1. Type 1 diabetes—autoimmune β-cell destruction resulting in an absolute insulin deficiency

2. Type 2 diabetes—progressive defects resulting in increased insulin resistance and a relative insulin deficiency

3. Gestational diabetes—diabetes appearing during pregnancy

4. Diabetes due to other causes—such as genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis, pancreatitis, or pancreatectomy), and drug- or chemical-induced diabetes⁴

Epidemiology

DKA has high morbidity rates, mortality rates, and financial costs despite numerous advances in the treatment of DM. The incidence of DKA in the United States is estimated at 5.9 to 12.9 cases per 100,000 people.10,11 The 120,000 patients admitted to the hospital for DKA each year¹² account for approximately $1.4 billion in hospital reimbursement.¹³ DKA carries a mortality rate of 1% to 5%.^9,14 Though the highest mortality rate is in the elderly and in patients with comorbid conditions, DKA remains the leading cause of death in diabetic patients below the age of 24.¹⁵

Although most patients will have a history of diabetes, 27% to 37% of patients with DKA carry no prior diagnosis.16,17 This is especially true in young children.¹⁸ Although the development of DKA is classically associated with type 1 DM, some patients lack the classic clinical presentation, autoimmune markers, or diminished β-cell reserve of type 1 diabetes.^19–21 This subgroup, known as “ketosis-prone type 2 diabetes,” represents patients with type 2 DM who present with DKA and often are African American or Latino, male, middle-aged, and overweight or obese; have a family history of diabetes; and have newly diagnosed diabetes.^22,23 Patients with ketosis-prone type 2 DM account for 1 in 5 cases of DKA.²² Patients with “classic” type 2 diabetes may also develop DKA in situations of extreme stress.

HHS occurs far less commonly than DKA, with an estimated prevalence of 1 in 1000,²⁴ though the increasing incidence of type 2 DM is expected to increase the prevalence of HHS. HHS typically occurs in patients with type 2 DM and 30% to 40% cases of HHS may be the initial finding leading to diagnosis of type 2 DM.^25,26 The mortality rate in HHS tends to be higher than in DKA, with the patient’s comorbid conditions and severity of presentation significantly affecting risk of death.²⁷

Pathophysiology

The pathophysiology of DKA is driven by insulin deficiency and a rise in the counterregulatory hormones, particularly glucagon, but also epinephrine, cortisol, and growth hormone (Fig. 58.1).^28,29 Insulin deficiency results in decreased glucose uptake by peripheral tissues, resulting in elevated serum glucose levels, and hyperglycemia worsens when an increase in glucagon (and an imbalanced insulin/glucagon ratio) results in unrestrained hepatic glycogenolysis and gluconeogenesis.^9,24,28 Osmotic diuresis results in total body loss of water and electrolytes, causing intravascular volume depletion. Cellular dehydration occurs as water and electrolytes move from the intracellular to extracellular space. With volume depletion, impaired renal function limits the clearance of glucose and worsens the hyperglycemia.^9,24 In an insulin-deficient state proteolysis and lipolysis drive accelerated gluconeogenesis as amino acids and free fatty acids are shunted to the liver.³⁰ At the same time, oxidation of free fatty acids results in the production of the keto acids acetoacetate and β-hydroxybutyrate.^9,24 These weak acids react with bicarbonate and diminish the body’s bicarbonate stores. The development of metabolic acidosis in DKA results when the increase in acid production exceeds the body’s buffering capacity.³¹

HHS is also caused by a relative insulin deficiency and a rise in counterregulatory hormones. Decreased peripheral glucose uptake and increased glycogenolysis and gluconeogenesis result in hyperglycemia followed by osmotic diuresis with volume depletion and dehydration. However, the amount of insulin is sufficient to limit the oxidation of free fatty acids,⁹ and significant keto acid production does not occur. In the absence of ketoacidosis, the process of dehydration is allowed to continue for longer than in DKA, and patients present with significant hyperosmolarity.

