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Cowie CC, Casagrande SS, Menke A, et al., editors. Diabetes in America. 3rd edition. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases (US); 2018 Aug.

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Diabetes in America. 3rd edition.

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CHAPTER 17Acute Metabolic Complications in Diabetes

, MD, PhD.

Author Information and Affiliations

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

Diabetic ketoacidosis (DKA) is a common and life-threatening complication of type 1 diabetes, particularly at the time of diagnosis. DKA is less common at diagnosis and during the course of type 2 diabetes.

DKA is caused by very low levels of effective circulating insulin and a concomitant increase in counterregulatory hormones levels, such as glucagon, catecholamines, cortisol, and growth hormone. This combination leads to catabolic changes in the metabolism of carbohydrates, fat, and protein. Impaired glucose utilization and increased glucose production by the liver and kidneys result in hyperglycemia. Lipolysis leads to increased production of ketones, especially beta-hydroxybutyrate (β-OHB), ketonemia, and metabolic acidosis, which is exaggerated by ongoing fluid and electrolyte losses. At the time of diagnosis, DKA is caused by underlying progressive beta cell failure in previously undiagnosed type 1 diabetes patients. In established patients, insulin omission, inadequate insulin dosing during infection, gastrointestinal illness, trauma and stress, or pump failure can precipitate DKA. In type 2 diabetes patients, DKA occurs during concomitant acute illness or during transition to insulin dependency.

Definition

The American Diabetes Association (1,2), the International Society for Pediatric and Adolescent Diabetes (3), and jointly the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society (4) agreed to define DKA as a triad of:

  • hyperglycemia, i.e., plasma glucose >250 mg/dL (>13.88 mmol/L)
  • venous pH <7.3 and/or bicarbonate <15 mmol/L
  • moderate or large ketone levels in urine or blood

In addition, pediatric experts agree that a lower level of hyperglycemia (>200 mg/dL [>11.10 mmol/L]) also meets criteria for DKA. Combination of near-normal glucose levels and ketoacidosis (“euglycemic ketoacidosis”) has been reported in pregnant adolescents, very young or partially treated children (5), and children fasting during a period of insulin deficiency (6).

Administrative data sets use International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10), codes to categorize diabetes and diabetic complications. The ICD-9 code for DKA is 250.1x (250.10–250.13). However, the code 250.3 (diabetes with other coma) is used for DKA coma, as well as for coma caused by severe hypoglycemia. In the ICD-10 categories for diabetes (E10–E14), subdivision E1x.1 denotes DKA, while E1x.0 denotes coma with or without ketoacidosis, hyperosmolar or hypoglycemic (x digit is used to define type of diabetes).

The incidence of DKA varies with the definition; therefore, it is important to standardize criteria for comparative epidemiologic studies.

Prevalence of Diabetic Ketoacidosis at the Diagnosis of Diabetes

In the United States, the large, population-based SEARCH for Diabetes in Youth study reported that 29% of patients with type 1 diabetes age <20 years presented in DKA at diagnosis (7). The Pediatric Diabetes Consortium reported slightly higher rates, but these data are not population based (8). These estimates are lower than prevalences reported from hospital series (9,10). Data from SEARCH showed that DKA prevalences are stable over time and high (11). Steady, high prevalences of DKA at diagnosis have been observed also in Australia, Germany, and Austria (12,13,14). In contrast, the prevalence of DKA at diagnosis decreased in Finnish children from 30% in 1982–1991 to 19% in 1992–2002 (15). Studies from some developing countries also show a significant decrease in the prevalences of DKA at diagnosis of type 1 diabetes (16,17,18).

Population-based epidemiologic data concerning the prevalence of DKA at the time of presentation of type 2 diabetes are sparse. In youth with type 2 diabetes, the frequency of DKA at presentation is less common than for youth with type 1 diabetes—about 10%—and has decreased over time from 11.7% in 2002–2003 to 6.3% in 2004–2005 and 5.7% in 2008–2010 (7,11).

DKA is a less common initial presentation of diabetes in adults. In the United States, among adults presenting with DKA at diagnosis, an estimated 20%–50% are initially diagnosed as having type 2 diabetes (19,20). However, the later clinical course suggests higher cumulative incidence of type 2 diabetes among these patients, reaching 39%–60% (21,22). A similar proportion (42%–64%) of ketosis-prone cases among type 2 diabetes patients has been reported among African Americans (23). In older studies conducted between 1945 and 1980, DKA was found less frequently as the initial manifestation of diabetes. DKA was present at diagnosis in 20% of patients in the Rhode Island Hospital Study, which was population based (24). A community-based Rochester, Minnesota, study found that 23% of diabetes patients presented with DKA as the initial manifestation. DKA was more frequent in patients diagnosed before age 30 years, reaching 26%, and was present in only 15% of those diagnosed at or after age 30 years (25).

Incidence of Diabetic Ketoacidosis in Established Diabetes

The incidence of DKA in children and adolescents with established type 1 diabetes ranges from 1 to 12 episodes per 100 person-years (26,27,28). The incidence of DKA among children and adolescents increases significantly with age in females, but not in males (26). There are no comparable population-based data for adults. In Rochester, the incidence rate was 8 per 1,000 person-years for DKA at all ages and was higher, reaching 13.4 per 1,000 person-years, among diabetic persons who were diagnosed before age 30 years (25). In the Rhode Island Hospital Study, the incidence of DKA among diabetic patients of all ages was 4.6 per 1,000 person-years (24). The rate was higher in women than men with diabetes.

