Hyperosmolar Hyperglycemic State

Also known as: Hyperosmolar coma, Hyperglycemic hyperosmolar non-ketotic coma, hyperosmolar syndrome

Related conditions: Diabetic ketoacidosis

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1. Description of the problem

What every physician needs to know

Hyperosmolar hyperglycemic state (HHS) is a serious and potentially devastating condition characterized by marked biochemical and metabolic derangements, including severe hyperglycemia, hyperosmolality and dehydration.

Historically it was labelled “Hyperosmolar hyperglycemic non-ketotic coma,”. Although an alteration in neurological status is common, frank coma is seen in only 20% of patients, thus the change in name to hyperosmolar hyperglycaemic state. HHS is usually seen as a complication of type 2 diabetes and is frequently precipitated by underlying stressor or comorbid conditions.

Unlike diabetic ketoacidosis, the severe elevation in blood glucose is not usually associated with ketoacidosis, although there is clearly some overlap between these two conditions. HHS can occur from childhood to adult life but is more common in the elderly, sometimes after decades of management for diabetes. It is considerably less common than diabetic ketoacidosis but carries a higher mortality rate and a high rate of devastating neurologic sequelae in survivors.

Clinical features: symptoms

Polydipsia, polyuria and weight loss may be present for 1-2 weeks prior to presentation. However polydipsia may be absent in patients at extremes of age (children and elderly), especially if a limited ability to regulate thirst and hydration exists, such as dementia or other debilitating neurologic diseases.

Symptoms may be non-specific and vary from lethargy and weakness to confusion, drowsiness and behavioral changes. In severe cases seizures or coma can occur as the predominant presenting symptom. In children, the diagnosis is not recognized on initial medical presentation in more than half of reported cases. Unlike adults, a history of diabetes is not usually present in children and adolescents, although many children go on to develop diabetes.

Progressive dehydration is secondary to glucose mediated osmotic diuresis and may be severe at presentation (10-15% of total body water), especially if associated with poor thirst, vomiting or a precipitating illness likes gastroenteritis.

The most frequent precipitating event is infection, usually from the urinary tract or lungs (pneumonia). Symptoms are often related to comorbid conditions such as acute coronary syndromes, pulmonary embolism, stroke and malignancy. A comorbid disease is present in more than 40% of patients, although it may not be initially obvious (e.g. silent myocardial infarction).

Concurrent medication and drugs may additionally aggravate or precipitate the disease process. These including diuretics, beta blockers and other antihypertensive agents, corticosteroids and alcohol. Drugs may modify the disease process by interfering with ability to excrete water, control glucose or by limiting the cardiovascular response to severe dehydration. For example, steroids may have a pronounced catabolic and hyperglycemic effect.

Dehydration and shock (tachycardia, hypotension) with hyperglycemia are the hallmark clinical features.

Dehydration can be severe (body water depletion of 7 to 15 L) but may be difficult to quantify in the presence of hypernatremia or obesity. Tachypnea is often present but is not Kussmal type respiration as seen in diabetic ketoacidosis. Blood pressure may be variable but can be deceptively preserved or high in patients with underlying hypertension despite volume depletion. Frank sepsis with hypovemic shock also can occur.

The diagnostic biochemical features are a blood glucose that is greater than 33 mmol/L (600 mg/dl) with hyperosmolality (>320 mOsm/kg H20) especially if blood ketones (beta-hydroxybutyrate) are not raised. Urinary ketones can be positive as this reflects predominantly acetoacetate, which can be produced in starvation.

Neurologic signs including confusion, agitation and delirium are not uncommon but marked depression of level of consciousness can occur in 20% of cases. Unresponsive coma should prompt a search for underlying neurologic disease such as intracerebral hemorrhage or infarction.

Other signs related to comorbid disease may be identified on physical examination, such as cardiac failure (e.g. myocardial infarction) and pulmonary embolus). Abdominal examination may be non-specific even if abdominal pain was the presenting symptom.

Key management points

Treatment guidelines are based largely on expert opinion as the evidence base is restricted to observational cohort studies.

Early recognition and diagnosis of the hyperosmolar state is important, as delayed management may worsen outcome. Close monitoring of fluid balance, electrolytes and osmolality are required sometimes as frequently as every 1-2 hours until control is achieved. Due to the complexity of fluid management, close monitoring, and high mortality, high-risk patients including children are best managed in an intensive care environment.

