Hyperosmolar hyperglycemic state

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

The hyperosmolar hyperglycemic state (HHS) is a life-threatening and acute complication in patients with poorly treated diabetes mellitus (chronic high blood sugar or hyperglycemia). HHS is more common in type II diabetics, and in individuals greater than 65 years of age. However, it has also been reported in children, younger adults and in type I diabetics. The basic pathogenesis is relative insulin deficiency and excess of counter-regulatory stress hormones which leads to hyperglycemia and hyperosmolality. Osmotic diuresis due to hyperglycemia causes dehydration, prerenal azotemia and furthers aggravates plasma osmolality. The common precipitating factor for hyperosmolar hyperglycemic state include infections (mostly GI and genitourinary), myocardial infarctions, stroke, aggravation of already existing chronic kidney disease and poorly controlled diabetes. The initial symptoms are due to hyperglycemia and dehydration which include lethargy, extreme fatigue, polyuria, excessive thirst and leg cramps. The neurological symptoms develop with increased plasma osmolality greater than 320 mOsm/kg and include confusion, seizures and eventually coma. Patients with the hyperosmolar hyperglycemic state may also appear dehydrated, lethargic, disoriented and in shock. Physical examination of patients with the hyperosmolar hyperglycemic state is usually remarkable for hypothermia, hypotension, tachycardia, tachypnea, nausea, vomiting and seizures or other focal neurological signs. HHS must be differentiated from diabetic ketoacidosis and other conditions that can present with an altered mental status or focal neurological signs and symptoms such as CNS infections and stroke. All these conditions may be differentiated on the basis of history findings, clinical features, and laboratory abnormalities. The symptoms of hyperosmolar hyperglycemic state (HHS) develop slowly over a period of days to weeks as compared to diabetic ketoacidosis which presents within hours of inciting event. If left untreated, patients may develop multiorgan failure and eventually death. Common complications are renal failure, thrombotic events, and cardiovascular complications. The prognosis of the hyperosmolar hyperglycemic state (HHS) depends on the hemodynamic status, comorbidities, and age at presentation. Laboratory findings consistent with the diagnosis of hyperosmolar hyperglycemic state (HHS) as outlined by the American Diabetes Association include plasma glucose > 600 mg/dl, serum osmolarity > 320 mOsm/kg, blood pH > 7.3, serum bicarbonate > 18 mEq/L and negative or trace positive urine or serum ketones. The mortality rate ranges from a low of less than 5000 per 100,000 individuals to a high of 20,000 per 100,000 individuals which is ten times higher than diabetic ketoacidosis. The mainstay of therapy for HHS is medical therapy including intravenous insulin, fluids, and potassium replacement therapy. The basic principles guiding therapy include rapid restoration of adequate circulation and perfusion, correction of hyperosmolality, electrolytes balance, hyperglycemia, identifying and treating the underlying precipitating cause and close monitoring to prevent and treat complications if they develop. The complications due to treatment can be cerebral edema, pulmonary edema, and hypoglycemia. The management of HHS is mainly derived from studies on patients with diabetic ketoacidosis (DKA) and there is a need for prospective clinical trials, which focus on HHS as a separate clinical entity, for the optimum treatment options.

The first cases of the Hyperosmolar hyperglycemic state were described by Von Frerichs and Dreschfeld in the 1880s in some patients with unusual diabetic coma. In 1971, Aerieff and Carroll proposed diagnostic criteria for patients presenting with diabetic coma and they named it as a hyperosmolar hyperglycemic nonketotic state. Now the term is changed to the hyperosmolar hyperglycemic state as most of the patients present without coma and with minimal ketosis. Before the discovery of insulin in 1922, it was rare for the patient of diabetes with an episode of diabetic coma to survive for more than few months. With the discovery of insulin, the development of diabetic coma in patients with diabetes became less frequent. The management of hyperosmolar hyperglycemic state has evolved over the years with the use of insulin and adjustment of doses of insulin to achieve optimum control of the disease.

There is no established system for the classification of hyperosmolar hyperglycemic state.

