Hyperosmolar Hyperglycemic Syndrome

Etiology

In children and young adults with type 1 and type 2 diabetes, infectious diseases and disorders of the respiratory, circulatory, and genitourinary systems can cause HHS. Obesity and incessant consumption of carbohydrate-rich beverages have led to an increase in the incidence of HHS.[10][11]

This is particularly true in the pediatric population, where the incidence of type 2 diabetes is on the rise.

As stated earlier, HHS is most commonly seen in patients with type 2 diabetes. If diabetes mellitus is well controlled, the chance of developing HHS is minimal. However, under certain conditions, some factors might initiate the development of HHS. The most frequent reason for this complication is infection. The infectious process in the respiratory, gastrointestinal, and genitourinary systems can act as the causative factor. The reason for this is the insensible water loss and the release of endogenous catecholamines. Approximately 50% to 60% of HHS is attributable to an infectious etiology.[11][12][13]

Some medications for the treatment of other ailments and conditions in elderly patients with type 2 diabetes can trigger HHS. Examples of such medications are thiazide diuretics, beta-blockers, glucocorticoids, and some atypical antipsychotics.[14][15]

A cardiovascular insult like stroke, angina pectoris, and myocardial infarction can also trigger a stress response. This leads to the release of counterregulatory hormones with the resultant effect of an increased level of blood glucose, causing osmotic diuresis and dehydration, with the final result being HHS.

Epidemiology

There is insufficient data on the epidemiology of HHS. Based on some studies, close to 1% of all hospital admission for diabetes is related to HHS.[16][17]

Most cases of HHS are seen in patients in the fifth and sixth decades of life. Typically DKA is more common in the younger population, with the peak age around the fourth decade of life.[17][18]

In the United States, because of the increase in childhood obesity which is related to the consumption of high amounts of carbohydrate-rich diet, there is a significant increase in the incidence of type 2 diabetes. This may lead to an increased incidence of HHS in the pediatric population.

There is a disproportionally high number of African Americans, Native Americans, and Hispanics who are afflicted with HHS. This might be related to a high prevalence of type 2 diabetes in these particular population groups. HHS can be fatal in morbidly obese African American males.

Pathophysiology

HHS has similar pathophysiology to DKA but with some mild dissimilarities. The hallmark of both conditions is the deficiency of insulin. As a consequence of deficiency of this key hormone, there is a decrease in glucose utilization by the peripheral tissue causing hyperglycemia.[19] The peripheral tissues enter a state of “starvation.”The release of counterregulatory hormones like glucagon, growth hormone, cortisol, and catecholamines stimulates gluconeogenesis and glycogenolysis.[19][20] This creates a system of vicious cycle where there is an increased level of glucose in the serum but decreased uptake by the peripheral tissues for tissue metabolism. The serum osmolality is determined by the formula 2Na + Glucose /18 + BUN / 2.8. The resultant hyperglycemia increases the serum osmolarity to a significant degree. The glucose level in HHS is usually above 600 mg/dL. Hyperglycemia also creates an increase in the osmotic gradient, with free water drawn out of the extravascular space due to the increased osmotic gradient. Free water with electrolytes and glucose is lost via urinary excretion producing glycosuria, causing moderate to severe dehydration. Dehydration is usually more severe in HHS as compared to DKA, and there is more risk for cardiovascular collapse.[21][22][23][24]

Compared to DKA, the production of ketone bodies is scant in HHS. As a result of the deficiency of insulin, there is increased lipolysis that causes an increased release of fatty acid as an alternative energy substrate for the peripheral tissues. Beta oxidation of fatty acids produces ketone bodies: acetone, acetoacetate, and beta oxybutyric acid. Accumulation of these substrates produces ketonemia and acidemia. Acidemia from ketone bodies stimulates the kidney to retain bicarbonate ions to neutralize the hydrogen ions. This accounts for the low serum bicarbonate level in DKA.

In HHS, however, because insulin is still being produced by the beta cells in the pancreas, the generation of ketone bodies is minimal. Insulin inhibits ketogenesis. That aside, in HHS, there is a higher level of insulin with an associated lower level of glucagon. Therefore, ketonemia and acidemia, if they happen, they are very mild in HHS.[20][25][26]

The effect of the increased serum osmolarity on the brain can be very profound. To preserve the intracellular volume, the brain produces idiogenic osmoles. Idiogenic osmoles are substances that are osmotically active. The net effect of the production of these substances is to prevent fluid from moving from the intracellular space into the extracellular space and maintain a balanced equilibrium.[24]

The risk of developing cerebral edema is mostly related to how fast the serum osmolarity is decreasing. If the decline is too rapid and the brain is not able to eliminate idiogenic osmoles at the same rate as the decline in serum osmolarity, then the chances of fluid moving into the brain cell and causing swelling are higher. Hence, in the treatment of HHS, the goal of treatment is a slow correction of hyperglycemia.

