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CHAPTER 227: Hyperosmolar Hyperglycemic State 1443 unclear, and it is not known if dietary supplements may contribute to pathologic acidosis.8  KETOGENIC DIET The ketogenic diet may be desired for several medical conditions; weight control and seizures are the two most common. Additional conditions (Alzheimer’s disease and Parkinson’s disease) may warrant future trials of a therapeutic ketogenic diet. In healthy volunteers, the ketogenic diet does not routinely induce metabolic acidosis due to ketosis.  TOXIC INGESTIONS In some toxin ingestions, ketone production is a primary result of the toxin, rather than the cause of the patient’s symptoms. Such ingestions include acetone, aspirin (salicylic acid), isoniazid, isopropanol , metha nol, and propylene glycol. Thus, routinely consider toxic overdose as a cause of unexplained ketosis.  INBORN ERRORS OF METABOLISM Consider inborn errors of metabolism in children with ketosis, espe cially if associated with hypoglycemia. Children who develop ketosis after a longer fast may have a fatty acid oxidation disorder. 10 See Chapter 146, “Metabolic Emergencies in Infants and Children, ” for detailed discussion of diagnosis and emergency treatment. DIFFERENTIAL DIAGNOSIS Urinary detection of ketones and an increased anion gap diagnose the presence of a ketoacidotic condition. History, physical examina tion, dietary review, and assessment of comorbidities are necessary to focus the diagnosis. As discussed earlier, lack of elevated urine ketone levels does not exclude the diagnosis in cases of alcoholic ketoacidosis. Elevated glucose levels are most commonly described in cases of alcoholic ketoacidosis 4 and less commonly in other causes of pathologic ketoacidosis. There are no published large series of ketoacidotic condi tions, so generalizations about serum glucose levels cannot be made. The conditions listed in column 1 of Table 226-1 are often associated with significant dehydration and electrolyte disturbances, including hypokalemia, hyperkalemia, hypomagnesemia, and hypophosphatemia. Patients with alcoholic ketoacidosis often have underlying liver disease and may have abnormal liver enzyme levels. Column 2 of Table 226-1 lists toxic ingestions and inborn errors of metabolism associated with ketonuria and metabolic acidosis. Elevated serum ketones may result from ingestion of an alcohol other than etha nol. Methanol and ethylene glycol ingestions do not produce ketosis, but the acidosis tends to be severe. Isopropyl alcohol ingestion results in production of ketones. The presence of a large osmolal gap suggests acute isopropyl, ethanol, methanol, or ethylene glycol ingestion. If the blood alcohol level is known, then its contribution to any osmolal gap can be calculated. Each 100 milligrams/dL (21.7 mmol/L) of ethanol raises the osmolal gap by 22. Details of osmolal gap are discussed in Chapter 17, “Fluids and Electrolytes. ” The presence of a mixed acid-base disturbance suggests a comorbid disorder (column 3 of Table 226-1) . TREATMENT Treatment of ketoacidosis is supportive.4,5,7,11,12 Reestablish intravascular volume. Published series of patients with pathologic ketoacidosis report the need for isotonic volume expansion, and supplemental dextrose is required. Monitor and correct electrolyte abnormalities. Correct hypomagnesemia.