The hyperosmolar hyperglycemic state (HHS) is the result of relative insulin deficiency and excess of counterregulatory hormones like glucagon, growth hormone, catecholamine, and cortisol. The decrease in insulin-to-glucagon ratio puts the body in the catabolic state and leads to hyperglycemia and hyperosmolar state. The hyperglycemia is secondary to activation of gluconeogenesis, glycogenolysis and decreased peripheral utilization of glucose. The increase in plasma osmolality is secondary to osmotic diuresis and dehydration. The advanced age, other underlying comorbidities such as congestive heart failure or chronic kidney disease and a decrease in fluid intake and activation of renal angiotensin aldosterone system (RAAS) further aggravate the plasma osmolality. There is enough insulin in the hyperglycemic hyperosmolar state (HHS) to prevent unrestrained ketosis but not enough to prevent hyperglycemia.

The hyperosmolar hyperglycemic state (HHS) is caused by a decrease in effective insulin-to-glucagon ratio. This process is triggered by a lack of insulin due to decreased production, noncompliance with insulin treatment, high demand of insulin or resistance to the action of insulin. The hyperosmolar hyperglycemic state (HHS) can be aggravated in conditions that cause dehydration or in certain disease states like the renal failure or congestive cardiac failure.

The hyperosmolar hyperglycemic state must be differentiated from other conditions presenting with hyperglycemia, hyperosmolality or an altered state of consciousness. The differentials include diabetes mellitus, diabetic ketoacidosis, impaired glucose tolerance, and conditions causing altered sensorium such as CNS infections or stroke. All these conditions may be differentiated on the basis of history findings, clinical features, and laboratory abnormalities.

The epidemiological parameters of the hyperosmolar hyperglycemic state (HHS) are difficult to predict because of lack of population-based studies in HHS. According to the national diabetes surveillance program of the centers for disease control (CDC), hyperosmolar hyperglycemic state accounts for less than 1000 hospital admissions per 100,000 diabetic admissions. The overall mortality rate of the hyperosmolar hyperglycemic state varies from a low of less than 5000 per 100,000 individuals to a high of 20,000 per 100,000 individuals. The incidence of the hyperosmolar hyperglycemic state is more common in men and Black population as compared to the Caucasian population. The hyperosmolar hyperglycemic state also affects older individuals more as compared to children and young adults.

Common risk factors in the development of hyperosmolar hyperglycemic state (HHS) are old age, high mean glycosylated hemoglobin A1c, acute stresses like infections, myocardial infarction, pancreatitis, poor diabetes control, noncompliance with insulin, poor cardiac and renal function and low socioeconomic status.

There is insufficient evidence to recommend routine screening for the hyperosmolar hyperglycemic state.

The symptoms of hyperosmolar hyperglycemic state (HHS) develop slowly over a period of days to weeks as compared to diabetic ketoacidosis which presents within hours of inciting event. The symptoms range from fatigue, weakness, leg cramps, polyuria, dehydration and eventually seizures and coma. If left untreated, patients may develop multiorgan failure and eventually death. Common complications are renal failure, thrombotic events, and cardiovascular complications. The complications due to treatment can be cerebral edema, pulmonary edema, hypoglycemia, and electrolyte imbalance. The mortality rate ranges from a low of less than 5000 per 100,000 individuals to a high of 20,000 per 100,000 individuals which is ten times higher than diabetic ketoacidosis. The prognosis of the hyperosmolar hyperglycemic state (HHS) depends on the hemodynamic status, comorbidities, and age at the time of presentation.

There are specific cut-offs for serum glucose level, ketone levels, body pH, serum bicarbonate levels and anion gap for the diagnosis of the hyperosmolar hyperglycemic state as outlined by the American Diabetes Association.

The majority of patients with the hyperosmolar hyperglycemic state are elderly, type 2 diabetics and having underlying other comorbidities as well as a limited fluid intake. However, some cases of a hyperosmolar hyperglycemic state have also been seen in children and young adults with type 1 diabetes. The initial symptoms are due to hyperglycemia and dehydration which include lethargy, extreme fatigue, polyuria, excessive thirst and leg cramps. The neurological symptoms develop with increase plasma osmolality greater than 320 mOsm/kg and include confusion, seizures and eventually coma.

Patients with the hyperosmolar hyperglycemic state may usually appear dehydrated, lethargic, disoriented and in shock. Physical examination of patients with the hyperosmolar hyperglycemic state is usually remarkable for hypothermia, hypotension, tachycardia, tachypnea, nausea, vomiting and seizures or other focal neurological signs.

