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 patients with diabetes mellitus 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 patients with obesity. 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 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, in 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.
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.
A 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 an 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 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.
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. 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 an increased level of glucose in the serum but decreases 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 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, the 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, 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 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 hyperglycemia.
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 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 HHS, signs, and symptoms include:
If the precipitating factor is a cardiac, vascular condition, signs and symptoms will include:
The typical clinical presentation of patients with HHS 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 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:
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 lesions might all indicate poor glycemic control. This is important if HHS is the initial presentation of type 2 diabetes.
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.
According to the recommendation of the American Diabetic Association and current international guideline, 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.
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.
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.
This is a measure of long-term glycemic control and is a useful tool in the assessment of new-onset diabetes mellitus.
The serum osmolality is very high in HHS. Levels between 320 to 400mOsm/kg is very common in HHS. Normal serum osmolarity is around 280 -290 mOsm/kg. In patients with higher serum osmolarity are 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.
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. 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 level is usually close to normal in HHS, 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 HHS is 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.
The magnesium level might be low in HHS.
Hyperphosphatemia is common in HHS 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 excreted by the kidneys as end-organ perfusion improves.
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 as a result of dehydration and compromised end-organ perfusion.
Arterial blood gases should be monitored every 2 to 3 hours in HHS.
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 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, urine culture, and a chest X-ray might be needed to find the source of infection.
Urine specific gravity is high in HHS. Glycosuria and ketonuria are also present.
Treatment of HHS 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 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 250ml/hour is the recommended rate 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.
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 HHS 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.
HHS is a potentially fatal medical condition. Knowledge of pathophysiology and clinical presentation is necessary for the best management outcome.
In general, the overall mortality is low and is usually due to the underlying illness that caused the hyperglycemic crisis. Elderly patients who present with severe coma and hypotension have a poor prognosis compared to younger cohorts.
Electrolyte 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 electrolyte 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.
Diabetic education including instructions on adequate hydration is essential to avoid recurrent episodes.
Hyperosmolar Hyperglycemic Nonketotic Coma is a serious complication of Type II Diabetes. Most patients will end up being admitted to the intensive care unit. To improve patient outcome, an interprofessional approach with good care communication and coordination between the Intensivist, nurse, dietician, and the endocrinologist is necessary.
|||Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment., Pasquel FJ,Umpierrez GE,, Diabetes care, 2014 Nov [PubMed PMID: 25342831]|
