A patient with hyperosmolar hyperglycemic state is likely to have which laboratory test result?

Laboratory Tests

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Hyperglycemia: Blood glucose >600 mg/dl (Box 1)

Serum osmolality: Usually >320 mOsm/kg

Complete metabolic panel: Serum creatinine, blood urea nitrogen (BUN), electrolytes, glucose

Serum sodium: May be low, normal, or high. Hyperglycemia increases plasma osmolality that translocates intracellular water to the extracellular compartment, decreasing serum sodium. Serum sodium can be corrected by adding 1.6 mmol/L to the measured serum sodium for each 100 mg/dl rise in serum glucose above 100 mg/dl. Marked osmotic diuresis induced by hyperglycemia may cause the serum sodium level to be normal or high

Serum potassium and phosphate: Total body potassium and phosphate deficits typically occur due to urinary losses from osmotic diuresis. However, these levels may be acutely normal or high due to extracellular shift secondary to insulin deficiency and hyperosmolality

Anion gap and serum lactate: Anion gap may be normal or elevated in the setting of lactic acidosis

Arterial blood gas: pH >7.30

Serum and urine ketones: Negative or small

Serum bicarbonate: >15 mmol/L

Hemoglobin A1c (if not performed in past 3 mo)

Complete blood count with differential (may indicate presence of underlying infection [leukocytosis >25,000 mm3], inflammatory condition, hemoconcentration. A leukocytosisof 10,000 to 15,000 mm3 is expected from the stress of illness alone)

Urinalysis, urine/sputum/blood cultures as indicated based on physical exam findings to evaluate the precipitating illness and other comorbidities

Hyperglycemic Hyperosmolar Syndrome

HHS is characterized by extreme elevations in serum glucose (>600 mg/dL) and hyperosmolarity (serum osm >330 mOsm/kg) in the absence of significant ketosis or acidosis (urine ketone concentration <1.5 mmol/L and serum bicarbonate >15 mEq/L). Although HHS is defined as a condition separate from DKA, 30% of cases occur in combination with substantial ketosis and acidosis meeting criteria for both HHS and DKA. Until recently, HHS was thought to occur infrequently in pediatrics. A recent increase in case reports of HHS in children suggest that the frequency may be increasing.91,92 As in adults, HHS in children has a relatively high mortality of 10% to 35%.93,94 The majority of HHS reports in children include acanthosis nigricans, obesity, African-American race, and family history of type 2 diabetes. Most cases of HHS are the initial presentation of diabetes, and most of these youth will subsequently have a clinical diagnosis of type 2 diabetes.

Occurrence of HHS during DKA poses challenges in terms of recognition and treatment. Generally, dehydration is more profound than the clinical assessment would suggest, reflecting difficulties in clinical evaluation due to obesity and relative preservation of intravascular volume because of hyperosmolarity. Electrolyte losses similarly exceed those of DKA as a result of more prolonged osmotic diuresis. Patients who meet criteria for both DKA and HHS require more prolonged and aggressive fluid and electrolyte replacement therapy than typical children with DKA. Replacement of ongoing urinary losses may be necessary. Frequent reassessment of circulatory status and fluid balance is critical. A high frequency of thromboses has been described in children with HHS as well as rhabdomyolysis and a malignant hyperthermia-like syndrome.95,96 Cerebral edema appears to be a rare complication of HHS, with only one case reported.97

Nonketotic Hyperosmolar Coma

This syndrome is characterized by severe hyperglycemia (blood glucose >800 mg/dL; 44 mmol/L), absence of or only slight ketosis, nonketotic acidosis, severe dehydration, depressed sensorium or frank coma, and various neurologic signs that may include grand mal seizures, hyperthermia, hemiparesis, and positive Babinski signs. Respirations are usually shallow, but coexistent metabolic (lactic) acidosis may be manifested by Kussmaul breathing. Serum osmolarity is commonly 350 mOsm/kg or greater. This condition is uncommon in children although may be increasing in frequency with the rise in the incidence of T2DM. Among adults, mortality rates are high, possibly in part because of delays in recognition and institution of appropriate therapy. In children, there has been a high incidence of preexisting neurologic injury. Profound hyperglycemia may develop over a period of days and, initially, the obligatory osmotic polyuria and dehydration may be partially compensated for by increasing fluid intake. With progression of disease,thirst becomes impaired, possibly because of alteration of the hypothalamic thirst center by hyperosmolarity and, in some instances, because of a preexisting defect in the hypothalamic osmoregulating mechanism.

