Chapter 31. Hyperglycemic Emergency

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) encompass two severe complications of diabetes mellitus (DM). The incidence is increasing in the United States, with 120,000 hospitalizations for DKA in 2005, which was a 20% increase compared with 2000.1 Of the hospitalizations for DKA in 2005, 72% were 44 years old or younger, 21% were between 45 and 64 years old, and <1% were 65 years old or older.1 Although the rate of hospitalizations for DKA continues to rise, mortality from DKA has been declining, and in 2005 mortality was 0.8 deaths per 100,000.1 HHS, on the other hand, has a lower rate of hospitalization but a higher mortality at a rate of 5–20%.2,3 The cost of DKA is profound and the aggregate cost of its hospitalizations is approximately $850 million.4

DKA is defined by the following criteria (Table 31-1): plasma glucose >250 mg/dL, arterial pH ≤7.30, serum bicarbonate ≤18 mEq/L, presence of urinary and serum ketones, and an anion gap >10 mEq/L.2 It is further divided into mild, moderate, and severe based on the degree of acidemia that corresponds to an arterial pH of 7.25–7.30, 7.00 to <7.24, and <7.00, respectively, or a serum bicarbonate level of 15–18, 10 to <15, and <10 mEq/L, respectively.2 HHS is defined by the following criteria: plasma glucose >600 mg/dL, an arterial pH >7.30, serum bicarbonate >18 mEq/L, an effective serum osmolality >320 mOsm/kg (where effective serum osmolality = 2[measured Na+ (mEq/L)] + glucose [mg/dL]/18).2,5 Although HHS was previously called hyperglycemic hyperosmolar nonketotic state (HHNKS), small urinary and serum ketones may be seen in this condition and thus their presence does not exclude the diagnosis of HHS.2 DKA and HHS in reality lie along a continuum, and up to 33% of patients may have a clinical presentation in which features of both are present in varying degrees.3

Traditionally, DKA was thought to occur only in type 1 DM and HHS in type 2 DM. There is a newly recognized entity, however, of ketosis-prone type 2 DM.6 These patients present with DKA resulting from decreased insulin secretion and action but they characteristically recover β-islet cell function within a few months.5,6 In long-term follow-up, up to 40% of these patients remain without exogenous insulin requirements 10 years after their initial presentation with DKA.5–7 Patients with ketosis-prone type 2 DM as a group tend to have obesity, family history of DM, lack of genetic HLA association, and low prevalence of autoimmune markers.6 There is a predilection for African, African American, and Hispanic patients—somewhere between 20% and 50% of patients with new-onset DKA in this demographic may fit this description—but cases have also been reported in other populations (Native American, Japanese, Chinese, Caucasian).6

DKA is characterized by a state of relative insulin deficiency and concurrent increase in counterregulatory hormones (such as glucagon, cortisol, catecholamines, and growth hormone).2,5 Hyperglycemia occurs due to increased gluconeogenesis and glycogenolysis, and decreased peripheral glucose utilization in the liver, muscle, and adipocytes.5 Insulin deficiency and elevated cortisol levels lead to: (a) increased proteolysis, which creates amino acid substrates that further fuel gluconeogenesis, and (b) increased lipolysis, which creates glycerol and free fatty acids (FFA).5 The latter undergo β-oxidation in the liver, which in turn generates ketone bodies, such as β-hydroxybutyrate and acetoacetate.5 Generation of these weakly acidic ketone bodies leads to the characteristic anion gap metabolic acidosis.5 Glycerol is used for further gluconeogenesis.5 Excess glucagon relative to insulin causes a decrease in malonyl CoA leading to the disinhibition of carnitine palmitoyl acyltransferase I (CPT I).8 CPT I facilitates ketogenesis by transporting FFA into the mitochondria for oxidation.8 Finally, as volume depletion causes prerenal azotemia, the ability to excrete glucose and ketoanions declines.9

