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Hyperosmolar Hyperglycemic State

  • Author: Robin R Hemphill, MD, MPH; Chief Editor: George T Griffing, MD  more...
 
Updated: Apr 30, 2014
 

Background

Hyperosmolar hyperglycemic state (HHS) is 1 of 2 serious metabolic derangements that occurs in patients with diabetes mellitus (DM) and can be a life-threatening emergency. It is less common than the other acute complication of diabetes, diabetic ketoacidosis (DKA). HHS was previously termed hyperosmolar hyperglycemic nonketotic coma (HHNC); however, the terminology was changed because coma is found in fewer than 20% of patients with HHS.[1]

HHS most commonly occurs in patients with type 2 DM who have some concomitant illness that leads to reduced fluid intake. Infection is the most common preceding illness, but many other conditions can cause altered mentation, dehydration, or both. Once HHS has developed, it may be difficult to differentiate it from the antecedent illness. The concomitant illness may not be identifiable. (See Etiology.) HHS has also been reported in patients with type 1 DM, in whom DKA is more common.

HHS usually presents in older patients with type 2 DM and carries a higher mortality than DKA, estimated at approximately 10-20%. (See Epidemiology.)

HHS is characterized by hyperglycemia, hyperosmolarity, and dehydration without significant ketoacidosis. Most patients present with severe dehydration and focal or global neurologic deficits.[2, 1, 3] In as many as one third of cases, the clinical features of HHS and DKA overlap and are observed simultaneously (overlap cases); this suggests that these 2 states of uncontrolled DM differ only with respect to the magnitude of dehydration and the severity of acidosis. (See Presentation.)

According to the consensus statement published by the American Diabetes Association, diagnostic features of HHS may include the following (see Workup)[2, 4] :

  • Plasma glucose level of 600 mg/dL or greater
  • Effective serum osmolality of 320 mOsm/kg or greater
  • Profound dehydration, up to an average of 9L
  • Serum pH greater than 7.30
  • Bicarbonate concentration greater than 15 mEq/L
  • Small ketonuria and absent-to-low ketonemia
  • Some alteration in consciousness

Detection and treatment of an underlying illness are critical. Standard care for dehydration and altered mental status is appropriate, including airway management, intravenous (IV) access, crystalloid administration, and any medications routinely given to coma patients. Although many patients with HHS respond to fluids alone, IV insulin in dosages similar to those used in DKA can facilitate correction of hyperglycemia. Insulin used without concomitant vigorous fluid replacement increases the risk of shock. (See Treatment.)

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Pathophysiology

Insulin-sensitive tissues normally take up glucose during meals, when the glycemic rise of ingested carbohydrates stimulates insulin secretion. The increased insulin levels inhibit glucagon release from the pancreatic islets, and the ratio of plasma insulin to glucagon becomes relatively high.

A high insulin-to-glucagon ratio favors storage of glucose as glycogen in liver and muscle and lipogenesis in adipocytes. Insulin-dependent transport of glucose across the cell membranes of insulin-sensitive tissues drives potassium into these cells. A high insulin-to-glucagon ratio during meals also favors amino acid uptake by muscle.

Between meals, insulin secretion is not stimulated, and the insulin-mediated glucagon inhibition in the pancreatic islets stops. The glucagon levels rise in the plasma, leading to a decrease in the plasma insulin-to-glucagon ratio. The consequence of this decrease is the breakdown of glycogen in the liver and muscle and gluconeogenesis by the liver, both of which maintain the plasma glucose concentration in the normal range. A fall in the insulin-to-glucagon ratio also favors lipolysis and the formation of ketone bodies by the liver.

Several tissues in the body use glucose regardless of the insulin-to-glucagon ratio. These insulin-independent tissues include the brain and the kidneys.

In patients with a preexisting lack of or resistance to insulin, a physiologic stress such as an acute illness can cause further net reduction in circulating insulin. The basic underlying mechanism of HHS is a relative or absolute reduction in effective circulating insulin with a concomitant elevation of counterregulatory hormones.[1, 2]

Decreased renal clearance and decreased peripheral utilization of glucose lead to hyperglycemia. Hyperglycemia and hyperosmolarity result in an osmotic diuresis and an osmotic shift of fluid to the intravascular space, resulting in further intracellular dehydration. This diuresis also leads to loss of electrolytes, such as sodium and potassium.[1, 2, 3]

Unlike patients with DKA, patients with HHS do not develop significant ketoacidosis, but the reason for this is not known. Contributing factors likely include the availability of insulin in amounts sufficient to inhibit ketogenesis but insufficient to prevent hyperglycemia. Additionally, hyperosmolarity itself may decrease lipolysis, limiting the amount of free fatty acids available for ketogenesis. In addition, levels of counterregulatory hormones are found to be lower in patients with HHS than in those with DKA.[1, 2, 3]

Obesity is the most prevalent cause of insulin resistance. Pregnancy is a state of insulin resistance largely due to the action of placental hormones on maternal circulation. High circulating levels of epinephrine, glucagon, growth hormone, and cortisol (the 4 major counterregulatory hormones) cause insulin resistance. Their levels increase during acute illnesses (eg, major infections, myocardial infarction [MI], or pancreatitis) or stress (eg, surgery, major psychiatric illness, or multiple injuries).

