Hyperosmolar hyperglycemic syndrome (HHS) is a clinical condition that arises from a complication of diabetes mellitus. This problem is most commonly seen in type 2 diabetes. Won Frerichs and Dreschfeld first described the disorder around 1880. They described diabetic patients with profound hyperglycemia and glycosuria without the classic Kussmaul breathing or acetone in the urine seen in diabetic ketoacidosis. This clinical condition was formerly called non-ketotic hyperglycemic coma; hyperosmolar hyperglycemic non-ketotic syndrome, and hyperosmolar non-ketotic coma (HONK).
Diabetes mellitus is a clinical condition associated with hyperglycemia as the main metabolic disorder .This is as a result of an absolute or relative deficiency of insulin. Insulin is an anabolic hormone produced by the beta cells in the islets of Langerhans in the pancreas. The main function of this hormone is to lower the level of glucose in the blood by promoting the uptake of glucose by the adipose tissue and skeletal muscle, known as glycogenesis. Insulin also inhibits the breakdown of fat in the adipose tissue, known as lipolysis. The metabolic effect of insulin is countered by hormones such as glucagon and catecholamines .
In type 1 diabetes, there is the autoimmune destruction of the beta cells in the pancreas. Only about 5% to 10% of all diabetes falls into this category. The most common complication of type 1 diabetes is diabetic ketoacidosis (DKA).
Type 2 diabetes accounts for about 90% to 95% of diabetes cases. It is most commonly seen in obese patients. As a consequence of the obesity and high body mass index (BMI), there is the resistance of the peripheral tissue to the action of insulin. The beta cell in the pancreas continues to produce insulin, but the amount is not enough to counter the effect of the resistance of the end organ to its effect.
HHS is a serious and potentially fatal complication of type 2 diabetes.
The mortality rate in HHS can be as high as 20% which is about 10 times higher than the mortality seen in diabetic ketoacidosis. Clinical outcome and prognosis in HHS are determined by several factors: age, the degree of dehydration, and the presence or lack of other comorbidities.
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.
This is particularly true in 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, in certain conditions, some factors might initiate the development of HSS. The most frequent reason for this complication is infection. Infectious process in the respiratory, gastrointestinal, and genitourinary system can act as the causative factor. The reason for this is insensible water loss and release of endogenous catecholamines. Approximately 50% to 60% of HHS is attributable to an infectious etiology.
Some medication for 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 antipsychotic.
Cardiovascular insult like stroke, angina pectoris, myocardial infarction can also trigger a stress response. This leads to the release of counterregulatory hormones with the resultant effect of increased level of blood glucose causing osmotic diuresis, dehydration with the result being HHS.
In the United States, because of the increase of childhood obesity which is related to 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 increase incidence of HHS in the pediatric population.
There is a disproportionally high number of African American, Native American, 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.
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 decrease glucose utilization by the peripheral tissue causing hyperglycemia. The peripheral tissues enter a state of “starvation” The release of counterregulatory hormones glucagon, growth hormone, cortisol, and catecholamines stimulates gluconeogenesis and glycogenolysis. This creates a system of vicious cycle where there is increase level of glucose in the serum but decreases uptake by the peripheral tissues for tissue metabolism. The serum osmolarity 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 from the extravascular space from 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.
Compared to DKA, production of ketone bodies is scant in HHS. As a result of a deficiency of insulin, there is increase lipolysis to release 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 substrate 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, generation of ketone bodies is minimal. Insulin inhibits ketogenesis. That aside, in HSS there is a higher level of insulin with an associated lower level of glucagon. Therefore, ketonemia and acidemia are very mild in HHS.
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 extracellular space and maintain a balanced equilibrium.
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 the hyperglycemia.
The history and physical examination are very important in the diagnosis of HSS. In many instances, there is 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 regiment, missed doses of the oral hypoglycemic agent, overconsumption of carbohydrate-rich diet, or simultaneous use of medications that can trigger hyperglycemia or cause dehydration.
If an infectious process precedes HSS, signs and symptoms include:
If the precipitating factor is a cardiac, vascular conditions, signs and symptoms will include:
The typical clinical presentation of patients with HSS is increased urination (polyuria) and increase 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 complaint.