In addition to the well-described metabolic disturbances outlined above, patients in states of hyperglycemic emergency also exhibit evidence of hypercoagulability and inflammation.8,10,11 Markers of coagulation, fibrinolysis, and platelet activity rise during DKA and may clinically manifest as thromboses, myocardial infarction (MI), and disseminated intravascular coagulation.8,10 In both DKA and HHS, a proinflammatory milieu develops as cytokines and other markers of cardiovascular risk and oxidative stress rise.11

The pathophysiology of HHS, on the other hand, is not completely understood but just as in DKA, osmotic diuresis leads to a loss of electrolytes and a free water deficit.3 The magnitude of total body water deficit is much greater in HHS and may exceed 9 L, whereas in DKA it typically ranges around 6 L.3 This leads to marked hyperosmolarity, hypovolemia, and intravascular and extravascular dehydration triggering an increase in counterregulatory hormones, which further worsens hyperglycemia and insulin resistance.5,8 In HHS, ketone production is minimal if not absent because enough insulin is present to suppress lipolysis.5,12

Patients typically present with fatigue, weakness, polyuria, polydipsia, weight loss, and possibly altered mental status depending on the severity of presentation.2 Additional history often present in DKA (but not HHS) includes generalized abdominal pain, nausea, and vomiting that tends to track the severity of acidemia.2,13 The pain may be of such severity that an acute abdomen is considered during the evaluation in 50–75%.5,13 The tempo of illness differs: DKA develops rather quickly within 24 hours, whereas HHS develops over a course of a few days to weeks.2 In DKA, the physical exam may reveal tachycardia, hypotension, lethargy, dry mucous membranes, poor skin turgor, breath with fruity odor (due to ketones), Kussmaul respirations, and abdominal tenderness.2 Altered mental status, lethargy, and even coma are possible in both conditions, although they are more common in HHS due to the degree of hyperosmolarity.3,14 In particular, obtundation and coma are typically seen when the effective osmolality is greater than 330 mOsm/kg.5 If the patient's osmolality is less than 320 mOsm/kg and obtundation is present, one must consider other etiologies for the altered mental status.2,5 In HHS, physical exam findings may include signs of dehydration as well as additional neurologic changes such as seizures or hemiparesis, making a thorough neurologic evaluation paramount.2

Initial evaluation should include an investigation for a precipitating factor. The most common precipitant for both DKA and HHS is infection.2 Others include intentional or accidental insulin noncompliance, pancreatitis, cerebrovascular accident, MI, and medications (e.g., corticosteroids, diuretics, β-blockers, calcium channel blockers, cimetidine, diazoxide, phenytoin, sympathomimetic agents, pentamidine, typical or atypical antipsychotics).2,3,15 Elderly patients in particular have a greater risk of developing HHS due to poor thirst response and their dependence on others for free water access.2,3 Other risk factors for DKA include psychological illness, eating disorders, and cocaine use.2,16 There are also some endocrine disorders that are associated with hyperglycemia: acromegaly, glucocorticoid excess, pheochromocytoma, thyrotoxicosis, and hyperaldosteronism.15 Some patients with Cushing's syndrome and DM may even develop HHS.15

Initial objective data should include an assessment of glycemia, readily obtained via fingerstick glucose, and a urinalysis to evaluate for ketones. A detailed initial laboratory evaluation is outlined in Table 31-2. Of note, leukocytosis is typically seen in DKA with or without the presence of infection.2 If the patient's white blood cell count is greater than 25 × 103/mm3 or bandemia is 10% or greater, however, one should suspect a true infection.2,17 Nonspecific elevations in lipase and amylase, up to greater than three times normal values, may also be seen in up to 25% of patients with DKA and thus one cannot diagnose acute pancreatitis by this laboratory value alone.18 An arterial blood gas (ABG) should be performed to determine the degree of acidemia.2 In general, admission to the intensive care unit (ICU) is warranted if there is evidence of airway compromise, hemodynamic instability, severe acidemia, or any other finding that would suggest impending decompensation (e.g., suspected gastric dilation, acute abdomen).

