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Hyperosmolar Hyperglicemic State

Obed Yosia (406127068)

Hyperosmolar Hyperglycemic State


Author Robin R Hemphill, MD, MPH Associate Professor, Director, Quality and Safety, Department of Emergency Medicine, Emory University School of Medicine Robin R Hemphill, MD, MPH is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Chief Editor
Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, MillsPeninsula Emergency Medical Associates Disclosure: Nothing to disclose.

Additional Contributors
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.

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Hyperosmolar Hyperglicemic State

Obed Yosia (406127068)

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

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Hyperosmolar Hyperglicemic State

Obed Yosia (406127068)

Background Hyperosmolar hyperglycemic state (HHS) is 1 of 2 serious metabolic derangements that occurs in patients with diabetes mellitus (DM) and can be a life-threatening emergency. It is less common than the other acute complication of diabetes, diabetic ketoacidosis (DKA). 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.[1] HHS most commonly occurs in patients with type 2 DM who have some concomitant illness that leads to reduced fluid intake. Infection is the most common preceding illness, but many other conditions can cause altered mentation, dehydration, or both. Once HHS has developed, it may be difficult to differentiate it from the antecedent illness. The concomitant illness may not be identifiable. (See Etiology.) HHS has also been reported in patients with type 1 DM, in whom DKA is more common. HHS usually presents in older patients with type 2 DM and carries a higher mortality than DKA, estimated at approximately 10-20%. (See Epidemiology.) HHS is characterized by hyperglycemia, hyperosmolarity, and dehydration without significant ketoacidosis. Most patients present with severe dehydration and focal or global neurologic deficits.[2, 1, 3] In as many as one third of cases, the clinical features of HHS and DKA overlap and are observed simultaneously (overlap cases); this suggests that these 2 states of uncontrolled DM differ only with respect to the magnitude of dehydration and the severity of acidosis. (See Presentation.) According to the consensus statement published by the American Diabetes Association, diagnostic features of HHS may include the following (see Workup)[2, 4] :

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

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Bicarbonate concentration greater than 15 mEq/L Small ketonuria and absent-to-low ketonemia Some alteration in consciousness

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 Pathophysiology Insulin-sensitive tissues normally take up glucose during meals, when the glycemic rise of ingested carbohydrates stimulates insulin secretion. 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 storage of glucose as glycogen in liver and muscle and lipogenesis in adipocytes. Insulin-dependent transport of glucose across the cell membranes of insulin-sensitive tissues drives potassium into these cells. A high insulin-to-glucagon ratio during meals also favors amino acid uptake by muscle. Between meals, insulin secretion is not stimulated, and the insulinmediated glucagon inhibition in the pancreatic islets stops. The glucagon levels rise in the plasma, leading to a decrease in the plasma insulin-toglucagon ratio. The consequence of this decrease is the breakdown of glycogen in the liver and muscle and gluconeogenesis by the liver, both of which 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-toglucagon ratio. These insulin-independent tissues include the brain and the kidneys. In patients with a preexisting lack of or resistance to insulin, a physiologic stress such as an acute illness can cause further net reduction in circulating insulin. The basic underlying mechanism of HHS is a relative or absolute reduction in effective circulating insulin with a concomitant elevation of counterregulatory hormones.[1, 2] Decreased renal clearance and decreased peripheral utilization of
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glucose lead to hyperglycemia. Hyperglycemia and hyperosmolarity result in an osmotic diuresis and an osmotic shift of fluid to the intravascular space, resulting in further intracellular dehydration. This diuresis also leads to loss of electrolytes, such as sodium and potassium.
[1, 2, 3]