Key management points are:

  • Rapid correction of hypovolemic shock.

  • Rehydration and correction of electrolyte abnormalities

  • Control of blood glucose and insulin therapy

  • Treat precipitating cause

2. Emergency Management

1. Rapid correction of hypovolemic shock

Aggressive correction of hypovalemia should be achieved with isotonic crystalloid (commonly 0.9% saline). In adults this may require 3-4L in the 2 hours (15-25 ml/kg/hr). Reversal of hypotension and restoration of organ perfusion is the target.

This also can be applicable in the pediatric setting but caution should be used if hyperosmolality occurs in association with diabetic ketoacidosis, as the risk of cerberal edema is increased with large volume fluid resuscitation. In this scenario, reversal of hypotension is the primary goal and fluid rate may be modified once this has been achieved.

Inotropes may be required if hypotension is refractory to 40-60 ml/kg of fluid and usually indicates septic shock.

The choice of 0.9% saline as the primary resuscitation solution is based on clinical experience, as there are no trials of fluid use in HHS. The advantage of 0.9% saline in this condition is that it glucose and pottasium free. Hypotonic fluids should not be used as primary volume expanders regardless of the severity of hyperosmolality as the primary aim is to restore circulating volume, not expand extracellular and intracellular space.

2. Rehydration and correction of electrolyte abnormalities

Typically there may be an 8-12L fluid deficit. Broadly the aim is to correct half this deficit in 12 hours and the remaining deficit over the next 24-48 hours. Typically 5-15 ml/kg/hr of 0.9% saline is required following initial volume expansion for gradual rehydration.

The rate of rehydration should be guided by patient status, as faster rates may not be tolerated if cardiac or renal disease is present. Renal replacement therapy is not uncommonly used in this setting, especially if other biochemical abnormalities are present with anuria (e.g. hyperkalemia).

It has been suggested that mortality is increased if fluid resuscitation is inadequate without shock reversal with less than 40 ml/kg given over the first 6 hours (PMID 18051930). This was, however, a case series of 43 patients of which two thirds had hyperosmolality complicating diabetic ketoacidosis.

The rehydration rate must be balanced against a gradual fall in osmolality by titrating the reduction of sodium and glucose, both of which lower tonicity. It has been suggested that the sodium and glucose should be lowered by 0.5 mmol/L and 5 mmol/L/hr respectively (PMID 21035820, 21035820). This would result in a fall in effective osmolality of 3.5 mOsm/L/hr and a fall in glucose corrected sodium over 8 hours of 1.5 mmol/kg/hr, as shown in Table I.

Table I.
Hour of therapy Glucose (mmol/L) Sodium (mmol/L) Corrected sodium (mmol/L Effective osmolality (mOsm/L)
1 50 150 167.8 350
2 47.5 149.5 166.3 346.5
3 45 149 164.8 343
4 42.5 148.5 163.3 339.5
5 40 148 161.8 336
6 37.5 147.5 160.3 332.5
7 35 147 158.8 329
8 32.5 146.5 157.3 325.5

The above theoretical values suggested would produce a fall in osmolality over 20 hrs of 60mOsm/kg if both glucose and sodium changed at a fixed rate simultaneously. In practice, rapid changes in plasma sodium can be avoided to slow the rate of omsolality decline as shown by Fadini. He demonstrated a fall in effective osmolality of 60 mOsm/L over 24 hours (2.5 mOsm/L/hr) with a fall in glucose from 50 to 20 mmol/L(1.25 mmol/L/hr), but importantly, plasma sodium briefly increased but did not change over 24 hours (150 mmol/L). Thus the corrected sodium remained static. This is probably a sensible strategy to protect against rapid fall in plasma osmolality by ensuring plasma sodium does not fall too rapidly.

Dialysis with added sodium may be required to guarantee a gradual fall in plasma osmolality if anuria exists or hyperosmolality is extreme (>380 mOsm/L). Pediatric HSS is not uncommonly complicated by rhabdomyolysis and acute renal injury, thus there is a strong possibility that renal replacement therapy may be required.