Additionally, diseases characterized by excessive production of these counterregulatory hormones (eg, pheochromocytoma, glucagonoma, acromegaly, and Cushing syndrome) may induce insulin resistance. Finally, parenteral nutrition and administration of some medications (notably, glucocorticoids, tretinoin, antiretrovirals, antipsychotics,[5, 6] and cyclosporine and other immunosuppressive agents) cause insulin resistance.

Insulin deficiency is due to autoimmune destruction of the beta cells in type 1 DM. In type 2 DM, a defect in the first-phase release of insulin occurs, which leads to relative insulinopenia. The defective insulin secretion in persons with type 2 DM is due to the direct toxic effect of glucose on beta cells. Many patients with diabetes treated with insulin become relatively insulinopenic when they fail to adjust the dose of insulin upwards during illnesses or periods of stress.

In the absence of adequate insulin activity, hyperglycemia develops. Decreased glucose use occurs in peripheral tissues, including adipocytes and muscles; glucose cannot be stored as glycogen in muscle and liver tissue; and hepatocytes, under the influence of glucagon, stimulate gluconeogenesis.

The resulting elevation in plasma glucose concentration leads to further impairment of insulin release by pancreatic beta cells. In this setting of inadequate insulin action, the magnitude of the rise in plasma glucose concentration also depends, in part, on the level of hydration and oral carbohydrate (or glucose) loading.

Under normal circumstances, all of the glucose filtered by the kidneys is reabsorbed. When glycemia reaches approximately 180 mg/dL, proximal tubular transport of glucose from the tubular lumen into the renal interstitium becomes saturated, and further glucose reabsorption is no longer possible. The glucose that remains in the renal tubules continues to travel into the distal nephron and, eventually, the urine, carrying water and electrolytes with it.

Osmotic diuresis then results. The direct consequence of this osmotic diuresis is a decrease in total body water. Within the vascular space, in which gluconeogenesis and dietary intake continue to add glucose, the loss of water results in further hyperglycemia and loss of circulating volume.

Hyperglycemia and the rise in the plasma protein concentration after intravascular water loss cause a hyperosmolar state. The hyperosmolarity of the plasma triggers release of antidiuretic hormone, which ameliorates renal water loss. Hyperosmolarity also stimulates thirst, a defense mechanism that is impaired in people dependent on others for care.

In the presence of HHS, if the renal water loss is not compensated for by oral water intake, dehydration leads to hypovolemia. Hypovolemia, in turn, leads to hypotension, and hypotension results in impaired tissue perfusion. Coma is the end stage of this hyperglycemic process, when severe electrolyte disturbances occur in association with hypotension.

Any process that accelerates water loss, such as diarrhea or severe burns, accelerates the development of hyperosmolarity and hypotension. In this severely dehydrated and hyperosmolar state, hypotension causes a massive stimulation of the renin-angiotensin-aldosterone system and, eventually, renal shutdown. Oliguria precludes further excretion of glucose from the kidneys, which conserves circulating volume but exacerbates hyperglycemia.

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Etiology

HHS most commonly occurs in patients with type 2 DM who have some concomitant illness that leads to reduced fluid intake. In general, any illness that predisposes to dehydration or to reduced insulin activity may lead to HHS.[1, 3] A wide variety of major illnesses may trigger HHS by limiting patient mobility and free access to water.

When considering treatment of a patient with HHS, assess for and address any acute illness and contributions from medications.

Acute febrile illnesses, including infections, account for the largest proportion of HHS cases. A preceding or intercurrent infection (in particular, pneumonia or urinary tract infection [UTI][1] ) is the single most common cause, but in a number of patients, the concomitant illness is not identifiable.

The stress response to any acute illness tends to increase hormones that favor elevated glucose levels. Cortisol, catecholamines, glucagon, and many other hormones have effects that tend to counter those of insulin. Examples of such acute conditions are as follows:

  • Stroke
  • Intracranial hemorrhage
  • Silent MI – Consider MI in all patients with HHS until it is excluded

Patients with underlying renal dysfunction, congestive heart failure (CHF), or both are at increased risk.

