Hyperglycemic Hyperosmolar State: ED presentation, evaluation, management, and complications

Authors: Rachel de Andrande Pereira, MD (Lincoln Medical Center Bronx New York); Muhammad Waseem, MD (Lincoln Medical Center & St. Georges University Grenada West Indies); Mushtaq Godil MD (Geisinger Health System, Danville, PA) // Reviewed by: Edward Lew, MD (@elewMD); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case

A previously healthy 12-year-old boy presents to the emergency department (ED) after being found confused and lethargic by his parents. The child’s parents are not sure if there has been increased urinary frequency, but patient has exhibited an increased thirst, for which they gave carbonated soda and fruit juices. Initial vital signs are as follows: HR 120, RR 32, BP 105/72, oxygen saturation 98% on room air and temperature 98.8°F. On examination, the patient demonstrates a decreased mental status, lethargy, and dry mucous membranes. He has diffuse abdominal tenderness but no guarding.  The initial plasma glucose level is 750 mg/dL.

What do you suspect as the diagnosis? What are your next steps?

Answer: A Hyperglycemic Emergency

 

Why do we care?

Hyperglycemic hyperosmolar state (HHS) is also known as hyperglycemic hyperosmolar non- ketotic coma (HONK). It was first described in 1986, (1) but it received little attention until seven decades later when it was described as “severe stupor without ketosis.” (2) Due to the increased prevalence of obesity and Type 2 Diabetes Mellitus (DM) in children, the incidence of HHS in this age group has also been rising. (3,4) Its true incidence is unknown, but it is significantly less than diabetic keto-acidosis. However, the mortality rate is much higher ranging from 10% to 20%, requiring early recognition and prompt treatment. (5,6)

 

Definition

Hyperglycemic hyperosmolar state is a life-threatening emergency characterized by mild to no ketosis, mild to no acidosis, severe hyperglycemia, high serum osmolality, and neurologic abnormality, (7) which is often a change in mental status ranging from confusion to coma. (8,9)

The standard diagnostic criteria are as follows: (10)

  • Blood glucose > 600 mg/dL
  • Serum osmolality >320 mOsm/L
  • pH > 7.3
  • HCO3 > 15 mmol/L
  • Minimal or no, serum or urinary ketones

However, the presence of ketones and significant acidosis does not exclude HHS. (11)

 

Epidemiology

The incidence of HHS is difficult to ascertain due to a limited number of epidemiologic reports regarding its incidence. It is estimated to be much less than DKA and less than 1% of all diabetes-related presentations. (12) With an increasing prevalence of Type 2 DM, the incidence of HHS is expected to rise. (13) This earlier onset of Type 2 diabetes in children is a cause of concern. HHS occurs in all ethnicities and is increasingly reported around the world. (14) Up to 3.7% of adolescents with Type 2 DM present with HHS. (15) It is usually precipitated by infections, inter-current illnesses, drugs such as glucocorticoids, and limited access to water, particularly among the elderly. Mortality among patients with HHS is considerably higher than DKA and ranges between 5% and 35% depending upon age, severity of mental status changes, and associated co-morbid conditions. (16,17)

 

Etiology

HHS is the most serious acute hyperglycemic emergency condition among patients with diabetes, mainly Type 2. It is the result of disturbances in glucose metabolism and fluid balance. (18) It is usually precipitated by the following conditions.

The 4 “I”s:

  • Infection: pneumonia, urinary tract infection, intra-abdominal, etc.
  • Inter-current illness: such as myocardial infarction, pulmonary embolism, or stroke
  • Insulin Insufficiency
  • Inadequate hydration

In addition, trauma and advanced age are also potential precipitants for HHS.

 

Pathophysiology

It is estimated that Type 2 DM represents 8-45% of all patients with DM, though this is likely an underestimation.  It is commonly associated with obesity. Obesity is considered both a pro-inflammatory and a pro-coagulant state which leads to a state of insulin resistance. The exact pathophysiology of HHS is unknown. The fundamental cause is a critical deficit of insulin activity from pancreatic beta cell dysfunction associated with insulin resistance. This results in a reduction of glucose utilization leading to severe hyperglycemia and dehydration.  There is sufficient insulin to suppress ketogenesis, but not enough to control hyperglycemia.

