Glucose metabolism chart
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.
According 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.
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.)
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.
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 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.
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.
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.
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:
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.
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]
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]
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.
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.
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]
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]
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.
Most patients with hyperosmolar hyperglycemic state (HHS) have a known history of type 2 DM. In 30-40% of cases, HHS is the patient’s initial presentation of diabetes.[7]
HHS usually develops over a course of days to weeks, unlike diabetic ketoacidosis (DKA), which can develop in hours to a few days. Often, a preceding illness or comorbidity (eg, dementia, immobility) results in several days of increasing dehydration due to inadequate oral hydration or water loss (eg, vomiting, diarrhea).
Patients may present with polydipsia and polyuria, depending on hydration status. Other common symptoms include nausea, vomiting, weakness, lethargy, and muscle cramps. They do not typically report abdominal pain, a complaint that is often noted in patients with DKA. In more advanced HHS, presentation is more likely to be altered mental status, seizures and/or coma. Patients may also present with an underlying fever, a clue to an underlying infection.[5]
A wide variety of acute focal and global neurologic changes may be present, including the following:
It is very important to obtain a complete history from the patient or a companion, with an emphasis on recent illnesses or other conditions leading to altered insulin requirements, lack of compliance with hypoglycemic medications (including insulin), and dietary indiscretion. Emphasize identification of potential causes of HHS. Prior hospitalizations for management of hyperglycemia are important to note and indicate a patient at risk for future episodes.[12]
To quench the thirst they may experience, many HHS patients consume beverages containing glucose, including juices and soda. Attempt to quantitate the volume ingested over the preceding 24 hours to try to estimate the degree of osmotic diuresis with which the patient is presenting.
Examine the patient for evidence of HHS, focusing on hydration status, mentation, and signs of possible underlying causes, such as a source of infection. General appearance and hygiene may provide clues to the state of hydration, the presence of chronic illness, and the level of mentation. Assessment of airway, breathing and circulation (ABC) should always be the initial step for patients presenting with hyperglycemic crisis. Assessment for volume status is very important in patients with HHS. Vitals signs and physical examination will offer important clues regarding dehydration in patients with HHS.
Vital signs related to HHS include the following:
Physical exam findings and signs related to HHS include the following:
The presence of needle pricks or calluses on the fingertips (from home glucose monitoring) may indicate glycemic derangement as the cause of a change in mental status. Similarly, ecchymosis on the abdomen, thighs, and arms may be signs of insulin injection. Many patients carry cards in their wallets or purses or wear bracelets or chains with a metallic plate identifying them as having DM.
Obesity, acanthosis nigricans, diabetic dermopathy, necrobiosis on the pretibial surfaces, lower-extremity ulcerations, soft tissue infections (eg, cellulitis or carbuncles), balanitis or vulvovaginitis, thrush, gingivitis, tooth decay, and the moon face of Cushing syndrome are also associated with underlying DM and should indicate consideration of HHS.
A careful cardiovascular examination is indicated in all patients with hypotension. Both cardiac pump failure from acute myocardial infarction (MI) and pulmonary embolism (PE) can be underlying causes of HHS. Distinguishing hypotension due to cardiac pump failure from that of severe dehydration is often difficult, especially when the two coexist.
Hypotension also may be due to sepsis. Exclusion of an infectious process must be included in the physical examination of patients with HHS. Low-grade fever is usually present in patients with HHS, secondary to a reduction in sweating. High-grade fever suggests infection. Hypothermia from underlying infection is a poor prognostic indicator.
Altered mentation, cranial neuropathies, and visual field losses, which are symptoms of HHS, may be appreciated. HHS may be associated with several other neurologic findings, including seizures, hemianopsia, aphasia, paresis, a positive Babinski sign, myoclonic jerks, change in muscle tone, nystagmus, eye deviation, and gastroparesis. For many patients, these neurologic symptoms and signs could be the manifestation of an underlying cerebrovascular accident. Cerebral dehydration, neurotransmitter level changes in the central nervous system (CNS), and microvascular ischemia may contribute to these findings.
When HHS causes neurologic dysfunction, treatment results in resolution of signs and symptoms. When neurologic events cause HHS, signs and symptoms fail to improve with correction of the metabolic derangements.