Predictors and Precipitating Factors of Diabetic Ketoacidosis

The most important risk factor for presence of DKA at diagnosis is younger age (7,27,29), with children age <2 years having three times higher risk of DKA compared to older children (8,30). Lower socioeconomic status, low family income, lack of private health insurance, and lower parental education are also risk factors for the presence of DKA at diagnosis (7,9,31,32). The frequency of DKA is also higher among ethnic minority groups (7,26). Low societal awareness of diabetes symptoms in areas with low incidence of type 1 diabetes is associated with higher risk of DKA. Family history of diabetes, particularly the presence of a first-degree relative with type 1 diabetes, shows a protective effect. A similar protective effect is observed among children involved in longitudinal etiological studies. In addition, medications (glucocorticoids, atypical antipsychotics, and diazoxide) can contribute to precipitation of DKA in individuals without a previous diabetes diagnosis (33,34).

Most episodes of DKA beyond diagnosis are associated with insulin omission, pump failure, or treatment error (35,36). Parental supervision of insulin treatment in children decreases the frequency of DKA (28). Lack of adequate adjustment of insulin therapy during illness or surgery may also lead to the development of DKA (27,28,37). Socioeconomic status and insufficient access to outpatient diabetes care are often the primary precipitating factors for DKA; however, major psychiatric disorders also play a significant role (26).

Continuous subcutaneous insulin infusion (CSII) is effective and safe in both adults and adolescents with type 1 diabetes (38); however, CSII interruption can quickly lead to DKA (39). The incidence of DKA appears to be unchanged during long-term (4 years) follow-up after introduction of CSII in children and youth (40).

Similar to children, for adults with type 1 diabetes, the main precipitating factors are noncompliance with treatment and infections (41,42). Lack of money to buy insulin is a significant cause of stopping insulin in an adult inner city population (43). DKA may also be associated with drug abuse and cigarette smoking (44). Patients with type 2 diabetes may develop DKA when hospitalized for other medical or surgical conditions (45). The risk of DKA is higher in patients with a history of previous episodes (24,26).

Hospital Discharge Data

New analyses of data from the U.S. National Hospital Discharge Survey, a study conducted by the National Center for Health Statistics, were performed for Diabetes in America, 3rd edition. The proportion of hospitalizations due to acute complications among diabetic patients between 2001 and 2010 (Table 17.1) decreased compared to the time period 1981–1991 (46), except for an increase in hospitalizations due to acidosis. This finding may reflect an increase in the rates of lactic acidosis (LA) among patients with underlying diabetes and better recognition of this condition. DKA was an underlying cause of more than 43% of hospitalizations among diabetic patients age <18 years, but it decreased dramatically with increasing age, and it was unlikely to present in diabetic patients age ≥65 years. DKA rates were highest among blacks and lowest among Asians (Table 17.2). During 2001–2010, there were 157,700 hospitalizations in which DKA was listed as an underlying cause and 7,900 in which diabetic coma was listed. DKA-related hospitalizations represent 3.0% of all hospitalizations among diabetic patients.

Morbidity and Mortality

DKA-related mortality among patients with diabetes was estimated for Diabetes in America using data from the National Vital Statistics System. 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 (Figure 17.1). Mortality rates due to DKA were 2.5 times higher in those age <18 years compared to those age ≥65 years. Another new analysis showed that the rates during this period varied among youth with diabetes, reaching 42.5 per 100,000 people with diabetes in 2002 and decreasing to 18.6 per 100,000 people with diabetes in 2009 (Figure 17.2). The decrease in mortality rates during this time period was greater among youths age <10 years (78%) than among youths age 10–19 years (52%) (47).

The most common cause of death in youth with type 1 diabetes is cerebral edema in the course of DKA (48,49). The reported incidence of clinically overt cerebral edema varies between 0.3% and 1.0% (50,51,52). However, asymptomatic or subclinical cerebral edema in the course of DKA is present in >50% of pediatric patients (53). Hypokalemia, hyperkalemia, thrombosis (42), other neurological complications (54,55), stroke (56,57), sepsis and other infections, such as rhinocerebral mucormycosis (58,59), aspiration pneumonia, and pulmonary edema (60,61) are less frequent complications of DKA.

TABLE 17.1. Hospitalizations for Acute Complications of Diabetes, by Age, U.S., 2001–2010.

TABLE 17.1

Hospitalizations for Acute Complications of Diabetes, by Age, U.S., 2001–2010.

Cost

Direct medical care charges attributed to DKA episodes are high, reaching 28% of the direct medical care charges for all diabetic patients and 56% for those with recurrent DKA (62). In a study among youth with type 1 diabetes who had DKA, predicted mean annual total medical expenditures were $5,837 higher than among those without DKA. As DKA is treated primarily in hospital settings, the inpatient expenditures attributed to DKA accounted for >90% of the total excess medical expenditures attributed to DKA (63). Among adults with type 1 diabetes, reported medical expenditures are twice as high ($13,046 [2007 dollars]), most likely due to coexisting comorbidities (62). Tieder et al. examined a retrospective cohort of children age 2–18 years with a diagnosis of DKA between 2004 and 2009. The mean hospital-level total standardized cost of DKA treatment was $7,142 (64).

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

TABLE 17.2

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

According to National Hospital Ambulatory Medical Care Surveys between 1993 and 2003, DKA accounted for approximately 753,000 visits or an average 68,000 visits per year. The majority of DKA patients (87%) were admitted, with most admissions to a non-intensive care unit setting. The rate of emergency department visits for DKA was 64 per 10,000 U.S. diabetic patients, and the number of visits increased between 1993–1998 (315,000) and 1999–2003 (438,000) (65).