Pseudohyponatremia may be present in the setting of hyperglycemia due to the shift of water to the extracellular space. For each 100 mg/dL of glucose greater than 100, 1.6 mEq/L must be added to the measured serum sodium level to arrive at the corrected sodium value.3 Although this is the traditional teaching, reevaluation of this correction factor showed that for serum glucose greater than 400 mg/dL, a factor of 2.4 mEq/L was more appropriate and thus may be helpful in HHS.3,8

The patient's serum potassium level may initially be elevated or near normal, which is falsely reassuring as total body potassium levels are typically quite depleted.3 Insulin normally drives potassium into the intracellular space—as such, in the setting of absolute or relative insulin deficiency, potassium shifts to the extracellular space.9 Once treatment with insulin is initiated, the astute clinician must be prepared for a rapid decrease in the serum potassium level. Patients are at risk of developing cardiac arrhythmias and should be kept on telemetry.9

The goals in the treatment of DKA and HHS are to treat the hypovolemia, free water deficit, hyperglycemia, electrolyte abnormalities, and the precipitating factor if one is present. A recent consensus statement proposed a revised treatment algorithm for DKA and HHS (Figure 31-1).2 Both conditions require frequent monitoring of mental status, vital signs, and urine output. Laboratory monitoring may need to occur at 2- to 4-hour intervals until resolution.2

Initial treatment with intravenous fluids (IVF) is necessary in both DKA and HHS to replete the intravascular and interstitial spaces. Correction of hyperosmolarity has the added benefit of improving the patient's response to insulin.19 First, normal saline (0.9% NaCl) should be given at a rate of 15–20 mL/kg body weight/h or 1–1.5 L over the first hour. At this point, based on the patient's hemodynamics, hydration status, serum sodium level, and urine output, the next composition of IVF is determined as outlined in Figure 31-1. If the patient remains hypotensive, isotonic fluids are continued. Insulin infusion is held until hemodynamic stability is achieved because when insulin is given, water moves from the extracellular to the intracellular space and thus can worsen hypotension.8 Once the patient is normotensive, insulin infusion should begin at 0.1 U/kg/h. When determining the resuscitation rate, the patient's cardiac and renal functions are also taken into consideration. When the plasma glucose reaches 200–250 mg/dL in DKA (300 mg/dL in HHS), dextrose is added to the IVF to prevent hypoglycemia and insulin is continued at a lower rate, as ketoacidosis persists longer than hyperglycemia. It is important to continue insulin treatment well after resolution of hyperglycemia in order to suppress lipolysis and subsequent ketoacid production.

Regular intravenous (IV) insulin is typically used due to its relatively short half-life (5–17 minutes) and ease of administration. Studies have shown, however, that insulin therapy may be administered intravenously, subcutaneously, or intramuscularly with good effect.20 In particular, treatment of mild and moderate DKA with rapid-acting insulin every 1–2 hours outside of the ICU has been demonstrated to be as effective as regular IV insulin therapy in the ICU.2,21 As for the use of bolus insulin, the traditional treatment protocol involves giving a 0.1-U/kg body weight bolus followed by a continuous infusion of 0.1 U/kg/h.2 A recent study, however, demonstrated that an initial bolus of insulin is unnecessary if patients are given 0.14 U/kg body weight/h.22 Thus, at this time it appears that either method may be used to initiate treatment. In general, blood glucose should decline at a steady rate of 50–75 mg/dL/h. Until this is achieved, the rate of the insulin infusion may be doubled every hour.23

Given the expected decline in serum potassium level with the initiation of insulin therapy, insulin should be held if the patient's potassium is less than 3.3 mEq/L as the intracellular shift of potassium triggered by insulin may further worsen hypokalemia and place the patient at risk for cardiac arrhythmias. The goal of potassium repletion is to maintain a level around 4–5 mEq/L. Repletion should begin when the level is at the upper limit of normal (5 mEq/L). Typically, adding 20–30 mEq/L of potassium to each liter of IVF will help prevent hypokalemia.2