Severe dehydration from HSS 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:
A system based approach is necessary for the physical assessment:
The physical examination should also focus on other comorbidities associated with diabetes mellitus. Acanthosis nigricans, oral thrush, vulvovaginitis, multiple pustular skin lesion might all indicate poor glycemic control. This is important if HSS is the initial presentation of type 2 diabetes.
The diagnostic criteria for HSS 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 
According to the recommendation of the American Diabetic Association and current international guideline, HSS is defined by plasma glucose level greater than 600 mg/dL, plasma effective osmolarity greater than 320 mOsm/L, and absence of significant ketoacidosis.
Hyperosmolar hyperglycemic non-ketotic coma is no longer accepted as a diagnostic nomenclature because not all patients with HSS 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 HSS 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.
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 HSS. The risk of cerebral edema is higher in HSS.
This is a measure of long-term glycemic control and is a useful tool in the assessment of new-onset diabetic patients.
The serum osmolarity is very high in HSS. Levels between 320 to 400mOsm/kg is very common in HSS. Normal serum osmolarity is around 280 -290 mOsm/kg. In patients with higher serum osmolarity is associated with alteration in the level of consciousness and might eventually lead to coma
Comprehensive metabolic panel allow for determination of electrolyte derangements seen in HSS
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)
The level of potassium might be high or low. 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 HSS and DKA. Care must be taken to avoid aggressive correction of hypokalemia in HSS because of decreased glomerular filtration rate from dehydration
Bicarbonate level is usually close to normal in HSS, around 8 to 12 mmol/L because the production of ketone bodies is minimal as compared to DKA where bicarbonate level is usually very low. The anion gap in HSS is close to normal. On the contrary, the anion gap is usually above 12 mmol/L in DKA. Anion gap is determined by the formula:
(Na +K) -(Cl +HC0)
If the anion gap is high in HSS, it is usually because of the production of lactic acid from tissue hypoperfusion and decreased circulation.
The magnesium level might be low in HSS.
Hyperphosphatemia is common in HSS especially if rhabdomyolysis is a complication. This is as 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 renally excreted as end-organ perfusion improves.
Ketonemia is very minimal in HSS. Electrolytes should be monitored serially every 2 to 3 hours in the management of HSS.
Arterial Blood Gases
The role of the blood gas is to determine the level of acidosis. In HSS, 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 HSS is mainly as a result of dehydration and compromised end-organ perfusion.
Arterial blood gases should be monitored every 2 to 3 hours in HSS.
The BUN and creatine levels are usually elevated reflecting prerenal azotemia. As hydration and insulin therapy is initiated, these values will usually drop and eventually normalized.
The level of serum enzymes like creatinine kinase, aldolase, transaminases are usually high from hemoconcentration and dehydration
Complete Blood Count
The white blood cell count might be high because of stress response or as a result of an infectious process triggering HSS. In most case, hemoglobin and hematocrit level are elevated. If the white count is elevated, blood, urine culture, and a chest X-ray might be needed to find the source of infection.
Urine specific gravity is high in HSS. Glycosuria and ketonuria are also present.
Treatment of HSS requires a multidisciplinary approach. Consultation with an endocrinologist and intensive care specialist is recommended. Appropriate resuscitation with attention to the principle of Airway, Breathing, Circulation (ABC) should be initiated. Patients with HSS 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 HSS. An initial fluid bolus of 15 to 20 ml/kg followed by an infusion rate of 200 to 250ml/hour is the recommended rate for adults. In pediatric patient, 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 HSS. The use of this alone can reduce the serum glucose by about 75 to 100 mg/hour. The serum potassium in HSS 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 .
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 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.
The differential diagnosis in HSS is divided into 2 broad groups: clinical conditions causing altered mental status and clinical conditions causing hyperglycemia.
The following are some examples of condition that can cause an alteration in mental status:
Hyperglycemia can develop with diabetic ketoacidosis and diabetic insipidus.
A detailed history, thorough physical examination and use of ancillary studies can help to establish a diagnosis quickly.
HSS is a potentially fatal medical condition. Knowledge of pathophysiology and clinical presentation is necessary for the best management outcome.
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