During 2004, there were 120,000 admissions due to DKA, 15,000 due to hyperosmolar hyperglycemic state (HHS), and an additional 5,000 due to “diabetic coma” (66). Based on the Diagnostic Related Group codes in the inpatient records, the total hospital cost for DKA was estimated at $1.4–$1.8 billion. An independent analysis by Kitabchi et al. estimated the annual hospital cost of DKA in the United States in excess of $1 billion (67). Approximately 25% of the cost is related to DKA at diabetes diagnosis (68).

Prevention

Prevention of DKA should be one of the main goals of diabetes education. Knowledge of the signs and symptoms of diabetes, such as the classic triad of polydipsia, polyuria, and polyphagia with weight loss, is the best strategy for early detection of type 1 diabetes and prevention of DKA at the time of diagnosis. Both public and health professional education should make people aware of those symptoms, as patients admitted with severe DKA are often seen hours or days earlier by health care providers who missed the diagnosis, particularly in the youngest children (69,70). The Diabetes Autoimmunity Study in the Young, an observational study following children at genetically high risk for type 1 diabetes by periodic testing for diabetes autoantibodies, glycosylated hemoglobin (A1c), and random blood glucose, demonstrated that prevention of DKA in newly diagnosed children is possible. The prevalence of DKA at the time of diagnosis among children enrolled in this study was significantly lower compared to the community level (71). Similar findings came from the Diabetes Prevention Trial (72). A community intervention to raise awareness of the signs and symptoms of childhood diabetes in the Parma region of Italy reduced the prevalence of DKA at diagnosis of type 1 diabetes from 83% to 13% (73). The effect persisted 8 years later, but there was an indication that the campaign should be periodically renewed (74).

Most studies have shown that most episodes of DKA beyond disease diagnosis are preventable by identification of at-risk patients and use of targeted interventions. Comprehensive diabetes programs and telephone help lines reduced the rates of DKA from 15–60 to 5–6 per 100 patient-years (75,76,77). In the adolescent cohort of the Diabetes Control and Complications Trial (DCCT), intensive diabetes management was associated with less DKA (conventional and intensive treatment groups: 4.7 and 2.8 episodes per 100 patient-years, respectively) (78). In patients treated with insulin pumps, episodes of DKA can be reduced with introduction of treatment algorithms (79). The extent to which home measurement of whole blood or urine β-OHB concentration may assist in the prevention of hospitalization should be further assessed (80).

Treatment

The goal of therapy is to correct dehydration by restoring extracellular and intracellular fluid volume and correcting electrolytes imbalances, hyperglycemia, and acidosis. The recommended therapy differs between adults and children given the higher risk of development of cerebral edema in children. The pediatric recommendation for initial volume expansion is slow intravenous infusion of 10–20 mL/kg of normal saline (0.9%) over the first 1–2 hours. Subsequent fluid replacement should be done with 0.45%–0.9% normal saline. To correct ketoacidosis, a “low dose” continuous IV insulin administration is needed as a regular insulin drip at a dose of 0.1 units/kg per hour (1) or even lower doses, such as 0.05 units/kg per hour (81). Pediatric DKA should be treated in a facility with appropriate pediatric expertise.

In adults, in the absence of cardiac compromise, isotonic saline is given at a rate of 15–20 mL/kg per hour or 1–1.5 L during the first hour. Subsequent fluid replacement depends on hemodynamic status, serum electrolyte levels, and urinary output. Treatment algorithms recommend the administration of an initial intravenous dose of regular insulin (0.1 units/kg) followed by the infusion of 0.1 units/kg per hour. A prospective randomized study reported that a bolus dose of insulin is not necessary, if patients receive an hourly insulin infusion of 0.14 units/kg body weight (82).

Line graph showing diabetic ketoacidosis listed as the underlying cause of mortality decreased from 12.9 per 100,000 people with diabetes in 2000 to 8.4 per 100,000 with diabetes in 2009

FIGURE 17.1

Trends in Age-Standardized Mortality Rate Coded to Diabetic Ketoacidosis Per 100,000 People With Diabetes, U.S., 2000–2009. Ketoacidosis is defined as International Classification of Diseases, Tenth Revision (ICD-10), codes E10.1, E11.1, E12.1, (more...)

Line graph showing diabetic ketoacidosis listed as the underlying cause of mortality in youth less than 18 years of age was as high as 42.5 per 100,000 with diabetes in 2002 and as low as 18.6 per 100,000 with diabetes in 2009

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. Ketoacidosis is defined as International Classification of Diseases, Tenth Revision (ICD-10), codes (more...)

Hyperglycemic Hyperosmolar State

Pathogenesis

Decrease in the effective action of circulating insulin coupled with a concomitant elevation of counter regulatory hormones is the underlying mechanism for both HHS and DKA. These alterations lead to increased hepatic and renal glucose production and impaired glucose utilization in peripheral tissues, which result in hyperglycemia and parallel changes in osmolality of the extracellular space (83). HHS is associated with glycosuria, leading to osmotic diuresis, with loss of water, sodium, potassium, and other electrolytes. In HHS, insulin levels are inadequate for glucose utilization by insulin sensitive tissues but sufficient (as determined by residual C-peptide) to prevent lipolysis and ketogenesis (83).

Definition

HHS is defined as extreme elevation in blood glucose >600 mg/dL (>33.30 mmol/L) and serum osmolality >320 mOsm/kg in the absence of significant ketosis and acidosis. Small amounts of ketones may be present in blood and urine (84).