History and Physical

The history and physical examination are very important in the diagnosis of HHS. In many instances, there is a significant overlap in the signs and symptoms seen in HHS and DKA. In the history taking and the initial assessment, particular attention should be focused on the insulin regimen, missed dosages of oral hypoglycemic agents, overconsumption of carbohydrate-rich diet, or simultaneous use of medications that can trigger hyperglycemia or cause dehydration.

If an infectious process precedes HHS, signs and symptoms include:

• Fever
• Malaise
• General weakness
• Tachypnea
• Tachycardia

If the precipitating factor is a cardiac or vascular condition, signs and symptoms will include:

• Chest pain
• Chest tightness
• Headache
• Dizziness
• Palpitations

The typical clinical presentation of patients with HHS is increased urination (polyuria) and increased water intake (polydipsia). This is a result of the stimulation of the thirst center in the brain from severe dehydration and increased serum osmolarity. Weakness, malaise, and lethargy can also be part of the complaints.

Severe dehydration from HHS can also affect the skin and integumentary system. Typically, the skin and the oral mucosa are dry with a delayed capillary refill.

The most important distinguishing factor in HHS is the presence of neurological signs. Decreased cerebral blood flow from severe dehydration can cause:

• Focal neurological deficit
• Disturbance in visual acuity
• Delirium
• Coma

A system-based approach is necessary for the physical assessment:

• General appearance: Patients with HHS are generally ill-appearing with altered mental status
• Cardiovascular: Tachycardia, orthostatic hypotension, weak and thready pulse
• Respiratory: Rate can be normal, but tachypnea might be present if acidosis is profound
• Skin: Delayed capillary refill, poor skin turgor, and skin tenting might not be present even in severe dehydration because of obesity
• Genitourinary: Decreased urine output
• Central Nervous System (CNS): Focal neurological deficit, lethargy with low Glasgow coma score, and in severe cases of HHS, the patient might be comatose.

The physical examination should also focus on other comorbidities associated with diabetes mellitus. Acanthosis nigricans, oral thrush, vulvovaginitis, and multiple pustular skin lesions might all indicate poor glycemic control. This is particularly important if HHS is the initial presentation of type 2 diabetes.

Evaluation

The diagnostic criteria for HHS were developed as a result of cases series reported by Gerich et al. Arieff and Carroll also contributed to this work in a separate study, both of which were published in 1971.[27]

According to the recommendation of the American Diabetic Association and current international guidelines, HHS is defined by plasma glucose level greater than 600 mg/dL, plasma effective osmolarity greater than 320 mOsm/L, and absence of significant ketoacidosis.[28]

Hyperosmolar hyperglycemic non-ketotic coma is no longer accepted as a diagnostic nomenclature because not all patients with HHS will present with coma, even in the presence of significant hyperglycemia and hyperosmolarity.

The evaluation of HHS requires a detailed history and physical examination. The onset of symptoms and the precipitating factors are very important to elicit from patients. That apart, ancillary studies are also necessary as part of the diagnostic workup.

The first test in HHS is a fingerstick to determine the serum glucose level. The value is usually between 600 to 1200 mg/dl. The higher the level of glucose, the greater the serum osmolarity and the higher the degree of dehydration.

Glucose

The glucose level should be monitored hourly to guard against a sudden and precipitous drop during treatment with isotonic fluid and insulin. This is to prevent the development of cerebral edema, which is the most dreaded complication in both DKA and HHS. The risk of cerebral edema is higher in HHS.

Hemoglobin A1C

This is a measure of long-term glycemic control and is a useful tool in the assessment of new-onset diabetes mellitus.

Serum Osmolarity

The serum osmolality is very high in HHS. Levels between 320 to 400mOsm/kg are very common in HHS. Normal serum osmolarity is around 280 -290 mOsm/kg. Higher serum osmolarity is associated with alteration in the level of consciousness and might eventually lead to a coma.

The comprehensive metabolic panel allows for the determination of electrolyte derangements seen in HHS.

Sodium

The sodium level is falsely low (pseudohyponatremia). The hyperglycemic state creates an osmotic gradient, drawing water from the intracellular space into the extracellular space. The correct or true sodium level is usually calculated using the formula:

Corrected Sodium = Measured sodium + (((Serum glucose - 100)/100) x 1.6)

Potassium

The level of potassium might be high or low. A low level of insulin can cause an extracellular shift of potassium. However, because of ongoing urinary losses, the total body potassium is low in both HHS and DKA. Care must be taken to avoid aggressive correction of hypokalemia in HHS because of decreased glomerular filtration rate from dehydration.