Common complications of HHS are seen secondary to rapid correction of hyperglycemia. Patients are normally administered insulin during treatment of HHS, which may lead to hypoglycemia. Hypokalemia may also result with insulin and bicarbonate administration. It is important to frequently check electrolytes during HHS treatment.[12]
Cerebral edema is a rare, but frequently fatal, complication in HHS. This occurrence is usually seen in newly diagnosed diabetic children with DKA. Cerebral edema occurs from rapid lowering of glucose levels and an ensuing rapid drop in plasma osmolarity. Brain cells, which trap osmotically active particles, preferentially absorb water and swell during rapid rehydration. Cerebral edema follows, and, given the constraints of the cranium, uncal herniation may be the cause of death in persons with HHS.[12]
Signs and symptoms of cerebral edema may progress rapidly. Signs of increased intracranial pressures include headache, decreased level of consciousness, and lethargy. As worsening brain stem herniation occurs, patients may present with seizures, papilledema, bradycardia, and respiratory arrest.
However, death from cerebral edema due to HHS is rare, presumably because the older population that it affects has underlying cerebral atrophy. Thus, even with the edema of rehydration, the intracranial volume does not reach the critical level that causes uncal herniation. (The few fatal cases of cerebral edema in HHS were mainly patients in their 20s.) Aggressive correction of hyperglycemia and hyperosmolarity with frequent laboratory monitoring is indicated, especially in older patients.
Acute respiratory distress syndrome (ARDS) is also a rare, but potentially fatal, complication of HHS. The precise mechanism by which ARDS develops in persons with HHS remains unclear, although the thought at this time is that it is due to pulmonary pressure changes. Patients, on admission, usually present with normal lung pressures. The evolution of ARDS in HHS is thought to result from a drop in partial pressure of oxygen secondary to a reduction is osmotic colloid pressure during therapy for HHS. The pressure changes from rapid correction of hyperglycemia and hyperosmolarity lead to pulmonary edema and a decreased lung compliance.[12, 23] To compensate for hypoxia and mild acidosis, an increase in the minute ventilation with tachypnea develops. Continuing pulmonary disease may lead to acute respiratory failure that necessitates full respiratory support, including mechanical ventilation. Always monitor pulmonary function carefully during therapy for HHS. ARDS may also develop in association with underlying diseases, such as pancreatitis and MI.
The severe dehydration and contracted vascular volume associated with HHS lead to hypotension and hyperviscosity of the blood, both of which predispose patients to thromboembolic disease of the coronary, cerebral, pulmonary, and mesenteric beds. This is especially true in patients who already have atherosclerosis. Disseminated intravascular coagulation (DIC) also may complicate HHS. Low-dose subcutaneous heparin is advisable for all patients without a contraindication. With aggressive treatment in HHS, vascular complication rates can be reduced to as low as 2%.[5]
On the basis of the consensus statement published by the American Diabetes Association, diagnostic features of hyperosmolar hyperglycemic state (HHS) may include the following[6, 8] :
HHS should be considered in children presenting with hyperglycemia and hyperosmolarity without significant ketoacidosis. It is particularly important to distinguish HHS from diabetic ketoacidosis (DKA) in children, because younger persons are at higher risk for the development of cerebral edema as a complication of aggressive fluid repletion.
A fingerstick blood sugar measurement is the simplest first step in the evaluation. The serum glucose level usually is elevated dramatically, most often to greater than 600 mg/dL. Many patients present with glucose concentrations greater than 1000 mg/dL. Blood sugar levels of 65-250 mg/dL exclude significant glycemic derangement and should prompt a search for other causes of present symptoms.
The concentration of glucose in the plasma is directly proportional to the degree of dehydration. Higher concentrations of glucose relate to higher degrees of dehydration, higher plasma osmolality, and a worse prognosis.
Monitor the plasma glucose concentration hourly during the first 24-48 hours of treatment.
Although hemoglobin A1c (glycosylated hemoglobin) levels are not useful in the acute phase of therapy, they may be obtained as an indicator of the patient’s glucose control over the previous several weeks. An elevated A1c level may help in determining medication noncompliance or undiagnosed DM. A normal A1c is useful in determining whether the episode of HHS is secondary to an underlying acute process (ie, infection, myocardial infarction [MI]).
