CHAPTER 17 ACUTE METABOLIC COMPLICATIONS IN DIABETES Arleta Rewers, MD, PhD

Dr. Arleta Rewers is Associate Professor, Department of Pediatrics at University of Colorado Denver School of Medicine, Aurora, CO.

SUMMARY

Diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), lactic acidosis (LA), and hypoglycemia are acute and potentially life-threatening complications of diabetes. DKA and severe hypoglycemia are more common in type 1 diabetes, while HHS without ketoacidosis is associated more frequently with type 2 diabetes. In the United States, the SEARCH for Diabetes in Youth study reported that 29% of patients age <20 years with type 1 diabetes and 10% with type 2 diabetes presented in DKA at diagnosis. The frequency of DKA among adult patients at diagnosis is unknown. A small group of high-risk patients accounts for most recurring DKA in longstanding type 1 diabetes, but the incidence remains high—approximately 1–12 episodes per 100 patient-years. Deaths in the United States with DKA listed as the underlying cause during 2000–2009 decreased 35%, from an annual rate of 12.9 per 100,000 people with diabetes in 2000 and 2001 to 8.4 per 100,000 people with diabetes in 2009. Estimated rates of hospital admissions for HHS are lower compared to DKA. HHS accounted for <1% of all admissions related to diabetes. HHS remains uncommon, but recognition of the state has increased, partially because of high case fatality, exceeding 20% in some patient groups. In 2001–2010, LA accounted for 1.2% of all hospitalizations in diabetic patients. Also in 2001–2010, hypoglycemia was listed as an underlying cause in nearly 288,000 hospitalizations, which represented 5.4% of total hospitalizations due to diabetes. Severe hypoglycemia, i.e., coma or seizure secondary to diabetes treatment, remains high (up to five episodes per 10 patient-years) and has increased among patients who aim for lower glycosylated hemoglobin (A1c) targets without appropriate initial education and ongoing support. All four acute complications are theoretically preventable; unfortunately, they still account for enormous morbidity, hospitalizations, and mortality among diabetic patients and contribute significantly to the high costs of diabetes care.

DIABETIC KETOACIDOSIS

PATHOGENESIS undiagnosed type 1 diabetes patients. In In addition, pediatric experts agree that a Diabetic ketoacidosis (DKA) is a common established patients, insulin omission, lower level of hyperglycemia (>200 mg/dL and life-threatening complication of type inadequate insulin dosing during infection, [>11.10 mmol/L]) also meets criteria for 1 diabetes, particularly at the time of diag- gastrointestinal illness, trauma and stress, DKA. Combination of near-normal glucose nosis. DKA is less common at diagnosis or pump failure can precipitate DKA. In levels and ketoacidosis (“euglycemic and during the course of type 2 diabetes. type 2 diabetes patients, DKA occurs ketoacidosis”) has been reported in preg- during concomitant acute illness or during nant adolescents, very young or partially DKA is caused by very low levels of effec- transition to insulin dependency. treated children (5), and children fasting tive circulating insulin and a concomitant during a period of insulin deficiency (6). increase in counterregulatory hormones DEFINITION levels, such as glucagon, catecholamines, The American Diabetes Association (1,2), Administrative data sets use International cortisol, and growth hormone. This the International Society for Pediatric Classification of Diseases, Ninth Revision combination leads to catabolic changes and Adolescent Diabetes (3), and jointly (ICD-9) or Tenth Revision (ICD-10), codes in the metabolism of carbohydrates, fat, the European Society for Paediatric to categorize diabetes and diabetic and protein. Impaired glucose utilization Endocrinology and the Lawson Wilkins complications. The ICD-9 code for DKA and increased glucose production by the Pediatric Endocrine Society (4) agreed to is 250.1x (250.10–250.13). However, the liver and kidneys result in hyperglycemia. define DKA as a triad of: code 250.3 (diabetes with other coma) is Lipolysis leads to increased production used for DKA coma, as well as for coma of ketones, especially beta-hydroxybu- § hyperglycemia, i.e., plasma glucose caused by severe hypoglycemia. In the tyrate (β-OHB), ketonemia, and metabolic >250 mg/dL (>13.88 mmol/L) ICD-10 categories for diabetes (E10–E14), acidosis, which is exaggerated by ongoing § venous pH <7.3 and/or bicarbonate subdivision E1x.1 denotes DKA, while fluid and electrolyte losses. At the time of <15 mmol/L E1x.0 denotes coma with or without keto- diagnosis, DKA is caused by underlying § moderate or large ketone levels in urine acidosis, hyperosmolar or hypoglycemic progressive beta cell failure in previously or blood (x digit is used to define type of diabetes).

Received in final form March 12, 2016. 17–1 DIABETES IN AMERICA, 3rd Edition

The incidence of DKA varies with the was found less frequently as the initial first-degree relative with type 1 diabetes, definition; therefore, it is important to manifestation of diabetes. DKA was shows a protective effect. A similar protec- standardize criteria for comparative epide- present at diagnosis in 20% of patients in tive effect is observed among children miologic studies. the Rhode Island Hospital Study, which involved in longitudinal etiological studies. was population based (24). A community- In addition, medications (glucocorticoids, PREVALENCE OF DIABETIC based Rochester, Minnesota, study found atypical antipsychotics, and diazoxide) KETOACIDOSIS AT THE that 23% of diabetes patients presented can contribute to precipitation of DKA in DIAGNOSIS OF DIABETES with DKA as the initial manifestation. DKA individuals without a previous diabetes In the United States, the large, popula- was more frequent in patients diagnosed diagnosis (33,34). tion-based SEARCH for Diabetes in Youth before age 30 years, reaching 26%, study reported that 29% of patients with and was present in only 15% of those Most episodes of DKA beyond type 1 diabetes age <20 years presented diagnosed at or after age 30 years (25). diagnosis are associated with insulin in DKA at diagnosis (7). The Pediatric omission, pump failure, or treatment Diabetes Consortium reported slightly INCIDENCE OF DIABETIC error (35,36). Parental supervision of higher rates, but these data are not popu- KETOACIDOSIS IN insulin treatment in children decreases lation based (8). These estimates are lower ESTABLISHED DIABETES the frequency of DKA (28). Lack of than prevalences reported from hospital The incidence of DKA in children and adequate adjustment of insulin therapy series (9,10). Data from SEARCH showed adolescents with established type 1 during illness or surgery may also lead that DKA prevalences are stable over time diabetes ranges from 1 to 12 episodes to the development of DKA (27,28,37). and high (11). Steady, high prevalences per 100 person-years (26,27,28). The Socioeconomic status and insufficient of DKA at diagnosis have been observed incidence of DKA among children and access to outpatient diabetes care are also in Australia, Germany, and Austria adolescents increases significantly with often the primary precipitating factors (12,13,14). In contrast, the prevalence of age in females, but not in males (26). for DKA; however, major psychiatric DKA at diagnosis decreased in Finnish There are no comparable population- disorders also play a significant role 26( ). children from 30% in 1982–1991 to 19% based data for adults. In Rochester, the in 1992–2002 (15). Studies from some incidence rate was 8 per 1,000 person- Continuous subcutaneous insulin infusion developing countries also show a signifi- years for DKA at all ages and was higher, (CSII) is effective and safe in both adults cant decrease in the prevalences of DKA reaching 13.4 per 1,000 person-years, and adolescents with type 1 diabetes (38); at diagnosis of type 1 diabetes (16,17,18). among diabetic persons who were however, CSII interruption can quickly diagnosed before age 30 years (25). In lead to DKA (39). The incidence of DKA Population-based epidemiologic data the Rhode Island Hospital Study, the appears to be unchanged during long- concerning the prevalence of DKA at the incidence of DKA among diabetic patients term (4 years) follow-up after introduction time of presentation of type 2 diabetes of all ages was 4.6 per 1,000 person-years of CSII in children and youth (40). are sparse. In youth with type 2 diabetes, (24). The rate was higher in women than the frequency of DKA at presentation men with diabetes. Similar to children, for adults with type 1 is less common than for youth with diabetes, the main precipitating factors type 1 diabetes—about 10%—and has PREDICTORS AND are noncompliance with treatment and decreased over time from 11.7% in 2002– PRECIPITATING FACTORS OF infections (41,42). Lack of money to buy 2003 to 6.3% in 2004–2005 and 5.7% in DIABETIC KETOACIDOSIS insulin is a significant cause of stopping 2008–2010 (7,11). The most important risk factor for pres- insulin in an adult inner city population ence of DKA at diagnosis is younger (43). DKA may also be associated with DKA is a less common initial presentation age (7,27,29), with children age <2 drug abuse and cigarette smoking (44). of diabetes in adults. In the United States, years having three times higher risk of Patients with type 2 diabetes may develop among adults presenting with DKA at DKA compared to older children (8,30). DKA when hospitalized for other medical diagnosis, an estimated 20%–50% are Lower socioeconomic status, low family or surgical conditions (45). The risk of initially diagnosed as having type 2 income, lack of private health insurance, DKA is higher in patients with a history of diabetes (19,20). However, the later and lower parental education are also previous episodes (24, 26). clinical course suggests higher cumulative risk factors for the presence of DKA at incidence of type 2 diabetes among these diagnosis (7,9,31,32). The frequency of HOSPITAL DISCHARGE DATA patients, reaching 39%–60% (21,22). DKA is also higher among ethnic minority New analyses of data from the U.S. A similar proportion (42%–64%) of ketosis- groups (7,26). Low societal awareness National Hospital Discharge Survey, a prone cases among type 2 diabetes of diabetes symptoms in areas with low study conducted by the National Center patients has been reported among incidence of type 1 diabetes is associated for Health Statistics, were performed African Americans (23). In older studies with higher risk of DKA. Family history of for Diabetes in America, 3rd edition. conducted between 1945 and 1980, DKA diabetes, particularly the presence of a The proportion of hospitalizations due