Drugs that raise serum glucose levels, inhibit insulin, or cause dehydration may cause HHS. Examples include the following:

  • Atypical antipsychotics (clozapine, olanzapine)
  • Alcohol and cocaine
  • Antiarrhythmics (eg, encainide and propranolol)
  • Antiepileptics (eg, phenytoin)
  • Antihypertensives (eg, calcium channel blockers and diazoxide)
  • Antipsychotics (eg, chlorpromazine, clozapine, loxapine, and olanzapine) [5, 6]
  • L-asparaginase
  • Beta blockers
  • Corticosteroids
  • Diuretics (eg, chlorthalidone, ethacrynic acid, and thiazides)
  • Histamine-receptor blockers (eg, cimetidine)
  • Immunosuppressive agents
  • Total parenteral nutrition (TPN) solutions and fluids that contain dextrose

Noncompliance with oral hypoglycemics or insulin therapy can result in HHS.

Other conditions and illnesses associated with HHS include the following:

  • Acromegaly
  • Anesthesia
  • Burns
  • Cerebrovascular accident
  • Cushing syndrome (eg, endogenous, exogenous, ectopic)
  • Hemodialysis and peritoneal dialysis
  • Gastrointestinal (GI) hemorrhage
  • Heatstroke
  • Hypothermia
  • Intestinal obstruction
  • Mesenteric thrombosis
  • Neuroleptic malignant syndrome
  • Pancreatitis
  • Rhabdomyolysis
  • Sepsis
  • Subdural hematoma
  • Surgery (especially cardiac surgery)
  • Thyrotoxicosis
  • Trauma
  • UTI

Elder abuse and neglect also may contribute to underhydration.

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Epidemiology

United States statistics

No population-based studies of HHS have been conducted. According to the US National Hospital Discharge Survey funded by the National Center for Health Statistics, there were 10,800 annual discharges for HNS in the United States from 1989 to 1991. HHS affects approximately 1 of 500 patients with DM. The overall incidence of HHS is less than 1 case per 1000 person-years, making it significantly less common than DKA. As the prevalence of type 2 DM increases, the incidence of HHS will likely increase as well.[1]

Age-related demographics

HHS has a mean age of onset early in the seventh decade of life. The average age of patients with HHS is 60 years. Most published series report an average age of 57-69 years at diagnosis.[1, 3, 7] In contrast, the mean age of onset for DKA is early in the fourth decade of life. HHS may also occur in younger people. In particular, as rates of obesity increase in children, the prevalence of type 2 DM is also rising in this age group and may lead to an increased incidence of HHS in this population.[8, 9, 10]

Nursing home populations are at risk for HHS. Underlying comorbidities that prevent adequate hydration, including immobility, advanced age, debility, dementia, agitation, and restraint use, place these patients at risk. Impaired senses, such as deafness and blindness, may lead to social isolation and also increase the risk of HHS.

Sex-related demographics

No sex predilection is noted in most published series of HHS. However, some data suggest that the prevalence is slightly higher in females than in males. In the US National Hospital Discharge Survey (see above), 3700 persons were male and 7100 were female.

Race-related demographics

African Americans, Hispanics, and Native Americans are disproportionately affected by HHS as a consequence of an increased prevalence of type 2 DM.[1] In the US National Hospital Discharge Survey of 10,800 hospital discharges listing HHS in the United States between 1989 and 1991, there were 6300 white patients and 2900 African American patients; the remainder of the discharges were people of other races or of unknown race.

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Prognosis

Overall mortality for HHS is typically 10-20%, though figures as high as 58% have been reported. Older age, the presence of concurrent illnesses, and severity of the metabolic derangements (especially dehydration) contribute to this high mortality, as do delay in establishing the diagnosis and failure to treat HHS aggressively from the outset also may contribute to this high mortality rate. In children, mortality from HHS also appears to be higher than mortality from DKA, but too few cases have been reported to allow accurate calculation of pediatric mortality.

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Patient Education

Diabetic teaching, provided both in the hospital and after discharge by the primary care physician, a visiting home nurse, or both, is essential for modifying behavior and enhancing compliance. A certified diabetes educator should instruct all patients on management of sick days and provide a thorough review of self-care. A home evaluation by a visiting nurse may help identify factors limiting adequate access to water.

Having had HHS places patients at risk for further episodes. Diabetic teaching is vital for preventing a recurrence of HHS. Warn patients to avoid poor glycemic control and dehydration.

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Contributor Information and Disclosures
Author

Robin R Hemphill, MD, MPH Associate Professor, Director, Quality and Safety, Department of Emergency Medicine, Emory University School of Medicine

Robin R Hemphill, MD, MPH is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

Howard A Bessen, MD Professor of Medicine, Department of Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Program Director, Harbor-UCLA Medical Center

Howard A Bessen, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Joseph Michael Gonzalez-Campoy, MD, PhD, FACE Medical Director and CEO, Minnesota Center for Obesity, Metabolism, and Endocrinology

Joseph Michael Gonzalez-Campoy, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, Association of Clinical Researchers and Educators (ACRE), and Minnesota Medical Association

Disclosure: Nothing to disclose.