Precipitating Factors

The precipitating factors for the development of DKA and HHS are listed in the Table 58.2. Omission of antidiabetic medications is an important factor in the development of DKA and HHS. Omission of insulin may result in DKA in a patient with type 1 diabetes in a matter of hours. In contrast, the development of HHS (or DKA) in a patient with type 2 diabetes occurs over days to weeks in a patient omitting insulin or oral agents. In addition to the factors listed in the table, impaired thirst or lack of access to water, particularly in the elderly, will contribute to the development of HHS.³² Eating disorders may account for up to 20% of cases of recurrent DKA.⁹

Presentation

The presentation of DKA and HHS varies with the severity of the metabolic derangement and any intercurrent illnesses or comorbid conditions. DKA can occur in a patient without a history of diabetes who presents with only mild symptoms; a high index of suspicion is needed to make the diagnosis in this setting, particularly in children under the age of 6. A detailed evaluation should reveal precipitating factors, especially infection and medication nonadherence, which are common triggers of DKA and HHS (see Table 58.2).²⁴ Patients may present with symptoms of hyperglycemia (polyuria, polyphagia, polydipsia, or blurred vision) or with nonspecific symptoms of fatigue, abdominal pain, nausea, vomiting, and headache. Mental status can vary from somnolence to lethargy and even coma as the acidosis or hyperosmolarity worsens. Volume depletion may be manifested by tachycardia, poor skin turgor, dry mucous membranes, and orthostatic hypotension. In patients with DKA, metabolic acidosis causes rapid deep breathing (known as Kussmaul respiration), and acetone (derived from acetoacetate) can be sensed as a fruity smell on the patient’s breath.

Diagnosis

The diagnosis of DKA is based on a serum glucose level greater than 250 mg/dL, presence of ketones, arterial pH less than 7.3, and a CO₂ concentration less than 18 mmol/L.5,9 The anion gap will be elevated, reflecting the presence of the unmeasured keto acids. The laboratory findings and changes in mental status help the clinician gauge the severity of DKA and distinguish DKA from HHS. Although arterial blood had previously been the standard for determining pH, current evidence supports the use of venous pH as a less expensive, more accessible alternative.^33,34 Exceptions to the typical presentation include pregnant patients or those with poor oral intake who may have a serum glucose value below 250 mg/dL, or even in the normal range.^35,36 In patients with severe vomiting, the bicarbonate value may be normal or elevated.

The serum sodium may be normal, low, or elevated depending on the degree of dehydration and hyperglycemia. Patients with hyperglycemia have dilutional hyponatremia from a shift in fluids from the intracellular to extracellular compartment. The serum sodium may be “corrected” for hyperglycemia (i.e., adjusted to estimate the serum sodium concentration once the hyperglycemia has resolved) by adding 1.6 mEq/L to the measured sodium for every 100 mg/dL of plasma glucose above 100 mg/dL. As the measured serum sodium will underestimate the “corrected” sodium level in patients, measured serum sodium in the “normal” range may represent significant dehydration and hypernatremia.

The serum potassium level may also be normal, low, or elevated depending on factors such as the degree of acidosis or osmotic diuresis and the duration of the process. Insulin deficiency and acidosis decrease cellular uptake of potassium, although hyperosmolality enhances cellular efflux of potassium.³⁷ Large amounts of potassium shift from the intracellular space to the extracellular space and are then lost in the urine. Regardless of the serum potassium level, all patients with DKA and HHS have substantial depletion of total body potassium.^9,37,38

The serum osmolality (in mOsm/kg) can be estimated by the following calculation:

Serum osmolarity is generally normal or mildly elevated in DKA but is often profoundly elevated in patients with HHS.

Semiquantitative nitroprusside assays for urine and serum ketones are commonly employed but test only for acetone and acetoacetate, not β-hydroxybutyrate. This can be problematic, although β-hydroxybutyrate is the predominant keto acid, accounting for 75% of the keto acid load in DKA.³⁹ In addition, nitroprusside assays may remain positive long after resolution of the metabolic acidosis, so serial measurements may be misleading and are not recommended. Quantitative assays for β-hydroxybutyrate are available and may be useful for diagnosis, especially if the nitroprusside test is negative. A small pilot study found that a serum level above 3.5 mmol/L has 100% specificity for DKA.⁴⁰ Unlike the nitroprusside assay, the β-hydroxybutyrate test can also be used to monitor the management of DKA because appropriate treatment will be accompanied by a progressive fall in β-hydroxybutyrate levels.