Normal serum osmolality ranges from 280 to 290 mOsm/kg. A serum osmolality of 320 mOsm/kg or higher defines HHS. Rarely, serum osmolality may exceed 400 mOsm/kg. In HHS, higher serum osmolality relates to greater impairment of the level of consciousness. Serum osmolality may be calculated from sodium, blood urea nitrogen (BUN), and glucose values, as follows:
Osm = (2 × Na) + (glucose/18) + (BUN/2.8)
The osmole gap is the difference between the measured osmolality and the calculated osmolality (at low solute concentrations, they are nearly equivalent measures). Although the measured osmolality is very high in patients with HHS, the osmole gap should be unimpressive, because the calculated osmolality includes the elevated serum glucose concentration. If the osmole gap is very large, consider toxic alcohol ingestion.
As HHS progresses and osmotic diuresis occurs, electrolytes are lost in the urine. All electrolytes are extremely deficient at the time of presentation, at which time the relative deficiencies of water and electrolytes determine their plasma concentrations. Additionally, the presence of hypertriglyceridemia affects the concentration of electrolytes. Triglycerides exert an osmotic drag and displace electrolytes in the plasma.
Sodium
Hyponatremia or hypernatremia may be present. In the setting of hyperglycemia, pseudohyponatremia is common as a result of the osmotic effect of glucose drawing water into the vascular space. The measured serum sodium concentration can be corrected upward in proportion to increases in serum glucose to yield an estimate of what the serum sodium level would be in the absence of hyperglycemia and its associated osmotic effect. To correct sodium for hyperglycemia, the following calculation can be used[24] :
Corrected Na = Na + ([Gluc - 5]/3.5)
Some patients may present with elevated serum sodium concentrations. Patients with hypernatremia usually have elevated plasma osmolality and are more often found with neurologic symptoms.[25]
Potassium
Hypokalemia or hyperkalemia may be present. Commonly, at time of presentation of HHS, serum potassium may be elevated due to an extracellular shift caused by insulin deficiency. However, total body potassium is likely low regardless of its serum value. The average potassium deficit in normally about 300-600 mEq. A low measured serum potassium suggests profound total body losses, and patients should be placed on cardiac monitoring. During treatment, insulin drives potassium into cells, and intravenous (IV) hydration dilutes potassium in the circulation. Aggressively replace potassium to maintain plasma levels in the normal range during treatment.
Magnesium
Serum magnesium levels are also a poor indicator of true total body magnesium. In the presence of hypokalemia, concomitant hypomagnesemia should be presumed and treated.
Bicarbonate and anion gap
The bicarbonate concentration in a patient with HHS is usually normal or mildly reduced. This is because there is minimal ketone formation in the process of HHS, in contrast to DKA, in which bicarbonate levels can be markedly reduced (bicarbonate < 15mEq/L).
The anion gap is calculated according to the following formula:
(Na+ + K+) - (Cl– + HCO3–)
The calculated anion gap in HHS is usually within normal limits (8-12 mmol/L). A wide anion gap can be observed in patients with HHS, reflecting mild metabolic acidosis. The mild acidosis in HHS is often multifactorial and results, in part, from the accumulation of minimal ketoacids in the absence of effective insulin activity. Some patients with profound dehydration may have high anion gaps, reflecting the additional contribution of lactic acid produced by hypoperfusion of tissues. Underlying renal disease with uremia also may contribute to a high anion gap.
Monitor plasma electrolyte levels at least every 4 hours during the first 24-48 hours of treatment.
Arterial blood gas (ABG) values are obtained to measure serum pH. 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. Hypocarbia may be due to respiratory alkalosis as a compensatory mechanism to a primary metabolic acidosis. Hypocarbia also may be due to tachypnea in response to an elevated alveolar-arterial oxygen gradient from pulmonary disease.
Venous blood gas (VBG) values may be substituted in patients with normal oxygen saturation on room air. VBGs provide comparable information, are easier to draw, and are less painful to the patient. The pH measured by a VBG assessment is 0.03 pH units less than the pH measured by ABG assessment[26] .
A mild degree of ketosis is usually observed in any patient who is dehydrated. In those with HHS, despite the significant degree of dehydration, ketosis is mild and responds readily to treatment. Profound ketosis that does not respond readily to IV rehydration is the norm in persons with DKA. Mild to moderate ketosis can be present when the disease has features of both HHS and DKA (overlap cases).