The low production of ketones is attributed mainly to the hyperosmolarity, which in vitro blunts the lipolytic effect of epinephrine and the antilipolytic effect of residual insulin; blunting of lipolysis by the therapeutic use of β-adrenergic blockers may contribute to the syndrome. Depression of consciousness is closely correlated with the degree of hyperosmolarity in this condition as well as in DKA. Hemoconcentration may also predispose to cerebral arterial and venous thromboses before therapy is initiated.

Treatment of nonketotic hyperosmolar coma is directed at rapid repletion of the vascular volume deficit with normal saline, andvery slow correction of the hyperosmolar state. The fluid deficit should be estimated at 12–15% of body weight. Additional normal saline boluses may be required to reduce tachycardia and poor perfusion. One-half isotonic saline (0.45% NaCl; may use normal saline) is administered at a rate estimated to replace 50% of the volume deficit in the 1st 12 hr, and the remainder is administered during the ensuing 24 hr. The rate of infusion and the saline concentration are titrated to result in a slow decline of serum osmolality. When the blood glucose concentration approaches 300 mg/dL, the hydrating fluid should be changed to 5% dextrose in 0.225% NaCl. Approximately 20 mEq/L of potassium chloride should be added to each of these fluids to prevent hypokalemia. Serum potassium and plasma glucose concentrations should be monitored at 2 hr intervals for the 1st 12 hr and at 4 hr intervals for the next 24 hr to permit appropriate adjustments of administered potassium and insulin.

Insulin can be given by continuous intravenous infusion only after serum glucose levels no longer decline with fluid administration. The IV insulin should be initiated at a low dose of 0.025-0.05 units/kg/hr and titrated to achieve a slow decline in serum glucose of 50-75 mg/dL/hr (2.8-4.2 mmol/L/hr). The presence of ketosis or more severe acidosis may necessitate earlier insulin initiation.

Clinical Findings

HHS has a clinical presentation that commonly resembles the signs and symptoms seen in DKA. Patients in HHS may present with polyuria, polydipsia, severe dehydration, weight loss, blurred vision, and changes in mental status. However, a distinguishing feature is the timing of the symptoms. Patients in DKA will often present with more acute symptoms, whereas patients in HHS may have symptoms develop over several days to weeks. A careful history should be performed to assess for any precipitating factors such as infection, cardiovascular compromise, dietary indiscretions, changes in medications, and general compliance with prescribed diabetic regimen.

On physical examination, patients may appear dehydrated with dry mucous membranes, decreased skin turgor, tachycardia, and hypotension. Unlike DKA, patients in HHS typically do not develop gastrointestinal distress. Neurologic symptoms such as decreased alteration, stupor, delirium, seizure, and focal neurologic deficits such as transient hemiplegia may also be present.

Hyperglycemic Hyperosmolar Syndrome

Hyperglycemic hyperosmolar syndrome is characterized by severe hyperglycemia, hyperosmolarity, and dehydration. It usually occurs in the context of an acute illness in patients with type 2 diabetes who are older than 60 years. The syndrome evolves over days to weeks, with a persistent glycosuric diuresis. The patient experiences polyuria, polydipsia, hypovolemia, hypotension, tachycardia, and organ hypoperfusion. Hyperosmolarity (>340 mOsm/L) is responsible for mental obtundation or coma (Table 23.5). Patients may have some degree of metabolic acidosis but do not demonstrate ketoacidosis.

Treatment includes significant fluid resuscitation, insulin administration, and electrolyte supplementation. If plasma osmolarity is greater than 320 mOsm/L, large volumes of hypotonic saline (1000–1500 mL/h) should be administered until the osmolarity is less than 320 mOsm/L, at which time large volumes of isotonic saline (1000–1500 mL/h) can be given. Insulin therapy is initiated with an IV bolus of 15 units of regular insulin followed by a 0.1-unit/kg/h infusion. The insulin infusion is decreased to 2–3 units/h when the glucose level decreases to approximately 250–300 mg/dL. Electrolyte deficits are significant but usually less severe than in DKA.