The diagnostic criteria that distinguish HHS from DKA include higher plasma glucose (>600 mg/dL), a lack of acidosis (pH > 7.3, CO₂ > 18 mEq/L), more profound dehydration (serum osmolality > 320 mOsm/kg), and a change in mental status.⁹ Patients with HHS often have low levels of ketones (β-hydroxybutyrate between 0.3 and 3.0 mmol/L) compared with DKA patients, whose β-hydroxybutyrate levels will be greater than 3.0 mmol/L.

Initial laboratory studies should include electrolytes, phosphorus, blood urea nitrogen (BUN), creatinine, urinalysis, complete blood count with differential, and electrocardiogram (see Table 58.2). Further evaluation should be undertaken based on the patient’s presentation. A variety of laboratory abnormalities are frequently seen in DKA. Amylase, from both salivary and pancreatic sources, may be increased in up to 90% of patients with DKA. Lipase, normally a sensitive marker for pancreatitis, may also be elevated in DKA. However, the clinician should be aware that 10% to 15% of DKA patients do have concomitant pancreatitis.^41,42 Leukocytosis of 10,000 to 15,000 white blood cells/mm³ is common, but levels greater than 25,000 cells/mm³ or the presence of greater than 10% band neutrophils should increase the clinical suspicion for an active infection. Elevated hemoglobin due to the volume depletion may be present. High liver function studies occur commonly, especially in patients with fatty liver,⁴³ and mild increases in creatine kinase and troponin may occur in the absence of myocardial damage.⁴⁴

Intercurrent illnesses contribute to the morbidity and mortality rates in a hyperglycemic emergency, and every patient with DKA or HHS should undergo a thorough assessment with a focus on infectious and cardiovascular causes.³⁴ Appropriate management should be started immediately and continue concurrent to the treatment of the DKA and HHS.

Additional causes of acidosis or ketosis should be considered in the differential diagnosis including starvation ketosis; alcoholic ketoacidosis; lactic acidosis; intoxication from methanol, salicylate, or ethylene glycol; chronic renal failure; and rhabdomyolysis.³⁴

Management

The treatment of HHS and DKA in adults and children follows similar principles of intravenous (IV) fluid, insulin, and electrolyte management. Children require more attention to weight-based regimens for fluid management in order to avoid cerebral edema.⁴⁵ The details of the management of HHS and DKA in patients older than 20 years are detailed in Figure 58.2.

Prevention

Despite improvements in insulin treatment and glucose monitoring⁷⁸ the incidence of DKA is increasing.³ Prevention is paramount. Health care providers should recognize signs of DM in all age groups. Patients with DM and their caregivers should be familiar with sick day recommendations (Box 58.3), and patients with type 1 DM should check urine ketones by dipstick if the glucose is greater than 240 mg/dL.⁷⁹ Home measurement of serum ketones with a commercial glucometer may allow earlier detection of DKA and decreased hospital visits,⁸⁰ though most meters lack this capability.

Nonadherence to medical regimens is often cited as the cause of recurrent DKA, and in fact, 5% of patients account for more than 25% of all cases of DKA.⁸¹ Health care providers need to recognize disparities in the health care system that limit access to appropriate DM care or otherwise contribute to nonadherence with insulin or other antidiabetic medications. Diabetes education enhances patient knowledge of appropriate monitoring and prevention of DKA,⁸² and diabetes educators are an excellent resource to help assess a patient’s barriers to optimal care including financial, social, and cultural issues.⁸²

