Hyperglycemic hyperosmolar state

OVERVIEW: What every practitioner needs to know

Pediatric hyperglycemic hyperosmolar state (HHS) is increasing in conjunction with increased rates of obesity and type 2 diabetes. Unlike adult HHS in which comorbid conditions frequently play a role, pediatric HHS occurs most often in otherwise healthy children who are not known to have diabetes and become severely dehydrated and electrolyte depleted. Therapy of HHS or diabetic ketoacidosis (DKA) complicated by severe hyperosmolality needs to be more aggressive and the practitioner more cognizant of the complications that result in high case fatality in those who are obese, including renal failure, persistent hypotension, hyperthermia, rhabdomyolysis, pancreatitis, arrhythmia and arrest with hypokalemia and hypophosphatemia, and pulmonary embolization.

Are you sure your patient has HHS? What are the typical findings for this disease?

Key symptoms and signs of the disease

• abdominal pain with or without vomiting; polyuria/polydipsia; lethargy/weakness/confusion.

• coma; combativeness; seizures.

• The biochemical definition of HHS is serum glucose concentration >600 mg/dL (33 mmol/L), with serum osmolality >330 mOsm/kg and absence of significant ketosis and acidosis (serum bicarbonate >15 mEq/L, and minimal ketonuria).

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What other disease/condition shares some of these symptoms?

• Diabetic ketoacidosis (DKA) with hyperosmolality. Some acidosis may be present in HHS due to hypoperfusion and lactic acidosis. 25-30% of HHS patients will have sufficient ketonuria to suggest overlap with DKA. (See Table I)

• Alcohol or drug intoxication

• Head trauma

• Gastroenteritis

Table I.

What caused this disease to develop at this time?

• gradually increasing polyuria and polydipsia, typically unrecognized, as the result of progressive deficit of insulin action

• obesity (BMI >2 SDS) – 75% of cases contributing to the insulin resistance

• African-American ethnicity – 70% of cases

• family history of type 2 diabetes – 90% of cases

• retardation/severe psychiatric problems – 20% of cases

• previously undiagnosed diabetes in all pediatric cases

• consumption of large quantities of sugar containing fluids

• signs of severe dehydration may be difficult to elicit because of the hyperosmolality and obesity, delaying diagnosis

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

• serum glucose

• serum sodium, potassium, chloride, CO2, phosphorus, pH, urea nitrogen, creatinine, urine or serum ketones and serum beta hydroxybutyrate (if available)

• lactic acid (elevated because of hypoperfusion and will lower pH, creating diagnostic confusion with DKA)

• hemoglobin, hematocrit, HbA1c, white blood count and differential

• serum lipase, amylase (pancreatitis common complication)

• ECG (hypokalemia common)

Would imaging studies be helpful? If so, which ones?

Chest x-ray study may be necessary in comatose patient to rule out aspiration.

Confirming the diagnosis

The diagnosis of HHS is straightforward, but may occur in association with substantial ketosis and acidosis, requiring consideration of potential complications of both HHS and DKA. Patients with substantial ketosis (moderate or large ketonuria by dipstick) require insulin treatment following the initial fluid bolus.

If you are able to confirm that the patient has HHS, what treatment should be initiated?

Fluids

(See Figure 1)

Figure 1.

Rapid reperfusion is critical to minimize mortality from rhabdomyolysis, renal failure, thrombosis and embolization, and malignant hyperthermia. Minimum initial bolus is 20 mL/kg isotonic saline, repeated as necessary to restore peripheral perfusion. The higher the serum osmolality, blood urea nitrogen and creatinine, the more serious the dehydration and need for isotonic fluid replacement. This is different from the typical patient with isolated DKA and fairly normal BUN and creatinine. Fluid deficit can be assumed to be 12-15% of body weight. One half normal to three quarters normal (0.45-0.75%) saline should be used following the initial reperfusion, replacing the remaining deficit over 48 hours.

Failure of corrected or measured serum sodium levels to decline with IVF has been frequent in fatal cases. Such an observation may require more dilute fluids and consideration of dialysis. Hemodialysis has been more successful than peritoneal dialysis. Rates of fluid replacement are more rapid and need for >20 mL/kg bolus more common than in DKA. Also, unlike in DKA, urinary losses should be replaced with 0.45% saline.

Potassium replacement needs to be early and adequate, as pretreatment losses and ongoing diuresis, correction of lactic acidosis, and eventual insulin therapy will continue to lower serum levels. Initial rhythm strip may indicate hypokalemia, so that administration need not await a report of serum concentration. Serum concentration should be monitored hourly, or at least every 2-3 hours, along with cardiac monitoring.

As with potassium, phosphate losses before treatment can be substantial and hypophosphatemia contributes to the complication of rhabdomyolysis and mortality. Therefore, potassium should be administered as a one to one mixture of potassium phosphate and potassium chloride. This avoids the potential for hypocalcemia from phosphate administration.

Bicarbonate must not be administered because of increased risk of hypokalemia, decreased tissue oxygen uptake, and absence of any evidence of therapeutic benefit.