Laboratory findings consistent with the diagnosis of hyperosmolar hyperglycemic state (HHS) include plasma glucose > 600 mg/dl, serum osmolarity > 320 mOsm/kg, blood pH > 7.3, serum bicarbonate > 18 mEq/L and negative or trace positive urine or serum ketones.

Patients suffering from the hyperosmolar hyperglycemic state may exhibit electrocardiographic (EKG) changes characteristic of toxic hyperkalemia. Common abnormalities observed on EKG include tall peaking T waves, prolonged QT interval, and widening of QRS complex.

An x-ray may be helpful in identifying pneumonia as the precipitating factor for the development of the hyperosmolar hyperglycemic state.

There are no echocardiography/ultrasound findings associated with the hyperosmolar hyperglycemic state.

CT scan may be helpful in the workup of hyperosmolar hyperglycemic state when a patient presents with an altered state of consciousness or with focal neurological signs and symptoms to rule out stroke. CT scan can also help in the diagnosis of cerebral edema which can occur as a complication of treatment of hyperosmolar hyperglycemic state.

MRI may be helpful in the workup of hyperosmolar hyperglycemic state to rule out conditions that present with an altered state of consciousness such as meningitis, cerebral abscess, encephalitis or stroke. MRI can also be helpful in the diagnosis of cerebral edema which can be a complication of the treatment hyperosmolar hyperglycemic state.

There are no other imaging findings associated with the hyperosmolar hyperglycemic state.

Other diagnostic studies such as blood culture, urine culture or lumbar puncture can be done to find out the infection or the underlying cause that precipitated the hyperosmolar hyperglycemic state.

Hyperosmolar hyperglycemic state (HHS) is a medical emergency and acute complication of diabetes mellitus. The basic principles guiding therapy include rapid restoration of adequate circulation and perfusion, correction of hyperosmolality, electrolytes balance, hyperglycemia, identifying and treating the underlying precipitating cause and close monitoring to prevent and treat complications if they develop. The mainstay of therapy for HHS is medical therapy including intravenous insulin, fluids, and potassium replacement therapy.

Surgical intervention is not recommended for the management of hyperosmolar hyperglycemic state (HHS).

Effective measures for the primary prevention of hyperosmolar hyperglycemic state (HHS) include recognition of early signs of HHS, implementation of early and aggressive interventions (especially in patients with recurrent episodes of (HHS), tight glycemic control especially in patients with chronic illnesses, and education of patients and their family members.

Secondary prevention of hyperosmolar hyperglycemic state (HHS) is similar to primary prevention.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

The first cases of the hyperosmolar hyperglycemic state (HHS) were described by Von Frerichs and Dreschfeld in the 1880s in some patients with unusual diabetic coma. In 1971, Aerieff and Carroll proposed the diagnostic criteria for patients presenting with diabetic coma and named it as a hyperosmolar hyperglycemic nonketotic state. In the recent times, the term has been changed to the hyperosmolar hyperglycemic state as most of the patients present without coma and with minimal ketosis. Before the discovery of insulin in 1922, it was rare for the patient of diabetes with an episode of diabetic coma to survive for more than a few months. With the discovery of insulin, the development of diabetic coma in patients with diabetes became less frequent. The management of hyperosmolar hyperglycemic state has evolved over the years with the use of insulin and adjustment of doses of insulin to achieve optimum control of the disease.

The notable events regarding the history of hyperosmolar hyperglycemic state include:^{[1][2][3][4][5][6][7][8][9]}