The typical presentation of HHS includes features of uncontrolled hyperglycemia followed by dehydration, lethargy, and altered mental status. Hyperglycemia is usually more severe (>600 mg/dL) in comparison with DKA. The insidious onset of Type 2 diabetes allows osmotic diuresis to continue unabated which leads to progressive volume depletion. Increased counter-regulatory hormones (such as glucagon, cortisol, catecholamines, and growth hormone) also lead to decreased insulin sensitivity, which in turn results in increased glycogenolysis and gluconeogenesis. This further exacerbates hyperglycemia with massive osmotic diuresis, which then results in severe dehydration. In adults, the fluid deficit in HHS has been estimated to be twice (100-200 ml/kg) that found in DKA. (19) The guidelines for DKA and HHS in pediatric populations suggest an assumption of a 12-15% fluid deficit in HHS. (7) Hypovolemia leads to a decrease in renal perfusion and glucose clearance. Hyper-osmolarity can also inhibit lipolysis decreasing the influx of fatty acids, which can explain decreased ketosis as compared to DKA. HHS is usually associated with precipitating factors such as infection, trauma, and drugs (steroids, thiazide diuretics). Such conditions can exacerbate progressive insulin resistance, which results in progressive hyperglycemia and hyper-osmolarity, eventually manifesting as mental status changes. Long-standing hyperglycemia and osmotic diuresis can also result in a severe total body potassium deficit, in spite of apparent normal values at presentation. (20)

 

Similarities and differences between HHS and DKA

DKA and HHS are life-threatening manifestations of diabetes mellitus. It is also believed that HHS and DKA occur on a continuum rather than as two distinct conditions. (21) Both present with hyperglycemia and dehydration. Although HHS symptoms exhibit a considerable overlap with those of DKA (22) and some HHS patients manifest the presence of small ketones and mild to moderate acidosis, most HHS patients have the following unique findings:

  • The onset in HHS is insidious over a period of days or weeks.
  • A considerably greater water-deficit resulting in a more profound state of dehydration, wherein a water deficit in DKA is 3-6 L and in HHS, it may be 8-10 L.
  • Ketosis is usually minimal and is not significant.
  • None to minimal acidosis, partly due to lactic acidosis resulting from severe dehydration.
  • A significant potassium deficit.
  • Neurological symptoms associated with a change in mental status mainly due to increased osmolality.

Thus, HHS differs from DKA in terms of the time of onset, the degree of dehydration, and the severity of both ketosis and acidosis.

What are the challenges in the diagnosis and management of HHS?

The diagnosis of HHS can be challenging because it can mimic many other causes of altered mental status, particularly in patients with new onset diabetes. Although most symptoms relate to severe dehydration, this may be difficult to recognize particularly in obese patients. Physical examination usually reveals a decrease skin turgor, tachycardia, hypotension, hypothermia, and an altered sensorium depending upon the severity of presentation. A focal neurologic deficit and seizures may also occur. Abdominal pain, common in DKA, is usually not seen in the absence of ketosis/acidosis.   Abdominal pain may be due to intra-abdominal pathology inciting HHS.

Beware that patients may present with a mixed picture of DKA and HHS, and significant overlap may occur. (23) This may pose distinct challenges. In the presence of acidosis, other causes of high anion gap metabolic acidosis should also be considered. Such causes include salicylates, methanol, ethylene glycol, and paraldehyde. Similarly, if high sugar-containing drinks are consumed, it may cause severe hyperglycemia in DKA. (24)

 

ED Evaluation

The initial laboratory evaluation should include the following:

Serum glucose

Serum electrolytes

  • Serum Sodium: Urinary losses and fluid shifts out of the cell and into the extracellular compartment causing hyponatremia
  • Caution for interpretation: Correct for hyperglycemia (add 1.6–2.4 mg/dL sodium per 100 mg/dL of glucose). See MDCalc.
  • Serum Potassium: Usually normal or low but there is a total body deficit
  • Check for anion gap. It is useful to assess severity of acidosis and to follow progress of treatment. It is variable in HHS depending on precipitating cause. Anion Gap = [Na] – ([Cl] + [HCO3]), Normal = 8–16, See MDCalc.

Beware that patients with hypoperfusion may have increased anion gap (high lactate and beta hydroxybutyric acid)

BUN and Creatinine

BUN often markedly elevated due to dehydration

Rehydrate and establish urine output before potassium replacement

Venous blood gas (look for metabolic acidosis ± respiratory compensation)

Serum Ketones: Beta-hydroxybutyrate if present is helpful when monitoring the response to treatment

Calculated osmolality: Serum osmolality = 2[Na] + (glucose/18) + (blood urea nitrogen/2.8), See MDCalc.

