Author: Mehdi Teeli, Rafeeq Ahmed Sulaiman / Editor: Lauren Fraser / Codes: EnC4, RP7, SLO3Published: 08/11/2022


Hyperosmolar hyperglycaemic state (HHS) is a common presentation to the emergency department.

  • Although the precise prevalence and incidence of HHS is difficult to determine because of the lack of population-based studies and the multiple comorbidities often found in these patients, the overall prevalence is estimated at less than 1% of all diabetes-related hospital admissions10.
    • The incidence of HHS has been estimated at a rate of 17.5 per 100,000 patient years11.
    • HHS have been reported to have a mortality of between 5% and 20%, which is 10 times higher than that reported for DKA12.
    • Mortality rises significantly in the patients aged more than 70 years13.
    • HHS is seen more commonly in older patients.

The presentation can mimic many other disease processes. The ED physician must be able to diagnose, appropriately investigate, initiate treatment, and manage complications.


A precise definition of HHS does not exist and would be inappropriate, but there are characteristic features that differentiate it from other hyperglycaemic states such as DKA.

These are:

  • Hypovolaemia
  • Marked hyperglycaemia (30 mmol/L or more) without significant hyperketonaemia (Less than 3 mmols/L or Acidosis pH>7.3, bicarbonate >15 mmol/L)
  • Osmolality usually 320 mosmol/kg or more

Learning bite

A mixed picture of HHS and DKA may occur.

People with HHS are generally older, but increasingly, as the diabetes pandemic crosses generational boundaries, it may be seen in young adults and even children as the first presentation (Fourtner 2005).

In HHS there is usually no significant ketosis/ketonaemia (ketones <3 mmol/L), though a mild acidosis (pH greater than 7.3, bicarbonate greater than 15 mmol/L) may accompany the pre-renal failure. Some patients have severe hypertonicity and ketosis and acidosis (mixed DKA and HHS). This presumably reflects insulin deficiency, due to beta cell exhaustion as a result of temporary glucotoxicity. These patients may require a modification of this treatment guideline to take into account which aspect predominates.

Elevated levels of counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone) initiate HHS by stimulating hepatic glucose production through glycogenolysis and gluconeogenesis, leading to hyperglycaemia, intracellular water depletion, and subsequent osmotic diuresis. High levels of catecholamines combined with low levels of insulin reduce peripheral glucose uptake. Glycosuria causes greater loss of water than of sodium, resulting in hyperosmolarity and dehydration. Decreased intravascular volume, often combined with underlying renal disease, decreases the glomerular filtration rate, thereby decreasing glucose clearance and further increasing blood glucose levels.

Although the insulin level is not adequate to control blood glucose, it can suppress lipolysis and ketogenesis5.Proinflammatory cytokines (e.g., tumour necrosis factor α, interleukin β, interleukin-6, interleukin-8), plasminogen activator inhibitor-1, reactive oxygen species, and lipid peroxidation increase two- to threefold during the acute crisis, but return to normal within 24 hours. These increases create a temporary prothrombotic environment that increases the risk of vascular occlusion, mesenteric artery thrombosis, myocardial infarction, low-flow syndrome, disseminated intravascular coagulopathy, cerebrovascular accident, and bilateral femoral artery thrombosis. Figure 114.


Precipitating factors of hyperosmolar hyperglycaemic state (HHS) include:

  • Infection
  • Inadequate insulin or non-adherence to diabetic treatment.
  • New onset of diabetes mellitus or other physiological stress (such as trauma or surgery).
  • Other medical conditions (such as hypothyroidism or pancreatitis).
  • Drugs (such as corticosteroids, diuretics, atypical antipsychotics, and sympathomimetic drugs such as salbutamol).

Markers of Severity Indicating the Need for High Dependency / Level 2 Care:

Consider the need for admission to a high-dependency unit / level 2 environment, when one or more of the following are present:

  • osmolality greater than 350 mosmol/kg
  • sodium above 160 mEq/L
  • venous ⁄ arterial pH below 7.1
  • hypokalaemia (less than 3.5 mEq/L) or hyperkalaemia (greater than 6 mEq/L) on admission
  • Glasgow Coma Scale (GCS) less than 12 or abnormal
  • oxygen saturation below 92% on air (assuming normal baseline respiratory function)
  • systolic blood pressure below 90 mmHg
  • pulse over 100 or below 60 bpm
  • urine output less than 0.5 ml/kg/hr
  • serum creatinine >200 µmol/L
  • hypothermia
  • macrovascular event such as myocardial infarction or stroke
  • other serious co-morbidity

Initial bedside tests include:

  • Capillary blood glucose
  • Blood gases to determine pH, bicarbonate and potassium
  • Urine dipstick for ketones and urinalysis
  • ECG to investigate the possibility of a myocardial infarction, which may be silent
  • Measure or calculate osmolality (2 sodium + glucose + urea) frequently to monitor the response to treatment.