• The known history of diabetes dates back to the Egyptian era and the first documented evidence was found in an Egyptian papyrus dating back to 1552 BC.
• In 1828, Von Stosch for the first time described diabetic coma in detail.
• In 1857, Petters discovered acetone in the urine of patients with diabetes.
• In 1865, Gerhardt discovered acetoacetic acid in the urine of patients with diabetes.
• In 1874, Kussmaul also described diabetic coma in detail.
• In 1878, Foster described some cases of diabetic coma and ketonemia.
• In 1883–1884, Stadelmann, Külz, Minkowski found out that in addition to acetone patients with diabetic coma also have β-hydroxybutyric acid.
• In 1884–1886, Von Frerichs and Dreschfeld described some cases of patients with diabetic coma but without kussmaul breathing or ketones.
• In 1922, insulin was discovered and isolated by Banting and Best.
• In 1909–1923, Lépine, Revillet, McCaskey and Bock et al also described some cases of patients with diabetic coma without ketonuria.
• In 1930–1935, Lawrence and Joslin described the management of diabetic coma.
• In 1957, Sament, Schwartz, Graeff, and Lips also described some case reports of diabetic coma without ketones and hyperosmolality.
• In 1962, Singer et al explained the relationship of hyperglycemia and osmolality.
• In 1971, Arieff, Carroll and Gerich et al described the modern definition and initial diagnostic criteria of the hyperosmolar hyperglycemic state which they termed as hyperosmolar hyperglycemic non-ketotic state.
• In 1973, Arieff and Kleeman explained the mechanism of cerebral edema occurring during the treatment of hyperosmolar hyperglycemic state.
• In 1976–1977, Alberti, Hockaday and Kitabchi et al described the low-dose insulin protocols for the treatment of HHS.
• In 2004–2009, American Diabetes Association published the guidelines for the management of the hyperosmolar hyperglycemic state in adults.
• In 2011, Pediatric Endocrine Society guidelines for treatment of HHS in children were published.

The landmark events in the treatment of hyperosmolar hyperglycemic state are:^{[1][2][3][4][5][6][7]}

Preinsulin era •The treatment modalities used for diabetic coma include blood transfusion, castor oil with potassium citrate, and saline solutions with sodium carbonate among other therapies.

1930–1950 •The usual practice was to use insulin in 20–100 units i.v. or s.c. bolus followed by 20 units s.c. every 30–60 min depending on glucosuria.

1950–1970s • In that period, the insulin was given as 2 units/kg bolus of crystalline insulin; up to 920 units in the first 7 h.

Early 1970s • Insulin was given as low-dose insulin regimens with regular insulin 0.1 units/kg i.v. followed by 0.1–0.3 units/h i.v., s.c., or i.m.

1990s • Insulin was administered as 0.1 units/kg i.v. bolus, then 0.1 units/kg/h as continuous infusion until glucose level <13.8 mmol/L (250 mg/dL)

2004–2009 • ADA consensus for treatment of DKA and HHS in adult patients according to which initial bolus (0.1 units/kg i.v.), followed by 0.1 units/kg/h until glucose <250 mg/dL, then reduce insulin by 50%

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

There is no established system for the classification of hyperosmolar hyperglycemic state.

There is no established system for the classification of hyperosmolar hyperglycemic state.

Template:WH Template:WS​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

The hyperosmolar hyperglycemic state (HHS) is the result of relative insulin deficiency and excess of counter-regulatory hormones like glucagon, growth hormone, catecholamine, and cortisol. The decrease in insulin-to-glucagon ratio puts the body in the catabolic state and leads to hyperglycemic and hyperosmolar state. The hyperglycemia is secondary to activation of gluconeogenesis, glycogenolysis and decreased peripheral utilization of glucose. The increase in plasma osmolality is secondary to osmotic diuresis and dehydration. Advanced age and other underlying comorbidities such as congestive heart failure or chronic kidney disease, decrease in fluid intake and osmotic diuresis leading to activation of renal angiotensin aldosterone system (RAAS) further aggravate the increase in plasma osmolality. There is enough endogenous insulin secretion in the hyperglycemic hyperosmolar state (HHS) to prevent unrestrained ketosis but not enough to prevent hyperglycemia.

• During fed-state, high glycemic levels cause increased insulin release from pancreatic beta cells.
• Increased insulin levels inhibit the secretion of glucagon from pancreatic alpha cells which leads to increased insulin-to-glucagon ratio.^[1]
• High insulin-to-glucagon ratio favors anabolic state, during which insulin mediated uptake of glucose occurs in the liver and muscles where it is stored as glycogen.
• Insulin dependent uptake of glucose also drives potassium into the cells.
• The high insulin-to-glucagon ratio also favors uptake of amino acids by muscle.

• Between meals, the decrease in insulin and rise in glucagon leads to low plasma insulin-to-glucagon ratio which favors the catabolic state.
• During catabolic state, there is a breakdown of glycogen in the liver and muscles and gluconeogenesis is initiated in the liver.
• Both these processes maintain plasma glucose concentration within normal range.
• The low insulin-to-glucagon ratio also favors lipolysis and ketone body formation.
• Several insulin-independent tissues such as the brain and kidneys utilize glucose as a major source of energy, regardless of the insulin-to-glucagon ratio.