Complete blood count: A mild leukocytosis is common in DKA/HHS; consider infection as a cause for HHS/DKA depending on clinical scenario.

Urinalysis: Suspect DKA in the presence of glycosuria and ketonuria

Depending on the patient’s history further evaluation may be needed to determine the precipitating cause.

 

General Management

Since there are no prospective, randomized studies to guide best treatment strategies in HHS, its management has largely been extrapolated from DKA research, and many patients particularly children with HHS are often treated with DKA protocols.

Goals of treatment:

  • Fluid resuscitation
  • Treatment of the precipitating cause, if present
  • Gradual correction of hyperglycemia and hyperosmolarity
  • Treatment of electrolyte imbalance
  • Monitoring of neurologic status
  • Intake and output monitoring
  • Glucose, electrolytes, BUN, creatinine, osmolality (actual and calculated) monitoring
  • Observation and assessment for complications

Infection is the most common precipitating factor besides insulin deficiency. (25) Empiric antibiotic treatment is recommended if infection is suspected. Suspected drugs (steroids, thiazides, and beta blockers) should be held if possible. A search for associated comorbidities (such as myocardial infarction, cerebrovascular accident) should be made and treated promptly.

Keep in mind that patients with HHS need rehydration, but as this disease is more insidious and chronic in nature than DKA, fluid should be replaced over several days. The degree of dehydration is greater than in DKA and the risk of cerebral edema with HHS is unknown. Large deficits of both potassium and magnesium should be corrected simultaneously.

 

What are the practical issues in management?

The treatment of hyperglycemic emergencies continues to evolve. Treatment is multidisciplinary, and consultation with an endocrinologist and intensive care specialist is often necessary. In HHS, fluid losses are more severe than DKA. (26) As with the treatment of DKA in adult patients, fluid resuscitation plays a central role in the management of HHS. It increases circulatory volume, improves tissue perfusion, decreases glucose and osmolality, decreases counter-regulatory hormones concentration (thus improving insulin sensitivity).

Poor outcomes have been associated with inadequate fluid resuscitation. In such situation, fluid deficits of approximately 12-15% of body weight may be present. (21, 27) 50% of the fluid deficit should be replaced over 8-12 hours. Avoid rapid changes of effective osmolality after initial resuscitation to prevent possible risk of cerebral edema. (1) Replacement of ongoing urinary losses is an important aspect of HHS.

Insulin infusion can be delayed until the restoration of circulatory volume. (28) To ensure more gradual correction of hyperosmolarity, insulin dose may be started at a lower rate. There are no controlled studies with different doses of insulin in HHS patients. DKA is usually treated with 0.1 u/kg/h and in HHS insulin requirement is less than that. (16) As a starting point, 0.025-0.05 u/kg/h has been suggested. (7)

Factors associated with poor prognosis include:

  • Low pH
  • Hypotension
  • Marked hyperosmolarity (>350 mosmol/kg)
  • High BUN

Mental status changes in HHS are related directly to the effective serum osmolality, and coma is often associated with serum osmolality greater than 340 mOsm/kg. (19)

 

The specifics (Please see “Flow Diagram 1: Treatment of HHS”)

The ADA advocates for initial replacement fluids in hyperglycemic crises of normal saline (0.9% NaCl) bolus 10-20 ml/kg (1-1.5 liter over 1 hour) which may be repeated if necessary. Normal saline should be used to restore hemodynamic stability and adequate renal perfusion. Restoring renal perfusion improves glomerular filtration rate which reduces hyperglycemia significantly. Subsequent fluid replacement should include maintenance fluid plus deficits plus ongoing urinary loses and electrolytes (NS or 1/2 NS with KCL and KPO4) depending upon the labs. In general, infusion at a rate of 250–500 ml/h is appropriate with a goal to replace fluid deficit over 24 to 48 hours maintaining a gradual drop in serum osmolality. (26)  Dextrose should be added in the intravenous fluid once glucose is <300 mg/dl.

