Practice EssentialsHyperosmolar hyperglycemic state (HHS) is one of two serious metabolic derangements that occur in patients with diabetes mellitus (DM). [1] It is a life-threatening emergency that, although less common than its counterpart, diabetic ketoacidosis (DKA), has a much higher mortality rate, reaching up to 5-10%. (See Epidemiology.) HHS was previously termed hyperosmolar hyperglycemic nonketotic coma (HHNC); however, the terminology was changed because coma is found in fewer than 20% of patients with HHS. [2, 3, 4] Show
HHS is most commonly seen in patients with type 2 DM who have some concomitant illness that leads to reduced fluid intake, as seen, for example, in elderly institutionalized persons with decreased thirst perception and reduced ability to drink water. [5] Infection is the most common preceding illness, but many other conditions, such as stroke or myocardial infarction, can cause this state. [5] Once HHS has developed, it may be difficult to identify or differentiate it from the antecedent illness. (See Etiology.) HHS is characterized by hyperglycemia, hyperosmolarity, and dehydration without significant ketoacidosis. Most patients present with severe dehydration and focal or global neurologic deficits. [2, 6, 7] The clinical features of HHS and DKA overlap and are observed simultaneously (overlap cases) in up to one third of cases. Signs and symptoms of hyperosmolar hyperglycemic stateVital signs related to HHS include the following:
Physical exam findings and signs related to HHS include the following:
Workup in hyperosmolar hyperglycemic stateAccording to a consensus statement published by the American Diabetes Association, diagnostic features of HHS may include the following (see Workup) [6, 8] :
Electrocardiography (ECG) is indicated in all patients with HHS because myocardial infarction (MI) and pulmonary embolism (PE) can precipitate the condition. Cerebrospinal fluid (CSF) cell count, glucose, protein, and culture are indicated in patients with an acute alteration of consciousness and clinical features suggestive of possible central nervous system (CNS) infection. When meningitis or subarachnoid hemorrhage is suspected, lumbar puncture (LP) is indicated. If meningitis is suspected clinically, do not withhold antibiotics while waiting for the LP to be completed. ManagementDetection and treatment of an underlying illness are critical. Standard care for dehydration and altered mental status is appropriate, including airway management, intravenous (IV) access, crystalloid administration, and any medications routinely given to coma patients. Although many patients with HHS respond to fluids alone, IV insulin in dosages similar to those used in DKA can facilitate correction of hyperglycemia. Insulin used without concomitant vigorous fluid replacement increases the risk of shock. (See Treatment.) PathophysiologyNormal metabolic physiologyIn a normal postprandial state, insulin production is stimulated primarily by the glycemic rise of ingested carbohydrates. This promotes glucose uptake by insulin-sensitive tissues after meals. The increased insulin levels inhibit glucagon release from the pancreatic islets, and the ratio of plasma insulin to glucagon becomes relatively high. A high insulin-to-glucagon ratio favors an anabolic state, storage of glucose as glycogen in liver and muscle, and lipogenesis in adipocytes. The insulin-dependent transport of glucose across the cell membranes of insulin-sensitive tissues also drives potassium into these cells. A high insulin-to-glucagon ratio during meals also favors amino acid uptake by muscle. Between meals, insulin secretion decreases, as does the insulin-mediated glucagon inhibition in the pancreatic islets. The glucagon levels rise in the plasma. The resultant low plasma insulin-to-glucagon ratio favors a catabolic state, with a breakdown of glycogen in the liver and muscle and gluconeogenesis by the liver; both of these processes maintain the plasma glucose concentration in the normal range. A fall in the insulin-to-glucagon ratio also favors lipolysis and the formation of ketone bodies by the liver. Several tissues in the body use glucose regardless of the insulin-to-glucagon ratio. These insulin-independent tissues include the brain and the kidneys. Insulin ResistanceResistance to insulin is most often caused by obesity, but is also seen in a multitude of settings, including, but not limited to, the body’s response to pregnancy, stress, some medications, illness, and some genetic disorders. Any condition or medication that increases counterregulatory hormones—such as the four major ones, ie, epinephrine, glucagon, growth hormone, and cortisol—can cause insulin resistance. The levels of these hormones increase during an acute illness (eg, major infections, myocardial infarction [MI], or pancreatitis) or stress (eg, surgery, major psychiatric illness, or multiple injuries), when counterregulatory hormones are given as therapy (eg, glucocorticoid medications), and as a result of their overproduction (eg, in Cushing syndrome or acromegaly). Often, parenteral nutrition and administration of some medications (notably, tretinoin, antiretrovirals, antipsychotics, [9, 10] and immunosuppressive agents, such as cyclosporine) also cause insulin resistance. Some causes are still poorly understood, as in the common finding of insulin resistance in patients with hepatitis C. Type 2 DMType 2 DM is characterized by insulin resistance with concomitant insulin deficiency. Initially, during the evolution of type 2 DM, there is insulin resistance in peripheral tissues. This causes beta-islet cells to compensate by hypersecreting insulin. Over time, the beta-islet cells begin to decompensate and fail, leading to glucose intolerance. (The extent of beta-cell function in the pancreas determines the amount of hyperglycemia in persons with type 2 DM. [11] ) The resulting elevation in plasma glucose concentration leads to further impairment of insulin release by pancreatic beta cells because of the toxic effects of glucose on those cells. In this setting of inadequate insulin action, the magnitude of the rise in plasma glucose concentration also depends, in part, on the level of hydration and oral carbohydrate (or glucose) loading. HHSThe basic underlying mechanism of HHS is a relative reduction in effective circulating insulin with a concomitant rise in counterregulatory hormones. [2, 6] Unlike patients with DKA, most patients with HHS do not develop significant ketoacidosis. Insulin remains available in amounts sufficient to inhibit lipolysis and ketogenesis but insufficient to prevent hyperglycemia. Hyperosmolarity itself may also decrease lipolysis, limiting the amount of free fatty acids available for ketogenesis [7] . Under normal circumstances, all of the glucose filtered by the kidneys is reabsorbed. When blood glucose levels reach approximately 180 mg/dL, proximal tubular transport of glucose from the tubular lumen into the renal interstitium becomes saturated, and further glucose reabsorption is no longer possible. The glucose that remains in the renal tubules continues to travel, passing into the distal nephron and, eventually, the urine, carrying water and electrolytes with it. Osmotic diuresis results, causing a decrease in total body water. Diuresis also leads to loss of electrolytes, such as sodium and potassium. Glucose concentration increases due to loss of circulating volume. In an insulinopenic state, hyperglycemia is exacerbated by continued gluconeogenesis and inability to clear glucose. [2, 6, 7] Due to loss of circulating water volume, patients with HHS can have up to 9L of water deficit because of hyperosmolarity and diuresis. The hyperosmolarity of the plasma triggers the release of antidiuretic hormone to ameliorate renal water loss by reabsorbing water through collecting ducts in the kidney. Hyperosmolarity stimulates thirst, a defense mechanism that may prove disadvantageous in patients who are dependent on others for care, such as the institutionalized elderly. In the presence of HHS, if the renal water loss is not compensated for by oral water intake, dehydration leads to hypovolemia. The development of hyperosmolarity and hypotension can be accelerated by any process that accelerates water loss, such as diarrhea or severe burns. In a severely dehydrated and hyperosmolar state, hypotension causes a massive stimulation of the renin-angiotensin-aldosterone system and, eventually, renal shutdown. Oliguria precludes further excretion of glucose from the kidneys, which conserves circulating volume but exacerbates hyperglycemia. Hypotension also results in impaired tissue perfusion. Coma is the end stage of this hyperglycemic process, when severe electrolyte disturbances occur in association with hypotension. EtiologyHHS most commonly occurs in patients with type 2 DM who have some concomitant illness that leads to reduced fluid intake. The most at-risk population consists of the elderly or chronically ill, who in many cases have decreased thirst perception or limited free access to water. In general, any illness that predisposes to dehydration or to reduced insulin activity may lead to HHS. Acute febrile illnesses, including infections, account for the largest proportion of HHS cases. A preceding or intercurrent infection (in particular, pneumonia or urinary tract infection [UTI] [2] ) is the single most common cause, but in a number of patients, the concomitant illness is not identifiable. When considering treatment of a patient with HHS, it is imperative to assess for and address any acute illness or contributions from medications. The stress response to any acute illness tends to increase counterregulatory hormones that favor elevated glucose levels. In addition to infection, examples of such acute conditions are as follows:
Patients with underlying renal dysfunction, congestive heart failure (CHF), or both are at increased risk. Drugs that raise serum glucose levels, inhibit insulin, or cause dehydration may contribute to development of HHS. Examples include the following:
Noncompliance with oral hypoglycemics or insulin therapy can result in HHS. Patients taking total parenteral nutrition solutions and fluids that contain dextrose are also at risk for HHS. Parenteral nutrition with fat supplements can cause dramatic insulin resistance and hyperglycemia out of proportion to that expected from the dextrose in the preparation. Other conditions and illnesses associated with HHS include the following:
Elder abuse and neglect also may contribute to underhydration. EpidemiologyUnited States statisticsThe exact incidence of HHS is not known, because population-based studies of HHS have not been conducted. It has been estimated that out of all primary diabetic hospital admissions, less than 1% are for HHS. [12, 13] As the prevalence of type 2 DM increases, the incidence of HHS will likely increase as well. [2] A retrospective cohort study by Agrawal et al of 390 pediatric hyperglycemic emergencies that led to hospitalization determined that 13.8% of the admissions involved a combination of DKA and HHS, while only 0.8% involved HHS alone. [14] Age-related demographicsThe average age of patients with HHS is 60 years (57-69 years on most published series) [2, 7, 15] . This contrasts the mean age of DKA, which is early in the fourth decade of life. HHS can also occur in younger people. As rates of obesity and type 2 DM increase in children, so may the incidence of HHS in this population [16, 17, 18] . As mentioned above, the elderly, the chronically ill, and institutionalized populations are at increased risk for HHS. Any living situation or comorbidity that prevent adequate hydration, including for example immobility, advanced age, debility, dementia, agitation, impaired thirst response, restricted access to water, and restraint use, place these patients at risk. Sex-related demographicsNo sex predilection is noted in most published series of HHS. However, some data suggest that the prevalence is slightly higher in females than in males. In the US National Hospital Discharge Survey (see below), 3700 persons who were discharged from the hospital for HHS between 1989 and 1991 were male and 7100 were female. Race-related demographicsAfrican Americans, Hispanics, and Native Americans are disproportionately affected by HHS. This may be due to an increased prevalence of type 2 DM in these populations. [2] In the US National Hospital Discharge Survey of 10,800 hospital discharges listing HHS in the United States between 1989 and 1991, there were 6300 white patients and 2900 African American patients; the remainder of the discharges were people of other races or of unknown race. [2] PrognosisOverall mortality for HHS is estimated at 5-20% [5] and is usually due to the underlying illness that caused the hyperglycemic crisis. Prognosis is worse for elderly patients and patients in whom coma and hypotension are found. This is in contrast to the mortality rate of DKA, which is estimated to be about 1-5%. [19] In children, mortality from complications from HHS also appears to be higher than mortality from DKA, but too few cases have been reported to allow accurate calculation of pediatric mortality. A study by Kao et al found that in nonelderly patients with diabetes, those with hyperglycemic crisis episodes (HHS or DKA) had a mortality hazard ratio that was four-fold higher than for patients without such episodes. [20] A study by Issa et al indicated that approximately 3% of adult patients admitted to the hospital with acute decompensated diabetes (specifically, those with DKA or HHS) experience a non–ST-segment elevation myocardial infarction (NSTEMI) during their stay. Moreover, NSTEMI patients were found to have a 60% increase in inhospital mortality compared with those individuals with decompensated diabetes who did not suffer an NSTEMI. The incidences of stroke, acute kidney injury, and blood transfusion and the length of hospital stay were also greater in patients with NSTEMI. [21] A retrospective study by Schaapveld-Davis et al indicated that in patients being treated for DKA or HHS, those with end-stage renal disease (ESRD) have a greater likelihood of suffering adverse glucose events (specifically, hypoglycemia or a reduction in glucose >200 mg/dL/h) than do patients with normal kidney function, with the odds ratio for such events in patients with ESRD being 8.27. According to the investigators, the evidence suggests that cumulative insulin doses may need to be reduced in DKA and HHS patients with ESRD. [22] A study by Pasquel et al indicated that patients with a combination of DKA and HHS have a greater in-hospital mortality risk than do individuals suffering from either condition alone. The report, which involved 1211 patients, found the in-hospital mortality rate to be 8% for patients with combined DKA/HHS, compared 5% and 3% for individuals