George T Griffing, MD Professor of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, InternationalSocietyfor Clinical Densitometry, and Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Lewis S Nelson, MD, FACEP, FAACT, FACMT Associate Professor, Department of Emergency Medicine, New York University School of Medicine; Attending Physician, Department of Emergency Medicine, Bellevue Hospital Center, New York University Medical Center and New York Harbor Healthcare System

Lewis S Nelson, MD, FACEP, FAACT, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

David S Schade, MD Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center

David S Schade, MD is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, New Mexico Medical Society, New York Academy of Sciences, and Society for Experimental Biology and Medicine

Disclosure: Nothing to disclose.

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society

Disclosure: Nothing to disclose.

Paulina B Sergot, MD Staff Physician, Department of Emergency Medicine, New York University/Bellevue Hospital Center

Paulina B Sergot, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Nugent BW. Hyperosmolar hyperglycemic state. Emerg Med Clin North Am. 2005 Aug. 23(3):629-48, vii. [Medline].

  2. 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):131-53. [Medline].

  3. Trence DL, Hirsch IB. Hyperglycemic crises in diabetes mellitus type 2. Endocrinol Metab Clin North Am. 2001 Dec. 30(4):817-31. [Medline].

  4. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2006 Dec. 29(12):2739-48. [Medline].

  5. Campanella LM, Lartey R, Shih R. Severe hyperglycemic hyperosmolar nonketotic coma in a nondiabetic patient receiving aripiprazole. Ann Emerg Med. 2009 Feb. 53(2):264-6. [Medline].

  6. Ahuja N, Palanichamy N, Mackin P, Lloyd A. Olanzapine-induced hyperglycaemic coma and neuroleptic malignant syndrome: case report and review of literature. J Psychopharmacol. 2010 Jan. 24(1):125-30. [Medline].

  7. MacIsaac RJ, Lee LY, McNeil KJ, Tsalamandris C, Jerums G. Influence of age on the presentation and outcome of acidotic and hyperosmolar diabetic emergencies. Intern Med J. 2002 Aug. 32(8):379-85. [Medline].

  8. Kershaw MJ, Newton T, Barrett TG, Berry K, Kirk J. Childhood diabetes presenting with hyperosmolar dehydration but without ketoacidosis: a report of three cases. Diabet Med. 2005 May. 22(5):645-7. [Medline].

  9. Bhowmick SK, Levens KL, Rettig KR. Hyperosmolar hyperglycemic crisis: an acute life-threatening event in children and adolescents with type 2 diabetes mellitus. Endocr Pract. 2005 Jan-Feb. 11(1):23-9. [Medline].

  10. Singhi SC. Hyperglycemic hyperosmolar state and type 2 diabetes mellitus: yet another danger of childhood obesity. Pediatr Crit Care Med. 2005 Jan. 6(1):86-7. [Medline].

  11. Middleton P, Kelly AM, Brown J, Robertson M. Agreement between arterial and central venous values for pH, bicarbonate, base excess, and lactate. Emerg Med J. 2006 Aug. 23(8):622-4. [Medline]. [Full Text].

  12. Bartoli E, Sainaghi PP, Bergamasco L, Castello L. Hyperosmolar coma due to exclusive glucose accumulation: recognition and computations. Nephrology (Carlton). 2009 Apr. 14(3):338-44. [Medline].

  13. Bartoli E, Bergamasco L, Castello L, Sainaghi PP. Methods for the quantitative assessment of electrolyte disturbances in hyperglycaemia. Nutr Metab Cardiovasc Dis. 2009 Jan. 19(1):67-74. [Medline].

  14. Rosa EC, Lopes AC, Liberatori Filho AW, Schor N. Rhabdomyolysis due to hyperosmolarity leading to acute renal failure. Ren Fail. 1997 Mar. 19(2):295-301. [Medline].

  15. [Guideline] Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, et al. Hyperglycemic crises in diabetes. Diabetes Care. 2004 Jan. 27 Suppl 1:S94-102. [Medline]. [Full Text].

  16. Kitabchi AE, Nyenwe EA. Hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Endocrinol Metab Clin North Am. 2006 Dec. 35(4):725-51, viii. [Medline].

  17. Munoz C, Villanueva G, Fogg L, et al. Impact of a subcutaneous insulin protocol in the emergency department: Rush Emergency Department Hyperglycemia Intervention (REDHI). J Emerg Med. 2011 May. 40(5):493-8. [Medline].

  18. Kitabchi AE, Murphy MB, Spencer J, Matteri R, Karas J. Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis?. Diabetes Care. 2008 Nov. 31(11):2081-5. [Medline]. [Full Text].

 
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