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Diabetic Emergencies, Diagnosis and Clinical Management: Hyperosmolar Non-ketotic Hyperglycemia, Part 1

Apr 8, 2013

Konstantinos Makrilakis, MD, PhD

Nikolaos Katsilambros, MD, PhD.



Hyperosmolar non-ketotic hyperglycemia (also called hyperosmolar hyperglycemic state [HHS]) is one of the most serious acute complications of diabetes, with significant morbidity and mortality.

Together with diabetic ketoacidosis (DKA) it represents an extreme in the spectrum of hyperglycemic states, and in fact significant overlap between these two conditions has been reported in more than one third of cases.1…. 

HHS is characterized by usually extreme hyperglycemia (serum glucose >600 mg/dl [33.3 mmol/L]), hyperosmolality, and profound dehydration, without significant ketoacidosis.2 The essential difference from DKA is that in HHS there is little or no ketoacid accumulation (most patients with HHS have an admission pH >7.30, a serum bicarbonate >18 mEq/L, and test negative for ketones in serum and urine, although mild ketonemia may be present); the serum glucose concentration is usually much higher (frequently exceeding 1000 mg/dl [56 mmol/L]); the plasma osmolality is high (it may reach 380 mOsm/kg); and neurological abnormalities are frequently present (including coma in 25-50% of cases).

Summary box
HHS is usually characterized by:
  • extreme hyperglycemia (serum glucose >600 mg/dl [33.3 mmol/L])
  • hyperosmolality (serum osmolality >320 mOsm/kg H 2 O)
  • profound dehydration
  • lack of significant ketoacidosis



HHS is most commonly seen in older individuals (> 65 years of age) with Type 2 diabetes. 4 The incidence of HHS is difficult to determine because of the lack of population-based studies and the multiple combined illnesses often found in these patients. In general, it is estimated that the rate of hospital admissions due to HHS is lower than the rate due to DKA and accounts for <1% of all primary diabetic admissions.5 The mortality attributed to HHS is higher than that of DKA, with rates ranging from 5% to 20%; as in DKA, mortality is most often due to the underlying precipitating illness. The prognosis is substantially worsened at the extremes of age and in the presence of coma, hypotension, and severe co-morbidities.1-7

Potential causes

The commonest factors that predispose to HHS are not much different than those in DKA. HHS most frequently occurs in older patients with Type 2 diabetes mellitus who have some concomitant illness that leads to reduced fluid intake. Infection (usually of the respiratory or the urinary tract) is the most frequent cause, but many other conditions can lead to altered mentation, dehydration, or both. Such precipitating factors include discontinuation of or inadequate insulin therapy, pancreatitis, myocardial infarction, cerebrovascular accident, endocrine disorders, and drugs (Box 3.1).1 The fact also that these patients have either impaired physical activity and/or reduced thirst drive due to their older age contributes to their propensity for dehydration. In some instances the concomitant illness may not be identifiable.

Summary box

HHS most frequently occurs in older patients with Type 2 diabetes mellitus who have some concomitant illness that leads to reduced fluid intake



Box 3.1 Predisposing or precipitating factors for HHS

Inadequate insulin treatment or non-compliance (21 – 41%)

Acute illness
  • Infection (32 – 60%)
    • Pneumonia
    • Urinary tract infection
    • Sepsis
  • Cerebrovascular accident
  • Myocardial infarction
  • Acute pancreatitis
  • Acute pulmonary embolus
  • Intestinal obstruction
  • Dialysis, peritoneal
  • Mesenteric thrombosis
  • Renal failure
  • Heat stroke
  • Hypothermia
  • Subdural hematoma
  • Severe burns
  • Acromegaly
  • Thyrotoxicosis
  • Cushing’ s syndrome
  • Beta-adrenergic blockers
  • Calcium-channel blockers
  • Chlorpromazine
  • Chlorthalidone
  • Cimetidine
  • Clozepine
  • Diazoxide
  • Ethacrynic acid
  • Immunosuppressive agents
  • L-asparaginase
  • Loxapine
  • Olanzapine
  • Phenytoin
  • Propranolol
  • Steroids
  • Thiazide diuretics
  • Total parenteral nutrition

Previously undiagnosed diabetes




The basic mechanism underlying both DKA and HHS is a reduction in the net effective action of insulin, with concomitant elevation of counter-regulatory hormones, primarily glucagon, but also catecholamines, cortisol, and growth hormone. In patients with a pre-existing lack of or resistance to insulin, a physiological stress such as an acute illness can cause further net reduction in circulating insulin. Decreased renal clearance and decreased peripheral utilization of glucose lead to hyperglycemia. Hyperglycemia and hyperosmolality result in an osmotic diuresis and an osmotic shift of fluid from the intracellular to the intravascular space, resulting in further intracellular dehydration. The increased diuresis also leads to loss of electrolytes such as sodium and potassium.8