226-1) . TREATMENT Treatment of ketoacidosis is supportive.4,5,7,11,12 Reestablish intravascular volume. Published series of patients with pathologic ketoacidosis report the need for isotonic volume expansion, and supplemental dextrose is required. Monitor and correct electrolyte abnormalities. Correct hypomagnesemia. Hypophosphatemia can slow the resolution of acidosis as phosphorus is necessary for mitochondrial utilization of glucose and for oxidation of the reduced form of nicotinamide adenine dinucleotide. However, phosphate replacement generally is unwarranted unless levels are very low (<1.0 milligram/dL or <0.323 mmol/L). Administer supplemental dextrose. Insulin therapy is needed only for DKA, as brisk hypoglycemia can occur when insulin is given to patients with a starvation-type ketoacidotic syndrome. 13 In alcoholic or malnourished patients, some feel that thiamine supplementation prior to glucose administration should be given to prevent Wernicke’s encephalopathy and Korsakoff ’s syndrome. Serum ketone levels, correlated with clinical status, may be used to help guide therapy and will decrease as the ketoacidosis resolves, while an increasingly positive reaction in urinary ketones during treatment signifies improvement, as results lag behind clinical status. Acidosis should clear within 12 to 24 hours. For severe ketoacidosis in a patient on a ketogenic diet for seizure control, obtain consultation to weigh the risks and benefits of all aspects of supportive therapy. DISPOSITION AND FOLLOW-UP Adults with an uncomplicated ED course may be safely discharged home if there is resolution of acidosis and the patient is able to tolerate oral fluids. When caring for complicated conditions (e.g., children with hypo glycemia, inborn error of metabolism, therapeutic ketogenic diet, toxic ingestions, medical comorbidities), coordinate care with the primary team treating the underlying disorder. Patients with alcoholic ketoacidosis should receive counseling on alcohol dependence, be encouraged to use multivitamins, and be offered treatment in an alcohol detoxification program. Patients with persistent acidosis or a complicated course will require hospital admission. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Hyperosmolar Hyperglycemic State Charles S. Graffeo INTRODUCTION AND EPIDEMIOLOGY The hyperosmolar hyperglycemic state (HHS) is characterized by progressive hyperglycemia and hyperosmolarity typically found in a debilitated patient with poorly controlled or undiagnosed type 2 diabetes mellitus, limited access to water, and commonly, a precipitating illness. Although most cases of HHS occur in the elderly, the incidence of HHS in children is increasing, with the common risk factors being obesity and African American race. PATHOPHYSIOLOGY The basic pathophysiology of diabetes is discussed in Chapter 223, “Type 1 Diabetes Mellitus, ” and Chapter 224, “Type 2 Diabetes Mel litus, ” and is also outlined in Figure 227-1. The development of HHS is attributed to three main factors: (1) insulin resistance and/or deficiency; (2) an inflammatory state with marked elevation in proinflammatory cytokines (C-reactive protein, interleukins, tumor necrosis factors) and counterregulatory stress hormones (catecholamines, growth hormone, glucagon, cortisol) that cause increased hepatic gluconeogenesis and glycogenolysis; and (3) osmotic diuresis followed by impaired renal excretion of glucose. 2,3 In patients with type 2 diabetes, physiologic stresses combined with inadequate water intake in an environment of insulin resistance or deficiency lead to HHS.

ucagon, cortisol) that cause increased hepatic gluconeogenesis and glycogenolysis; and (3) osmotic diuresis followed by impaired renal excretion of glucose. 2,3 In patients with type 2 diabetes, physiologic stresses combined with inadequate water intake in an environment of insulin resistance or deficiency lead to HHS. As serum glucose concentration increases, an osmotic gradient develops, shifting water from the intracellular space into the intravascular compartment, causing cellular dehydration. The initial increase in intravascular volume is accompanied by a temporary increase in the glomerular filtration rate. As serum glucose increases, the capacity of the kidneys to reabsorb glucose is exceeded, and an osmotic diuresis occurs with total body water losses that can CHAPTER Tintinalli_Sec17_p1419-1460.indd 1443 8/2/19 12:23 PM