Patients with HHS present with acute elevations in BUN and creatinine secondary to prerenal azotemia from volume depletion. Initially, BUN and creatinine concentrations are likely to be elevated, and the BUN-to-creatinine ratio may exceed 30:1. When possible, these values should be compared with previous values; many patients with diabetes have baseline renal insufficiency. If a patient's renal function does not normalize after treatment, this may indicate irreversible or underlying renal damage.
Dehydration causes a rise in the plasma levels of albumin, amylase, bilirubin, calcium, creatinine kinase (CK), lactate dehydrogenase, lipase, total protein, and transaminases. Up to two thirds of patients with HHS have elevated serum enzyme levels. Accordingly, serum levels of CK and isoenzymes should be measured routinely because both MI and rhabdomyolysis can trigger HHS and both can be secondary complications of HHS.[27] Also, elevated amylase and lipase does warrant an exclusion of underlying pancreatitis even though these enzymes may be elevated during HHS. Clinical correlation is needed.
Avoid the assumption that enzyme level elevation is due to dehydration. Exclude underlying disease associated with each of these abnormal blood levels in patients with HHS. This is especially true in the case of CK elevations.
Leukocytosis is frequently observed in HHS. It can be secondary to HHS itself or result from an underlying infection. Elevated levels of counterregulatory hormones, stress, dehydration, and demargination of leukocytes during HHS may give rise to leukocytosis. Even though HHS can cause leukocytosis, a leukocyte count of over 25,000 or bands greater than 10% may suggest an underlying infection, and workup is warranted.[28] A complete history and physical exam will help determine the source of infection. Obtain a chest radiograph, a urine culture, and possibly a blood culture, in patients with leukocytosis with suspicion of infection.
Urinalysis can reveal elevated specific gravity (evidence of dehydration), glycosuria, small ketonuria, and evidence of urinary tract infection (UTI). However, urine for analysis may be difficult to obtain in a severely dehydrated patient with HHS. Catheterization of the urinary bladder may be necessary.
Urinalysis may provide further information about the patient’s metabolic state. Ketones are rarely present in persons with HHS. Glycosuria may be a sign of uncontrolled diabetes in a patient presenting with HHS. Gross proteinuria suggests underlying renal disease. Urinary osmolality and the urine specific gravity can be very high in patients with HHS secondary to dehydration.
Urine cultures may be obtained if clinical suspicion is high for UTI and if urinalysis shows signs of infection. Send cultures as clinically indicated.
In the initial evaluation of patients with HHS, a chest radiograph is advisable to exclude pneumonia. Radiographic findings may be falsely negative at first because of the profound dehydration in some patients, and serial studies may document pneumonia once the patient has been volume resuscitated.
Abdominal radiographs are indicated if the patient has abdominal pain or is vomiting.
Patients with HHS who present with altered mental status may have an underlying CNS disease. Computed tomography (CT) of the head 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. It may be useful for patients who show no clinical improvement after several hours of treatment, even in the absence of clinical signs of intracranial pathology.
Repeat CT scanning is indicated if cerebral edema is a concern during the treatment of HHS.
Electrocardiography (ECG) is indicated in all patients with HHS because myocardial infarction (MI) and pulmonary embolism (PE) can precipitate HHS. The height of the T waves in the ECG tracings may point to a potassium derangement. The duration of the QT interval may be abnormal as a consequence of calcium abnormalities.
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 CNS infection. Patients who are immunocompromised may require additional studies of the CSF, such as polymerase chain reaction (PCR) assay for herpes simplex virus (HSV) and cryptococcal antigen.
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.
A study by Hu and Lin indicated that in type 2 DM patients, the CHA2DS2-VASc score can be used to predict the incidence of new-onset atrial fibrillation but that this ability is diminished in individuals with comorbid HHS.[29]
Diagnosis and management guidelines for hyperglycemic crises are available from the American Diabetes Association.[8, 12, 30]
The main goals in the treatment of hyperosmolar hyperglycemic state (HHS) are as follows:
In an emergency situation, whenever possible, contact the receiving facility while en route to ensure preparation for a comatose, dehydrated, or hyperglycemic patient. When appropriate, notify the facility of a possible cerebrovascular accident or myocardial infarction (MI). Initiation of insulin therapy in the emergency department (ED) through a subcutaneous insulin pump may be an alternative to intravenous (IV) insulin infusion.[31]
Airway management is the top priority. In comatose patients in whom airway protection is of concern, endotracheal intubation may be indicated.