Epidemiology and Significance of Hyperglycemia

Hyperglycemia is a common occurrence in hospitalized patients and is associated with increased morbidity and mortality rates,83–85 including higher rates of surgical infections after cardiothoracic surgery,^86,87 increased mortality rates after MI,^88–90 and poor outcome in critically ill patients.^91,92 Forty percent of patients in the ICU and 80% of those undergoing cardiac surgery have elevated glucose levels.⁹³ Of hyperglycemic patients in the hospital, two thirds have a history of diabetes, although the remainder have no prior history.⁸⁵ This latter group includes patients with previously unrecognized diabetes as well as those with “stress hyperglycemia” (patients who are normoglycemic on follow-up testing). Only 15% of patients with new-onset hyperglycemia have confirmed diabetes 1 year after the hospital admission.⁹⁴ Hyperglycemic patients with no prior history of diabetes have a worse prognosis than patients with preexisting diabetes, including greater mortality rates after MI⁸³ and a significantly increased 30-day and 1-year mortality rate.⁹⁵ This is particularly true of patients with stress hyperglycemia, a condition of acutely elevated glucose related to illness-related increases in counterregulatory hormones seen (Fig. 58.3)⁹³ in patients with otherwise normal glucose metabolism. Stress hyperglycemia is consistently associated with increased adjusted mortality rates for patients with unstable angina, acute MI, CHF, arrhythmia, ischemic and hemorrhagic stroke, gastrointestinal bleeding, acute renal failure, pneumonia, pulmonary embolism, and sepsis.⁹⁶

Glucose variability, measured as the standard deviation of glucose excursions around the mean, adds to the metabolic burden.⁹⁷ Glycemic variability may be a better predictor of morbidity and mortality rates than the level of hyperglycemia in patients with preexisting diabetes.^98–100 In a retrospective analysis, the odds ratio for ICU death is significantly greater in patients with higher hourly change in glucose.¹⁰¹ Glycemic variability may be a better predictor of morbidity and mortality rates than the level of hyperglycemia in patients with preexisting diabetes.^98–100

Synopsis of Trials of Glycemic Control

The benefits of improved glucose control were initially suggested by several retrospective or nonrandomized trials in patients with acute MI,¹⁰² with stroke,⁸⁴ after coronary artery bypass surgery,⁸⁷ and in the ICU.¹⁰³ A landmark single-center prospective study in surgical ICU patients was published in 2001, in which intensive insulin therapy (IIT) was reported to decrease ICU and in-hospital mortality rates, as well as significant comorbid conditions such as bloodstream infections, acute renal failure requiring dialysis or hemofiltration, the median number of red blood cell transfusions, critical-illness polyneuropathy, and prolonged mechanical ventilation. The number of patients who received red-cell transfusions did not differ significantly between the two groups. However, the median number of transfusions in the intensive-treatment group was only half that in the conventional-treatment group. This difference was not due to more liberal use of transfusions in the conventional-treatment group, as indicated by the lower hemoglobin and hematocrit values in that group.¹⁰⁴ Based on this study, many ICUs initiated IV insulin protocols designed to achieve glucose levels in the 70- to 110-mg/dL range. Soon, however, enthusiasm over the benefits of normoglycemia from IIT in the critically ill patient were tempered by (1) an inability to extend the initial results across multiple centers,^105,106 (2) concern over the risk of hypoglycemia,^105,106 (3) questions over the role of early nutrition,¹⁰⁴ and (4) a less pronounced improvement for patients with preexisting diabetes.¹⁰⁷ Additionally, nonrandomized and observational studies suggested a J-shaped curve for mortality rate related to glycemic control in the ICU with increasing mortality rate for glucose levels less than 90 mg/dL and greater than 120 mg/dL.^{96,103,108–110} In the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation) study,¹¹¹ a randomized controlled, multicenter trial, in which ICU patients were randomized to intensive glycemic control or conventional glucose control, no mortality rate benefit was seen with IIT. In a meta-analysis of studies evaluating the impact of intensive glycemic control, including the results from NICE-SUGAR, the relative risk of death was not significantly different with IIT compared with conventional therapy, but the risk of severe hypoglycemia was significantly greater.¹¹² Figure 58.4 summarizes key studies on the impact of intensive glycemic control.