Hypomagnesemia can contribute to hypocalcemia during treatment, and as with potassium and phosphorus, pretreatment losses may have been substantial. While documented benefits of replacement therapy are lacking, low magnesium concentrations deserve attention, especially with low calcium levels; replacement is 25-50 mg/kg/dose for 3 to 4 doses every 4-6 hours with maximum infusion rate of 150 mg/minute and 2 g/hour.

Insulin

(See Figure 1)

Despite the very high glucose levels, the early administration of insulin is not indicated in the absence of substantial ketosis as indicated by moderate to large ketonuria, and should be held until glucose concentrations are no longer declining from fluid administration alone.

Early administration of insulin will increase the risk of hypokalemia and cardiac arrhythmia/arrest, because of insulin-induced shift of potassium from the circulation to the intracellular space.

The osmotic effect of glucose in the circulation helps to maintain blood volume, so that rapid declines in serum glucose concentration and osmolality could compromise circulation and enhance thromboembolism before adequate fluid replacement.

Initial continuous infusion is 0.025-0.05 units/kg/hour following bolus fluid replacement. Do not bolus insulin.

Patients with substantial ketosis (mixed HHS and DKA) will require insulin infusion (not a bolus) following initial bolus administration of fluids. This should be in a dose of 0.05-0.1 units/kg/hour.

Monitoring

(See Figure 1)

Hourly: serum glucose, vital signs, hydration, Glasgow coma scale.

Every 2 to 3 hours: serum electrolytes, lactic acid, urea nitrogen, creatinine, osmolality, creatine kinase (or urinalysis for myoglobin), intake and output.

Every 3 to 4 hours: serum calcium, phosphate, and magnesium.

Continuous cardiac monitoring.

What are the possible outcomes of HHS?

Severe dehydration and electrolyte loss may result in collapse and arrest before medical intervention. With treatment, the reduction in serum osmolality may result in an osmolar gradient with water moving from the intravascular to the intracellular space compromising intravascular volume. This vascular collapse results in rhabdomyolysis, renal failure, and thrombosis with embolization. The electrolyte disturbances, unless aggressively treated, can result in cardiac arrest. Pancreatitis and hyperthermia are also common complications.

The family needs to be made aware of the gravity of the condition, the high frequency of complications, and the high mortality rate, which appears to be almost exclusively among the obese individuals with HHS.

What causes this disease and how frequent is it?

Pathophysiology

DKA and HHS are the result of a critical deficit of insulin action, with hyperglycemia and release of counterregulatory stress hormones (glucagon, catecholamines, cortisol, growth hormone), likely mediated by pro-inflammatory cytokines. Hepatic and renal glucose production are increased by the counterregulatory hormones which also reduce glucose utilization in insulin dependent peripheral tissues (muscle, liver, fat) contributing to hyperglycemia and release of free fatty acids (lipolysis). Hepatic oxidation of these fatty acids results in production of massive amounts of ketones bodies which cannot be metabolized in the absence of glucose metabolism. In HHS, while insulin action may not be adequate for glucose utilization by insulin sensitive tissues, there may be sufficient activity to prevent lipolysis and ketogenesis. (See Figure 2)

Figure 2.

HHS usually occurs after prolonged and gradually increasing polyuria and polydipsia with severe fluid losses. This results in profound dehydration; in adults, fluid losses with HHS are estimated to be twice those of DKA. There is also severe electrolyte loss, greater than in DKA because of longer duration of the osmotic diuresis. Hypertonicity preserves the intravascular volume, contributing to the masking of clinical signs of dehydration.

Epidemiology

The first report of HHS in a child was in 1966. Only 25 additional cases were reported over the next 35 years. Only one had pre-existing diabetes. One fourth of instances were in children with mental retardation, commonly Down syndrome. Case fatality was 23% from multiple organ failure, persistent coma and hyperthermia, or thrombosis.

From 2001 to 2010, 71 cases were reported, thought related to the increase in incidence of pediatric type 2 diabetes. This series differs markedly from those reported between 1966 and 2000. 3/4 of the earlier group were <9 years of age (6.25 +5.0) while all of the cases after 2000 were > 9 years of age (14.8 + 2.6). Sex ratio was normal in the earlier group, but 3.5:1 males in recent cases, despite greater frequency of type 2 diabetes in female adolescents. Obesity was nonexistent in the earlier series, but present in 75% of cases after 2000. Acanthosis nigricans and family history of type 2 diabetes were common only in the more recent series. Case fatality rate was higher in the recent series (37% versus 23%). Type 1 diabetes (except one with cystic fibrosis) was diagnosed in all survivors in the earlier cases, but in only one third of survivors since 2000.

HHS in adults has long been recognized, typically occurring in elderly, often disabled individuals with established type 2 diabetes, in contrast to its occurrence only in previously undiagnosed children and adolescents. High-risk adults, frequently with cardiovascular disease, had case fatality rates of ~50%, but rates are now estimated at ~15% as a result of improved management, principally aggressive rehydration.