Rapid and aggressive intravascular volume replacement is always indicated as the first line of therapy for patients with HHS. Isotonic sodium chloride solution is the fluid of choice for initial treatment because sodium and water must be replaced in these severely dehydrated patients.
Although many patients with HHS respond to fluids alone, IV insulin in dosages similar to those used in diabetic ketoacidosis (DKA) can facilitate correction of hyperglycemia.[32] Insulin used without concomitant vigorous fluid replacement increases the risk of shock. Adjust insulin or oral hypoglycemic therapy on the basis of the patient’s insulin requirement once serum glucose level has been relatively stabilized.
All patients diagnosed with HHS require hospitalization; virtually all need admission to a monitored unit managed by medicine, pediatrics, or the intensive care unit (ICU) for close monitoring. When available, an endocrinologist should direct the care of these patients.
Frequent reevaluation of the patient’s clinical and laboratory parameters is necessary. Recheck glucose concentrations every hour. Electrolytes and venous blood gases should be monitored every 2-4 hours or as clinically indicated.
When an underlying disease is responsible for HHS, it must be promptly identified and treated. Resolution of HHS often lags while the underlying process remains unresolved. Some authors advocate prophylactic heparin treatment and broad-spectrum antibiotic coverage, but these measures have not yet been studied thoroughly enough to allow recommendation of their use.
Standard care for dehydration and altered mental status is appropriate, including airway management, IV access, crystalloid fluid replacement, and administration of any medications routinely given to coma patients.
Protection of the airway is mandatory in patients presenting with mental status changes, obtundation, or unconsciousness. Patients may present with respiratory failure and circulatory collapse and must be ventilated mechanically.
If patients are presenting with metabolic acidosis, take care to hyperventilate them when mechanical ventilation is instituted. Hyperventilation generates respiratory alkalosis, which compensates for the metabolic acidosis and also decreases the risk of cerebral edema.
IV access, large bore if possible, or central venous access is useful, provided attempts to obtain it do not significantly delay transfer to the nearest emergency department (ED). A centrally placed catheter offers an avenue for vigorous rehydration, especially if means for intravenous (IV) access are difficult secondary to profound dehydration.
Aggressive fluid resuscitation is key in the treatment of HHS. This is to avoid cardiovascular collapse and to perfuse vital organs. Fluid deficits in adults are large in HHS, being about 9 L on average.
According to American Diabetes Association guidelines, fluid resuscitation with 0.9% saline at the rate of 15-20 mL/kg/h or greater is indicated to expand the extracellular volume quickly in the first hour. This amounts to about 1-1.5 L in an average-sized person. (In patients with contraindications to rapid fluid resuscitation [ie, cardiac or renal disease], slower rates are indicated.) A greater rate of fluid resuscitation is needed in patients with severe volume depletion but should not exceed 50 mL/kg in the first 4 hours. The choice of fluids after initial resuscitation depends on the patient's hydration status, serum electrolytes, and urinary output. If the patient's sodium level is normal or elevated, 0.45% normal saline may be used at a rate of 10 mL/kg/h. If the patient is hyponatremic, 0.9% normal saline may be used instead. In the first 18-24 hours, the first half of the patient's fluid deficit should be corrected. The plasma osmolality should not change over 3 mmol/kg/hr during fluid resuscitation.[5]
When the blood glucose concentration, initially checked hourly, reaches 250 mg/dL, change the infusion to 5% dextrose in 0.45-0.7% normal saline. This helps to prevent a precipitous fall in glucose, which may be associated with cerebral edema.[6] In pediatric patients with suspected HHS, correcting fluid deficits over a longer period (48 h) may help to reduce the risk of cerebral edema.[16]
The IV fluids should also include 20-40 mEq/L of potassium chloride to treat hypokalemia, which is seen in patients with HHS.
Patients with persistent hypotension may require pressor support in the ICU while rehydration is being accomplished.
Basic medications given to coma patients in the field may include dextrose (50 mL of % dextrose in water [D50]). This is of benefit to many comatose patients with few adverse effects.