se in intravascular volume is accompanied by a temporary increase in the glomerular filtration rate. As serum glucose increases, the capacity of the kidneys to reabsorb glucose is exceeded, and an osmotic diuresis occurs with total body water losses that can CHAPTER Tintinalli_Sec17_p1419-1460.indd 1443 8/2/19 12:23 PM 1444 SECTION 17: Endocrine Disorders RelativeInsulin DeficiencyAbsolute Lipolysis Glucose utilization Ketoacidosis Hyperglycaemia HyperosmolalityDyslipidaemia Thrombosis GlycogenolysisProteolysis Protein synthesis Counter-regulator hormones Cortisol Gluconeogenic substratesFree fatty acids Gluconeogenesis Glycosuria Loss of H2O & electrolytes Dehydration Hypovolaemia Impaired renal function Haemoconcentration Ketogenesis Alkali reserve Triacylglycerols Glucagon Growth hormoneCatecholamines Hypotension/shock K+, Na+, PO4 3– Infection Stress HHSDKA FIGURE 227-1. Pathophysiology of hyperglycemic emergencies. HHS = hyperosmolar hyperglycemic state. [Reproduced with permission from Cardoso L et al: Controversies in the management of hyperglycaemic emergencies in adults with diabetes. Metabolism 68: 43, 2017 [PMID: 28183452]. Fig. 1. Copyright Elsevier.] exceed 20% to 25% of total body weight, or approximately 8 to 12 L in a 70-kg patient. During osmotic diuresis, significant urinary loss of sodium and potassium and more modest losses of calcium, phosphate, and magnesium occur. With ongoing volume losses, renal perfusion and glomerular filtration are reduced, and renal tubular excretion of glucose is further impaired. The relative lack of severe ketoacidosis in HHS is poorly understood and has been attributed to three possible mechanisms: (1) higher levels of endogenous insulin than are seen in DKA; (2) lower levels of counterregulatory “stress” hormones; and (3) inhibition of lipolysis by the hyperosmolar state itself. Evidence of significant ketoacidosis in a patient thought to have type 2 diabetes should bring into question the possibility of variants of type 1 diabetes, such as latent autoimmune diabetes in adults. 5 Additionally, a greater proportion of ketosis-prone type 2 diabetes has been described in African American, Hispanic, and Asian populations. CLINICAL FEATURES  HISTORY AND COMORBIDITIES The typical patient with HHS is elderly and often institutionalized, with baseline cognitive impairment and comorbid medical illnesses, who is referred for abnormalities in vital signs, lab results, and/or mental status changes that have evolved over days to weeks. Patient complaints are often nonspecific and may include malaise, weakness, anorexia, fatigue, vomiting, and cognitive impairment. Up to 15% of patients may present with seizures, which are typically focal, although generalized seizures may occur. In other cases, HHS is noted in patients with no prior his tory of diabetes mellitus who present with acute illnesses such as stroke, myocardial infarction, pneumonia, abdominal emergencies, and sepsis. Patients taking antipsychotics or antidepressants may present a particular risk, and HHS should be considered as part of the medical screening process for psychiatric patients. HHS is associated with a host of conditions ( Table 227-1) and drugs (Table 227-2) that may predispose to hyperglycemia and volume depletion.  PHYSICAL EXAMINATION The physical findings in HHS generally include signs of severe volume depletion such as poor skin turgor, dry mucous membranes, sunken eyes, tachycardia, and hypotension. The degree of lethargy and coma has a linear relationship to serum osmolality. Patients with coma tend to be older and have higher osmolality, more severe hyperglycemia, acidosis, and greater volume contraction.