17–2 Acute Metabolic Complications in Diabetes to acute complications among diabetic TABLE 17.1. Hospitalizations for Acute Complications of Diabetes, by Age, U.S., patients between 2001 and 2010 2001–2010 (Table 17.1) decreased compared to the AVERAGE ANNUAL PERCENT (SE) time period 1981–1991 (46), except ACUTE COMPLICATIONS NUMBER OF DISCHARGES OF TOTAL* DIABETES for an increase in hospitalizations due (ICD-9-CM), BY AGE (YEARS) (THOUSANDS) DISCHARGES to acidosis. This finding may reflect an Diabetic ketoacidosis (250.1) increase in the rates of lactic acidosis (LA) All 157.7 3.0 (0.05) among patients with underlying diabetes <18 22.2 43.2 (1.38) and better recognition of this condition. 18–44 81.9 14.5 (0.32) DKA was an underlying cause of more 45–64 37.8 2.1 (0.07) than 43% of hospitalizations among ≥65 15.9 0.6 (0.03) diabetic patients age <18 years, but it Diabetic with other coma (250.3) decreased dramatically with increasing All 7.9 0.2 (0.01) age, and it was unlikely to present in <18 0.3 0.5 (0.31)2 diabetic patients age ≥65 years. DKA 18–44 2.1 0.4 (0.06) rates were highest among blacks and 45–64 2.3 0.1 (0.02) lowest among Asians (Table 17.2). During ≥65 3.2 0.1 (0.01) 2001–2010, there were 157,700 hospi- talizations in which DKA was listed as Diabetic hyperosmolar coma (250.2) an underlying cause and 7,900 in which All 23.9 0.5 (0.02) 1 diabetic coma was listed. DKA-related <18 0.2 0.3 (0.13) hospitalizations represent 3.0% of all 18–44 4.6 0.8 (0.08) hospitalizations among diabetic patients. 45–64 10.3 0.6 (0.04) ≥65 8.8 0.3 (0.02) MORBIDITY AND MORTALITY Acidosis (276.2) DKA-related mortality among patients All 65.2 1.2 (0.03) with diabetes was estimated for Diabetes <18 0.8 1.6 (0.34) in America using data from the National 18–44 8.3 1.5 (0.10) Vital Statistics System. Deaths in the 45–64 24.2 1.3 (0.06) United States with DKA listed as the ≥65 32.0 1.1 (0.05) underlying cause during 2000–2009 Hypoglycemia (250.8, 251.2) decreased 35%, from an annual rate of All 287.6 5.4 (0.07) 12.9 per 100,000 people with diabetes <18 1.8 3.6 (0.37) in 2000 and 2001 to 8.4 per 100,000 18–44 28.9 5.1 (0.19) people with diabetes in 2009 (Figure 17.1). 45–64 100.8 5.5 (0.11) Mortality rates due to DKA were 2.5 times ≥65 156.1 5.5 (0.09) higher in those age <18 years compared Diabetes hospitalizations are defined as ICD-9-CM codes 250, 357.2, 362.0, 366.41, 648.0, and 775.10, as any to those age ≥65 years. Another new diagnosis listed on the hospital discharge record. Standard errors (SE) were most likely underestimated because analysis showed that the rates during this the National Hospital Discharge Survey sampling variables were not available, and consequently, it was not possible to take into account the complex sampling design. There were only 11 patients with hypoglycemia coma among period varied among youth with diabetes, people with diabetes, and none of the estimates were reliable enough to present (all relative standard errors >50%). reaching 42.5 per 100,000 people with ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification. * Average annual number of discharges (thousands) with any diabetes diagnosis: 5,180 discharges among all ages, diabetes in 2002 and decreasing to 18.6 51 discharges <18 years, 558 discharges 18–44 years, 1,800 discharges 45–64 years, and 2,772 discharges ≥65 per 100,000 people with diabetes in 2009 years. 1 Relative standard error >30%–40% (Figure 17.2). The decrease in mortality 2 Relative standard error >40%–50% rates during this time period was greater SOURCE: National Hospital Discharge Surveys 2001–2010 among youths age <10 years (78%) than among youths age 10–19 years (52%) (47). in the course of DKA is present in >50% COST of pediatric patients (53). Hypokalemia, Direct medical care charges attributed The most common cause of death in hyperkalemia, thrombosis (42), other to DKA episodes are high, reaching 28% youth with type 1 diabetes is cerebral neurological complications (54,55), stroke of the direct medical care charges for all edema in the course of DKA (48,49). The (56,57), sepsis and other infections, such diabetic patients and 56% for those with reported incidence of clinically overt as rhinocerebral mucormycosis (58,59), recurrent DKA (62). In a study among cerebral edema varies between 0.3% aspiration pneumonia, and pulmonary youth with type 1 diabetes who had DKA, and 1.0% (50,51,52). However, asymp- edema (60,61) are less frequent complica- predicted mean annual total medical tomatic or subclinical cerebral edema tions of DKA. expenditures were $5,837 higher than

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TABLE 17.2. Annual Hospitalizations for Diabetic Ketoacidosis and Diabetic Coma, by Age, Sex, and Race, U.S., 2001–2010