Unlike patients with DKA, patients with HHS do not develop significant ketoacidosis, but the reason for this is not known. Contributing factors likely include the availability of insulin in amounts sufficient to inhibit ketogenesis but insufficient to prevent hyperglycemia. Additionally, hyperosmolarity itself may decrease lipolysis, limiting the amount of free fatty acids available for ketogenesis. In addition, levels of counterregulatory hormones are found to be lower in patients with HHS than in those with DKA.[1, 2, 3] Obesity is the most prevalent cause of insulin resistance. Pregnancy is a state of insulin resistance largely due to the action of placental hormones on maternal circulation. High circulating levels of epinephrine, glucagon, growth hormone, and cortisol (the 4 major counterregulatory hormones) cause insulin resistance. Their levels increase during acute illnesses (eg, major infections, myocardial infarction [MI], or pancreatitis) or stress (eg, surgery, major psychiatric illness, or multiple injuries). Additionally, diseases characterized by excessive production of these counterregulatory hormones (eg, pheochromocytoma, glucagonoma, acromegaly, and Cushing syndrome) may induce insulin resistance. Finally, parenteral nutrition and administration of some medications (notably, glucocorticoids, tretinoin, antiretrovirals, antipsychotics, [5, 6] and cyclosporine and other immunosuppressive agents) cause insulin resistance. Insulin deficiency is due to autoimmune destruction of the beta cells in type 1 DM. In type 2 DM, a defect in the first-phase release of insulin occurs, which leads to relative insulinopenia. The defective insulin secretion in persons with type 2 DM is due to the direct toxic effect of glucose on beta cells. Many patients with diabetes treated with insulin become relatively insulinopenic when they fail to adjust the dose of insulin upwards during illnesses or periods of stress. In the absence of adequate insulin activity, hyperglycemia develops. Decreased glucose use occurs in peripheral tissues, including adipocytes and muscles; glucose cannot be stored as glycogen in muscle and liver tissue; and hepatocytes, under the influence of glucagon, stimulate gluconeogenesis. The resulting elevation in plasma glucose concentration leads to further impairment of insulin release by pancreatic beta cells. In this setting of inadequate insulin action, the magnitude of the rise in plasma glucose
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concentration also depends, in part, on the level of hydration and oral carbohydrate (or glucose) loading. Under normal circumstances, all of the glucose filtered by the kidneys is reabsorbed. When glycemia reaches 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 into the distal nephron and, eventually, the urine, carrying water and electrolytes with it. Osmotic diuresis then results. The direct consequence of this osmotic diuresis is a decrease in total body water. Within the vascular space, in which gluconeogenesis and dietary intake continue to add glucose, the loss of water results in further hyperglycemia and loss of circulating volume. Hyperglycemia and the rise in the plasma protein concentration after intravascular water loss cause a hyperosmolar state. The hyperosmolarity of the plasma triggers release of antidiuretic hormone, which ameliorates renal water loss. Hyperosmolarity also stimulates thirst, a defense mechanism that is impaired in people dependent on others for care. In the presence of HHS, if the renal water loss is not compensated for by oral water intake, dehydration leads to hypovolemia. Hypovolemia, in turn, leads to hypotension, and hypotension results in impaired tissue perfusion. Coma is the end stage of this hyperglycemic process, when severe electrolyte disturbances occur in association with hypotension. Any process that accelerates water loss, such as diarrhea or severe burns, accelerates the development of hyperosmolarity and hypotension. In this 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. Etiology HHS most commonly occurs in patients with type 2 DM who have some concomitant illness that leads to reduced fluid intake. In general, any illness that predisposes to dehydration or to reduced insulin activity may lead to HHS.[1, 3] A wide variety of major illnesses may trigger HHS by limiting patient mobility and free access to water. When considering treatment of a patient with HHS, assess for and address any acute illness and contributions from medications.
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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][1] ) is the single most common cause, but in a number of patients, the concomitant illness is not identifiable. The stress response to any acute illness tends to increase hormones that favor elevated glucose levels. Cortisol, catecholamines, glucagon, and many other hormones have effects that tend to counter those of insulin. Examples of such acute conditions are as follows:

Stroke Intracranial hemorrhage Silent MI Consider MI in all patients with HHS until it is excluded Pulmonary embolism (PE)

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 cause HHS. Examples include the following:

Atypical antipsychotics (clozapine, olanzapine) Alcohol and cocaine Antiarrhythmics (eg, encainide and propranolol) Antiepileptics (eg, phenytoin) Antihypertensives (eg, calcium channel blockers and diazoxide) Antipsychotics (eg, chlorpromazine, clozapine, loxapine, and olanzapine)[5, 6] L-asparaginase Beta blockers Corticosteroids Diuretics (eg, chlorthalidone, ethacrynic acid, and thiazides) Histamine-receptor blockers (eg, cimetidine) Immunosuppressive agents Total parenteral nutrition (TPN) solutions and fluids that contain dextrose