In the ICD-9, the HHS code is 250.2: diabetes with hyperosmolarity or hyperosmolar (nonketotic) coma. The ICD-10 does not have a specific code for HHS; E1x.0 denotes coma with or without ketoacidosis, hyperosmolar or hypoglycemic (x digit is used to define type of diabetes).

Incidence and Prevalence

The incidence of HHS is unknown because of the lack of population-based studies and multiple comorbidities often found in these patients. Estimated rates of hospital admissions for HHS are lower compared to DKA. HHS accounts for <1% of all admissions related to diabetes but may affect up to 4% of new type 2 diabetes patients (83).

The prevalence of isolated HHS in adult patients with acute, significant hyperglycemia varies from 15% to 45% (85,86). HHS occurs at any age, but it is more prevalent in elderly patients who have additional comorbidities. Presence of other conditions, such as infection, cardiovascular disease, and cancer, seems to be responsible for the higher mortality associated with HHS compared to DKA (86).

The incidence of HHS is most likely underestimated in children, as the presenting clinical picture in many patients has elements of both HHS and DKA (87,88).

Several studies of pediatric and adolescent diabetic patients, mostly case series or single-institution reviews, have described more than 50 cases of HHS (7,89,90,91,92). Most patients were adolescents with newly diagnosed type 2 diabetes, and many were of African American descent. A study based on data from the Kid’s Inpatient Database provided the first national estimate of hospitalizations due to HHS among U.S. children between 1997 and 2009. The estimated population rate for HHS diagnoses for children age 0–18 years was 2.1 per 1,000,000 children in 1997, rising to 3.2 in 2009. The majority (70.5%) of HHS hospitalizations occurred among children with type 1 diabetes (93).

Risk Factors

The majority of HHS episodes are precipitated by an infectious process; other precipitants include cerebrovascular accident, alcohol abuse, pancreatitis, myocardial infarction, trauma, and drugs. In a case series of 119 patients with HHS, nearly 60% of the patients had an infection, and 42% had a stroke (94). Medications affecting carbohydrate metabolism, such as corticosteroids, thiazides, and sympathomimetic agents (e.g., dobutamine and terbutaline), may also precipitate the development of HHS. Elderly individuals, particularly those with new-onset diabetes are at risk for HHS. A comparison of 135 patients with hyperosmolar syndrome with 135 age-matched, randomly selected diabetic controls hospitalized in the same time period found female sex (71% in HHS cases vs. 53% in diabetic controls), newly diagnosed diabetes (36% per 100 HHS hospitalizations vs. 7% in diabetic controls), and presence of acute infection (39% per 100 HHS hospitalizations vs. 19% in diabetic controls) to be independently associated with the presence of HHS (95). Among 200 HHS patients in Rhode Island, nursing home residents accounted for 18% of the cases (85).

Morbidity and Mortality

Hospitalization data from the National Hospital Discharge Surveys 2001–2010 were analyzed for Diabetes in America, confirming that HHS occurs rarely (Tables 17.1 and 17.3). The 18–44 years age group had the highest percentage of hospitalizations listing HHS. The average annual number of hospital discharges listing HHS as a cause doubled to 23,900 during 2001–2010 compared to 10,800 in 1989–1991.

In adults, mortality rates attributed to HHS range from 5% to 25% (82,85,86,94,96). The mortality increases sharply with age from none in patients age <35 years to 1.2% in those age 35–55 years and 15.0% in patients age >55 years. A U.S. study of 613 adult patients hospitalized for hyperglycemic crises reported similar findings (85). Fatality rates for DKA, mixed DKA-HHS, and isolated HHS alone were, respectively, 4%, 9%, and 12%. In both studies, older age and the degree of hyperosmolarity were the most powerful predictors of a fatal outcome. Deaths due to hyperglycemic crisis in adults with diabetes dropped from 2,989 in 1985 to 2,459 in 2002, according to data from the National Vital Statistics System. During the time period, age-adjusted death rates decreased from 42 to 24 per 100,000 adults with diabetes (97); the decrease was found in all age groups (Figure 17.3) (97). During the period between 1997 and 2009, the mortality rate among children was reported at 2.7 per 100 HHS hospitalizations compared to previously described rates of 33 and 72 per 100 HHS hospitalizations of children dying in the course of HHS (98,99).

Cost

Data concerning the cost of HHS are limited, due to the lack of exact incidence data. However, on an individual basis, the cost per event is several times higher than that for uncomplicated DKA (66).

TABLE 17.3. Annual Hospitalizations for Diabetic Hyperosmolar Nonketotic Coma, by Age, Sex, and Race, U.S., 2001–2010.

TABLE 17.3

Annual Hospitalizations for Diabetic Hyperosmolar Nonketotic Coma, by Age, Sex, and Race, U.S., 2001–2010.

Line graph showing that the mortality rate due to hyperglycemic crisis decreased in each age strata among adults with diabetes

FIGURE 17.3

Age-Specific Death Rates for Hyperglycemic Crisis Among Persons With Diabetes Age ≥18 Years, by Age, U.S., 1985–2002. Data are based on the National Vital Statistics System 1985–2002. Denominators are based on National Health Interview (more...)

Prevention and Treatment

Appropriate diabetes education, adequate treatment, and frequent self-monitoring of blood glucose help to prevent HHS in patients with known diabetes. HHS can be precipitated by dehydration and medications, such as corticosteroids, thiazides, and sympathomimetic agents. Careful use of these medications is indicated in vulnerable patients, e.g., elderly cared for in nursing homes at risk of dehydration and unable to promptly communicate their medical problems. Patients with HHS require hospitalization, which can be prolonged due to underlying conditions. In cases not complicated by underlying conditions, treatment modalities are similar to DKA (82,100). Intravenous rehydration and insulin to correct hyperglycemia lead to prompt resolution of HHS.