DIABETIC KETOACIDOSIS DIABETIC COMA NEC

DIABETES ALL Percent (SE) Percent (SE) DISCHARGES DISCHARGES* Among All Among All (NUMBER IN (NUMBER IN Number Diabetes Among All Number Diabetes Among All CHARACTERISTICS THOUSANDS) THOUSANDS) (Thousands) Discharges Discharges (Thousands) Discharges Discharges Total 5,180 38,619 157.7 3.0 (0.05) 0.4 (0.01) 7.9 0.2 (0.01) 0.02 (0.002) Age (years) <18 51 6,787 22.2 43.2 (1.38) 0.3 (0.01) 0.3 0.5 (0.31)2 3 18–44 558 10,040 81.9 14.5 (0.32) 0.8 (0.02) 2.1 0.4 (0.06) 0.02 (0.003) 45–64 1,800 8,569 37.8 2.1 (0.07) 0.4 (0.01) 2.3 0.1 (0.02) 0.03 (0.004) ≥65 2,772 13,223 15.9 0.6 (0.03) 0.1 (0.01) 3.2 0.1 (0.01) 0.02 (0.003) Sex Male 2,355 15,928 75.6 3.1 (0.07) 0.5 (0.01) 3.6 0.2 (0.02) 0.02 (0.003) Female 2,825 22,691 82.1 2.8 (0.07) 0.4 (0.01) 4.2 0.2 (0.02) 0.02 (0.002) Race† White 3,047 23,312 83.4 2.7 (0.06) 0.4 (0.01) 4.3 0.1 (0.02) 0.02 (0.002) Black 820 4,806 35.4 4.2 (0.14) 0.7 (0.02) 1.2 0.1 (0.03) 0.02 (0.004) AI/AN 29 166 1.0 3.3 (0.85) 0.6 (0.16) 0.1 0.2 (0.14)2 0.04 (0.025)2 Asian 66 612 1.3 1.9 (0.40) 0.2 (0.05) 0.1 0.1 (0.06)2 0.01 (0.007) Other 135 1,027 4.0 2.9 (0.25) 0.4 (0.03) 0.1 0.1 (0.03)1 0.01 (0.004) Diabetic ketoacidosis and diabetic coma are defined as ICD-9-CM codes 250.1 and 250.3, respectively. Diabetes hospitalizations are defined as ICD-9-CM codes 250, 357.2, 362.0, 366.41, 648.0, and 775.10, as any diagnosis listed on the hospital discharge record. Standard errors (SE) were most likely underestimated because the National Hospital Discharge Survey sampling variables were not available, and consequently, it was not possible to take into account the complex sampling design. AI/AN, American Indian/Alaska Native; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; NEC, not elsewhere classifiable. * All discharges include patients with diabetes and those without diabetes. † Twenty-three percent of participants were missing race data. 1 Relative standard error >30%–40% 2 Relative standard error >40%–50% 3 Estimate is too unreliable to present; ≤1 case or relative standard error >50%. SOURCE: National Hospital Discharge Surveys 2001–2010 among those without DKA. As DKA is visits for DKA was 64 per 10,000 U.S. polydipsia, polyuria, and polyphagia with treated primarily in hospital settings, the diabetic patients, and the number of visits weight loss, is the best strategy for early inpatient expenditures attributed to DKA increased between 1993–1998 (315,000) detection of type 1 diabetes and preven- accounted for >90% of the total excess and 1999–2003 (438,000) (65). tion of DKA at the time of diagnosis. medical expenditures attributed to DKA Both public and health professional (63). Among adults with type 1 diabetes, During 2004, there were 120,000 education should make people aware of reported medical expenditures are twice admissions due to DKA, 15,000 due to those symptoms, as patients admitted as high ($13,046 [2007 dollars]), most hyperosmolar hyperglycemic state (HHS), with severe DKA are often seen hours likely due to coexisting comorbidities (62). and an additional 5,000 due to “diabetic or days earlier by health care providers Tieder et al. examined a retrospective coma” (66). Based on the Diagnostic who missed the diagnosis, particularly cohort of children age 2–18 years with Related Group codes in the inpatient in the youngest children (69,70). The a diagnosis of DKA between 2004 and records, the total hospital cost for DKA Diabetes Autoimmunity Study in the 2009. The mean hospital-level total was estimated at $1.4–$1.8 billion. Young, an observational study following standardized cost of DKA treatment was An independent analysis by Kitabchi et al. children at genetically high risk for type 1 $7,142 (64). estimated the annual hospital cost of DKA diabetes by periodic testing for diabetes in the United States in excess of $1 billion autoantibodies, glycosylated hemo- According to National Hospital Ambulatory (67). Approximately 25% of the cost is globin (A1c), and random blood glucose, Medical Care Surveys between 1993 and related to DKA at diabetes diagnosis (68). demonstrated that prevention of DKA 2003, DKA accounted for approximately in newly diagnosed children is possible. 753,000 visits or an average 68,000 visits PREVENTION The prevalence of DKA at the time of per year. The majority of DKA patients Prevention of DKA should be one of diagnosis among children enrolled in this (87%) were admitted, with most admis- the main goals of diabetes education. study was significantly lower compared sions to a non-intensive care unit setting. Knowledge of the signs and symptoms to the community level (71). Similar find- The rate of emergency department of diabetes, such as the classic triad of ings came from the Diabetes Prevention

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Trial (72). A community intervention to In adults, in the absence of cardiac compro- administration of an initial intravenous dose raise awareness of the signs and symp- mise, isotonic saline is given at a rate of of regular insulin (0.1 units/kg) followed toms of childhood diabetes in the Parma 15–20 mL/kg per hour or 1–1.5 L during by the infusion of 0.1 units/kg per hour. region of Italy reduced the prevalence of the first hour. Subsequent fluid replace- A prospective randomized study reported DKA at diagnosis of type 1 diabetes from ment depends on hemodynamic status, that a bolus dose of insulin is not necessary, 83% to 13% (73). The effect persisted 8 serum electrolyte levels, and urinary output. if patients receive an hourly insulin infusion years later, but there was an indication Treatment algorithms recommend the of 0.14 units/kg body weight (82). that the campaign should be periodically renewed (74). FIGURE 17.1. Trends in Age-Standardized Mortality Rate Coded to Diabetic Ketoacidosis Per 100,000 People With Diabetes, U.S., 2000–2009 Most studies have shown that most episodes of DKA beyond disease Underlying cause* Multiple causes† diagnosis are preventable by identification 25 of at-risk patients and use of targeted interventions. Comprehensive diabetes 20 programs and telephone help lines reduced the rates of DKA from 15–60 15 to 5–6 per 100 patient-years (75,76,77). 10 In the adolescent cohort of the Diabetes Control and Complications Trial (DCCT), 5