Frequency of this recently recognized problem in pediatrics is uncertain. The only more or less population-based data to estimate the frequency of HHS with type 2 diabetes is an analysis of 190 patients diagnosed over 5.7 years at Children’s Hospital of Philadelphia (CHOP), 8 (4.2%) of whom had HHS, all obese African-American children. An annual incidence of ~2600 cases of type 2 diabetes in children can be projected from the SEARCH for Diabetes in Youth study. Using the CHOP estimate, this would be associated with ~100 episodes of HHS annually. This estimate does not include the substantial number of type 1 patients who can have a predominantly HHS presentation.

Mortality risk factors

In adults, mortality with HHS is related to age and osmolality. In reported cases since 2000, mean + SD osmolality in survivors (378 + 30) did not differ from that in fatal cases (382 + 32) in contrast to the 41 mOsm/L difference between survivors and fatalities in adults. Differences were also not seen between survivors and fatalities for serum creatinine levels.

The overwhelming risk factor for mortality is obesity. All of the 22 nonobese patients since 2000, defined as BMI SDS <2.5, survived while only 47% of the obese individuals did. The obese individuals were 90% African-American, while only 27% of the non-obese were. Whereas 90% of the surviving obese individuals had type 2 diabetes, only 26% of the nonobese did.

What complications might you expect from the disease or treatment of the disease?

Among 71 reported cases from 2000 to 2010, renal failure occurred in ~1/3 with a case fatality of 68%; hemodialysis was most effective for survival. Four of 5 receiving hemodialysis survived while only 1 of 4 who received peritoneal dialysis did. Rhabdomyolysis occurred in 20%, with a 57% case fatality. Hyperthermia occurred in 17%, with a case fatality of 67%. Only 2 of the 7 individuals who had pancreatitis survived. Persistent hypernatremia was associated with progressive deterioration and multiple organ failure.

Multiple organ failure was associated with mortality in 18 of the 26 deaths and included renal failure in 15, persistent hypotension in 12, hyperthermia in 8, rhabdomyolysis in 8, pancreatitis in 5, and terminal arrhythmia/arrest in 11. The other eight fatalities were attributed to hypokalemia (3), pulmonary embolism (4), and cerebral edema (1).

How can HHS be prevented?

At least 50% of reported instances of HHS could have been prevented by appropriate clinical and laboratory evaluation in a physician’s office or emergency department where the youngster had been seen. These are also the most seriously ill youngsters.

Prevention of HHS requires that primary care and emergency physicians have a high index of suspicion for diabetes in seriously ill youngsters, particularly those who are obese, African-American, or with a family history of type 2 diabetes. Because all reported cases thus far are in youngsters with previously undiagnosed diabetes, early recognition and treatment of diabetes by routine testing of obese children and adolescents during school and sports examinations can be preventive.

VII. What's the evidence?

Kitabchi, AE, Umpierrez, GE, Miles, JM, Fisher, JN. “Hyperglycemic crises in adult patients with diabetes”. Diabetes Care. vol. 32. 2009. pp. 1335-43.

Morales, A, Rosenbloom, AL. “Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes”. J Pediatr. vol. 144. 2004. pp. 270-3.

Fourtner, SH, Weinzimer, SA, Katz, LEL. “Hyperglycemic hyperosmolar nonketotic syndrome in children with type 2 diabetes”. Pediatric Diabetes. vol. 6. 2005. pp. 129-135.

Carchman, RM, Dechert-Zeger, M, Calikoglu, AS, Harris, BD. “A new challenge in pediatric obesity: Pediatric hyperglycemic hyperosmolar syndrome”. Pediatr Crit Care Med. vol. 6. 2005. pp. 20-4.

Cochran, JB, Walters, S, Losek, JD. “Pediatric hyperglycemic hyperosmolar syndrome: diagnostic difficulties and high mortality rate”. Am J Emerg Med. vol. 24. 2006. pp. 297-301.

Canarie, MF, Bogue, CW, Banasiak, KJ, Weinzimer, SA, Tamborlane, WV. “Decompensated hyperglycemic hyperosmolarity without significant ketoacidosis in the adolescent and young adult population”. J Pediatr Endocrinol Metab. vol. 20. 2007. pp. 1115-24.

Rosenbloom, AL. “Hyperglycemic hyperosmolar state: an emerging pediatric problem”. J Pediatr. vol. 156. 2010. pp. 180-4.

Zeitler, P, Glaser, N, Haqq, A, Rosenbloom, AL. “Hyperglycemic hyperosmolar syndrome in children; pathophysiologic considerations and suggested Guidelines for treatment”. J Pediatr. vol. 158. 2011. pp. 9-14.

Wolfsdorf, JI, Allgrove, J, Craig, M, Edge, J. “Hyperglycemic crises in pediatric patients with diabetes: a consensus statement from the International Society for Pediatric and Adolescent Diabetes”. Pediatric Diabetes Suppl. vol. 20. 2014. pp. 154-179.

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