Expansion of extracellular space with hypotonic fluid (0.45-0.7% saline) may be required after a few hours of 0.9% saline, especially if plasma sodium is increasing. A slight rise in sodium may occur in the first 24 hours and does not necessarily mandate a change to hypotonic fluid. This should be balanced against the risk of cerebral edema which, although unusual, has been reported in HHS and more commonly in hyperosmolality complicating diabetic ketoacidosis. Urine replacement is frequently recommended but can easily be adjusted for by modifying the rehydration rate, especially if 0.45% saline is used.

Hyperchloremia has not been reported as a complication of 0.9% saline, although it is clear that it develops with plasma chloride ranging form 110 to 120 mmol/L. There have been no studies on the use of alternate crystalloid solutions like Hartmans or Ringers Lactate in HSS. These solutions may have a role once glucose and potassium abnormalities are under control, as they provide some protection against the development of hypernatremia.

Potassium is usually normal in HHS but is more closely related to renal function or diseases in which epotassium production is increased, such as rhabdomyolysis. Potassium may fall during rehydration with insulin therapy, and hence supplementation at 20-40 mml/L often is required. Hypophosphatemia can also occur and may require rpelacement with caution as therapy may also lower serum calcium.

3. Control of blood glucose and insulin therpay

There is no immediate need to start insulin until fluid resuscitation has been accomplished. Blood glucose levels may initially fall rapidly following intial fluid resuscitation (5mmol/L/hr).

Blood ketones are not usually elevated, hence there is no need to inhibit ketone production and lipolysis as seen with diabetic ketoacidosis. The main role for insulin is to facilitate the distribution of unmetabolised circulating gluocose into glucose sensitive tissues (e.g. liver, muscle). This is dose dependent, with about 60% of the reduction in blood glucose following insulin due to hepatic metabolism.

Insulin should be started when the rate of glucose fall declines post fluid resucitation to about 2-3 mmol/L/hr. The dose of insulin may vary between 0.025-0.1 u/kg/hr and should be titrated according to the rate of glucose fall. The rate of glucose decline should be about 1 to 2 mmol/L/hr although in practice this may be difficult to achieve. Bolus doses of insulin are not recommended.

Glucose should be added to intravenous rehydration fluid when blood readings reach about 12 to 14 mmol/L. Once glucose control is achieved, insulin can be reduced and often stopped if glucose delivery is optimized. Occasionally prolonged use of insulin is required if insulin resistance is marked or the patient has diabetic ketoacidosis.

4. Treat precipitating cause

In the majority of cases, a precipitating event like infection can be identified. Consequently, there should be a low threshold to start intravenous antibiotics. A thorough evaluation of concurrent disease should be performed, especially for occult disease (e.g. silent myocardial infarction).

If coma is present, neuroimaging is mandatory, as the differential diagnosis is wide. Intracerebral hemorrhage has been reported in HHS as well as infarction and thrombosis but these may be related to underlying disease. Occasional cerebral edema can occur and develop following treatment.

Although the risk of thrombosis is increased with the hyperosmolar state there is no evidence that prophylactic heparin should be used or of the efficacy of low dose anticoagulation. Prognosis is influenced by depth of coma although the exact mechanism of brain injury in this condition is unknown and frequently extrapolated from hypernatremic states (e.g. salt poisoning or dehydration).

In children, rhabdomyolysis with a hyperpyrexia is not unusual. The most effective means of treating hyperpyrexia is aggressive cooling, which can be achieved efficiently with hemofiltration. The use of dantrolene is tempting in this scenario, but the pathogenesis of hyperpyrexia differs considerably from malignant hyperthermia syndrome, in which heat production and muscle rigidity are the main problems. Additionally, dantrolene is not without side effects, including potential liver toxicity and negative inotropy, so the evidence for its use in HHS is lacking.

Tonicity balance

Clinical judgments in fluid therapy and insulin should include calculation of effective plasma osmolality and glucose corrected sodium, the aim being to avoid precipitous changes to protect the brain. For example, central pontine myelinolysis has been reported in hyperosmolar states where osmolar shifts have been rapid, especially if chronic debilitating disorders such as malnutrition or alcohol abuse are present.