Lactic Acidosis

Definition

LA consists of elevation of lactic acid above 5.0 mEq/L with acidosis (pH <7.3) and without ketoacidosis. There may be low levels of ketones present (1:4 on serum dilution or β-OHB >0.4–<0.6 mmol/L). The ICD-9 code 276.2 describes acidosis, primarily LA.

Incidence

Data on incidence rates for LA are sparse. It is a rare, but important, adverse event in patients with diabetes. National Hospital Discharge Survey data on hospitalizations in 2001–2010 with an LA code in patients with and without a concomitant diagnosis of diabetes were analyzed for Diabetes in America (Tables 17.1 and 17.4). Whereas the highest absolute number of LA cases occurred in patients age >45 years, in women, in whites, and in patients for whom diabetes was not listed on the hospital discharge summary, the percentage of diabetes discharges with LA was greater in younger people.

The frequency of hospitalizations due to LA increased from 0.6% to 1.2% among patients with diabetes and from 0.3% to 1.0% among those without diabetes in comparison to previous data from 1989–1991 (46).

Precipitating Factors

The usual precipitating factors for LA are conditions of impaired oxygenation, such as hypoxemia, shock, sepsis, carbon monoxide poisoning, and some medications, including phenformin and metformin, particularly when used in patients with renal failure. Phenformin, a biguanide, increases the risk of life-threatening LA and is no longer available in the United States. Also, metformin is thought to increase the risk of LA in patients with diabetes and is contraindicated in conditions associated with LA, such as cardiovascular, renal, hepatic, and pulmonary diseases, and advanced age. However, a Cochrane Database review of prospective comparative trials and observational cohort studies showed no difference in the incidence of LA during metformin treatment compared to other antihyperglycemic treatments. In this review, the incidence of metformin-associated LA was 8.4 cases per 100,000 patient-years, and in the non-metformin group, it was 9 cases per 100,000 patient-years (101). In other studies, the reported incidence of metformin-associated LA in type 2 diabetes patients ranged from 10 to 47 cases per 100,000 patient-years (102,103). Most studies have found no significant difference in the incidence of LA during treatment with metformin in patients with and without renal impairment defined as a reduced glomerular filtration rate (102).

Morbidity and Mortality

LA leads to neurologic impairment. Rapid correction of the acid-base and electrolyte disturbances may induce cerebral edema. The mechanism of cerebral edema in the course of LA is unclear. The mortality rates from LA are high and associated with higher lactic acid levels. Based on data from National Hospital Discharge Surveys 2001–2010, LA accounts for 1.2% of all hospitalizations in diabetic patients (Table 17.4).

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

TABLE 17.4

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

Prevention and Treatment

LA is usually associated with unexpected and catastrophic hypoxic events and is therefore less likely to be amenable to preventive measures. Long-term prevention of cardiovascular disease or sepsis among diabetic patients through improved glucose control and alteration of other risk factors could decrease the incidence of LA.

The only effective treatment for LA is cessation of lactic acid production by the improvement of tissue oxygenation. Treatment of underlying conditions, such as shock or myocardial infarction, includes restoration of the fluid volume, improvement of cardiac function, amelioration of sepsis, and correction of hyperglycemia (104).

Hypoglycemia

Pathogenesis

Hypoglycemia is the most common, life-threatening acute complication of diabetes treatment. It is characterized by multiple risk factors and complex pathophysiology (105). The brain depends on a continuous supply of glucose for energy, although it can also utilize ketone bodies. Young children and adolescents are at higher risk for hypoglycemia, and the spectrum of outcomes ranges from mild cognitive impairment to coma, seizure, and sudden death.

Missed meals, inadvertent insulin dosing error, and rapid insulin absorption due to intramuscular injection or hot shower/bath shortly after injection are common causes of hypoglycemia in insulin-treated patients. Rarely, secondary gain or suicide attempt may lead to insulin overdose. In all these situations, insulin overdose reduces hepatic glucose output. Physical activity increases glucose utilization and may lead to hypoglycemia, if not matched by lowering of insulin dose and increased carbohydrate intake. Oral hypoglycemic agents may lead to hypoglycemia by either decreasing hepatic glucose output or increasing insulin levels. In contrast, enhancers of peripheral glucose utilization (thiazolidinediones) do not cause hypoglycemia in patients with residual insulin and glucagon secretion. Release of glucagon—the major counterregulatory response to hypoglycemia in nondiabetic persons—is progressively lost within a few years after diagnosis of type 1 diabetes. Catecholamine release, the other powerful counterregulatory mechanism, is also impaired in diabetic patients, especially in those with type 1 diabetes and those on beta blocker treatment (106).

Definition

Various definitions of hypoglycemia are in use; for comparative epidemiologic studies, it is important to standardize criteria. The American Diabetes Association Workgroup on Hypoglycemia defined hypoglycemia broadly as all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm (107,108). According to the Workgroup, a hypoglycemic episode could be:

  • Severe hypoglycemia: an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. The episode may lead to a significant neuroglycopenia and seizure or coma. Plasma glucose measurements may be missing during an event, but neurological recovery is sufficient evidence that the event was induced by a low plasma glucose concentration.
  • Documented symptomatic hypoglycemia: an event with typical symptoms of hypoglycemia and a measured plasma glucose concentration ≤70 mg/dL (≤3.89 mmol/L).
  • Asymptomatic hypoglycemia: an event with a measured plasma glucose concentration ≤70 mg/dL, but without typical symptoms of hypoglycemia.
  • Probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia are not accompanied by a plasma glucose determination.
  • Relative hypoglycemia: an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia, with a measured plasma glucose concentration >70 mg/dL.