intensive diabetes management was Mortality rate (per 100,000) associated with less DKA (conventional 0 and intensive treatment groups: 4.7 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Year and 2.8 episodes per 100 patient-years, respectively) (78). In patients treated with Ketoacidosis is defined as International Classification of Diseases, Tenth Revision (ICD-10), codes E10.1, E11.1, insulin pumps, episodes of DKA can be E12.1, E13.1, or E14.1. Data are standardized to the National Health Interview Survey 2010 diabetes population using age categories <18, 18–44, 45–64, and ≥65 years. reduced with introduction of treatment * The disease or injury that initiated the train of events leading directly to death algorithms (79). The extent to which home † In addition to the underlying cause, death certificates list up to 20 additional “multiple” causes of death. measurement of whole blood or urine SOURCE: Number of deaths are derived from the National Vital Statistics System 2000–2009; number of people with diabetes are derived from the National Health Interview Surveys 2000–2009. β-OHB concentration may assist in the prevention of hospitalization should be further assessed (80). FIGURE 17.2. Trends in Age-Standardized Mortality Rate Coded to Diabetic Ketoacidosis Per 100,000 People With Diabetes Age <18 Years, U.S., 2000–2009 TREATMENT Underlying cause* Multiple causes† The goal of therapy is to correct dehy- 50 dration by restoring extracellular and intracellular fluid volume and correcting 40 electrolytes imbalances, hyperglycemia, and acidosis. The recommended therapy 30 differs between adults and children given 1 the higher risk of development of cerebral 20 edema in children. The pediatric recom- mendation for initial volume expansion 10 Mortality rate (per 100,000) is slow intravenous infusion of 10–20 0 mL/kg of normal saline (0.9%) over the 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 first 1–2 hours. Subsequent fluid replace- Year ment should be done with 0.45%–0.9% Ketoacidosis is defined as International Classification of Diseases, Tenth Revision (ICD-10), codes E10.1, E11.1, normal saline. To correct ketoacidosis, a E12.1, E13.1, or E14.1. “low dose” continuous IV insulin adminis- * The disease or injury that initiated the train of events leading directly to death † In addition to the underlying cause, death certificates list up to 20 additional “multiple” causes of death. tration is needed as a regular insulin drip 1 Relative standard error >30%–40% for the 2009 estimates at a dose of 0.1 units/kg per hour (1) or SOURCE: Number of deaths are derived from the National Vital Statistics System 2000–2009; number of people even lower doses, such as 0.05 units/kg with diabetes are derived from the National Health Interview Surveys 2000–2009. per hour (81). Pediatric DKA should be treated in a facility with appropriate pedi- atric expertise.

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HYPERGLYCEMIC HYPEROSMOLAR STATE

PATHOGENESIS disease, and cancer, seems to be respon- controls) to be independently associated Decrease in the effective action of circu- sible for the higher mortality associated with the presence of HHS (95). Among lating insulin coupled with a concomitant with HHS compared to DKA (86). 200 HHS patients in Rhode Island, elevation of counter regulatory hormones nursing home residents accounted for is the underlying mechanism for both The incidence of HHS is most likely under- 18% of the cases (85). HHS and DKA. These alterations lead estimated in children, as the presenting to increased hepatic and renal glucose clinical picture in many patients has MORBIDITY AND MORTALITY production and impaired glucose utiliza- elements of both HHS and DKA (87,88). Hospitalization data from the National tion in peripheral tissues, which result in Hospital Discharge Surveys 2001–2010 hyperglycemia and parallel changes in Several studies of pediatric and were analyzed for Diabetes in America, osmolality of the extracellular space (83). adolescent diabetic patients, mostly case confirming that HHS occurs rarely (Tables HHS is associated with glycosuria, leading series or single-institution reviews, have 17.1 and 17.3). The 18–44 years age group to osmotic diuresis, with loss of water, described more than 50 cases of HHS had the highest percentage of hospital- sodium, potassium, and other electrolytes. (7,89,90,91,92). Most patients were izations listing HHS. The average annual In HHS, insulin levels are inadequate for adolescents with newly diagnosed type number of hospital discharges listing HHS glucose utilization by insulin sensitive 2 diabetes, and many were of African as a cause doubled to 23,900 during 2001– tissues but sufficient (as determined by American descent. A study based on 2010 compared to 10,800 in 1989–1991. residual C-peptide) to prevent lipolysis data from the Kid’s Inpatient Database and ketogenesis (83). provided the first national estimate of In adults, mortality rates attributed to hospitalizations due to HHS among HHS range from 5% to 25% (82,85,86, DEFINITION U.S. children between 1997 and 2009. 94,96). The mortality increases sharply HHS is defined as extreme elevation in blood The estimated population rate for HHS with age from none in patients age <35 glucose >600 mg/dL (>33.30 mmol/L) diagnoses for children age 0–18 years years to 1.2% in those age 35–55 years and serum osmolality >320 mOsm/kg was 2.1 per 1,000,000 children in 1997, and 15.0% in patients age >55 years. in the absence of significant ketosis and rising to 3.2 in 2009. The majority (70.5%) A U.S. study of 613 adult patients hospi- acidosis. Small amounts of ketones may of HHS hospitalizations occurred among talized for hyperglycemic crises reported be present in blood and urine (84). children with type 1 diabetes (93). similar findings (85). Fatality rates for DKA, mixed DKA-HHS, and isolated HHS alone In the ICD-9, the HHS code is 250.2: RISK FACTORS were, respectively, 4%, 9%, and 12%. In diabetes with hyperosmolarity or hyper- The majority of HHS episodes are precip- both studies, older age and the degree of osmolar (nonketotic) coma. The ICD-10 itated by an infectious process; other hyperosmolarity were the most powerful does not have a specific code for HHS; precipitants include cerebrovascular predictors of a fatal outcome. Deaths E1x.0 denotes coma with or without keto- accident, alcohol abuse, pancreatitis, due to hyperglycemic crisis in adults with acidosis, hyperosmolar or hypoglycemic myocardial infarction, trauma, and diabetes dropped from 2,989 in 1985 to (x digit is used to define type of diabetes). drugs. In a case series of 119 patients 2,459 in 2002, according to data from the with HHS, nearly 60% of the patients National Vital Statistics System. During INCIDENCE AND PREVALENCE had an infection, and 42% had a stroke the time period, age-adjusted death rates The incidence of HHS is unknown because (94). Medications affecting carbohydrate decreased from 42 to 24 per 100,000 of the lack of population-based studies metabolism, such as corticosteroids, adults with diabetes (97); the decrease and multiple comorbidities often found in thiazides, and sympathomimetic agents was found in all age groups (Figure 17.3) these patients. Estimated rates of hospital (e.g., dobutamine and terbutaline), may (97). During the period between 1997 and admissions for HHS are lower compared also precipitate the development of HHS. 2009, the mortality rate among children to DKA. HHS accounts for <1% of all Elderly individuals, particularly those with was reported at 2.7 per 100 HHS hospital- admissions related to diabetes but may new-onset diabetes are at risk for HHS. izations compared to previously described affect up to 4% of new type 2 diabetes A comparison of 135 patients with hyper- rates of 33 and 72 per 100 HHS hospital- patients (83). osmolar syndrome with 135 age-matched, izations of children dying in the course of randomly selected diabetic controls HHS (98,99). The prevalence of isolated HHS in adult hospitalized in the same time period patients with acute, significant hypergly- found female sex (71% in HHS cases vs. COST cemia varies from 15% to 45% (85,86). 53% in diabetic controls), newly diagnosed Data concerning the cost of HHS are HHS occurs at any age, but it is more prev- diabetes (36% per 100 HHS hospital- limited, due to the lack of exact incidence alent in elderly patients who have additional izations vs. 7% in diabetic controls), and data. However, on an individual basis, the comorbidities. Presence of other condi- presence of acute infection (39% per 100 cost per event is several times higher than tions, such as infection, cardiovascular HHS hospitalizations vs. 19% in diabetic that for uncomplicated DKA (66).