The progression to hyperosmolar hyperglycemic state (HHS) can occur due to the reduction in the net effective concentration of insulin relative to glucagon and other counter-regulatory stress hormones (catecholamines, cortisol, and growth hormone), which may be seen in a multitude of settings:^[2][3][4]

• In type 1 diabetics, there is an immune-mediated destruction of insulin-producing pancreatic β cells, which leads to either an absolute or relative deficiency of insulin in the body.
• In type 2 diabetics, although the major mechanism of hyperglycemia is peripheral insulin resistance and there is some basal production of insulin; patients may develop a failure of pancreatic β cells at late stages of the disease.
• Increased levels of counter-regulatory stress hormones may also cause insulin resistance. The levels of counter-regulatory stress hormones may increase during an acute illness (e.g., infections such as UTI or pneumonia, myocardial infarction [MI], or pancreatitis), stress (e.g., surgery or trauma), when counter-regulatory hormones are given as therapy (e.g., dexamethasone), and as a result of their overproduction (eg, in Cushing’s syndrome).
• Some pharmacologic agents may also cause insulin resistance. Notable pharmacologic agents which may lead to insulin resistance include:
  • Antipsychotics (such as clozapine, olanzapine, risperidone)
  • Immunosuppressive agents (such as cyclosporine, interferon, pentamidine)
  • Sympathomimetic agents (such as albuterol, dobutamine, terbutaline)
• All these situations may cause a decrease effective insulin-to-glucagon ratio which may lead to hyperosmolarity and hyperglycemia seen in the hyperosmolar hyperglycemic state (HHS).

Hyperglycemia in HHS develops as a result of three processes:^{[5][6][7][8][9][10][11][12][13][14][15]}

• Gluconeogenesis takes place in the liver and it increases in HHS due to:
  • Increased gluconeogenic precursors, such as:
    • Amino acids (alanine and glutamine), which are increased due to proteolysis and decreased protein synthesis.
    • Lactate, which comes from muscle glycogenolysis.
    • Glycerol, which comes from lipolysis.
  • Increased activity of gluconeogenic enzymes, which are further stimulated by stress hormones including:
    • Phosphoenolpyruvate carboxykinase (PEPCK)
    • Fructose-1,6-Biphosphatase
    • Pyruvate carboxylase
    • Glucose-6-phosphatase
• The low insulin-to-glucagon ratio also inhibits production of an important metabolic regulator, fructose-2,6-biphosphate (FBPase-2) by triggering the production of cyclic adenosine monophosphate (cAMP), which activates a cAMP-dependent protein kinase. This kinase phosphorylates the phosphofructokinase 2 (PFK-2) and FBPase-2 enzymes which leads to activation of FBPase-2 activity and inhibition of PFK-2 activity, thereby decreasing the levels of fructose 2,6-bisphosphate in the cell. With decreasing amounts of fructose 2,6-bisphosphate, glycolysis is inhibited while gluconeogenesis is activated.
• Reduction of fructose-2,6-biphosphate stimulates the activity of fructose-1,6-bisphosphatase (an enzyme that converts fructose-1,6-biphosphate to fructose-6-phosphate) and inhibits phosphofructokinase (PFK), the rate-limiting enzyme in the glycolytic pathway.

• The low insulin-to-glucagon ratio promotes glycogenolysis by stimulating glycogen phosphorylase, a key enzyme of glycogen breakdown.

• The low insulin-to-glucagon ratio also decrease the insulin dependent uptake of glucose by peripheral tissues.

The main mechanisms involved in ketone metabolism in hyperosmolar hyperglycemic state include the following:^{[16][17][11][18][10][19][20]}