The DCCT defined severe hypoglycemia as an episode in which the patient required assistance with treatment from another person to recover; blood glucose level had to be documented as <50 mg/dL (<2.78 mmol/L) and/or the clinical manifestations had to be reversed by oral carbohydrate, subcutaneous glucagon, or intravenous glucose (109). This definition is of limited value in children, particularly the youngest, as they require assistance even for mild episodes of hypoglycemia. There is lack of a uniform definition of hypoglycemia for children and adolescents with diabetes. Most experts agree that blood glucose values <60–70 mg/dL (<3.33–3.89 mmol/L) put the patient at risk for severe hypoglycemia. Those blood glucose levels lead to alterations in the counterregulatory hormones essential to the spontaneous reversal of hypoglycemia. For clinical use, the value of <65 mg/dL (<3.61 mmol/L) has been most often used as the level for defining hypoglycemia in the pediatric population. Other studies have limited the definition of severe hypoglycemia in children to episodes leading to unconsciousness or seizure (110,111).

In the ICD-9, hypoglycemic coma secondary to diabetes treatment is coded 250.3; however, this code is also used for coma with DKA. Other forms of diabetic hypoglycemia are coded 250.8. Hypoglycemia not associated with diabetes is coded 251.2. An additional E code is recommended to identify the drug that induced hypoglycemia. In the ICD-10, E1x.0 denotes coma with or without ketoacidosis, hyperosmolarity or hypoglycemia (with the x digit used to define type of diabetes), while E16.0 denotes diabetic drug-induced hypoglycemia without coma.

Incidence in Type 1 Diabetes Patients

The incidence of moderate or mild hypoglycemia is unknown; those events are frequent among patients treated with insulin and are often unrecognized or underreported. Severe hypoglycemia is more likely to be recognized. Pre-DCCT incidence rates of severe hypoglycemia varied from 3 to 86 per 100 patient-years depending on definition, age, duration of diabetes, and treatment modality (112,113,114,115,116).

Among adolescents participating in the DCCT, the incidences of hypoglycemia were 86 per 100 patient-years in intensively treated and 28 per 100 patient-years in conventionally treated participants (78). The incidences of coma and seizure in the adolescents were 27 per 100 patient-years and 10 per 100 patient-years, respectively. In all DCCT participants, intensive treatment of type 1 diabetes increased the frequency of severe hypoglycemia from two to six times that observed with conventional treatment (117).

Several studies examined the incidence rates of severe hypoglycemia in youth during the post-DCCT era. Few used a prospective design or were population based. The incidence of severe hypoglycemia of 19 per 100 patient-years was reported from a large cohort of type 1 diabetic children age 0–19 years followed by the Barbara Davis Center for Childhood Diabetes (26). A Joslin Clinic study with a similar definition found a lower rate of 8 per 100 patient-years in a cohort of older children age 7–16 years. However, this study excluded children with psychiatric disorders and difficult social situations (118). Similar rates were reported from other European, American, and Australian studies (119,120,121,122,123), with an exception of very low incidence (<4 per 100 person-years) in a study from Finland (124).

Incidence in Type 2 Diabetes Patients

Patients with type 2 diabetes treated with diet and exercise do not suffer from severe hypoglycemia. It occurs rarely in patients treated with oral hypoglycemic agents. However, the risk of hypoglycemia increases with transition to insulin-dependence. In the United Kingdom Prospective Diabetes Study (UKPDS), the risk of severe hypoglycemia was 1.0 per 100 patient-years in those intensively treated with chlorpropamide, 1.4 per 100 patient-years with glibenclamide, and 1.8 per 100 patient-years with insulin (125). Long-acting sulfonylureas confer higher risk compared to shorter-acting ones (126), particularly in older patients and those with a longer duration of diabetes, polypharmacy, and a recent hospitalization (127). One study suggested an increase in risk of hypoglycemia in patients treated with sulfonylurea and angiotensin-converting enzyme (ACE) inhibitors (128), but that finding was not confirmed in a large trial (129). Hospital admission rates for hypoglycemia in U.S. have declined since 2007; however, rates among black Medicare beneficiaries and those older than 75 years remain high (130).

Risk Factors

There is a strong relationship between severe hypoglycemia and tight glycemic control (131), especially in children and older adults (118,120,132,133,134). Age (infancy and adolescence) (120,135), male sex (26), and increased duration of diabetes (136) are the most commonly reported predictors of severe hypoglycemia in patients with type 1 diabetes. The risk of hypoglycemia increases with duration of diabetes, partially due to progressive loss of alpha cell glucagon response to hypoglycemia, and is inversely related to preservation of beta cells (137). In the DCCT, presence of residual endogenous insulin secretion predicted 65% lower risk of severe hypoglycemia (138). Sudden loss of endogenous insulin production is seen more frequently in patients with the human leukocyte antigen (HLA)-DR3/4 genotype (139,140,141) and those with multiple islet autoantibodies (140,142).