volume depletion such as poor skin turgor, dry mucous membranes, sunken eyes, tachycardia, and hypotension. The degree of lethargy and coma has a linear relationship to serum osmolality. Patients with coma tend to be older and have higher osmolality, more severe hyperglycemia, acidosis, and greater volume contraction. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS HHS is “defined” by severe hyperglycemia with serum glucose usually >600 milligrams/dL (>33.3 mmol/L), an elevated calculated plasma osmolality of >315 mOsm/kg (>315 mmol/kg), serum bicarbonate Tintinalli_Sec17_p1419-1460.indd 1444 8/2/19 12:23 PM

volume depletion such as poor skin turgor, dry mucous membranes, sunken eyes, tachycardia, and hypotension. The degree of lethargy and coma has a linear relationship to serum osmolality. Patients with coma tend to be older and have higher osmolality, more severe hyperglycemia, acidosis, and greater volume contraction. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS HHS is “defined” by severe hyperglycemia with serum glucose usually >600 milligrams/dL (>33.3 mmol/L), an elevated calculated plasma osmolality of >315 mOsm/kg (>315 mmol/kg), serum bicarbonate Tintinalli_Sec17_p1419-1460.indd 1444 8/2/19 12:23 PM CHAPTER 227: Hyperosmolar Hyperglycemic State 1445 >15 mEq/L (>15 mmol/L), an arterial pH >7.3, and serum ketones that are negative to mildly positive. Metabolic acidosis or ketonemia associated with HHS is likely to be due to tissue hypoperfusion, star vation ketosis, and azotemia in various combinations, although there is growing evidence for ketosis-prone type 2 diabetic subgroups. 6 It is important to recognize the potential for a variety of mixed acid-base patterns in patients with HHS. A comparison of the laboratory features of DKA and HHS is shown in Table 227-3.  LABORATORY TESTING AND IMAGING Laboratory tests and diagnostic imaging should be tailored to the indi vidual patient. Laboratory workup commonly includes a CBC with dif ferential, comprehensive metabolic profile, magnesium and phosphate, urinalysis, serum and urine osmolality, lactate, β-hydroxybutyrate, and blood and urine cultures. In addition, cardiac markers, creatine phosphokinase, arterial or venous blood gas, thyroid function studies, procalcitonin, and coagulation profiles should be considered. Chest radiographs and ECGs are generally recommended. Diagnostic studies, such as CT, lumbar puncture, toxicologic studies, and echocardiography, should be patient specific. In general, electrolyte abnormalities vary. Initially, contraction alka losis due to a profound water deficit may occur. An anion gap metabolic acidosis is often attributable to sepsis, poor tissue perfusion, starvation ketosis, or renal impairment. Sodium Serum sodium level varies and is not a reliable indicator of the degree of volume contraction. Hyperglycemia has a dilutional effect on measured serum sodium: Standard teaching is that serum Na + decreases by approximately 1.6 mEq/L (1.6 mmol/L) for every 100 milligrams/dL (5.6 mmol/L) increase in serum glucose >100 milligrams/ dL (5.6 mmol/L). For glucose > 400 milligrams/dL (22.2 mmol/L), a correction factor of 2.4 is more accurate. Formula for glucose 100-400 milligrams/dL (>5.55-22mmol/L) Corrected [Na+] = Measured [Na+] + 1.6 × (glucose in mg/dL - 100) Formula for glucose in mmol/L Corrected [Na+] = Measured [Na+] + 1.6 × (glucose in mmol/L - 5.6) 5.6 Osmolality Serum osmolality correlates positively with severity of disease as well as mental status changes and coma. In the United States, many authors suggest using calculated effective serum osmo lality, which excludes osmotically inactive urea. Although osmoti cally inactive, urea is known to be elevated in dehydration, shock, renal impairment, and catabolic states. 8 Recent guidelines from the United Kingdom suggest that including urea when calculating serum osmolality may more accurately reflect severity of dehydration and help protect against overzealous correction of osmolality, which can predispose patients to cerebral edema and osmotic demyelination syndrome.