• The low insulin-to-glucagon ratio affects lipid metabolism and mobilization because insulin normally promotes triglycerides clearance from circulation and inhibits lipolysis.
• The low insulin-to-glucagon ratio stimulates lipolysis from adipose tissue by activating hormone – sensitive lipase (HSL). This lipolysis leads to the abundant supply of free fatty acids (FFA) to the liver.
• The free fatty acid levels may be as high in the hyperosmolar hyperglycemic state (HHS) as in diabetic ketoacidosis (DKA).
• The increase in free fatty acids in the liver diverts the hepatic fatty acid metabolism toward the ketogenesis.
• The ketogenesis occurs in the hepatic mitochondria and the transport of free fatty acids across the mitochondrial membrane is enhanced by the glucagon-mediated decrease in the cytosolic malonyl-CoA, which removes inhibition of carnitine palmitoyltransferase 1 (CPT1).
• The activation of carnitine palmitoyltransferase I allows free fatty acids to cross the mitochondrial membrane in the form of fatty acyl-CoA after their esterification with carnitine.
• The insulin-to-glucagon ratio in the hyperosmolar hyperglycemic state (HHS) does not decrease to a level where unrestrained ketoacidosis occurs.
• The hyperosmolar hyperglycemic state (HHS) was also named hyperosmolar hyperglycemic nonketotic state, but findings of moderated ketonemia in several patients has lead to the use of current term.

• The hyperosmolar state in HHS is a combination of a decrease in total body water, loss of electrolytes, dehydration, and hyperglycemia.^[21][22]
• The osmotic diuresis in HHS results when the glucose concentration reaches greater than 180 to 200 mg/dl.
• A glucose concentration greater than 180 to 200 mg/dl saturates the reabsorbing capacity of the proximal tubular transport system in the kidneys.
• The saturation of glucose transport system prevents further reabsorption and glucose eventually starts losing in the urine along with water and electrolytes and causing a decrease in the total body water.
• The blood glucose concentration keeps on rising due to continued gluconeogenesis, glycogenolysis, and decrease in total body water which further increases the plasma osmolarity.
• The increase in plasma osmolarity and water loss stimulates antidiuretic hormone (ADH) secretion, which leads to increased water reabsorption through the collecting ducts in the kidney.
• The renal water loss in the hyperosmolar hyperglycemic state (HHS) leads to dehydration especially in the elderly and in the patients who are dependent on others for care as they have decreased oral water intake.
• The decrease in effective circulatory volume due to dehydration leads to activation of renal angiotensin aldosterone system (RAAS), which conserves water but further exacerbates hyperglycemia due to oliguria which decreases renal excretion of glucose.
• The decrease in effective circulatory volume or hypotension eventually leads to coma due to a decrease in tissue perfusion, and the massive activation of renal angiotensin aldosterone system eventually leading to a renal shutdown.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

The hyperosmolar hyperglycemic state (HHS) is caused by a decrease in effective insulin-to-glucagon ratio. This process is triggered by a lack of insulin due to decreased production, noncompliance with insulin treatment, high demand of insulin or resistance to the action of insulin. The hyperosmolar hyperglycemic state (HHS) can be aggravated in conditions that cause dehydration or in certain disease states like the renal failure or congestive cardiac failure.

Common causes of hyperosmolar hyperglycemic state (HHS) include:

• Infections:
  • Pneumonia^[1]
  • Sepsis^[2][3][4]
  • Genitourinary tract infections^[5]
• Drugs:^[6][7]
  • Antipsychotic agents (clozapine, olanzapine, risperidone)
  • Illicit drugs (cocaine and alcohol)
  • Corticosteroids^[8]
  • Glucagon^[9]
  • Interferon^[10]
  • Pentamidine^[11][12]
  • Sympathomimetic agents (albuterol, dopamine, dobutamine, terbutaline, ritodrine, thiazide diuretics)^[13][14]
• Noncompliance to insulin treatment:^[15][16]
  • Body dysmorphic disorders
  • Financial problems
  • Lack of insulin^[4]
  • Psychological factors
  • Self-neglect
  • Accidental
  • Neglect by caregivers
• Others:
  • Myocardial infarction^[17]
  • Pancreatitis^[18]
  • Shock/hypovolemia^[19]
  • Trauma^[20]
  • Undiagnosed diabetes mellitus^[21]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

The hyperosmolar hyperglycemic state must be differentiated from other conditions presenting with hyperglycemia, hyperosmolarity or an altered state of consciousness. The differentials include diabetes mellitus, diabetic ketoacidosis, impaired glucose tolerance, and conditions causing altered sensorium such as CNS infections or stroke. All these conditions may be differentiated on the basis of history findings, clinical features, and laboratory abnormalities.

• Hyperosmolar hyperglycemic state must be differentiated from other diseases that present with hyperglycemia, hyperosmolarity, and altered state of consciousness.^{[1][2][3][4][5][6][7][8]}
• Hyperosmolar hyperglycemic state should also be differentiated from conditions that can cause focal neurological signs or an altered state of consciousness such as CNS infections and stroke by doing a simple finger stick glucose testing.