Unlike patients with DKA, those with HHS do not develop significant ketoacidosis, but the reason for this is not completely understood. Contributing factors likely include the availability of insulin in amounts sufficient to inhibit ketogenesis (by inhibiting lipolysis in adipose tissue) but not sufficient to prevent hyperglycemia (the available insulin is not able to suppress gluconeogenesis and glycogenolysis in the liver). Additionally, hyperosmolality itself may decrease lipolysis, limiting the amount of free fatty acids available for ketogenesis. Also, lower levels of counter-regulatory hormones have been found in patients with HHS compared to those with DKA. 9

Patients with HHS also usually exhibit much higher hyperglycemia than those with DKA. Two factors are responsible for this effect:

  • People with HHS usually present late in the course of their disease because they lack the early symptoms of ketoacidosis (shortness of breath, abdominal pain) and thus have more long-standing deterioration of their illness, with signs of mental compromise due to hyperosmolality.
  • The second reason is that people with HHS are older, with more compromised renal function, and thus have a lower capacity to excrete glucose in the urine compared to persons with DKA. Older people also have other physical limitations to seek water intake or have diminished thirst drive, which accentuate their dehydration potential and their propensity to hyperosmolality.10

Next text will present: The Diagnosis

  1. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes (technical review). Diabetes Care 2001; 24: 131-53.
  2. Daugirdas JT, Kronfol NO, Tzalaloukas AH, et al. Hyperosmolar coma: Cellular dehydration and the serum sodium concentration. Ann Intern Med 1989; 110: 855-7.
  3. Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2009; 32: 1335-43.
  4. Fishbein HA, Palumbo PJ. Acute metabolic complications in diabetes. In: Diabetes in America. National Diabetes Data Group, National Institutes of Health, 1995, p. 283 (NIH publ. no: 95-1468).
  5. www.cdc.gov/diabetes/statistics/ (accessed August 1, 2010).
  6. Katsilambros N. Epidemiology of acute manifestations and complications. In: Williams R, Papoz L, Fuller J (ed), Diabetes in Europe, A Monograph on Diabetes Epidemiology in Europe produced as part of the "Eurodiab" Concerted Action Programme of the European Community, London, UK: John Libbey & Company Ltd, 1994: 39-45.
  7. Ennis ED, Stahl EJVB, Kreisberg RA. The hyperosmolar hyperglycemic syndrome. Diabetes Rev 1994; 2: 115-26.
  8. Delaney MF, Zisman A, Kettyle WM. Diabetic ketoacidosis and hyperglycaemic hyperosmolar nonketotic syndrome. Endocrinol Metab Clin North Am 2000; 29: 683-705.
  9. Kitabchi AE, Fisher JN, Murphy MB, et al. Diabetic ketoacidosis and the hyperglycemic hyperosmolar nonketotic state. In: Kahn CR, Weir GC (ed), Joslin’s Diabetes Mellitus, 13th edn, Philadelphia, USA: Lea & Febiger, 1994: 738-70.
  10. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006; 29: 2739-48.
  11. Al-Kudsi RR, Daugirdas JT, Ing TS, et al. Extreme hyperglycemia in dialysis patients. Clin Nephrol 1982; 17: 228-31.

Nikolaos Katsilambros, MD, PhD, FACP
SCOPE Founding Fellow
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ‘Christeas Hall’
Athens, Greece
Christina Kanaka-Gantenbein, MD, PhD
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Athens, Greece
Stavros Liatis, MD
Consultant in Internal Medicine and Diabetology
Laiko General Hospital
Konstantinos Makrilakis, MD, MPH, PhD
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Athens, Greece
Nikolaos Tentolouris, MD, PhD
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital
Athens, Greece
A John Wiley & Sons, Ltd., Publication This edition first published 2011 © 2011 by John Wiley & Sons, Ltd.
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Diabetic Emergencies: Diagnosis and Clinical Management provides emergency room staff, diabetes specialists and endocrinologists with highly practical, clear-cut clinical guidance on both the presentation of serious diabetic emergencies like ketoacidosis, hyperosmolar coma and severe hyper- and hypoglycemia, and the best methods of both managing the emergencies and administering appropriate follow-up care.
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