  • Insulin has also been considered as a secondary adjunct to fluid replacement in the initial management of HHS. Early use of insulin in the under-resuscitated patient is not recommended. In an under-resuscitated patient, a more rapid decline in serum glucose concentration and osmolality after insulin administration may result in circulatory compromise. Insulin administration may be held until initial fluid resuscitation has been completed and glucose level is no longer falling with fluid management alone. Initial dosing of insulin is 0.025-0.05 units/kg per hour to ensure a more gradual correction of hyper-osmolarity. Osmolality should not decrease more than 3 mOsm/kg/hour and neither should glucose levels by more than 50-70 mg/dl/hour. (7)
  • Electrolytes should be monitored carefully and replaced as needed. Patients with HHS should be closely evaluated for hypernatremia, hypokalemia, and hypophosphatemia. After each bolus, if sodium is normal or low, replacement fluid should be normal saline. If sodium is high, 1/2 Normal saline may be used. (29) Potassium should be added in the intravenous fluid as long as potassium is <5.5 mol/L and the patient is voiding. (23) To avoid arrythmias, cardiac arrest, and respiratory depression, serum potassium levels should be >2.5 mmol/L before starting insulin treatment. (7) To avoid severe hypophosphatemia (<1 mg/dl) and its associated skeletal and cardiac-muscle weakness, hemolytic anemia, and decreased tissue oxygen delivery (i.e., a left shift of the oxyhemoglobin curve), one-half of the potassium can be administered as KPO4. (30, 31)

Flow Diagram_HHS_Muhammad

Complications

  • Mortality in HHS is due to circulatory collapse with shock and cardiac arrest, arrhythmias, pulmonary thromboembolism, malignant hyperthermia, and multisystem organ failure. Fatal cases of cerebral edema have also been reported in HHS in adults. (32, 33)

 

What are the pediatric considerations?

Children with HHS are typically obese and usually have Type 2 diabetes.

  • Development of polyuria and polydipsia is gradual and may remain unrecognized.
  • Dehydration and electrolyte derangements develop slowly but are profound. Therefore, frequent evaluation of fluid balance and peripheral perfusion is required along with frequent monitoring of electrolytes.
  • Despite severe dehydration, intravascular volume may be relatively maintained therefore signs of dehydration may be less evident.
  • Insulin boluses are not recommended, especially for children. Also, since there is minimal ketosis, insulin should be delayed until after initial fluid resuscitation and administered at a lower rate. (34)
  • Some children with DKA may present with severe hyper-osmolarity; this may complicate recognition of HHS as a distinct entity. (35)

 

Take Home Points

  • HHS is a medical emergency and therefore early recognition and aggressive resuscitation with fluids are critical for survival. It is important that physicians have a high index of suspicion particularly with obese patients presenting with altered mental status and hyperglycemia. Beware that there can be overlap between DKA and HHS. Consequently, patients may present with features of both conditions.
  • HHS is driven by osmotic diuresis with an overwhelming dehydration. Fluid replacement with Normal saline is an important initial step.
  • Insulin is more effective following fluid replacement and decreases osmolality and plasma glucose continually.
  • Monitor and replace electrolyte as necessary.
  • Continuous monitoring of vital signs and mental status are important.

 

References/Further Reading:

  1. Dreschfeld J. The Bradshawe Lecture on Diabetic Coma. Br Med J.1886 Aug 21;2(1338):358-63.
  2. Sament S, Schwartz M: Severe diabetic stupor without ketosis. South African Medical Journal 1957; 31:893.
  3. Rosenbloom AL Hyperglycemic hyperosmolar state: an emerging pediatric problem. J Pediatr. 2010 Feb;156(2):180-184.
  4. Zubkiewicz-Kucharska A, Chrzanowska J, Noczyńska A. Hyperosmolar hyperglycaemic state (HHS) as the first manifestation of type 2 diabetes in a child. Pediatr Endocrinol Diabetes Metab. 2019;25(2):85-89.
  5. Bassham B, Estrada C, Abramo T. Hyperglycemic hyperosmolar syndrome in the pediatric patient: a case report and review of the literature. Pediatr Emerg Care 2012 Jul;28(7):699-702.
  6. Hollander AS, Olney RC, Blackett PR, Marshall BA. Fatal malignant hyperthermia-like syndrome with rhabdomyolysis complicating the presentation of diabetes mellitus in adolescent males. Pediatrics 2003 Jun;111(6 Pt 1):1447-1452.
  7. Wolfsdorf JI, Allgrove J, Craig ME, Edge J, Glaser N, Jain V, Lee WW, Mungai LN, Rosenbloom AL, Sperling MA, Hanas R; International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2014. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2014 Sep;15 Suppl 20:154-179.
  8. Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001 Jan;24(1):131-153.
  9. Nyenwe EA, Kitabchi AE. Evidence-based management of hyperglycemic emergencies in diabetes mellitus. Diabetes Res Clin Pract 2011 Dec;94(3):340-351.
  10. American Diabetes Association. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care 2001 Nov;24(11):1988-1996.
  11. Sellers EA, Dean HJ. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 2000 Aug;23(8):1202-1204.
  12. Fishbein HA, Palumbo PJ. Acute metabolic complications in diabetes. In National Diabetes Data Group in America. NIH publication No. 95-1458. Bethesda, Maryland, USA. National Institute of Health, National Institute of Diabetes and Digestive and Kidney Disease 1995: 283-291.
  13. Nugent BW. Hyperosmolar hyperglycemic state. Emerg Med Clin North Am. 2005 Aug;23(3):629-648.
  14. Reinehr T. Type 2 diabetes mellitus in children and adolescents. World J Diabetes. 2013 Dec 15;4(6):270-278.
  15. Fourtner SH, Weinzimer SA, Levitt Katz LE. Hyperglycemic hyperosmolar non-ketotic syndrome in children with type 2 diabetes. Pediatr Diabetes. 2005 Sep;6(3):129-135.
  16. Pasquel FJ, Umpierrez GE. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. Diabetes Care. 2014 Nov;37(11):3124-3131.
  17. Ennis ED, Stahl EJVB, Kreisberg RA: The hyperosmolar hyperglycemic syndrome. Diabetes Review 1994; 2: 115-126.
  18. Maletkovic J, Drexler A. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Endocrinol Metab Clin North Am. 2013 Dec;42(4):677-695.
  19. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic crisis in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006; 29: 2738-2748.
  20. Wachtel TJ, Silliman RA, Lamberton P. Predisposing factors for the diabetic hyperosmolar state. Arch Intern Med 1988 Mar;148(3):747.
  21. Kitabchi AE, Umpierrez GE, Fisher JN, Murphy MB, Stentz FB. Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. J Clin Endocrinol Metab 2008 May;93(5):1541-1552.
  22. Magee MF, Bhatt BA. Management of decompensated diabetes. Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Crit Care Clin 2001 Jan;17(1):75-106.
  23. Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, et al. Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med. 1991 Nov-Dec;6(6):495-502.
  24. McDonnell CM, Pedreira CC, Vadamalayan B, Cameron FJ, Werther GA. Diabetic Ketoacidosis, hyperosmolarity and hypernatremia; are high carbohydrate drinks worsening initial presentation? Pediatr Diabetes 2005; 6(2):90-94.
  25. Wachtel TJ, Silliman RA, Lamberton P. Predisposing factors for the diabetic hyperosmolar state. Arch Intern Med 1987; 147:499-501.
  26. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009 Jul;32(7):1335-1343.
  27. Nugent BW. Hyperosmolar hyperglycemic state. Emerg Med Clin North Am 2005; 23:629-648.
  28. Zeitler P, Haqq A, Rosenbloom A, Glaser N, Drugs and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Hyperglycemic hyperosmolar syndrome in children: pathophysiological considerations and suggested guidelines for treatment. J Pediatr 2011 Jan;158(1):9-14, 14.e1-2.
  29. Pasquel FJ, and Umpierrez GE. Hyperosmolar Hyperglycemic State: A Historic Review of the Clinical Presentation, Diagnosis, and Treatment. Diabetes Care 2014;37:3124–3131.
  30. Kitabchi AE, Umpierrez GE, Murphy MB. Diabetic ketoacidosis and hyperosmolar state. In: DeFronzo RA, Ferrannuini E, Zimmet P, Alberti KGMM, Ed. International Textbook of Diabetes Mellitus, 4th ed. Willey Blackwell, 2015:799-814.
  31. Wolfsdort JI, Glaser N, Agus M, Fritch M, Hanas R, Rewers A, Sperling MA, Codner, E. ISPAD Clinical Practice Consensus Guidelines 2018: Diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Pediatric Diabetes care 2018; 19(suppl 27):155-177.
  32. Stoner GD. Hyperosmolar Hyperglycemic State. Am Fam Physician. 2017;96(11):729-736.
  33. Cochran JB, Walters S, Losek JD. Pediatric hyperglycemic hyperosmolar syndrome: diagnostic difficulties and high mortality rate. American Journal of Emergency Medicine (2006) 24, 297–301.
  34. Ng SM, Edge Hyperglycaemic Hyperosmolar State (HHS) in children: a practical guide to management. Paediatrics and Child Health. 2017: 27 (4) 171-175.
  35. Zeitler P, Haqq A, Rosenbloom A, Glaser N, Drugs and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Hyperglycemic hyperosmolar syndrome in children: pathophysiological considerations and suggested guidelines for treatment. J Pediatr 2011 Jan;158(1):9-14, 14.e1-2.

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