Noncompliance with oral hypoglycemics or insulin therapy can result in HHS. Other conditions and illnesses associated with HHS include the following:

Acromegaly Anesthesia Burns Cerebrovascular accident Cushing syndrome (eg, endogenous, exogenous, ectopic)

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Obed Yosia (406127068)

Hemodialysis and peritoneal dialysis Gastrointestinal (GI) hemorrhage Heatstroke Hypothermia Intestinal obstruction Mesenteric thrombosis Neuroleptic malignant syndrome Pancreatitis Rhabdomyolysis Sepsis Subdural hematoma Surgery (especially cardiac surgery) Thyrotoxicosis Trauma UTI

Elder abuse and neglect also may contribute to underhydration. Epidemiology United States statistics No population-based studies of HHS have been conducted. According to the US National Hospital Discharge Survey funded by the National Center for Health Statistics, there were 10,800 annual discharges for HNS in the United States from 1989 to 1991. HHS affects approximately 1 of 500 patients with DM. The overall incidence of HHS is less than 1 case per 1000 person-years, making it significantly less common than DKA. As the prevalence of type 2 DM increases, the incidence of HHS will likely increase as well.[1] Age-related demographics HHS has a mean age of onset early in the seventh decade of life. The average age of patients with HHS is 60 years. Most published series report an average age of 57-69 years at diagnosis.[1, 3, 7] In contrast, the mean age of onset for DKA is early in the fourth decade of life. HHS may also occur in younger people. In particular, as rates of obesity increase in children, the prevalence of type 2 DM is also rising in this age group and may lead to an increased incidence of HHS in this population. [8, 9, 10] Nursing home populations are at risk for HHS. Underlying comorbidities that prevent adequate hydration, including immobility, advanced age, debility, dementia, agitation, and restraint use, place these patients at risk. Impaired senses, such as deafness and blindness, may lead to social isolation and also increase the risk of HHS. 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 above), 3700
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persons were male and 7100 were female. Race-related demographics African Americans, Hispanics, and Native Americans are disproportionately affected by HHS as a consequence of an increased prevalence of type 2 DM.[1] 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. Prognosis Overall mortality for HHS is typically 10-20%, though figures as high as 58% have been reported. Older age, the presence of concurrent illnesses, and severity of the metabolic derangements (especially dehydration) contribute to this high mortality, as do delay in establishing the diagnosis and failure to treat HHS aggressively from the outset also may contribute to this high mortality rate. In children, mortality 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. Patient Education Diabetic teaching, provided both in the hospital and after discharge by the primary care physician, a visiting home nurse, or both, is essential for modifying behavior and enhancing compliance. 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 identify factors limiting adequate access to water. Having had HHS places patients at risk for further episodes. Diabetic teaching is vital for preventing a recurrence of HHS. Warn patients to avoid poor glycemic control and dehydration. History Most patients with hyperosmolar hyperglycemic state (HHS) have a known history of diabetes mellitus (DM), which is usually type 2. In 3040% of cases, HHS is the patients initial presentation of diabetes.[3] HHS usually develops over a course of days to weeks, unlike diabetic ketoacidosis (DKA), which develops more rapidly, over the course of a few days. Often, a preceding illness results in several days of increasing dehydration. Adequate oral hydration may be impaired by concurrent acute illness (eg, vomiting) or chronic comorbidity (eg, dementia, immobility). Patients may complain of increasing thirst, polydipsia, polyuria, weight loss, and weakness. They do not typically report abdominal pain, a complaint that is often noted in patients with DKA.
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A wide variety of focal and global neurologic changes may be present, including the following:

Drowsiness and lethargy Delirium Coma Focal or generalized seizures Visual changes or disturbances Hemiparesis Sensory deficits