Bicarbonate

Bicarbonate level is usually close to normal in HHS, around 22 to 32 mmol/L, because the production of ketone bodies is minimal as compared to DKA, where the bicarbonate level is usually very low. The anion gap in HHS is normal or close to normal. On the contrary, the anion gap is usually above 12 mmol/L in DKA. The anion gap is determined by the formula:

(Na +K) - (Cl +HC0)

If the anion gap is high in HHS, it is usually because of the production of lactic acid from tissue hypoperfusion and decreased circulation.

Magnesium

The magnesium level might be low in HHS.

Phosphorus

Hyperphosphatemia is common in HHS, especially if rhabdomyolysis is a complication. This is a result of muscular tissue breakdown. Administration of insulin and hydration with fluid might lower the phosphorus level as it is driven back into cells. Some of the phosphorus also get excreted by the kidneys as end-organ perfusion improves.

Ketones

Ketonemia is very minimal in HHS. Electrolytes should be monitored serially every 2 to 3 hours in the management of HHS.

Arterial Blood Gases

The role of blood gas is to determine the level of acidosis. In HHS, pH is usually above or around 7.30. The pC0 might be low from hyperventilation. In DKA, serum pH is usually much lower ranging from 6.8 to around 7.2 on initial presentation. Acidosis in HHS is mainly a result of dehydration and compromised end-organ perfusion.

Arterial blood gases should be monitored every 2 to 3 hours in HHS.

Renal Function

The BUN and creatine levels are usually elevated, reflecting prerenal azotemia. As hydration and insulin therapy are initiated, these values will usually drop and eventually normalize.

Serum Enzymes

The level of serum enzymes like creatinine kinase, aldolase, and transaminases is usually high from hemoconcentration and dehydration.

Complete Blood Count

The white blood cell count might be high because of the stress response or as a result of an infectious process triggering HHS. In most cases, hemoglobin and hematocrit levels are elevated. If the white count is elevated, blood culture, urine culture, and a chest X-ray might be needed to find the source of infection.

Urine Analysis

Urine-specific gravity is high in HHS. Glycosuria and ketonuria are also present.

Treatment / Management

Treatment of HHS requires a multidisciplinary approach. Consultations with an endocrinologist and an intensive care specialist are recommended. Appropriate resuscitation with attention to the principle of Airway, Breathing, Circulation (ABC) should be initiated. Patients with HHS can present with altered mental status as a result of significant fluid depletion and decreased cerebral perfusion. A good rule of thumb is to secure the airway if the Glasgow coma score is less than 8.

Aggressive hydration with isotonic fluid with electrolyte replacement is the standard practice in the management of HHS. An initial fluid bolus of 15 to 20 ml/kg followed by an infusion rate of 200 to 250 ml/hour are the recommended rates for adults. In pediatric patients, the infusion should run at about twice the maintenance rate. Hydration with isotonic fluid has been shown to help in reducing the amount of counterregulatory hormones produced during HHS. The use of this alone can reduce serum glucose by about 75 to 100 mg/hour. The serum potassium in HHS is usually high, but the total body potassium is low as a result of the extracellular shift from lack of insulin. Potassium replacement should be started when the serum potassium is between 4 to 4.5 mmol/L.[29]

Care should be taken to avoid starting insulin drip in the initial stage of treatment as this might cause a rapid drop in serum glucose levels leading to cerebral edema. It is recommended to try to keep the glucose level around 300 mg/dL to prevent the development of cerebral edema.

In pediatrics, rehydration and electrolyte correction over a longer period of 48 hours may help in the prevention of cerebral edema.[29][30](B3)

Differential Diagnosis

The differential diagnosis in HHS is divided into 2 broad groups: clinical conditions causing altered mental status and clinical conditions causing hyperglycemia.

The following are some examples of conditions that can cause an alteration in mental status:

• Hypoglycemia
• Hyponatremia
• Hypernatremia
• Hyperammonemia
• Severe intoxication with drugs or alcohol
• Uremic encephalopathy

Hyperglycemia can develop with diabetic ketoacidosis and diabetes insipidus.

A detailed history, thorough physical examination, and use of ancillary studies can help to establish a diagnosis quickly.[23]

HHS is a potentially fatal medical condition. Knowledge of pathophysiology and clinical presentation is necessary for the best management outcome.

Prognosis

In general, the overall mortality is low, and it is usually due to the underlying illness that caused the hyperglycemic crisis. Elderly patients who present with severe coma and hypotension have a poorer prognosis compared to younger cohorts.

Complications

Electrolytic abnormalities as a consequence of the treatment of HHS are quite frequent. Care needs to be taken to ensure frequent monitoring and avoid adverse side effects. Common electrolytic disturbances include hypokalemia and hypoglycemia. 

Cerebral edema is a feared but rare complication in HHS. This is more common in the pediatric population and occurs due to the rapid lowering of glucose levels.