tabolic states. 8 Recent guidelines from the United Kingdom suggest that including urea when calculating serum osmolality may more accurately reflect severity of dehydration and help protect against overzealous correction of osmolality, which can predispose patients to cerebral edema and osmotic demyelination syndrome. 9,10 gl ucose Osmolality 2[Na+] + + BUN/2.8 glucose Effective Osmolality 2[Na+] + TABLE 227-1 Conditions That May Precipitate Hyperosmolar Hyperglycemic State •   Diabetes •   Infection, especially pneumonia or urinary tract infection •   Myocardial infarction •   Renal insufficiency •   Cerebrovascular events •   Mesenteric ischemia •   GI hemorrhage •   Pulmonary embolism •   Pancreatitis •   Severe burns •   Parenteral or enteral alimentation •   Peritoneal or hemodialysis •   Heat-related illness •   Rhabdomyolysis •   Pregnancy •   Trauma TABLE 227-2 Some Drugs That May Predispose Individuals to the Development of HHS •   Diuretics •   Statins •   β-Blockers •   Chlorpromazine •   Cimetidine •   Glucocorticoids •   β-Agonists •   Antipsychotics •   Antidepressants •   Phenytoin •   Calcium channel blockers •   Pentamidine •   Immunosuppressive drugs (tacrolimus, cyclosporine) •   Diazoxide •   L-asparaginase •   Protease inhibitors •   Nicotinic acid •   Nucleoside reverse transcriptase inhibitors •   Interferons TABLE 227-3 Diagnostic Criteria for DKA and Hyperosmolar Hyperglycemic State (HHS) DKA HHS Plasma glucose >250 milligrams/dL (>13.8 mmol/L) >600 milligrams/dL (>33.3 mmol/L) Serum bicarbonate ≤18 mEq/L (<18 mmol/L) >15 mEq/L (>15 mmol/L) Urine acetoacetate* + – or small Serum beta hydroxybutyrate + – or small Serum ketones † + – or small Serum osmolality‡ Variable >320 mOsm/kg (>320 mmol/kg) Anion gap # >12 mEq/L (>12 mmol/L) <12 mEq/L (<12 mmol/L) Arterial/venous pH <7.30 >7.30 *Nitroprusside method. †Gas chromatography method or nitroprusside method. ‡Osmolality calculation: 2(measured [Na+] + glucose (milligrams/dL or mmol/L)/18. #Anion gap calculation: [Na+] – [Cl– ] + [HCO3 – ]. Tintinalli_Sec17_p1419-1460.indd 1445 8/2/19 12:23 PM

/L) <12 mEq/L (<12 mmol/L) Arterial/venous pH <7.30 >7.30 *Nitroprusside method. †Gas chromatography method or nitroprusside method. ‡Osmolality calculation: 2(measured [Na+] + glucose (milligrams/dL or mmol/L)/18. #Anion gap calculation: [Na+] – [Cl– ] + [HCO3 – ]. Tintinalli_Sec17_p1419-1460.indd 1445 8/2/19 12:23 PM 1446 SECTION 17: Endocrine Disorders The normal serum osmolality range is approximately 275 to 295 mOsm/kg. Values >300 mOsm/kg are usually indicative of significant hyperosmolality, and those >320 mOsm/kg are commonly associated with alterations in cognitive function. In general, serum osmolality correction should not exceed 3.0 Osm/kg/h. Potassium On average, potassium losses range from 4 to 6 mEq/kg. Despite these total-body deficits, initial serum laboratory measurements may be normal or even high in the presence of acidosis when intravascular [H +] ions are exchanged for intracellular [K +] ions. As intravascular volume is replaced and acidosis is reversed, [K +] deficiency becomes more apparent. Other Laboratory Testing Hypomagnesemia is common, and serum magnesium levels should be monitored and replaced. Consequences of hypophosphatemia, such as CNS abnormalities, cardiac dysfunc tion, and rhabdomyolysis, are uncommon and usually associated with serum phosphate levels below 1.0 milligram/dL. Routine replacement of phosphate, unless severe, is usually unnecessary. Prerenal azotemia is common, with plasma BUN-to-creatinine ratios often exceeding 30:1, indicating severity of dehydration and the catabolic state. TREATMENT Improvement of tissue perfusion is the key to effective recovery in HHS. Treatment includes correction of hypovolemia, identifying and treating precipitating causes, correcting electrolyte abnormalities, gradual correction of hyperglycemia and hyperosmolarity, and fre quent monitoring. The therapeutic plan must be carefully considered and adjusted for concurrent medical illnesses such as cardiac, renal, and pulmonary disease. Overzealous resuscitation can result in significant harms and should be avoided. A protocol for treating severely ill patients likely requiring intensive care unit–level care is shown in Figure 227-2.  