In patients with type 2 diabetes, aggressive glycemic control puts them at risk of hypoglycemia. A large, cross-sectional study of older adult patients in the Veterans Health Administration in 2009 identified patients at risk of hypoglycemia based on whether they were receiving insulin and/or sulfonylureas. Instances of overtreatment were defined as using one of these agents in patients with A1c levels below specific thresholds, such as <7.0% (<53 mmol/mol). Among patients age ≥75 years, who had a serum creatinine >2.0 mg/dL or an ICD-9-CM diagnosis of cognitive impairment or dementia (31.5% of patients), rates of overtreatment were 11.3% for those with A1c <6.0% (<42 mmol/mol), 28.6% for A1c <6.5% (<48 mmol/mol), and 50.0% for A1c <7.0%. Among patients with additional comorbidity, similar rates of overtreatment were found by A1c thresholds (134). Additional information about glycemic control and hypoglycemia risk in older adults is provided in Chapter 16 Diabetes in Older Adults.

Modifiable predictors of severe hypoglycemia include intensive insulin treatment, marked by lower A1c levels and higher insulin dose (26,119). The relation between severe hypoglycemia and tight glycemic control had been extensively explored, especially in children (118,120,132). Over 60% of the intensively treated adolescents who participated in the DCCT had coma or seizure during the trial compared to 25% of those treated conventionally (78). Intensive treatment, such as the use of insulin pumps, is beneficial in lowering A1c levels without a coincident higher risk of hypoglycemia in pediatric populations (143,144). The addition of continuous glucose monitoring to insulin pump therapy has further lowered the rates of hypoglycemia (145,146,147).

Another risk factor is the presence of hypoglycemia unawareness leading to an inability to recognize symptoms of hypoglycemia. It is present in about 10% of patients and is more common in patients with low average glucose levels (148,149). Even a single hypoglycemic episode can cause significant decrease in neurohormonal counterregulatory responses and worsen unawareness of hypoglycemia (150).

The main effect of exercise on glucose metabolism is blood glucose lowering via insulin-independent skeletal muscle uptake, which may result in hypoglycemia without modification of insulin dose and intake of carbohydrates (151).

Alcohol consumption is a significant risk factor for development of severe hypoglycemia. Alcohol suppresses gluconeogenesis and glycogenolysis and acutely improves insulin sensitivity (152,153) and may induce hypoglycemia unawareness (154). In combination with exercise, drinking alcohol can lead to severe hypoglycemia with a delay of symptoms up to 10–12 hours after alcohol consumption (155).

Family dynamics, behavioral factors, and psychiatric factors are important risk factors, particularly in the pediatric population. The DCCT showed that conventional risk factors explained only 8.5% of the variance in the occurrence of severe hypoglycemia (117). Factors such as inadequate diabetes education, low socioeconomic status, lack of insurance, unstable living conditions, behavioral factors, and psychiatric disorders affecting patients and their families have been shown to have significant influence on glycemic control and the rate of hypoglycemia. Family relationships and personality type have also had a significant effect on adaptation to illness and metabolic control among persons with diabetes (156). Presence of psychiatric disorders has a detrimental effect on metabolic control (157,158) and compliance with treatment (159). Prevalence of psychiatric disorders among patients with type 1 diabetes reached 48% by 10 years of diabetes duration and age 20 years in a small longitudinal cohort (160,161), the most prevalent being major depressive disorder (28%). Prevalence of psychiatric disorders, however, has been shown to be much lower in other studies, as discussed in Chapter 33 Psychiatric and Psychosocial Issues Among Individuals Living With Diabetes.

Coexisting autoimmune conditions, such as autoimmune thyroid, celiac, and Addison’s diseases, occurring in up to 30% of patients with type 1 diabetes, increase the risk of hypoglycemia (162,163,164,165). In pregnancy with type 1 diabetes, the incidence of mild and severe hypoglycemia is highest in early pregnancy, although metabolic control is usually tighter in the last part of pregnancy. Predictors for severe hypoglycemia are history of severe hypoglycemia and impaired awareness (166). Chronic kidney disease can be found in up to 23% of patients with diabetes. Chronic kidney disease is an independent risk factor for hypoglycemia and augments the risk already present in people with diabetes (167,168).

Morbidity and Mortality

A new analysis for Diabetes in America of the frequency of hypoglycemia (ICD-9 codes 250.8 and 251.2) as a discharge diagnosis for hospitalizations in the United States in 2001–2010 is shown in Tables 17.1 and 17.5, using data from the National Hospital Discharge Survey. Hypoglycemia was listed as an underlying cause in about 288,000 hospitalizations, which represented 5.4% of hospitalizations due to diabetes. Hospital discharges for hypoglycemia in diabetic patients occurred least often in patients age <18 years. The total number of hypoglycemic events was higher in females with diabetes compared to males, but the percentage of discharges was higher in males compared to females. The total number of hospitalizations due to hypoglycemia was greatest among whites followed by blacks, while the percentage of discharges was lower in whites than in the other race/ethnicity groups (Table 17.5).

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

TABLE 17.5

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

Hypoglycemia is a significant factor in excess mortality in patients with diabetes (169). Despite improvements in therapy, diabetes-related mortality among children did not decline in the time period between 1968 and 1998 (170). Sudden nocturnal death in young persons with type 1 diabetes has been described and is known as the “dead in bed” syndrome (171); it appears to be responsible for about 6% of deaths in diabetic patients age <40 years (172). In these cases, nocturnal hypoglycemia is a likely precipitant, consistent with demonstrated impairment of counterregulatory hormone response during sleep (173), as well as a high frequency of nocturnal hypoglycemia reported by the DCCT (117) and more recent studies using continuous glucose monitoring.