Hyperosmolar hyperglycaemic syndrome

HHS is more often seen in patients with type II diabetes and the dominant feature is hyperosmolarity (>320 mOsm/kg). HHS is typically observed in elderly patients with non-insulin-dependent diabetes mellitus, although it may rarely be a complication in younger patients with insulin-dependent diabetes, or those without diabetes following severe burns,11 parenteral hyperalimentation, peritoneal dialysis, or haemodialysis. Patients receiving certain drugs including diuretics, corticosteroids, β-blockers, phenytoin and diazoxide are at increased risk of developing this syndrome. HHS may be caused by lithium-induced diabetes insipidus.12 Not only may mental obtundation occur, but also occasionally focal neurological features or seizures are present.

Precipitating Events

HHS occurs most commonly in older subjects with type 2 diabetes, but may be seen in younger and in type 1 patients as well. Up to 20% of patients admitted with HHS do not have a previous diagnosis of diabetes.7 The most common precipitating causes are pneumonia and urinary tract infection, accounting for 30% to 50% of cases.116-118 Other acute medical illnesses as precipitating causes include acute coronary syndromes, trauma, surgery, and cerebrovascular accident, which provoke the release of counterregulatory hormones and/or compromise access to water. Certain medications that cause DKA may also precipitate the development of HHS, including glucocorticoids, thiazide diuretics, Dilantin, and β-blockers.119,120 During the last few years, several case reports and retrospective studies suggest an increased risk for developing diabetes mellitus in patients treated with atypical antipsychotics compared to schizophrenic patients treated with conventional antipsychotics or those without treatment.121-123 Most cases of hyperglycemic crises associated with the use of antipsychotics have been reported during treatment with clozapine and olanzapine.124-126

Clinical presentation

HHS is characterized by severe hyperglycemia (glucose level >600 mg/dL) and plasma hyperosmolality (>320 mOsm/kg) in the absence of significant ketoacidosis. A mild ketonemia, however, does not preclude the diagnosis (see Table 72.1).21 HHS patients are profoundly volume depleted with an average total body water deficit of 8–10 L.2,22

Altered mental status and neurologic symptoms are the most common presenting symptoms and typically manifest when the osmolality reaches 230–330 mOsm/kg.23,24 Other symptoms include polydipsia, polyuria, fatigue, visual disturbances, weakness, anorexia, weight loss, dizziness, confusion, and lethargy.18 Hallmarks of DKA including Kussmaul breathing, fruity odor, and positive urine ketones are not expected.

Definition and Epidemiology

Hyperglycemic hyperosmolar state used to be named hyperglycemic hyperosmolar nonketotic coma, but this term was not applicable to all patients as it was found that it frequently presents without coma. It was also named hyperglycemic hyperosmolar nonketotic state, but findings of moderate ketonemia in some patients lead to the acceptance of its updated term hyperglycemic hyperosmolar state (HHS). This is a potentially fatal hyperglycemic crisis that occurs as acute complication of uncontrolled diabetes mellitus.

HHS is most frequently encountered in middle-aged or elderly subjects with type 2 diabetes however it has also been reported in type 1 diabetes as a simultaneous occurrence with diabetic ketoacidosis (DeFronzo et al., 1994; Rosenbloom, 2010). The mortality rate from HHS is still high and approaches 20% (Wachtel et al., 1991). On the other hand, the incidence of HHS is less than 1 case per 1000 person-years.

11 What are the common precipitating events in HHS?

HHS occurs most often in patients with known type 2 diabetes although it is the first evidence of diabetes in 30% to 40% of patients. The most common cause is a medical crisis such as infection or sepsis, cardiovascular event, cerebrovascular accident, pancreatitis, or acute abdomen. Pharmaceuticals that raise glycemia also are sometimes at fault, with the best known high-dose thiazides, corticosteroids, sympathomimetic agents, atypical antipsychotics, and β-blockers. Another common feature is caregivers having restricted the patient's access to water because of incontinence or bed-wetting.