Hyperosmolar hyperglycemic state overview

# Overview
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.

# Historical Perspective
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.

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

# Pathophysiology
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.

# Causes
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.

# Differentiating hyperosmolar hyperglycemic state from Other Diseases
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.

# Epidemiology and Demographics
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.

# Risk Factors
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.

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

# Natural History, Complications, and Prognosis
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.

# Diagnosis

## Diagnostic study of choice
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.

## History and Symptoms
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.

## Physical Examination
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
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.

## Electrocardiogram
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.

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

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

## CT scan
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
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.

## Other Imaging Findings
There are no other imaging findings associated with the hyperosmolar hyperglycemic state.

## Other Diagnostic Studies
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.

# Treatment

## Medical Therapy
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.

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

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