Hypoglycemic episodes range from mild neurogenic symptoms to coma and seizures. There is an association between hypoglycemia and a decrease in cognitive functioning in children with type 1 diabetes (174,175,176), particularly among the youngest patients (176,177). Hypoglycemic seizures lead to significant declines in verbal abilities (178), memory skills (179), and the ability to organize and recall information (180), even after mild hypoglycemia (181). Severe hypoglycemia in children may lead to persistent electroencephalographic changes (182,183,184,185). On the other hand, intensive insulin treatment in the DCCT cohort (age 13–39 years at baseline), while increasing the incidence of hypoglycemia, did not lead to a significant worsening of neuropsychological or cognitive functioning during the trial (186,187), as well as 18 years after entry into the trial (188). However, risk of hypoglycemia should be balanced by emerging data on a detrimental effect of hyperglycemia on the development of a normal brain (189).

Cost

In a study among youth with diabetes, the predicted mean annual total medical expenditures were $12,850 and $8,970 for youth with and without severe hypoglycemia, respectively. The excess of expenditures was greater among those with more than one episode ($5,929) than among those with only one ($2,888) (63). A study from Germany, Spain, and the United Kingdom showed that hospital treatment of severe hypoglycemia was a major contributor to its high cost. Average severe hypoglycemia event treatment costs were higher for patients with type 2 diabetes (Germany, €533; Spain, €691; U.K., €537) than those with type 1 diabetes (€441, €577, and €236, respectively) (190). Reliable data are not available concerning the cost of hypoglycemia in adults with diabetes in the United States.

The personal, family, and societal cost of trauma of loss of consciousness, seizure, long-term disability, and fears are harder to measure. Further studies are needed to update these figures and to estimate, in addition, indirect costs (e.g., lost productivity and diminished quality of life).

Prevention

Improved insulin delivery and technological advances provide new opportunities to improve glycemic control with decreased risk of severe hypoglycemia, but they require intensified teaching and compliance (136,191,192). Intensive insulin therapy using insulin pumps, multiple daily injections, and new insulin analogues has been found effective in lowering A1c levels, but there is less evidence for a beneficial effect on the risk of hypoglycemia. Insulin pump treatment may lower A1c levels and improve quality of life compared to multiple daily injections of insulin and, of importance, reduce the rate of severe hypoglycemia (193,194).

The introduction of rapid-acting insulin analogues (e.g., lispro, aspart) has made insulin treatment more efficient and potentially less likely to induce hypoglycemia. An ecologic analysis explored the effects of the DCCT report in 1993 and that of the introduction of a rapid-acting insulin analogue (lispro) in 1996 on the risk of severe hypoglycemia in type 1 diabetic patients (195). A1c levels declined significantly during 1993–1996 (p<0.001), following the DCCT report, but the number of severe hypoglycemic events increased (p<0.001) during that time frame. A further decline in A1c levels was observed after the introduction of lispro insulin in 1996 (p<0.001), however, without a concomitant change in the incidence of severe hypoglycemia. The introduction of long-acting insulin analogues in 2003 also suggests a potential for improving glycemic control without an increased risk of hypoglycemia (196,197,198).

Continuous Glucose Monitoring

Frequent self-blood glucose monitoring has been found to be an important factor in attaining better glucose control for the intensively treated participants in the DCCT and the UKPDS. However, many patients do not accept frequent blood glucose monitoring, mainly because of pain and inconvenience. The results also give data valid for only a discrete point in time, without any information on glucose trends before or after the glucose value. In addition, patients infrequently measure blood glucose levels during the night, although >50% of severe hypoglycemic events occur during sleep (113,117).

Continuous glucose monitoring holds great promise for prevention of hypoglycemia. Clinical trials of continuous glucose monitoring have given reason to believe that tighter glycemic control may not necessarily lead to increased risk of hypoglycemia (199,200,201,202,203,204,205). The main goal of research on devices for diabetes management is the development of automatic glucose sensing and insulin delivery without patient intervention (206). Studies evaluating closed-loop insulin delivery suggest improved glucose control and a decreased risk of hypoglycemia (207,208). Data from the Automation to Simulate Pancreatic Insulin REsponse (ASPIRE) study confirmed that use of sensor-augmented insulin pump therapy with the threshold-suspend feature reduced nocturnal hypoglycemia, without increasing A1c values (209).

Behavioral Interventions

Behavioral interventions, including intensive diabetes education, good access to care, and psychosocial support, including treatment of psychiatric disorders, lower the risk of hypoglycemia (210,211).

Treatment

The goal of treatment of hypoglycemia is to immediately increase the blood glucose approximately 3–4 mmol/L (~55–70 mg/dL). This can be accomplished by giving glucose tablets or sweetened fluids, such as juice, glucagon injection in unconscious patients, or dextrose infusion in a hospital setting.

List of Abbreviations

A1c

glycosylated hemoglobin

β-OHB

beta-hydroxybutyrate

CSII

continuous subcutaneous insulin infusion

DCCT

Diabetes Control and Complications Trial

DKA

diabetic ketoacidosis

HHS

hyperglycemic hyperosmolar state

ICD-9-CM/ICD-10

International Classification of Diseases, Ninth Revision, Clinical Modification/Tenth Revision

LA

lactic acidosis

SEARCH

SEARCH for Diabetes in Youth study

UKPDS

United Kingdom Prospective Diabetes Study

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CONVERSIONS

Conversions for A1c and glucose values are provided in Diabetes in America Appendix 1 Conversions.

DUALITY OF INTEREST

Dr. Rewers reported no conflicts of interest.

Copyright Notice

Diabetes in America is in the public domain of the United States. You may use the work without restriction in the United States.

Bookshelf ID: NBK567993PMID: 33651551
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