Diseases	Laboratory Findings	Physical Examination	History and Symptoms	Other Findings
Diabetes mellitus	Hyperglycemia: Fasting blood glucose level: >126 mg/dl Random blood glucose level: >200 mg/dl HbA1C: >6.5 % Urinanalysis may show: Proteinuria Glucosuria Positive antibodies: (Type 1 diabetes) Anti-glutamic acid decarboxylase Anti-islet cell Anti-insulin	Autonomic and peripheral neuropathy Decreased visual acuity (diabetic retinopathy) Central obesity(BMI >25 kg/m2) Hypertension (Blood pressure >140/90 mmHg)	Family history of diabetes Sedentary lifestyle Stress Polyuria Polydipsia Polyphagia Weight loss	History of gestational diabetes Polycystic ovarian syndrome Acanthosis nigricans
Diabetic ketoacidosis	Blood pH < 7.3 Serum bicarbonate < 18 mEq/L Anion gap > 10 mEq/L Increased serum osmolarity	May have all clinical features of diabetes mellitus Hypotension Tachycardia Dehydration	Younger age with type 1 diabetes mellitus Prolonged hyperglycemia Undiagnosed type 1 diabetes mellitus
Impaired glucose tolerance	Hyperglycemia: Fasting blood glucose level: 100-125 mg/dl Oral glucose tolerance test: 140-200 mg/dl	May have all clinical features of diabetes mellitus Obesity (BMI >25 kg/m2)	Family history of diabetes Sedentary lifestyle

Differentiating hyperosmolar hyperglycemic state from diabetic ketoacidosis (DKA) based on laboratory findings.

Parameters	Diabetic ketoacidosis (DKA)	Hyperosmolar hyperglycemic state (HHS)
Plasma glucose	> 250 mg/dl	> 600 mg/dl
Serum osmolality	Variable	> 320 mOsm/kg
Plasma and urine ketones	Positive	None or trace
Serum bicarbonate	< 18 mEq/L	> 15 mEq/ L
Arterial ph	< 7.30	> 7.30
Anion gap	> 12	< 12

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

The epidemiological parameters of the hyperosmolar hyperglycemic state (HHS) are difficult to predict because of the lack of population-based studies on HHS. According to the national diabetes surveillance program of the Centers for Disease Control and Prevention (CDC), hyperosmolar hyperglycemic state accounts for less than 1000 hospital admissions per 100,000 diabetic admissions. The overall mortality rate of the hyperosmolar hyperglycemic state varies from a low of less than 5000 per 100,000 individuals to a high of 20,000 per 100,000 individuals. The incidence of the hyperosmolar hyperglycemic state is more common in African-American male population as compared to the Caucasian population. The hyperosmolar hyperglycemic state also affects the elderly more compared to children and young adults.

• The exact incidence of the hyperosmolar hyperglycemic state is not known due to lack of population-based studies. However, according to the the national diabetes surveillance program of the Centers for Disease Control and Prevention (CDC), HHS accounts for less than 1000 hospital admissions per 100,000 diabetic admissions.^[1][2]
• In the year 1995, the annual incidence of the hyperosmolar hyperglycemic state has been reported to be 17.5 persons per 100,000 persons per year.^[3][1]

• Case-fatality rate of hyperosmolar hyperglycemic state varies from a low of less than 5000 per 100,000 individuals to a high of 20,000 per 100,000 individuals.^[2]
• Case-fatality rate of hyperosmolar hyperglycemic state differ according to the level of care provided and healthcare setting.^[4]

• The hyperosmolar hyperglycemic state commonly affects type 2 diabetic individuals older than 65 years of age. It is less commonly seen in children and young adults.^[2]

• Hyperosmolar hyperglycemic state usually affects individuals of the African-Americans race.^[5][1]

• Men are more commonly affected by hyperosmolar hyperglycemic state than women.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

Common risk factors in the development of hyperosmolar hyperglycemic state (HHS) are old age, high mean glycosylated hemoglobin A1C, acute stresses like infections, myocardial infarction, pancreatitis, poor diabetes control, noncompliance with insulin, poor cardiac and renal function and low socioeconomic status.