with isolated HHS or DKA, respectively. [23] A retrospective, hospital-based, observational case series by Chan et al, involving six patients, indicated that individuals with diabetes who have coronavirus disease 2019 (COVID-19) are at greater risk of developing a combination of DKA and HHS. The mortality rate was 67% (four patients), with mortality risk being associated with Hispanic ethnicity, severe acidosis, and multiple comorbidities. [24] Patient EducationPrior episodes of HHS place patients at risk for further episodes. Diabetic education is vital to preventing a recurrence of HHS due to poor glycemic control and dehydration. Education of patients and their families and caregivers is essential to increasing their understanding of diabetes and of appropriate treatment and behaviors, as well as their ability to monitor and control a patient's condition and recognize the warning signs of impending serious illness. Instruction should come from a variety of sources, including providers, nurses, and certified educators (both inpatient and outpatient). If available, a certified diabetes educator should instruct all patients on management of sick days and provide a thorough review of self care. A home evaluation by a visiting nurse may help to identify factors limiting adequate access to water and recognize medication noncompliance.
Author Coauthor(s) Chief Editor George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine George T Griffing, MD is a member of the following medical societies: American Association for Physician Leadership, American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society, International Society for Clinical Densitometry, Southern Society for Clinical Investigation Disclosure: Nothing to disclose. Additional Contributors Acknowledgements Howard A Bessen, MD Professor of Medicine, Department of Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Program Director, Harbor-UCLA Medical Center Howard A Bessen, MD is a member of the following medical societies: American College of Emergency Physicians Disclosure: Nothing to disclose. Joseph Michael Gonzalez-Campoy, MD, PhD, FACE Medical Director and CEO, Minnesota Center for Obesity, Metabolism, and Endocrinology Joseph Michael Gonzalez-Campoy, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, Association of Clinical Researchers and Educators (ACRE), and Minnesota Medical Association Disclosure: Nothing to disclose. George T Griffing, MD Professor of Medicine, St Louis University School of Medicine George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, InternationalSocietyfor Clinical Densitometry, and Southern Society for Clinical Investigation Disclosure: Nothing to disclose. Lewis S Nelson, MD, FACEP, FAACT, FACMT Associate Professor, Department of Emergency Medicine, New York University School of Medicine; Attending Physician, Department of Emergency Medicine, Bellevue Hospital Center, New York University Medical Center and New York Harbor Healthcare System Lewis S Nelson, MD, FACEP, FAACT, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. David S Schade, MD Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center David S Schade, MD is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, New Mexico Medical Society, New York Academy of Sciences, and Society for Experimental Biology and Medicine Disclosure: Nothing to disclose. Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society Disclosure: Nothing to disclose. Paulina B Sergot, MD Staff Physician, Department of Emergency Medicine, New York University/Bellevue Hospital Center Paulina B Sergot, MD is a member of the following medical societies: American Medical Association Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment Which value in the patient's laboratory report indicates the presence of hyperosmolar hyperglycemic state HHS )?In most cases of HHS, the blood pH is greater than 7.30. ABG values also indicate underlying diseases associated with HHS. Hypoxemia may be observed in association with cardiac or pulmonary diseases.
Is sodium high or low in HHS?Serum potassium levels are usually normal, but sodium may be low or high depending on volume deficits.
Does HHS cause metabolic acidosis?Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are the two most serious metabolic complications of diabetes mellitus (DM). These disorders can occur in both type 1 and type 2 DM. DKA is characterized by hyperglycemia, ketone body formation and metabolic acidosis.
Are ketones elevated in HHS?Ketones usually are absent in HHS, although they may be present in a fasting state. Acidosis typically doesn't occur unless a patient has an underlying condition such as sepsis, myocardial infarction, or renal failure, all of which may present as lactic acidosis rather than DKA.
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What lab values is consistent with hyperglycemic hyperosmolar nonketotic syndrome?
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