (9).

Each year there are approximately 11,000 hospital discharges for HHS (4). HHS mortality varies from 10% to 50%, due to comorbid conditions and intercurrent illness, which may precipitate HHS in these patients (4). Elderly people, particularly those dependent on others for their daily care, are at greatest risk for development of HHS. There appears to be no sex predilection (10); most nursing home occupants are women, however, so a slight female predominance would be expected (1). The relationship between being in a nursing facility and development of HHS is a reflection of the patients level of dependence, the presence of multiple comorbid illnesses, and a predisposition to dehydration. Medical illness that limits mobility, mental function, and ability to tend to activities of daily living make the institutionalized patient dependent on others for his or her fluid requirements. Most patients who become hyperosmolar in nursing facilities have had their fluid requirements underestimated or unmet.

Figure 40.1. Severity of hyperglycemia and ketoacidosis in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS). Classic metabolic profiles are expressed at the extreme left and right of the diagram. A continuum of combinations of hyperglycemia and ketoacidosis is possible, which is consistent with the observation that approximately 33% of patients with decompensated diabetes mellitus have features of both syndromes. Pathogenesis Diabetic ketoacidosis occurs when there is an absolute or relative deficiency of insulin and an excess of the following glucose counterregulatory hormones (GCRHs): catecholamines, glucagon, cortisol, and growth hormone (11). When DKA occurs coincident with the initial diagnosis of type 1 DM, insulin deficiency may be absolute or near absolute. Insulin levels in patients with type 1 DM may be within the normal range, but are inappropriate for the magnitude of hyperglycemia (11). Insulin deficiency in patients with type 2 DM and DKA is usually relative. Measurable levels of insulin, sometimes severalfold higher than those found in patients with type 1 DM, are present, but they are clearly not high enough to prevent DKA. Stress, usually due to a coexistent medical illness, but also due to physical or mental stress, or both, provokes the release of GCRHs, which leads to the development of

DKA in the presence of fixed, but inadequate, insulin levels. When insulin levels are suboptimal, the release of and biologic responses to GCRHs are exaggerated. The degree of insulin deficiency probably determines the importance of stress as a precipitating factor. In patients with absolute or severe insulin deficiency, the release of GCRHs may be less important in causing metabolic decompensation than in patients whose insulin levels are higher but not adequate to prevent metabolic decompensation. The interaction between relative or absolute insulin deficiency and factors that increase the release of GCRHs may not be an either/ or situation: in most situations, both insulin deficiency and GCRH release interact to precipitate decompensation. It is common, however, for a medical illness to be accompanied by omission of insulin by the patient because of a combination of reduced intake of food, fear of hypoglycemia, or a poor understanding of DM. In HHS, a similar sequence of events probably occurs, but insulin deficiency is less obvious because many of these patients were not previously known to have DM. It is unclear why decompensation in patients with HHS is expressed primarily as severe hyperglycemia and hyperosmolality with only trivial to mild ketoacidosis. This issue is discussed in detail in the section on Pathophysiology.

Figure 40.2. Overlap between diabetic acidosis (DA) and the diabetic hyperosmolar state (DHS) in patients with decompensated diabetes mellitus. (Reproduced from Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, et al. Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med 1991;6:495 , with permission.) The role (or roles) played by cytokines and prostaglandins in the pathogenesis of DKA and HHS, particularly during medical illness, are largely unexplored but may be important because of their metabolic effects. A clearer understanding of the changes in metabolism that occur with sepsis may provide a better understanding of how medical illness causes metabolic decompensation in patients with DM.