Effective plasma osmolality = (2 x Na (mmol/L)) + glucose (mmol/L)

Glucose corrected sodium = plasma Na (mmol/L) + 0.4 (glucose in mmol/L – 5.5)

The true relationship between glucose and sodium in disease has not been evaluated in detail. In healthy volunteers, the relationship between glucose and sodium is not linear, being more pronounced at higher glucose levels

1.6 mmol/L fall plasma sodium is expected per 100 mg/dl rise in glucose between 100 and 400 mg/dl

2.4 mmol/L fall plasma sodium is expected per 100 mg/dl rise in glucose greater than 400 mg/dl

or per mmol/L change in glucose:

0.28 mmol/L fall plasma sodium is expected per 1 mmol/L rise in glucose between 5.6 and 22.2 mmol/L

0.42 mmol/L fall plasma sodium is expected per 1 mmol/L rise in glucose greater than 22.2 mmol/L

3. Diagnosis

The biochemical hallmark of hyperglycemic hyperosmolar coma is raised blood glucose (>33 mmol/L or 600 mg/dl), high plasma osmolality (>320 mOsm/kg H20) without elevation in blood ketones or acidosis (pH>7.3, bicarbonate >15 mmol/L)

Plasma osmolality can be extreme, with values above 400 mOsm/L and blood glucose greater than 60 mmo/L. Elevated blood glucose can be precipitated by high carbohydrate intake prior to admission.

Although there may be some overlap with diabetic ketoacidosis in about one third of cases, urine and blood ketones are usually normal or slightly elevated but severe metabolic acidosis is uncommon unless an underlying disorder is present (e.g. sepsis with raised lactate). See Table II.

Table II.
Value Level Comment
Plasma Na (mmol/L) >145 Usually increased despite dilution by high glucose. Can be markedly elevated.
Plasma K (mmol/L) 3.5-5.5 Usually normal but may be high if renal failure is present .
Urea (mmol/L) >20 Often elevated if renal impairment is present.
Creatinine (umol/l) >100 Elevated especially if renal impairment present.
Ionized calcium (mmol/L) 0.8-1.3 mmol/L Usually normal or low normal.
Phospate 0.5-1.4 mmol/L Usually normal to low following total body depletion.
Lactate (mmol/L) >2 mol/L Normal or raised especially if sepsis.
Anion gap 10-12 mEq/L Normal unless coexisting metabolic acidosis (e.g. lactate)
Hematocrit >45 Increased in proportion to degree of dehydration

Markers of systemic inflammation (raised white cell count, c-reactive protein) are commonly raised even in the absence of infection


Anemia may be related to underlying disease (e.g. malnutrition, malignancy, chronic renal failure)

Thrombocytopenia and raised dimers may be occur if thrombosis is present

Rhabdomyolysis may occasionally occur with raised creatinine kinase and myoglobin

Risk of thrombosis is greater in HSS in both adults and children compared to diabetic ketoacidosis

Differential diagnosis

The differential diagnosis of HHS includes any hyperosmolar state in which hyperglycemia or hypernatremia are present. Typically starvation and alcoholic ketosis may present with profound dehydration, especially if vomiting occurs. Blood ketones are usually elevated at 2-4 mmol/L in these conditions, but hypernatremia and hyperglycemia also may occur.

Hypernatremic disorders may present with similar symptoms and signs as HSS, especially with polyuria, if the mechanism of water loss is renal (e.g. diabetes insipidus or gastroenteritis). Severe depletion of body water may be seen but glucose is not usually markedly elevated. Consumption of oral carbohydrate beverages in the face of hypernatremic dehydraton may generate an acutely rapid rise in blood glucose, thus resembling the hyperosmolar hyperglycemic state.

Diabetic ketoacidosis may present with marked hyperosmolality and can be seen as one end of the spectrum of hyperosmolar coma. Children are more likely to present with a mixed presentation.


There are similarities in the pathogenesis of HHS and diabetic ketoacidosis, as both are characterized by an inability to maintain euglycemia in the setting of a catabolic stress response.

In HHS, blood glucose is elevated following an increase in the circulating counter regulatory hormones such as cortisol, glucagon and cathecholamines. Thus, gluocose is mobilized from liver and peripheral tissues via enhanced glycolysis and gluconeogenesis.