The foremost obstacle to the use of IIT is hypoglycemia. Patients managed with IIT for tight glycemic control have significantly greater rates and duration of hypoglycemia.112,113 Hypoglycemia from insulin therapy increases mortality risks in critically ill patients,^{105,114–118} which may mitigate any benefits of tight glucose control.¹⁰⁴ As expected, use of glucose control algorithms modified for a higher glucose target range significantly reduces the risk of severe hypoglycemia.^119,120

Intravenous Insulin Protocols

A standardized insulin protocol should be used to maintain goal glucose levels and reduce hypoglycemic episodes. Current practice requires the clinician to consider the multiple factors affecting glucose control, such as changes in nutrition, medication or medical acuity, and proactively respond to avoid large fluctuations in glucose levels. An effective IV insulin protocol allows for titration of IV insulin in the setting of changing glucose levels. Multiple published insulin protocols are available,54,57,121–126 though any protocol will need to be adapted and adjusted to fit the needs of the local environment. A multidisciplinary team consisting of intensivists, endocrinologists, nurses, and pharmacologists should be involved in the development, implementation, and continued evaluation of IV insulin protocols.

Technical Issues in Measuring Glucose

Accurate measurement of glucose in the ICU is essential to maintain glycemic control and limit the risk of severe hypoglycemia. The use of IIT magnified the importance of accurate point of care (POC) glucose monitoring. In the ICU measurements of glucose are affected by the clinical status of the patient, by certain medications, and by the type of blood sample.¹²⁷ Anemia may falsely elevate POC glucose levels, which can mask hypoglycemia.^128–130 This deserves attention given the high prevalence of anemia routinely encountered in ICUs.¹³¹ The accuracy of POC testing is also affected by several other common conditions (e.g., acidosis, hypothermia, and hypotension) and medications (dopamine, mannitol, acetaminophen, and pressor use).^132–135 The rates of intrapatient variability in glucose measurements are lowest from arterial samples. Variability increases in venous sampling with the greatest variability in capillary blood. Arterial blood analysis correlates better with central laboratory glucose values than capillary blood measurements. During hypoglycemia, the discrepancy is exaggerated. POC capillary and whole blood samples from patients with poor peripheral perfusion overestimate the laboratory glucose level by 20% in a significant proportion of samples.¹³⁶ The difference between capillary and arterial blood glucose measurements has led most insulin protocols for ICUs to recommend the use of arterial blood measurements when available.¹³⁶

Subcutaneous electrochemical sensors can measure glucose levels in the interstitial fluid and report an average glucose level every 1 to 10 minutes, although a lag time of 8 to 18 minutes exists between blood glucose and interstitial glucose equilibration.¹³⁷ Determining trends in glucose, the devices may provide earlier detection of hypoglycemia and hyperglycemia. Several small studies found excellent accuracy for continuous glucose monitoring (CGM) in the ICU as compared to POC testing.^137–140 However, there is currently insufficient evidence to support the general use of CGM in the ICU.¹⁴¹

Current Guidelines for Glycemic Control

The current guidelines for glycemic control in the ICU have transitioned from declarations for tight glycemic control (based on observational and retrospective data and a single-site randomized controlled study) to more moderated goals taking into account the increased mortality rate associated with hypoglycemia and the limited benefit from tight glycemic control seen in other trials.105,106,142,143

The 2009 American Academy of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control¹²² recommends insulin therapy for persistent hyperglycemia at a threshold no greater than 180 mg/dL, with a target range for glucose levels in the ICU of 140 to 180 mg/dL. The guideline recommends treatment with IV insulin using an established protocol associated with low rates of hypoglycemia and frequent glucose monitoring.

The 2012 Surviving Sepsis Guidelines (2012)¹⁴⁴ recommend:

The Effect of Parenteral Nutrition, Enteral Nutrition, and Glucocorticoids on Glycemic Control

Changes in nutrition and glucocorticoid dosing occur commonly, often quickly, in the intensively ill patient. Even when changes in enteral or parenteral nutrition are planned, or the patient is on a prescribed steroid taper, insulin adjustments need to be considered proactively to minimize glycemic variability.

Enteral feeding preparations have high concentrations of carbohydrates, and are associated with an increase in glucose concentration.145,146 Similarly, the majority of patients with type 2 DM who are not on insulin prior to ICU admission require insulin to maintain glycemic control once parenteral nutrition is initiated.¹⁴⁷ It is advisable to begin an IV or SC insulin regimen at the onset of total parenteral nutrition/peripheral parenteral nutrition (TPN/PPN) use,¹²² or alternatively, regular insulin can be added to parenteral nutrition. When nutrition is held or discontinued, the insulin dosing will usually need to be reduced, or dextrose-containing IV fluid started, to reduce the risk of hypoglycemia.