When possible, fingerstick glucose measurement is obtained before dextrose administration. Whenever fingerstick glucose measurement is unavailable or is likely to be delayed, D50 must be administered to comatose patients on an empiric basis without delay. Undiagnosed and untreated hypoglycemia, which may present with signs and symptoms very similar to those of HHS, is readily reversible but can be rapidly lethal if not treated promptly.
All patients with HHS require IV insulin therapy; however, immediate treatment with insulin is contraindicated in the initial management of patients with HHS. The osmotic pressure that glucose exerts within the vascular space contributes to the maintenance of circulating volume in these severely dehydrated patients. Institution of insulin therapy drives glucose, potassium, and water into cells. This results in circulatory collapse if fluid has not been replaced first.
IV insulin administration is accomplished most effectively in the ICU, where cardiovascular and respiratory support is available if needed. Infuse insulin separately from other fluids, and do not interrupt or suspend the infusion of insulin once therapy has been started.
The following steps may be used as a guideline for insulin infusion, as per American Diabetes Association recommendations[5, 33] :
Once the patient is alert and able to eat, an insulin regimen consisting of short-/rapid-acting insulin and long-acting insulin is needed to wean the patient off of IV insulin therapy and to control glucose levels. If the patient already had an insulin regimen before the onset of HHS, it is okay to continue the current regimen and adjust to better glycemic control. If the patient is new to insulin or a newly diagnosed diabetic, total subcutaneous insulin dosages should not exceed 0.5-1 U/kg/day. The IV insulin infusion should be continued for about 1-2 hours after subcutaneous insulin administration to avoid hyperglycemia.
When the glucose level has been between 200 and 300 mg/dL for at least 1 day and the patient’s level of consciousness has improved, glycemic control may be tightened. The recommended level of glycemia for most patients with type 2 diabetes mellitus (DM) is 80-120 mg/dL. This correlates to the hemoglobin A1c value of 7% recommended by the American Diabetes Association.
All patients who have experienced HHS will probably require intensive management of their diabetes initially, and this includes insulin therapy. The severe hyperglycemia with which these patients present implies profound beta cell dysfunction. In most instances, sufficient recovery of endogenous insulin production is a reasonable expectation, with safe dismissal of the patient from the hospital on oral therapy. After maintaining adequate glycemic control with insulin for several weeks after HHS, consider switching patients to an oral regimen.
Profound potassium depletion necessitates careful replacement. Patients may initially present with normal or elevated potassium levels. With rehydration, the potassium concentration is diluted. With the institution of insulin therapy, potassium is driven into cells, exacerbating hypokalemia. A precipitous drop in the potassium concentration may lead to cardiac arrhythmia.
Potassium may be added to the infusion fluid and should be started at a level of 3.5 mEq/L or less and with adequate urine output. Usually, replenishing potassium with 20-30 mEq of potassium chloride in each liter of IV fluid is sufficient. The goal is to keep a potassium level of between 4 and 5 mEq. It is important to replenish potassium before starting insulin infusion, especially when levels are below 3.5 mEq, to avoid cardiovascular compromise. Check the potassium level at least every 4 hours until the blood glucose concentration is stabilized.
Phosphate, magnesium, and calcium are not replaced routinely, even though patients may have whole body deficits in these electrolytes. A patient who is symptomatic with tetany requires replacement therapy for calcium.
The mortality associated with HHS remains high. The profound electrolyte and metabolic abnormalities present during treatment warrant careful cardiorespiratory monitoring. When gas exchange has been compromised, endotracheal intubation and mechanical ventilation are indicated.
Neurologic monitoring is indicated in all patients with HHS who present with altered mental status. Hyperosmolarity may trigger many neurologic syndromes. If a patient has seizures, phenytoin is not the agent of choice, because it inhibits endogenous insulin secretion and because, in general, it is ineffective in persons with HHS. Volume resuscitation and appropriate decrease is osmolality will decrease the chance of seizures.
Telemetry monitoring may be required in patients with electrolyte imbalances while treatment occurs. This is especially important with potassium abnormalities and electrocardiographic changes. Patients with HHS may also require telemetry monitoring if cardiac workup suggests a cardiac etiology, such as MI, for HHS.
Provide adequate nutritional support for all patients. Once the patient's mental status is back to normal and the patient is able to eat, starting an oral diet is indicated. Some HHS patients are unable to eat for several days as a consequence of the comorbidities with which they present.