The accumulation of unmetabolized glucose results in the expansion of extracellular volume as water is osmotically drawn from the intracellular space. Dilution of the extracellular space reduces plasma sodium, the major extracellular osmole. The renal threshold for resorption of glucose is rapidly overwhelmed, causing glycosuria and osmotic diuresis with loss of body water and electrolytes. At some point hypernatremia develops despite the dilutional effect of raised glucose. Therefore, hypernatremia occurs when the compensatory ability of the body to retain water via thirst or kidneys is overcome.

Depletion of body water is in the region of 7 to 12 litres, representing 10-15% of total body water.

Insulin levels are usually elevated above 250 pmol/L, in contrast to diabetic ketoacidosis, in which levels are low to absent. There is a reduced response to the hormonal effect of insulin, which limits peripheral utilisation of glucose. This contributes to hyperglycemia. Despite resistance to insulin a high degree of lipolysis and ketogenesis is not seen.

The exact mechanism of this remains poorly understood as circulating free fatty acids are raised in HSS as well as in diabetic ketoacidosis. Lack of ketone production is the main feature that differentiates this from diabetic ketoacidosis. Blood beta-hydroxybutyrate levels are not usually elevated above 2-3 mmol/L in HHS.

Dehydration is usually more severe than in diabetic ketoacidosis due to the lack of ketoacidosis which may be a flag for earlier admission to hospital. There is also a depletion of total body Na, K and phosphate. This may not be apparent as plasma sodium levels do not accurately reflect total body stores.

Prediction of plasma sodium levels in hyperosmolar states from water and sodium balance even after adjustment for glucose is sometimes misleading and inaccurate. Targeting a fall in plasma Na is not as simple as ensuring water gain exceeds water loss because the defence of plasma tonicity is not only modified by urinary excretion of solutes (sodium and potassium) but also by complex osmole exchanges at the intracellular/intertstitial fluid interface that may break down in disease.

For example, in rhabdomylosis a high osmotic gradient in damaged muscles can occur, pulling plasma and extracellular water into the muscle compartment. Muscle swelling ensues and may cause translocational hypernatremia without weight loss or direct evidence of water loss.

Muscle injury with hyperpyrexia and rhabdomyolysis is not unusual in children and may confound the interpretation of plasma sodium. The use of hypotonic fluid in this scenario may increase tissue capillary leak when endothelial barriers are compromised (e.g. sepsis) and aggravate muscle edema.


Type 2 diabetes is the most common disease associated with HSS, occurring in more than 60% of adult cases. Occasionally it is seen as the first presentation of diabetes. HHS is less common than diabetic ketoacidosis. Risk factors are strongly related to age, comorbid diseases such as cerebrovascular accidents, myocardial infarction, stroke and malignancy. It is more common in females.

There is a paucity of information on the epidemiology of HHS in children due to its rarity (less than 200 cases reported worldwide). This may be partly related to under-reporting and lack of awareness, as over 65 cases were reported between 2001 and 2008 compared to only 26 in the preceding 30 years.

In contrast to adults, children do not often have an underlying diagnosis of diabetes. HSS typically presents in older children (>9 years) with obesity a consistent feature in over 70% of cases. It is more common in males (3:1), a reversal from the pattern seen in adults. The rate of HHS in children (10-17 years of age) with type 2 diabetes followed up over an 8-year period was 4%.

Preventative strategies promoting diabetic patient education of the symptoms and warning signs of HHS may reduce morbidity and mortality. In children, the primary diagnosis is often not detected on presentation to medical services, highlighting the need to educate primary pediatric health care workers about this rare but devastating disease.


Historically the mortality of HHS was very high at more than 60%. Over the last decade reported hospital mortality varies between 10% and 20%. The wide variation in mortality may also be confounded by differences in study populations with different age groups and/or the inclusion of diabetic ketoacidosis. Timing of death is also important, as most in-hospital deaths frequently occur within the first 24 hours. This may partly reflect the late presentation of this condition.

In patients who survive hospital discharge, the death rate is significantly higher per year than expected for age. Commonly, the cause of death primarily relates to the underlying disease or to complications of HHS. In addition, a high rate of neurological sequelae may be seen.

Mortality is closely related to underlying comorbid disease including diabetes, infection, cardiovascular disease and malignacy. Prognostic factors for mortality include lower coma score on presentation, higher blood glucose, older age and female sex. There is no strong evidence relating the rate of change in osmolality, sodium or glucose to adverse outcome.

What's the evidence?