17–6 Acute Metabolic Complications in Diabetes

TABLE 17.3. Annual Hospitalizations for Diabetic Hyperosmolar Nonketotic Coma, by Age, PREVENTION AND TREATMENT Sex, and Race, U.S., 2001–2010 Appropriate diabetes education, adequate treatment, and frequent self-monitoring PERCENT (STANDARD ERROR) DIABETIC HYPEROSMOLAR of blood glucose help to prevent HHS NONKETOTIC COMA Among Diabetes Among All CHARACTERISTICS (NUMBER IN THOUSANDS) Discharges Discharges* in patients with known diabetes. HHS can be precipitated by dehydration and Total 23.9 0.5 (0.02) 0.06 (0.003) medications, such as corticosteroids, Age (years) thiazides, and sympathomimetic agents. 0.2 0.3 (0.13)1 3 <18 Careful use of these medications is 18–44 4.6 0.8 (0.08) 0.05 (0.004) indicated in vulnerable patients, e.g., 45–64 10.3 0.6 (0.04) 0.12 (0.009) elderly cared for in nursing homes at risk ≥65 8.8 0.3 (0.02) 0.07 (0.005) of dehydration and unable to promptly Sex communicate their medical problems. Male 11.7 0.5 (0.03) 0.07 (0.004) Patients with HHS require hospitalization, Female 12.2 0.4 (0.03) 0.05 (0.003) which can be prolonged due to underlying Race† conditions. In cases not complicated White 10.6 0.3 (0.02) 0.05 (0.003) by underlying conditions, treatment Black 8.1 1.0 (0.08) 0.17 (0.013) modalities are similar to DKA (82,100). AI/AN <0.1 0.1 (0.10)2 0.03 (0.018)2 Intravenous rehydration and insulin to Asian 0.3 0.4 (0.17)2 0.04 (0.019) correct hyperglycemia lead to prompt Other 0.9 0.6 (0.15) 0.08 (0.021) resolution of HHS. Hyperosmotic nonketotic coma is defined as ICD-9 code 250.2. Diabetes hospitalizations are defined as ICD-9-CM codes 250, 357.2, 362.0, 366.41, 648.0, and 775.10, as any diagnosis listed on the hospital discharge record. Standard errors were most likely underestimated because the National Hospital Discharge Survey sampling vari- ables were not available, and consequently, it was not possible to take into account the complex sampling design. AI/AN, American Indian/Alaska Native; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification. * All discharges include patients with diabetes and those without diabetes. † Twenty-three percent of participants were missing race data. 1 Relative standard error >30%–40% 2 Relative standard error >40%–50% 3 Estimate is too unreliable to present; ≤1 case or relative standard error >50%. SOURCE: National Hospital Discharge Surveys 2001–2010

FIGURE 17.3. Age-Specific Death Rates for Hyperglycemic Crisis Among Persons With Diabetes Age ≥18 Years, by Age, U.S., 1985–2002

18–44 years 45–64 years ≥65 years 90

80

70

60

50

40

30

20

Death rate (per 100,000 people with diabetes) 10 0

1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Year

Data are based on the National Vital Statistics System 1985–2002. Denominators are based on National Health Interview Surveys 1985–2002 data. SOURCE: Reference 97, copyright © 2006 American Diabetes Association, reprinted with permission from The American Diabetes Association

17–7 DIABETES IN AMERICA, 3rd Edition

LACTIC ACIDOSIS

DEFINITION The frequency of hospitalizations due to comparative trials and observational LA consists of elevation of lactic acid LA increased from 0.6% to 1.2% among cohort studies showed no difference in above 5.0 mEq/L with acidosis (pH <7.3) patients with diabetes and from 0.3% the incidence of LA during metformin and without ketoacidosis. There may to 1.0% among those without diabetes treatment compared to other antihyper- be low levels of ketones present (1:4 in comparison to previous data from glycemic treatments. In this review, the on serum dilution or β-OHB >0.4–<0.6 1989–1991 (46). incidence of metformin-associated LA mmol/L). The ICD-9 code 276.2 describes was 8.4 cases per 100,000 patient-years, acidosis, primarily LA. PRECIPITATING FACTORS and in the non-metformin group, it was The usual precipitating factors for LA 9 cases per 100,000 patient-years (101). INCIDENCE are conditions of impaired oxygenation, In other studies, the reported incidence Data on incidence rates for LA are such as hypoxemia, shock, sepsis, of metformin-associated LA in type 2 sparse. It is a rare, but important, adverse carbon monoxide poisoning, and some diabetes patients ranged from 10 to event in patients with diabetes. National medications, including phenformin and 47 cases per 100,000 patient-years Hospital Discharge Survey data on hospi- metformin, particularly when used in (102,103). Most studies have found no talizations in 2001–2010 with an LA code patients with renal failure. Phenformin, significant difference in the incidence of in patients with and without a concomi- a biguanide, increases the risk of LA during treatment with metformin in tant diagnosis of diabetes were analyzed life-threatening LA and is no longer patients with and without renal impair- for Diabetes in America ( Tables 17.1 available in the United States. Also, ment defined as a reduced glomerular and 17.4). Whereas the highest absolute metformin is thought to increase the risk filtration rate 102( ). number of LA cases occurred in patients of LA in patients with diabetes and is age >45 years, in women, in whites, and contraindicated in conditions associated MORBIDITY AND MORTALITY in patients for whom diabetes was not with LA, such as cardiovascular, renal, LA leads to neurologic impairment. Rapid listed on the hospital discharge summary, hepatic, and pulmonary diseases, and correction of the acid-base and electro- the percentage of diabetes discharges advanced age. However, a Cochrane lyte disturbances may induce cerebral with LA was greater in younger people. Database review of prospective edema. The mechanism of cerebral

TABLE 17.4. Annual Hospitalizations for Lactic Acidosis, by Diabetes Status, Age, Sex, and Race, U.S., 2001–2010

DIABETES NO DIABETES

Lactic Acidosis Percent (SE) Lactic Acidosis Percent (SE) and Diabetes Among Diabetes Among All and No Diabetes Among All CHARACTERISTICS (Number in Thousands) Discharges Discharges* (Number in Thousands) Discharges Total 65.2 1.2 (0.03) 0.17 (0.005) 340.3 1.02 (0.012) Age (years) <18 0.8 1.6 (0.34) 0.01 (0.003) 42.5 0.63 (0.020) 18–44 8.3 1.5 (0.10) 0.08 (0.006) 45.5 0.48 (0.015) 45–64 24.2 1.3 (0.06) 0.28 (0.013) 88.8 1.32 (0.030) ≥65 32.0 1.1 (0.05) 0.24 (0.010) 163.4 1.58 (0.027) Sex Male 31.6 1.3 (0.05) 0.20 (0.008) 158.9 1.18 (0.020) Female 33.6 1.2 (0.04) 0.15 (0.006) 181.4 0.92 (0.015) Race† White 35.7 1.1 (0.05) 0.15 (0.006) 205.0 1.02 (0.016) Black 13.8 1.6 (0.09) 0.29 (0.016) 49.4 1.25 (0.036) AI/AN 0.5 1.7 (0.65)1 0.31 (0.119) 1.7 1.24 (0.227) Asian 1.1 1.6 (0.39) 0.18 (0.043) 5.5 1.01 (0.115) Other 2.4 1.7 (0.18) 0.24 (0.025) 10.4 1.17 (0.069) Lactic acidosis is defined as ICD-9 code 276.2. Diabetes hospitalizations are defined as ICD-9-CM codes 250, 357.2, 362.0, 366.41, 648.0, and 775.10, as any diagnosis listed on the hospital discharge record. Standard errors (SE) were most likely underestimated because the National Hospital Discharge Survey sampling variables were not available, and consequently, it was not possible to take into account the complex sampling design. AI/AN, American Indian/Alaska Native; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification. * All discharges include patients with diabetes and those without diabetes. † Twenty-three percent of participants were missing race data. 1 Relative standard error >30%–40% SOURCE: National Hospital Discharge Surveys 2001–2010

17–8 Acute Metabolic Complications in Diabetes edema in the course of LA is unclear. PREVENTION AND TREATMENT The only effective treatment for LA is The mortality rates from LA are high and LA is usually associated with unexpected cessation of lactic acid production by associated with higher lactic acid levels. and catastrophic hypoxic events and is the improvement of tissue oxygenation. Based on data from National Hospital therefore less likely to be amenable to Treatment of underlying conditions, Discharge Surveys 2001–2010, LA preventive measures. Long-term preven- such as shock or myocardial infarc- accounts for 1.2% of all hospitalizations tion of cardiovascular disease or sepsis tion, includes restoration of the fluid in diabetic patients (Table 17.4). among diabetic patients through improved volume, improvement of cardiac function, glucose control and alteration of other risk amelioration of sepsis, and correction of factors could decrease the incidence of LA. hyperglycemia (104).