The 2012 Joint British Diabetes Societies (JBDS) guideline recommends monitoring serum osmolality to measure the patient’s response to treatment as follows:

  • Hourly for the first 6 hours
  • 2 hourly from 6 to 12 hours as long as serum osmolality is falling at 3 to 8 mOsm/kg/hour (3-8 mmol/kg/hour)
  • 4 hourly after 12 hours if serum osmolality continues to improve.

Learning bite

There is no need to take arterial blood routinely in suspected HHS. Venous blood can be used, as the mean difference between arterial and venous pH is 0.03. Arterial sampling should only be undertaken if there is a concern that there is respiratory failure.

Goals of treatment

The goals of treatment of HHS are to treat the underlying cause and to gradually and safely:

  • Normalise the osmolality
  • Replace fluid and electrolyte losses
  • Normalise blood glucose

Other goals include prevention of:

  • Arterial or venous thrombosis
  • Other potential complications e.g. cerebral oedema/ central pontine myelinolysis
  • Foot ulceration



Intravenous fluids (0.9% saline) in IV line 1
(Caution in HF / CKD / BW< 50 kg)

The key parameter is osmolality to which glucose and sodium are the main contributors and that too rapid changes are dangerous. Although for practical and safety reasons an infusion of insulin is often commenced simultaneously, rapid falls in blood glucose are not desirable (see below).

Isotonic versus hypotonic fluid replacement

  • Rapid changes in osmolality may be harmful. Use 0.9% sodium chloride solution as the principal fluid to restore circulating volume and reverse dehydration.
  • Measurement or calculation of osmolality should be undertaken every hour initially and the rate of fluid replacement adjusted to ensure a positive fluid balance sufficient to promote a gradual decline in osmolality.
  • Fluid replacement alone (without insulin) will lower blood glucose which will reduce osmolality causing a shift of water into the intracellular space. This inevitably results in a rise in serum sodium (a fall in blood glucose of 5.5 mmol/L will result in a 2.4 mmol/L rise in sodium). This is not necessarily an indication to give hypotonic solutions.
  • Isotonic 0.9% sodium chloride solution is already relatively hypotonic compared to the serum in someone with HHS.
  • Rising sodium is only a concern if the osmolality is NOT declining concurrently. Rapid changes must be avoided – a safe rate of fall of plasma glucose of between 4 and 6 mmol/hr is recommended (Kitabachi 2009). If the inevitable rise in serum Na+ is much greater than 2.4 mmol/L for each 5.5 mmol/L fall in blood glucose (Katz 1973) this would suggest insufficient fluid replacement. Thereafter, the rate of fall of plasma sodium should not exceed 10 mmol/L in 24 hours (Adrogue 2000).
  • The aim of treatment should be to replace approximately 50% of estimated fluid loss within the first 12 hours and the remainder in the following 12 hours though this will in part be determined by the initial severity, degree of renal impairment and co-morbidities such as heart failure, which may limit the speed of correction.
  • A target blood glucose of between 10 and 15 mmol/L is a reasonable goal. Complete normalisation of electrolytes and osmolality may take up to 72 hours.

Water replacement and hypotonic (0.45% sodium chloride solution) fluid

Ideally patients will recover quickly enough to replace the water deficit themselves by taking fluids orally. There is no experimental evidence to justify using hypotonic fluids less than 0.45% sodium chloride solution. However, if the osmolality is no longer declining despite adequate fluid replacement with 0.9% sodium chloride solution AND an adequate rate of fall of plasma glucose is not being achieved then 0.45% sodium chloride solution should be substituted.

Insulin dose and timing

  • If significant ketonaemia is present (3β-hydroxy butyrate is more than 1 mmol/L) this indicates relative hypoinsulinaemia and insulin should be started at time zero.
  • If significant ketonaemia is not present (3β-hydroxy butyrate is less than 1 mmol/L) do NOT start insulin.
  • Fluid replacement alone with 0.9% sodium chloride solution will result in falling blood glucose and because most patients with HHS are insulin sensitive there is a risk of lowering the osmolality precipitously. Insulin treatment prior to adequate fluid replacement may result in cardiovascular collapse as water moves out of the intravascular space, with a resulting decline in intravascular volume (a consequence of insulin-mediated glucose uptake and a diuresis from urinary glucose excretion)
  • The recommended insulin dose is a fixed rate intravenous insulin infusion (FRIII) given at 0.05 units per kg per hour (e.g. 4 units/hr in an 80 kg man) is used. A fall of glucose at a rate of up to 5 mmol/L per hour is ideal and once the blood glucose has ceased to fall following initial fluid resuscitation, reassessment of fluid intake and evaluation of renal function must be undertaken. Insulin may be started at this point, or, if already in place, the infusion rate increased by 1 unit/hr. As with DKA, a FRIII (fixed rate intravenous insulin infusion) is) is preferred, though generally lower doses are required.