Patients with DKA also have total body phosphate depletion but studies have not convincingly shown benefit in aggressively repleting phosphate in these patients and doing so may carry the risk of hypocalcemia.2,23,24 However, if serum phosphate levels are less than 1 mEq/L or if the patient has comorbid conditions including respiratory depression, cardiac or respiratory compromise, or anemia, then repletion is warranted.2,23

Resolution of DKA occurs when the blood glucose is less than 200 mg/dL and two of the following occur: serum bicarbonate level ≥15 mEq/L, venous pH >7.3, and/or anion gap ≤12 mEq/L. Resolution of HHS occurs when the osmolality and mental status have normalized. At this time, subcutaneous insulin may be initiated with at least 1–2 hours of overlap with the insulin infusion to prevent relapse. Regarding the dose of subcutaneous insulin, the patient's home insulin regimen may be used if it had been working well for the patient prior to the episode. In newly diagnosed diabetic patients, dosing should start at 0.5–0.8 U/kg per day. The total daily dose should be divided into a basal and bolus regimen. One approach is to allocate 50% of the total daily dose as long-acting insulin such as glargine and to divide the remainder into three equal mealtime boluses of rapid-acting insulin (e.g., aspart or lispro).2

Bicarbonate therapy is controversial in the treatment of DKA. As DKA is treated, ketoacidosis should improve because ketone bodies are metabolized in the citric acid cycle.8 This leads to the production of carbon dioxide and water, which leads to regeneration of bicarbonate.8 Studies have failed to demonstrate that bicarbonate therapy has any benefit in improving morbidity or mortality in patients with severe DKA (pH 6.9–7.1).2,25 There are no randomized controlled trials, however, that have examined the role of bicarbonate therapy in DKA patients with a pH <6.9.9 In severe acidemia, patients are at risk for developing cerebral vasodilatation, coma, decreased myocardial contractility, and gastrointestinal (GI) complications.2,26 Given these risks, the current recommendation is to give bicarbonate therapy to DKA patients with a pH <6.9. It is important to note that bicarbonate therapy carries the risks of worsening hypokalemia, worsened intracellular acidosis, cerebral edema, and paradoxical central nervous system acidosis.2 See Figure 31-1 for dosing.

Potential complications during treatment of DKA and HHS include cerebral edema, hypoglycemia, hypokalemia, hyperchloremic metabolic acidosis, fluid overload, acute respiratory distress syndrome (ARDS), thromboembolism, and acute gastric dilation due to gastroparesis.2,3,8,27

Cerebral edema is rarely seen in adult patients with DKA, and the exact mechanism of cerebral edema is not entirely clear. Most of the literature is in the pediatric population. There is evidence to support the following theories: inflammatory mediators, cerebral ischemia, hypoxia, and rapid decline in serum osmolality due to aggressive IVF.2 If present, patients may develop a headache, altered level of consciousness, papilledema, bradycardia, hypertension, seizures, incontinence, or even respiratory arrest.2,3,27 Treatment includes giving mannitol and mechanically ventilating the patient.27

A more common complication is development of hyperchloremic non-anion gap metabolic acidosis resulting from large amounts of normal saline given during treatment and the decrease in ketoanions as DKA resolves.9 In addition, fluid overload or ARDS could also occur and thus frequent cardiopulmonary assessment is vital.9 Given the possibility of gastroparesis and resulting gastric dilation, serial abdominal exams and an abdominal plain film should take place if there are sufficient clinical concerns.8

DKA and HHS lie along a continual spectrum, and are frequently encountered diabetic complications in the acute care setting with significant economic burden and morbidity for the patient. With prompt diagnosis and careful management, DKA and HHS can be successfully managed with improved patient outcomes.