Glucocorticoid-induced hyperglycemia is common in the critically ill patient. Glucocorticoids decrease insulin sensitivity, impair glucose disposal, and increase hepatic insulin resistance.¹⁴⁸ All patients should have regularly scheduled glucose monitoring for the first 48 hours after steroids are initiated. Subcutaneous insulin therapy may be started for glucocorticoid-induced hyperglycemia with an initial total daily dose (TDD) of 0.3 to 0.5 unit per kg body weight. IV insulin infusion is appropriate for moderate to severe hyperglycemia.¹⁴⁹ In patients started on insulin for glucocorticoid-induced hyperglycemia, the insulin dose will need to be titrated for changes in steroid dose.

Subcutaneous Insulin Use in the Hospitalized Patient

Insulin is the therapy of choice for glucose control in the ICU. Oral agents and noninsulin injectable agents should be discontinued on admission. The multiple contraindications and the inability to make rapid adjustments for changes in clinical or nutritional status make noninsulin therapy poorly suited for the care of the critically ill patient. The onset, peak, and duration of action of the currently available insulin preparations are listed in (Table 58.3). Insulin can be categorized based on the physiologic profile: basal insulin is either long or intermediate duration; short- or rapid-acting insulin is used for prandial control and for the correction of hyperglycemia. The lack of a defined peak and prolonged action profile make glargine (Lantus) and detemir (Levemir) advantageous for use as a basal insulin. Glargine is typically dosed once daily and detemir one to two times daily. NPH has an intermediate duration of action with peak effect at 6 to 8 hours after dosing and is usually dosed twice daily.

With a variety of insulin regimens available, the practitioner has several options available to manage hospitalized patients with diabetes or stress hyperglycemia. Patients who are not eating or who are receiving continuous nutrition (enteral or parenteral) should have a basal insulin in place. The basal insulin is given SC, or in the case of parenteral nutrition, regular insulin may be added to the PPN or TPN at an initial dose of 1 unit for each 15 g of dextrose.¹⁵⁰ In a patient on continuous nutrition or NPO (nothing by mouth), glargine is dosed daily, detemir every 12 to 24 hours, or NPH every 8 to 12 hours. No research is available to support the use of one basal insulin over another in the hospitalized patient. The potential risk of NPH is the peak effect, although the longer duration of glargine and detemir may result in longer periods of hypoglycemia. Glucose monitoring should be performed every 4 to 8 hours, depending on the stability of the patient.

In patients tolerating scheduled meals, a prandial insulin should be added. Lispro, aspart, and glulisine each have a more physiologic profile with a quicker onset of action, time to peak, and shorter duration of action than regular insulin. The use of a rapid-acting insulin analog is associated with better glycemic control compared to regular insulin.¹⁵¹ In patients who are eating, glucose monitoring is usually performed before the meal and at bedtime.

The lack of flexibility with premixed insulin (Humulin 70/30, Novolin 70/30, Novolog 70/30, and Humalog 75/25) makes their use less suitable for the hospital. Each of the premixed insulin preparations contains 70% to 75% NPH for intermediate-acting insulin and 25% to 30% of regular insulin or a rapid-acting insulin analog (lispro or aspart). Though not an optimal practice, if the practitioner wishes to continue a successful home regimen of premixed insulin in a hospitalized patient, the component doses of NPH and lispro, aspart, or regular insulin can be given separately.

In the hospitalized patient, there are several methods for determining insulin dosing for a basal-bolus regimen:

The use of correctional (sliding) scale insulin as sole therapy cannot be promoted for the patient with hyperglycemia. Reliance on sliding scale insulin is associated with worse glycemic control in hospitalized patients.153,154 In particular, patients with type 1 DM always require physiologic insulin dosing including a basal insulin to prevent the development of DKA. Correctional insulin doses may be used as an adjunct to a physiologic insulin regimen. Doses of correctional insulin should be aligned to the TDD of prescribed insulin; thus, a patient requiring 100 units of insulin a day will require more correctional dose insulin than a patient whose TDD is 30 units. The clinician can calculate the expected change in glucose for 1 unit of regular or rapid-acting insulin analog using the “Rule of 1500” formula: 1500/TDD = expected decrease in glucose (in mg/dL) for 1 unit of correctional dose insulin. For insulin-sensitive patients (e.g., type 1 DM, BMI < 25 kg/m², end-stage renal disease [ESRD], or hepatic failure), 1800 rather than 1500 is used for the numerator.