FLUID RESUSCITATION Fluid resuscitation alone replenishes intravascular volume, improves tissue perfusion, and decreases serum glucose about 35 to 70 milligrams/dL/h. Begin normal saline infusion before insulin therapy is started. The average fluid deficit in HHS is in the range of 20% to 25% of total body water, or 8 to 12 L. By using the patient’s usual weight in kilograms, normal total body water and water deficit can be calculated. One half of the fluid deficits should be replaced over the initial 12 hours and the balance over the next 24 hours when possible. The actual rate of fluid administration should be individualized for each patient, based on the level of renal and cardiac impairment. Begin fluid resuscitation with 0.9% normal saline at a rate of 15 to 20 mL/kg/h during the first hour, followed by rates from 4 to 14 mL/kg/h. Limit the rate of volume repletion during the first 4 hours to <50 mL/kg of normal saline. Once hypotension, tachycardia, serum hyponatremia, and urinary output improve, 0.45% NaCl can be used to replace the remaining free water deficit. Hourly glucose, electrolyte, and osmolality measurements should be taken to monitor progress in the critically ill.  ELECTROLYTES Hypokalemia is a risk for dysrhythmia and should be replaced dur ing volume repletion and insulin administration. If the initial serum potassium measurement is <3.3 mEq/L, begin potassium supplementa tion and withhold insulin therapy until potassium is replenished. In general, replace potassium at a rate of 10 to 20 mEq/h.

kalemia is a risk for dysrhythmia and should be replaced dur ing volume repletion and insulin administration. If the initial serum potassium measurement is <3.3 mEq/L, begin potassium supplementa tion and withhold insulin therapy until potassium is replenished. In general, replace potassium at a rate of 10 to 20 mEq/h. For lifethreatening hypokalemia, infusion rates of up to 40 mEq/h may be needed, and under these circumstances, central venous access is war ranted. Monitor serum potassium levels every hour until a steady state has been achieved. Sodium deficits are replenished fairly rapidly, considering the amount of normal saline given during IV fluid replacement. Replace magnesium deficits with 1 to 2 grams of magnesium given over 1 hour. Potassium NS at 4–14 mL/kg/h Serum Na high or normal Serum Na low NS at 4–14 mL/kg/h Administer NS 1 .0 L/h Treatment of Hyperosmolar Hyperglycemic State IV Fluids Insulin Evaluate corrected serum Na and hydration When serum glucose ≤300 milligram/dL (≤16.6 mmol/L) Check electrolytes, blood urea nitrogen, creatinine, and glucose every 2 h until stable. After resolution of HHS, provide SC insulin as needed. 0.1–0.14 units/kg/h IV insulin infusion Goal is glucose ↓ by 50 milligram/dL/h (2.8 mmol/L/h). If glucose ↓ >70 milligram/dL/h (>3.9 mmol/L/h), decrease insulin to 0.05 units/kg/h. If glucose ↓ <50 milligram/dL/h (<2.8 mmol/L), increase insulin to 0.14–0.20 units/kg/h. If serum K + is <3.3 mEq/L, give 40 mEq + until K+ ≥3.3 mEq/L. If serum K+ ≥5.0 mEq/L, do not give K+ but check potassium every 1–2 h. If serum K+ ≥3.3 but <5.0 mEq/L, provide K+ to maintain serum K = at 4–5 mEq/L.* Change to D5 NS and decrease insulin to 0.05 units/kg/h to maintain serum glucose between 200–250 milligram/dL (11–13.8 mmol/L) until plasma osmolality is ≤315 mOsm/kg. FIGURE 227-2. Protocol for the management of severely ill adult patients with hyperosmolar hyperglycemic state (HHS). *Concentrations of K+ ≥20 mEq/L should be administered via central line. D51/2NS = 5% dextrose in half-normal saline; NS = normal saline. Tintinalli_Sec17_p1419-1460.indd 1446 8/2/19 12:23 PM