HYPOGLYCEMIA

PATHOGENESIS DEFINITION The DCCT defined severe hypoglycemia as Hypoglycemia is the most common, Various definitions of hypoglycemia are in an episode in which the patient required life-threatening acute complication of use; for comparative epidemiologic studies, assistance with treatment from another diabetes treatment. It is characterized by it is important to standardize criteria. The person to recover; blood glucose level had multiple risk factors and complex patho- American Diabetes Association Workgroup to be documented as <50 mg/dL (<2.78 physiology (105). The brain depends on a on Hypoglycemia defined hypoglycemia mmol/L) and/or the clinical manifestations continuous supply of glucose for energy, broadly as all episodes of an abnormally had to be reversed by oral carbohydrate, although it can also utilize ketone bodies. low plasma glucose concentration that subcutaneous glucagon, or intravenous Young children and adolescents are at expose the individual to potential harm glucose (109). This definition is of limited higher risk for hypoglycemia, and the (107,108). According to the Workgroup, a value in children, particularly the youngest, spectrum of outcomes ranges from mild hypoglycemic episode could be: as they require assistance even for mild cognitive impairment to coma, seizure, episodes of hypoglycemia. There is lack of and sudden death. § Severe hypoglycemia: an event a uniform definition of hypoglycemia for requiring assistance of another person children and adolescents with diabetes. Missed meals, inadvertent insulin dosing to actively administer carbohydrate, Most experts agree that blood glucose error, and rapid insulin absorption due glucagon, or other resuscitative actions. values <60–70 mg/dL (<3.33–3.89 to intramuscular injection or hot shower/ The episode may lead to a significant mmol/L) put the patient at risk for severe bath shortly after injection are common neuroglycopenia and seizure or coma. hypoglycemia. Those blood glucose levels causes of hypoglycemia in insulin-treated Plasma glucose measurements may lead to alterations in the counterregulatory patients. Rarely, secondary gain or suicide be missing during an event, but hormones essential to the spontaneous attempt may lead to insulin overdose. neurological recovery is sufficient reversal of hypoglycemia. For clinical use, In all these situations, insulin overdose evidence that the event was induced by the value of <65 mg/dL (<3.61 mmol/L) reduces hepatic glucose output. Physical a low plasma glucose concentration. has been most often used as the level for activity increases glucose utilization and § Documented symptomatic hypogly- defining hypoglycemia in the pediatric may lead to hypoglycemia, if not matched cemia: an event with typical symptoms population. Other studies have limited by lowering of insulin dose and increased of hypoglycemia and a measured the definition of severe hypoglycemia in carbohydrate intake. Oral hypoglycemic plasma glucose concentration ≤70 children to episodes leading to uncon- agents may lead to hypoglycemia by mg/dL (≤3.89 mmol/L). sciousness or seizure (110,111). either decreasing hepatic glucose output § Asymptomatic hypoglycemia: an event or increasing insulin levels. In contrast, with a measured plasma glucose In the ICD-9, hypoglycemic coma enhancers of peripheral glucose utilization concentration ≤70 mg/dL, but without secondary to diabetes treatment is (thiazolidinediones) do not cause hypogly- typical symptoms of hypoglycemia. coded 250.3; however, this code is also cemia in patients with residual insulin and § Probable symptomatic hypoglycemia: used for coma with DKA. Other forms glucagon secretion. Release of glucagon— an event during which symptoms of of diabetic hypoglycemia are coded the major counterregulatory response to hypoglycemia are not accompanied by 250.8. Hypoglycemia not associated with hypoglycemia in nondiabetic persons—is a plasma glucose determination. diabetes is coded 251.2. An additional E progressively lost within a few years § Relative hypoglycemia: an event code is recommended to identify the drug after diagnosis of type 1 diabetes. during which the person with diabetes that induced hypoglycemia. In the ICD-10, Catecholamine release, the other powerful reports any of the typical symptoms E1x.0 denotes coma with or without keto- counterregulatory mechanism, is also of hypoglycemia and interprets acidosis, hyperosmolarity or hypoglycemia impaired in diabetic patients, especially in those as indicative of hypoglycemia, (with the x digit used to define type of those with type 1 diabetes and those on with a measured plasma glucose diabetes), while E16.0 denotes diabetic beta blocker treatment (106). concentration >70 mg/dL. drug-induced hypoglycemia without coma.

