Hyperosmolar Hyperglycemic State: Practice Essentials, Pathophysiology, Etiology
Shar
Practice Essentials
Hyperosmolar 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]
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.
Workup
According to a consensus statement published by the American Diabetes Association, diagnostic features of HHS may include the following (see Workup) [6, 8] :
Plasma glucose level of 600 mg/dL or greater
Effective serum osmolality of 320 mOsm/kg or greater
Profound dehydration, up to an average of 9L
Serum pH greater than 7.30
Bicarbonate concentration greater than 15 mEq/L
Small ketonuria and low to absent ketonemia
Some alteration in consciousness
Imaging studies can include the following:
Radiography of the chest and abdomen - A chest radiograph is advisable to exclude pneumonia; abdominal radiographs are indicated if the patient has abdominal pain or is vomiting
Computed tomography (CT) scanning of the head - This is indicated in many patients with focal or global neurologic changes to help exclude hemorrhagic strokes, subdural hematoma, subarachnoid bleeding, intracranial abscesses, and intracranial masses
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.
Management
Detection 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.)
Pathophysiology
Normal metabolic physiology
In 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 Resistance
Resistance 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 DM
Type 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.
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HHS
The 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.
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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.
Etiology
HHS 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:
Stroke
Intracranial hemorrhage
Silent MI - Consider MI in all patients with HHS until it is excluded
Epidemiology
United States statistics
The 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]
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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 demographics
The 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.
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Sex-related demographics
No 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 demographics
African 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]
Prognosis
Overall 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]
Patient Education
Prior 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.