|||Diagnosis and classification of diabetes mellitus. Diabetes care. 2010 Jan [PubMed PMID: 20042775]|
|||Röder PV,Wu B,Liu Y,Han W, Pancreatic regulation of glucose homeostasis. Experimental & molecular medicine. 2016 Mar 11 [PubMed PMID: 26964835]|
|||Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes care. 1997 Jul [PubMed PMID: 9203460]|
|||Milionis HJ,Elisaf MS, Therapeutic management of hyperglycaemic hyperosmolar syndrome. Expert opinion on pharmacotherapy. 2005 Sep [PubMed PMID: 16144505]|
|||Kitabchi AE,Umpierrez GE,Miles JM,Fisher JN, Hyperglycemic crises in adult patients with diabetes. Diabetes care. 2009 Jul [PubMed PMID: 19564476]|
|||Wachtel TJ,Silliman RA,Lamberton P, Predisposing factors for the diabetic hyperosmolar state. Archives of internal medicine. 1988 Mar [PubMed PMID: 3341875]|
|||Wachtel TJ,Silliman RA,Lamberton P, Prognostic factors in the diabetic hyperosmolar state. Journal of the American Geriatrics Society. 1987 Aug [PubMed PMID: 3611564]|
|||Wachtel TJ,Silliman RA,Lamberton P, Predisposing factors for the diabetic hyperosmolar state. Archives of internal medicine. 1987 Mar [PubMed PMID: 3827427]|
|||McDonnell CM,Pedreira CC,Vadamalayan B,Cameron FJ,Werther GA, Diabetic ketoacidosis, hyperosmolarity and hypernatremia: are high-carbohydrate drinks worsening initial presentation? Pediatric diabetes. 2005 Jun [PubMed PMID: 15963036]|
|||Kitabchi AE,Wall BM, Diabetic ketoacidosis. The Medical clinics of North America. 1995 Jan [PubMed PMID: 7808097]|
|||Wachtel TJ,Tetu-Mouradjian LM,Goldman DL,Ellis SE,O'Sullivan PS, Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. Journal of general internal medicine. 1991 Nov-Dec [PubMed PMID: 1765864]|
|||Wachtel TJ, The diabetic hyperosmolar state. Clinics in geriatric medicine. 1990 Nov [PubMed PMID: 2224747]|
|||Wilson DR,D'Souza L,Sarkar N,Newton M,Hammond C, New-onset diabetes and ketoacidosis with atypical antipsychotics. Schizophrenia research. 2003 Jan 1 [PubMed PMID: 12413635]|
|||Ananth J,Parameswaran S,Gunatilake S, Side effects of atypical antipsychotic drugs. Current pharmaceutical design. 2004 [PubMed PMID: 15281897]|
|||Bradford AL,Crider CC,Xu X,Naqvi SH, Predictors of Recurrent Hospital Admission for Patients Presenting With Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. Journal of clinical medicine research. 2017 Jan [PubMed PMID: 27924173]|
|||Trence DL,Hirsch IB, Hyperglycemic crises in diabetes mellitus type 2. Endocrinology and metabolism clinics of North America. 2001 Dec [PubMed PMID: 11727401]|
|||MacIsaac RJ,Lee LY,McNeil KJ,Tsalamandris C,Jerums G, Influence of age on the presentation and outcome of acidotic and hyperosmolar diabetic emergencies. Internal medicine journal. 2002 Aug [PubMed PMID: 12162394]|
|||Macaulay MB, Hyperosmolar non-ketotic diabetes. Postgraduate medical journal. 1971 Apr [PubMed PMID: 5576486]|
|||Kitabchi AE,Umpierrez GE,Murphy MB,Barrett EJ,Kreisberg RA,Malone JI,Wall BM, Management of hyperglycemic crises in patients with diabetes. Diabetes care. 2001 Jan [PubMed PMID: 11194218]|
|||Kitabchi AE,Nyenwe EA, Hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Endocrinology and metabolism clinics of North America. 2006 Dec [PubMed PMID: 17127143]|
|||Delaney MF,Zisman A,Kettyle WM, Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Endocrinology and metabolism clinics of North America. 2000 Dec [PubMed PMID: 11149157]|
|||Nugent BW, Hyperosmolar hyperglycemic state. Emergency medicine clinics of North America. 2005 Aug [PubMed PMID: 15982538]|
|||Rosenbloom AL, Hyperglycemic crises and their complications in children. Journal of pediatric endocrinology & metabolism : JPEM. 2007 Jan [PubMed PMID: 17315523]|
|||Gordon EE,Kabadi UM, The hyperglycemic hyperosmolar syndrome. The American journal of the medical sciences. 1976 May-Jun [PubMed PMID: 779472]|
|||Conley SB, Hypernatremia. Pediatric clinics of North America. 1990 Apr [PubMed PMID: 2184402]|
|||Arieff AI,Carroll HJ, Hyperosmolar nonketotic coma with hyperglycemia: abnormalities of lipid and carbohydrate metabolism. Metabolism: clinical and experimental. 1971 Jun [PubMed PMID: 4996168]|
|||Zeitler P,Haqq A,Rosenbloom A,Glaser N, Hyperglycemic hyperosmolar syndrome in children: pathophysiological considerations and suggested guidelines for treatment. The Journal of pediatrics. 2011 Jan [PubMed PMID: 21035820]|
|||Hockaday TD,Alberti KG, Diabetic coma. Clinics in endocrinology and metabolism. 1972 Nov [PubMed PMID: 4204136]|
|||Arieff AI,Kleeman CR, Studies on mechanisms of cerebral edema in diabetic comas. Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits. The Journal of clinical investigation. 1973 Mar [PubMed PMID: 4685082]|