17–9 DIABETES IN AMERICA, 3rd Edition

INCIDENCE IN TYPE 1 agents. However, the risk of hypoglycemia based on whether they were receiving DIABETES PATIENTS increases with transition to insulin-​ insulin and/or sulfonylureas. Instances of The incidence of moderate or mild hypo- dependence. In the United Kingdom overtreatment were defined as using one glycemia is unknown; those events are Prospective Diabetes Study (UKPDS), of these agents in patients with A1c levels frequent among patients treated with the risk of severe hypoglycemia was 1.0 below specific thresholds, such as <7.0% insulin and are often unrecognized or per 100 patient-years in those intensively (<53 mmol/mol). Among patients age underreported. Severe hypoglycemia is treated with chlorpropamide, 1.4 per 100 ≥75 years, who had a serum creatinine more likely to be recognized. Pre-DCCT patient-years with glibenclamide, and 1.8 >2.0 mg/dL or an ICD-9-CM diagnosis incidence rates of severe hypoglycemia per 100 patient-years with insulin (125). of cognitive impairment or dementia varied from 3 to 86 per 100 patient-years Long-acting sulfonylureas confer higher (31.5% of patients), rates of overtreatment depending on definition, age, duration risk compared to shorter-acting ones (126), were 11.3% for those with A1c <6.0% of diabetes, and treatment modality particularly in older patients and those (<42 mmol/mol), 28.6% for A1c <6.5% (112,113,114,115,116). with a longer duration of diabetes, poly- (<48 mmol/mol), and 50.0% for A1c <7.0%. pharmacy, and a recent hospitalization Among patients with additional comor- Among adolescents participating in the (127). One study suggested an increase bidity, similar rates of overtreatment were DCCT, the incidences of hypoglycemia in risk of hypoglycemia in patients found by A1c thresholds (134). Additional were 86 per 100 patient-years in inten- treated with sulfonylurea and angiotensin-​ information about glycemic control sively treated and 28 per 100 patient-years converting enzyme (ACE) inhibitors (128), and hypoglycemia risk in older adults is in conventionally treated participants (78). but that finding was not confirmed in a provided in Chapter 16 Diabetes in Older The incidences of coma and seizure in the large trial (129). Hospital admission rates Adults. adolescents were 27 per 100 patient-years for hypoglycemia in U.S. have declined and 10 per 100 patient-years, respec- since 2007; however, rates among black Modifiable predictors of severe hypo- tively. In all DCCT participants, intensive Medicare beneficiaries and those older glycemia include intensive insulin treatment of type 1 diabetes increased than 75 years remain high (130). treatment, marked by lower A1c levels the frequency of severe hypoglycemia and higher insulin dose (26,119). The from two to six times that observed with RISK FACTORS relation between severe hypoglycemia conventional treatment (117). There is a strong relationship between and tight glycemic control had been severe hypoglycemia and tight glycemic extensively explored, especially in children Several studies examined the incidence control (131), especially in children and (118,120,132). Over 60% of the intensively rates of severe hypoglycemia in youth older adults (118,120,132,133,134). treated adolescents who participated in during the post-DCCT era. Few used a Age (infancy and adolescence) (120,135), the DCCT had coma or seizure during the prospective design or were population male sex (26), and increased duration of trial compared to 25% of those treated based. The incidence of severe hypogly- diabetes (136) are the most commonly conventionally (78). Intensive treatment, cemia of 19 per 100 patient-years was reported predictors of severe hypogly- such as the use of insulin pumps, is reported from a large cohort of type 1 cemia in patients with type 1 diabetes. beneficial in lowering A1c levels without a diabetic children age 0–19 years followed The risk of hypoglycemia increases with coincident higher risk of hypoglycemia in by the Barbara Davis Center for Childhood duration of diabetes, partially due to pediatric populations (143,144). The addi- Diabetes (26). A Joslin Clinic study with a progressive loss of alpha cell glucagon tion of continuous glucose monitoring to similar definition found a lower rate of 8 response to hypoglycemia, and is inversely insulin pump therapy has further lowered per 100 patient-years in a cohort of older related to preservation of beta cells (137). the rates of hypoglycemia (145,146,147). children age 7–16 years. However, this In the DCCT, presence of residual endoge- study excluded children with psychiatric nous insulin secretion predicted 65% lower Another risk factor is the presence of disorders and difficult social situations risk of severe hypoglycemia (138). Sudden hypoglycemia unawareness leading to an (118). Similar rates were reported from loss of endogenous insulin production is inability to recognize symptoms of hypogly- other European, American, and Australian seen more frequently in patients with the cemia. It is present in about 10% of patients studies (119,120,121,122,123), with an human leukocyte antigen (HLA)-DR3/4 and is more common in patients with low exception of very low incidence (<4 per 100 genotype (139,140,141) and those with average glucose levels (148,149). Even a person-years) in a study from Finland (124). multiple islet autoantibodies (140,142). single hypoglycemic episode can cause significant decrease in neurohormonal INCIDENCE IN TYPE 2 In patients with type 2 diabetes, aggres- counterregulatory responses and worsen DIABETES PATIENTS sive glycemic control puts them at risk unawareness of hypoglycemia (150). Patients with type 2 diabetes treated of hypoglycemia. A large, cross-sectional with diet and exercise do not suffer from study of older adult patients in the The main effect of exercise on glucose severe hypoglycemia. It occurs rarely in Veterans Health Administration in 2009 metabolism is blood glucose lowering patients treated with oral hypoglycemic identified patients at risk of hypoglycemia via insulin-independent skeletal muscle

17–10 Acute Metabolic Complications in Diabetes uptake, which may result in hypoglycemia psychiatric disorders affecting patients and 30% of patients with type 1 diabetes, without modification of insulin dose and their families have been shown to have increase the risk of hypoglycemia intake of carbohydrates (151). significant influence on glycemic control (162,163,164,165). In pregnancy with and the rate of hypoglycemia. Family type 1 diabetes, the incidence of mild and Alcohol consumption is a significant relationships and personality type have severe hypoglycemia is highest in early risk factor for development of severe also had a significant effect on adaptation pregnancy, although metabolic control hypoglycemia. Alcohol suppresses to illness and metabolic control among is usually tighter in the last part of preg- gluconeogenesis and glycogenolysis persons with diabetes (156). Presence of nancy. Predictors for severe hypoglycemia and acutely improves insulin sensitivity psychiatric disorders has a detrimental are history of severe hypoglycemia and (152,153) and may induce hypoglycemia effect on metabolic control (157,158) impaired awareness (166). Chronic kidney unawareness (154). In combination and compliance with treatment (159). disease can be found in up to 23% of with exercise, drinking alcohol can lead Prevalence of psychiatric disorders among patients with diabetes. Chronic kidney to severe hypoglycemia with a delay patients with type 1 diabetes reached 48% disease is an independent risk factor for of symptoms up to 10–12 hours after by 10 years of diabetes duration and age hypoglycemia and augments the risk alcohol consumption (155). 20 years in a small longitudinal cohort already present in people with diabetes (160,161), the most prevalent being major (167,168). Family dynamics, behavioral factors, and depressive disorder (28%). Prevalence of psychiatric factors are important risk psychiatric disorders, however, has been MORBIDITY AND MORTALITY factors, particularly in the pediatric popula- shown to be much lower in other studies, A new analysis for Diabetes in America tion. The DCCT showed that conventional as discussed in Chapter 33 Psychiatric and of the frequency of hypoglycemia risk factors explained only 8.5% of the Psychosocial Issues Among Individuals (ICD-9 codes 250.8 and 251.2) as a variance in the occurrence of severe hypo- Living With Diabetes. discharge diagnosis for hospitalizations glycemia (117). Factors such as inadequate in the United States in 2001–2010 is diabetes education, low socioeconomic Coexisting autoimmune conditions, such shown in Tables 17.1 and 17.5, using data status, lack of insurance, unstable living as autoimmune thyroid, celiac, and from the National Hospital Discharge conditions, behavioral factors, and Addison’s diseases, occurring in up to Survey. Hypoglycemia was listed as

TABLE 17.5. Annual Hospitalizations for Hypoglycemia, by Diabetes Status, Age, Sex, and Race, U.S., 2001–2010

DIABETES NO DIABETES

Hypoglycemia Percent (SE) Hypoglycemia Percent (SE) and Diabetes Among All Diabetes Among All With No Diabetes Among All CHARACTERISTICS (Number in Thousands) Discharges Discharges* (Number in Thousands) Discharges Total 287.6 5.4 (0.07) 0.74 (0.009) 28.9 0.09 (0.003) Age (years) <18 1.8 3.6 (0.37) 0.03 (0.003) 7.9 0.12 (0.009) 18–44 28.9 5.1 (0.19) 0.29 (0.011) 5.9 0.06 (0.005) 45–64 100.8 5.5 (0.11) 1.18 (0.025) 5.6 0.08 (0.006) ≥65 156.1 5.5 (0.09) 1.18 (0.021) 9.6 0.09 (0.006) Sex Male 140.9 5.8 (0.10) 0.88 (0.016) 12.4 0.09 (0.005) Female 146.7 5.1 (0.09) 0.65 (0.012) 16.5 0.08 (0.004) Race† White 160.8 5.1 (0.09) 0.69 (0.012) 18.0 0.09 (0.004) Black 56.9 6.8 (0.17) 1.18 (0.031) 4.5 0.11 (0.010) 2 AI/AN 1.8 5.9 (0.96) 1.07 (0.180) 0.1 0.09 (0.041) 1 Asian 4.1 6.0 (0.65) 0.67 (0.074) 0.5 0.09 (0.032) Other 7.3 5.3 (0.31) 0.71 (0.042) 0.6 0.07 (0.014) ICD-9-CM codes used to identify hypoglycemia hospitalizations were 250.8 for those with diabetes and 251.2 for those without diabetes. Diabetes hospitalizations are defined as ICD-9-CM codes 250, 357.2, 362.0, 366.41, 648.0, and 775.10, as any diagnosis listed on the hospital discharge record. Standard errors (SE) were most likely underestimated because the National Hospital Discharge Survey sampling variables were not available, and consequently, it was not possible to take into account the complex sampling design. There were only 11 patients with hypoglycemia coma among people with diabetes, and none of the estimates were reliable enough to present (all relative standard errors >50%). AI/AN, American Indian/Alaska Native; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification. * All discharges include patients with diabetes and those without diabetes. † Twenty-three percent of participants were missing race data. 1 Relative standard error >30%–40% 2 Relative standard error >40%–50% SOURCE: National Hospital Discharge Surveys 2001–2010