The following factors are associated with an increased risk of hyperosmolar hyperglycemic state (HHS):^{[1][2][3][4][5][6][7][8][9][10][11]}

• Old age
• Obesity
• High mean glycosylated hemoglobin A1c (HbA1c)
• Infection
• Physiological stressors:
  • Acromegaly
  • Thrombosis
  • Cerebrovascular accident
  • Cushing’s disease
  • Hemochromatosis
  • Pregnancy

• Heatstroke
• Hypothermia
• Dialysis
• Burns
• Neuroleptic malignant syndrome
• Rhabdomyolysis
• Depression
• Lack of health insurance
• Low body mass index (BMI)
• Delayed or improper management of diabetes

The following factors are associated with a reduced risk of hyperosmolar hyperglycemic state (HHS):^[12]

• Optimum management of diabetes
• Optimum fluid intake
• Adequate renal functions
• Adequate cardiac functions
• Higher education level of patient
• Higher education level of care giver

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

There is insufficient evidence to recommend routine screening for hyperosmolar hyperglycemic state.

There is insufficient evidence to recommend routine screening for hyperosmolar hyperglycemic state.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

The symptoms of hyperosmolar hyperglycemic state (HHS) develop slowly over a period of days to weeks as compared to diabetic ketoacidosis (DKA) which presents within hours of inciting event. The symptoms range from fatigue, weakness, leg cramps, polyuria, dehydration and eventually seizures and coma. If left untreated, patients may develop multiorgan failure and eventually death. Common complications are renal failure, thrombotic events, and cardiovascular complications. The complications due to treatment can be cerebral edema, pulmonary edema, hypoglycemia, and electrolyte imbalance. The mortality rate ranges from a low of less than 5000 per 100,000 individuals to a high of 20,000 per 100,000 individuals which is ten times higher than diabetic ketoacidosis. The prognosis of the hyperosmolar hyperglycemic state (HHS) depends on the hemodynamic status, comorbidities, and age at the time of presentation.

If left untreated, the evolution of hyperosmolar hyperglycemic state (HHS) can be insidious. The following features are associated with the natural course of the disease:^{[1][2][3][4][5]}

• The symptoms of hyperosmolar hyperglycemic state (HHS) usually develop over several days to weeks as compared to diabetic ketoacidosis which presents within hours of inciting event.
• Early in the course of a disease, HHS usually presents with symptoms of hyperglycemia such as polyuria, polydipsia, leg cramps, weakness, nausea, and dehydration.
• As HHS progresses, it leads to increase in serum osmolality which can present with neurological manifestations such as altered sensorium, focal signs, confused state or even coma. Neurological symptoms rarely present with an osmolality of less than 320 mOsm/kg.
• The severity of dehydration in HHS is due to insidious onset and longer duration of metabolic decompensation and also due to the reduced fluid intake.
• The increase in plasma osmolality leads to water shifts out of the cells and causes intracellular dehydration and with insulin deficiency, it further exacerbates potassium movement out of the cell.
• The dehydration leads to decrease glomerular filtration rate (GFR) and renal clearance of glucose, which further exacerbates hyperglycemia and ultimately renal failure.
• Hypotension or shock during HHS is nearly always the result of dehydration and hypovolemia.
• Heart failure, myocardial infarction, and arrhythmias are seen commonly in an untreated hyperosmolar hyperglycemic state.
• If left untreated, HHS may progress to multi-organ failure, seizures, coma and eventually death.

People with hyperosmolar hyperglycemic state (HHS) need close and frequent monitoring for complications. Surprisingly, the most common complications of HHS are related to the treatment:^{[6][7][8][9][10]}

Complications of hyperosmolar hyperglycemic state (HHS) include:

• Cardiovascular complications
• Acute renal failure
• Thrombotic events
• Infectious complications

Complications due to the treatment of hyperosmolar hyperglycemic state (HHS) include:

• Cerebral edema due to aggressive hydration
• Pulmonary edema
• Hypoglycemia
• Hypokalemia

The mortality of hyperosmolar hyperglycemic state ranges from 5% to 20%, which is ten times higher than diabetic ketoacidosis. The signs of poor prognosis in hyperosmolar hyperglycemic state (HHS) at the time of diagnosis include:^{[11][12][13][14]}

• Advanced age
• Severe dehydration
• Hypothermia
• Coma
• Hemodynamic instability
• Comorbidities such as chronic kidney disease or heart failure

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