Physiologic Response to Hypoglycemia

The physiologic response to hypoglycemia is mediated through neural and humoral pathways and that involves both a reduction in insulin and activation of the counterregulatory response¹⁵⁹ (Fig. 58.5). The first humoral response to a decreasing glucose is inhibition of insulin secretion when the glucose level drops to less than 80 mg/dL.^159,160 The drop in insulin level causes decreased peripheral glucose utilization, as well as increased glucose production through glycogenolysis and gluconeogenesis.¹⁶¹ Glucagon, epinephrine, and growth hormone secretion increases as glucose levels fall below 70 mg/dL.^159,160 Cortisol release increases as the glucose drops below 60 mg/dL. Of the counterregulatory hormones, glucagon plays the key role in the minute-to-minute prevention of hypoglycemia.¹⁶² If glucagon secretion is diminished (e.g., in longstanding autoimmune diabetes), epinephrine release becomes critical for the reversal of hypoglycemia. Under normal circumstances, cortisol and growth hormone are not essential in the prevention of hypoglycemia but are necessary in the absence of glucagon.¹⁵⁹ The stepwise response to hypoglycemia and the redundancy in the counterregulatory hormones suggest the physiologic importance placed on the prevention of hypoglycemia.¹⁵⁹

Hypoglycemia in Patients with Diabetes or Who Receive Insulin

Although insulin is necessary to manage hyperglycemia in hospitalized patients, it is also the major risk factor for hypoglycemia. Additional risks for hypoglycemia are seen in (1) patients with comorbid conditions such sepsis, organ failure, or malnutrition; (2) patients receiving medications such as beta blockers that mask the neurogenic symptoms of hypoglycemia; or (3) patients who do not have the capacity to respond to a hypoglycemic episode (e.g., sedated patients).

In patients with diabetes, hypoglycemia occurs with decreased or interrupted carbohydrate consumption, increased glucose utilization from elevated energy expenditure, or an increase in insulin to a degree that overwhelms the glucose counterregulatory system. The source of insulin may be exogenous, from an insulin injection or infusion, or endogenous, caused by an insulin secretagogue drug such as a sulfonylurea or a glinide. A detailed description of the onset, peak, and duration of the various types of insulin is given in the earlier section “Glycemic Control in the Intensive Care Unit.” Sulfonylurea drugs such as chlorpropamide, tolbutamide, and glyburide, which have extended half-lives and are renally metabolized, predispose to prolonged hypoglycemia, particularly in patients with renal insufficiency.¹⁶⁸ Newer agents such as glipizide and glimepiride have dual hepatic and renal metabolism, which decreases the risk of prolonged hypoglycemia. The shorter duration of action of the glinides (repaglinide and nateglinide) reduce the risk of prolonged hypoglycemia. Diabetes medication affecting insulin resistance or carbohydrate consumption (i.e., metformin, thiazolidinediones, α-glucosidase inhibitors [AGIs], dipeptidyl peptidase IV inhibitors, amylin or incretin mimetics, bile acid sequestrants, or bromocriptine) do not typically cause clinically significant hypoglycemia unless taken in combination with insulin or an insulin secretagogue.

Hypoglycemia in Patients without Diabetes

Because of the tiered physiologic mechanisms to protect against low blood glucose, hypoglycemia is unusual in nondiabetic patients. Only 1.5% of hypoglycemic episodes occur in patients without diabetes or who are not receiving insulin,¹⁶⁷ and most conditions or medications will not cause hypoglycemia unless multiple factors occur simultaneously.¹⁶⁷ The acute management of hypoglycemia is similar in diabetic and nondiabetic individuals, but nondiabetic patients presenting with hypoglycemia require a careful diagnostic evaluation.

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