17–11 DIABETES IN AMERICA, 3rd Edition an underlying cause in about 288,000 baseline), while increasing the incidence of lower A1c levels and improve quality of hospitalizations, which represented hypoglycemia, did not lead to a significant life compared to multiple daily injections 5.4% of hospitalizations due to diabetes. worsening of neuropsychological or cogni- of insulin and, of importance, reduce the Hospital discharges for hypoglycemia in tive functioning during the trial (186,187), rate of severe hypoglycemia (193,194). diabetic patients occurred least often in as well as 18 years after entry into the patients age <18 years. The total number trial (188). However, risk of hypoglycemia The introduction of rapid-acting insulin of hypoglycemic events was higher in should be balanced by emerging data on analogues (e.g., lispro, aspart) has females with diabetes compared to a detrimental effect of hyperglycemia on made insulin treatment more efficient males, but the percentage of discharges the development of a normal brain (189). and potentially less likely to induce was higher in males compared to hypoglycemia. An ecologic analysis females. The total number of hospitaliza- COST explored the effects of the DCCT report tions due to hypoglycemia was greatest In a study among youth with diabetes, in 1993 and that of the introduction of a among whites followed by blacks, while the predicted mean annual total medical rapid-acting insulin analogue (lispro) in the percentage of discharges was lower expenditures were $12,850 and $8,970 1996 on the risk of severe hypoglycemia in whites than in the other race/ethnicity for youth with and without severe hypo- in type 1 diabetic patients (195). A1c groups (Table 17.5). glycemia, respectively. The excess of levels declined significantly during expenditures was greater among those 1993–1996 (p<0.001), following the Hypoglycemia is a significant factor with more than one episode ($5,929) DCCT report, but the number of severe in excess mortality in patients with than among those with only one ($2,888) hypoglycemic events increased (p<0.001) diabetes (169). Despite improvements (63). A study from Germany, Spain, and during that time frame. A further in therapy, diabetes-related mortality the United Kingdom showed that hospital decline in A1c levels was observed among children did not decline in the treatment of severe hypoglycemia was after the introduction of lispro insulin time period between 1968 and 1998 a major contributor to its high cost. in 1996 (p<0.001), however, without a (170). Sudden nocturnal death in young Average severe hypoglycemia event concomitant change in the incidence of persons with type 1 diabetes has been treatment costs were higher for patients severe hypoglycemia. The introduction described and is known as the “dead in with type 2 diabetes (Germany, €533; of long-acting insulin analogues in 2003 bed” syndrome (171); it appears to be Spain, €691; U.K., €537) than those with also suggests a potential for improving responsible for about 6% of deaths in type 1 diabetes (€441, €577, and €236, glycemic control without an increased diabetic patients age <40 years (172). respectively) (190). Reliable data are not risk of hypoglycemia (196,197,198). In these cases, nocturnal hypoglycemia available concerning the cost of hypo­ is a likely precipitant, consistent with glycemia in adults with diabetes in the Continuous Glucose Monitoring demonstrated impairment of counter- United States. Frequent self-blood glucose monitoring regulatory hormone response during has been found to be an important factor sleep (173), as well as a high frequency The personal, family, and societal cost of in attaining better glucose control for the of nocturnal hypoglycemia reported by trauma of loss of consciousness, seizure, intensively treated participants in the the DCCT (117) and more recent studies long-term disability, and fears are harder DCCT and the UKPDS. However, many using continuous glucose monitoring. to measure. Further studies are needed patients do not accept frequent blood to update these figures and to estimate, glucose monitoring, mainly because of Hypoglycemic episodes range from in addition, indirect costs (e.g., lost pain and inconvenience. The results also mild neurogenic symptoms to coma productivity and diminished quality of life). give data valid for only a discrete point in and seizures. There is an association time, without any information on glucose between hypoglycemia and a decrease PREVENTION trends before or after the glucose value. in cognitive functioning in children with Improved insulin delivery and tech- In addition, patients infrequently measure type 1 diabetes (174,175,176), particularly nological advances provide new blood glucose levels during the night, among the youngest patients (176,177). opportunities to improve glycemic although >50% of severe hypoglycemic Hypoglycemic seizures lead to significant control with decreased risk of severe events occur during sleep (113,117). declines in verbal abilities (178), memory hypoglycemia, but they require skills (179), and the ability to organize intensified teaching and compliance Continuous glucose monitoring holds and recall information (180), even (136,191,192). Intensive insulin therapy great promise for prevention of hypogly- after mild hypoglycemia (181). Severe using insulin pumps, multiple daily cemia. Clinical trials of continuous glucose hypoglycemia in children may lead to injections, and new insulin analogues monitoring have given reason to believe persistent electroencephalographic has been found effective in lowering that tighter glycemic control may not changes (182,183,184,185). On the A1c levels, but there is less evidence for necessarily lead to increased risk of hypo- other hand, intensive insulin treatment a beneficial effect on the risk of hypo- glycemia (199,200,201,202,203,204,205). in the DCCT cohort (age 13–39 years at glycemia. Insulin pump treatment may The main goal of research on devices for

17–12 Acute Metabolic Complications in Diabetes diabetes management is the development Behavioral Interventions accomplished by giving glucose tablets or of automatic glucose sensing and insulin Behavioral interventions, including sweetened fluids, such as juice, glucagon delivery without patient intervention (206). intensive diabetes education, good injection in unconscious patients, or Studies evaluating closed-loop insulin access to care, and psychosocial dextrose infusion in a hospital setting. delivery suggest improved glucose control support, including treatment of and a decreased risk of hypoglycemia psychiatric disorders, lower the risk of (207,208). Data from the Automation to hypoglycemia (210,211). Simulate Pancreatic Insulin REsponse (ASPIRE) study confirmed that use of TREATMENT sensor-augmented insulin pump therapy The goal of treatment of hypogly- with the threshold-suspend feature cemia is to immediately increase the reduced nocturnal hypoglycemia, without blood glucose approximately 3–4 increasing A1c values (209). mmol/L (~55–70 mg/dL). This can be

LIST OF ABBREVIATIONS CONVERSIONS A1c ...... glycosylated hemoglobin Conversions for A1c and glucose β-OHB ...... beta-hydroxybutyrate values are provided in Diabetes in CSII ...... continuous subcutaneous insulin infusion America Appendix 1 Conversions. DCCT ...... Diabetes Control and Complications Trial DKA ...... diabetic ketoacidosis HHS ...... hyperglycemic hyperosmolar state ICD-9-CM/ICD-10 ...... International Classification of Diseases, Ninth Revision, DUALITY OF INTEREST Clinical Modification/Tenth Revision Dr. Rewers reported no conflicts of LA ...... lactic acidosis interest. SEARCH ...... SEARCH for Diabetes in Youth study UKPDS...... United Kingdom Prospective Diabetes Study

REFERENCES

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