Patients with HHS are potassium deplete but less acidotic than those with DKA so potassium shifts are less pronounced, the dose of insulin is lower, and there is often co-existing renal failure. Hyperkalaemia can be present with acute kidney injury and patients on diuretics may be profoundly hypokalaemic. Potassium should be replaced or omitted as required

  • >5.5 mmol/l – none
  • 3.5-5.5 mmol /l – 20 mmol/500 ml bag (i.e. 40 mmol/l)
  • <3.5 mmol/l – senior advice is required, and pharmacy involvement may be needed. The patient MUST be looked after in a high dependency care.

Anti-infective therapy

As with all acutely ill patients, sepsis may not be accompanied by pyrexia. An infective source should be sought on clinical history and examination and C-reactive protein may be helpful (Gogos 2001). Antibiotics should be given when there are clinical signs of infection or imaging and/or laboratory tests suggest its presence.


Patients in HHS have an increased risk of arterial and venous thromboembolism.

All patients should receive prophylactic low molecular weight heparin (LMWH) for the full duration of admission unless contraindicated.

Other electrolyte imbalances and complications associated with HHS

Hypophosphataemia and hypomagnesaemia are common in HHS. As with the management of DKA there is no evidence of benefit of treatment with phosphate infusion. However, these patients are often elderly and may be malnourished, and the re-feeding syndrome could be precipitated once the person begins to eat. If hypophosphataemia persists beyond the acute phase of treatment of HHS, oral or IV replacement should be considered. Magnesium replacement has also not been shown to be beneficial so should only be considered if the patient is symptomatic or has symptomatic hypocalcaemia.

Learning bites

  • Always start with ABCD assessment.
  • An adequate history must be taken.
  • Examination performed searching for the underlying cause that precipitated HSS.


  • Unlike DKA, complete correction of electrolyte and osmolality abnormalities is unlikely to be achieved within 24 hours and too rapid correction may be harmful.
  • As many of these patients are elderly with multiple co-morbidities, recovery will largely be determined by their previous functional level and the underlying precipitant of HHS.
  • Early mobilisation is essential as is the need for good nutrition and, where indicated, multivitamins and phosphate (to prevent re-feeding syndrome).
  • IV insulin can usually be discontinued once they are eating and drinking but IV fluids may be required for longer if intake is inadequate.
  • Most patients should be transferred to subcutaneous insulin (the regime being determined by their circumstances).
  • For patients with previously undiagnosed diabetes or well controlled on oral agents, switching from insulin to the appropriate oral hypoglycaemic agent should be considered after a period of stability (weeks or months).
  • People with HHS should be referred to the specialist diabetes team as soon as practically possible after admission.
  • All patients will require diabetes education to reduce the risk of recurrence and prevent long-term complications.
  1. Umpierrez GE, Kelly JP, Navarrete JE, et al. Hyperglycemic crises in urban blacks. Arch Intern Med. 1997 Mar 24;157(6):669-75.
  2. Dhatariya K, James J, Kong MF, Berrington R; Joint British Diabetes Society (JBDS) for Inpatient Care Group and guidelines writing group. Diabetes at the front door. A guideline for dealing with glucose related emergencies at the time of acute hospital admission from the Joint British Diabetes Society (JBDS) for Inpatient Care Group. Diabet Med. 2020 Sep;37(9):1578-1589.
  3. Magee MF, Bhatt BA. Management of decompensated diabetes. Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Crit Care Clin. 2001 Jan;17(1):75-106.
  4. Pasquel FJ, Umpierrez GE. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. Diabetes Care. 2014 Nov;37(11):3124-31. doi: 10.2337/dc14-0984.
  5. Trence DL, Hirsch IB. Hyperglycemic crises in diabetes mellitus type 2. Endocrinol Metab Clin North Am. 2001 Dec;30(4):817-31.Abstract 
  6. Sypniewski E Jr, Mirtallo JM, Schneider PJ. Hyperosmolar, hyperglycemic, nonketotic coma in a patient receiving home total parenteral nutrient therapy. Clin Pharm. 1987 Jan;6(1):69-73.
  7. National Institute for Health and Care Excellence. NICE CG10 2004
  8. Diabetes UK. Putting Feet First. 2012.
  9. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD000567.
  10. Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE. Hyperglycemic crises in urban blacks. Arch Intern Med. 1997 Mar 24;157(6):669-75.
  11. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am. 1995 Jan;79(1):39-52.
  12. Abbas E. Kitabchi, Guillermo E. Umpierrez, et al. Hyperglycemic Crises in Adult Patients With Diabetes. Diabetes Care 1 July 2009; 32 (7): 1335–1343.
  13. Wachtel TJ, Silliman RA, Lamberton P. Prognostic factors in the diabetic hyperosmolar state. J Am Geriatr Soc. 1987 Aug;35(8):737-41.
  14. Francisco J. Pasquel, Guillermo E. Umpierrez; Hyperosmolar Hyperglycemic State: A Historic Review of the Clinical Presentation, Diagnosis, and Treatment. Diabetes Care 1 November 2014; 37 (11): 3124–3131.
  15. Beavers C, Harrison M, et al. Lethargy and Seizures in a 52-Year-Old Male, Laboratory Medicine, Volume 40, Issue 7, July 2009, Pages 405–407.

Additional resources