Patients in the ICU who require prolonged mechanical ventilation, patients with impaired airway defenses, and all patients with prolonged mental status changes are candidates for enteral or parenteral nutrition. The use of parenteral nutrition often induces insulin resistance and leads to increased insulin requirements.
Once HHS is resolved, provide dietary counseling for all patients. This probably is most effectively delivered by a registered dietitian who has expertise in counseling patients with diabetes.
Generally, no consultation is absolutely required to manage HHS in the ED; however, in occasional cases, consultations may be useful.
A consultation with an endocrinologist is suggested for patients with HHS. Consider a consultation with a neurologist for most patients with altered mental status. A neurologist should monitor the cases of any patients with underlying neurologic disease (eg, cerebrovascular accident or a history of seizures). A pulmonologist or critical care specialist should monitor the cases of patients requiring intubation and mechanical ventilation. Other consultations (eg, with infectious disease or psychiatry) may be obtained as appropriate.
Primary care follow-up is necessary for additional diabetic teaching and any appropriate immunizations. Visiting home nurse referral may be necessary to enhance compliance.
After any episode of HHS, enroll patients in a program of routine diabetes care. Adhere to American Diabetes Association guidelines for the care of people with diabetes. For patients with diabetes that was unrecognized before HHS, perform a routine diabetic care exam. This includes a routine eye exam and foot exam, as well as lab work to check for nephropathy and evaluation for signs of macrovascular disease. Advise patients treated with insulin to wear a bracelet or chain identifying them as having diabetes.
Aggressive rehydration with intravenous (IV) fluids, including 0.9% isotonic saline, is indicated in every patient with hyperosmolar hyperglycemic state (HHS). Insulin therapy and repletion of electrolytes (especially potassium) are the other cornerstones of management.[34] Antipyretics, antiemetic, and antibiotics are added when appropriate to control fever and vomiting and to treat an underlying infection if one is suspected.
Frequent monitoring of electrolyte and glucose concentrations is indicated when patients are treated with IV fluids. Volume overload is the only other potential problem associated with IV fluid replacement; therefore, regular assessment of the hydration status is indicated.
Clinical Context: Regular insulin has a rapid onset of action (within 0.5-1 hours), and a short duration of action (4-6 hours). Peak effects occur within 2-4 hours. Insulin is used to reduce blood glucose levels and decrease ketogenesis. Some authors favor lower bolus and infusion dosages, with the rationale that fluids are the cornerstone of therapy and that HHS is more a disorder of insulin resistance than it is one of insulin deficiency. Furthermore, lowering serum glucose and serum osmolarity overly rapidly can result in complications.
Clinical Context: Insulin aspart has a rapid onset of action (5-15 minutes) and a short duration of action (3-5 hours). Peak effects occurs within 30-90 minutes.
Clinical Context: Insulin glulisine has a rapid onset of action (5-15 minutes) and a short duration of action (3-5 hours).
Clinical Context: Insulin lispro has a rapid onset of action (5-15 minutes) and a short duration of action (4 hours).
Although many patients with hyperosmolar hyperglycemic state (HHS) respond to fluids alone, intravenous (IV) insulin in dosages similar to those used in diabetic ketoacidosis (DKA) can facilitate correction of hyperglycemia. Insulin used without concomitant vigorous fluid replacement increases the risk of shock.
Clinical Context: Sodium bicarbonate neutralizes hydrogen ions and raises urinary and blood pH.
No evidence is found that sodium bicarbonate provides any benefit to patients with HHS. It may be considered if a patient has significant acidosis (pH < 7.0), particularly if inotropic agents are required to maintain blood pressure.
Clinical Context: In virtually all cases of HHS, supplemental potassium is necessary because the serum level drops secondary to insulin therapy and correction of metabolic acidosis. Do not start IV potassium until the initial serum level is ascertained, as the initial level may be high related to hemoconcentration. Administer it cautiously, with attention to proper dosing and concentration. If the patient can tolerate oral medications or has a gastric tube in place, potassium chloride can be given orally in doses of up to 60 mEq, with dosing based on frequently obtained laboratory values.
Electrolytes are given to replenish electrolyte supplies depleted by the presence of a high blood glucose level.
Glucose metabolism chart