For patients who present with a change in mental status, obtain a rapid determination of their level of glycemia. Both hypoglycemia and decompensated hyperglycemia may manifest as mental status changes. A blood sugar level outside the range of 65-250 mg/dL suggests an acute diabetic problem. In this case, 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. To quench the thirst they 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. Physical Examination 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. Hypoxemia can be a concurrent problem affecting mentation. The extremities may manifest evidence of peripheral volume sequestration or of dehydration. Assessment of vital signs and body systems Tachycardia is an early indicator of dehydration; hypotension is a later sign suggestive of profound dehydration due to volume loss secondary to osmotic diuresis. Tachypnea may result from respiratory compensation for metabolic acidosis in overlap cases. Assess core temperature rectally. Abnormally high or low temperatures suggest sepsis as an underlying cause. Lack of fever does not rule out infection. Hypothermia is a poor prognostic factor.
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Orthostatic vital signs are neither sensitive nor specific for volume status. Perform a thorough skin examination. Skin turgor is another clue to hydration status. Examine the head, eyes, ears, nose, and throat. Examination may reveal signs indicating altered hydration status (eg, sunken eyes or dry mouth). Cranial neuropathies, visual field losses, and nystagmus may be appreciated, which are symptoms of HHS. They are usually reversible with therapy. HHS may be associated with several 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. Evaluation for underlying diabetes mellitus The presence of needle pricks or calluses on the fingertips (from home glucose monitoring) indicates glycemic derangement as the cause of a change in mental status. Similarly, ecchymoses 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 funduscopic examination showing findings of retinopathy, premature cataracts, and xanthelasmas are also clues suggestive of underlying DM. Assessment of degree of dehydration Body weight is the single most important measurement in assessing the degree of hydration. For every 1 L of body fluids lost, 1 kg of body weight is lost. Unfortunately, recently recorded weights are usually not available when patients with HHS are being assessed, and the weight reported by patients may not be accurate.
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In the early stages of dehydration, cardiac stroke volume decreases. The body is able to maintain constant cardiac output by increasing the heart rate. Therefore, tachycardia is one of the earliest signs of dehydration. With ongoing volume loss, despite the compensatory tachycardia, cardiac output falls. To compensate for a drop in cardiac output, peripheral resistance increases. With further volume loss, the mean arterial pressure can no longer be maintained by increasing the peripheral resistance. This is most apparent when the patient is sitting or standing; therefore, documentation of orthostatic changes in blood pressure and heart rate are very important in the assessment of volume status. With profound dehydration, hypotension occurs even in the supine position. With moderate-to-severe dehydration, urine output falls because the body engages the renin-angiotensin-aldosterone system and antidiuretic hormone to preserve volume. Dryness of the mucous membranes, anhidrosis, poor skin turgor, and sunken eyes indicate significant dehydration. 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 2 coexist. Cardiac imaging or central venous pressure measurements may be required. Hypotension also may be due to sepsis. Exclusion of an infectious process, especially one in the thorax, abdomen, or soft tissues, must be included in the physical examination of patients with HHS. Document body temperature. Low-grade fever is usually present in patients with HHS, secondary to a reduction in sweating. High-grade fever suggests infection. Complications Cerebral edema Cerebral edema is rare in HHS and is usually observed in patients much younger than the average age of 60 years. However, it may occur 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. 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
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volume does not reach the critical level that causes uncal herniation. Aggressive correction of hyperglycemia and hyperosmolarity is indicated, especially in older patients. Acute respiratory distress syndrome Always monitor pulmonary function carefully during therapy for HHS. A drop in the partial pressure of alveolar oxygen during therapy for HHS may signal acute respiratory distress syndrome (ARDS), PE, MI, or a pneumonitis that has worsened with rehydration. ARDS may develop in association with underlying diseases, such as pancreatitis and MI. Although the precise mechanism by which ARDS develops in persons with HHS remains unclear, a likely scenario is that rapid correction of hyperglycemia and hyperosmolarity gives rise to pulmonary edema in much the same manner as it gives rise to cerebral edema. 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. Vascular complications The severe dehydration of HHS leads to hypotension and hyperviscosity of the blood, both of which predispose patients to thromboembolic disease of the coronary, cerebral, pulmonary, and mesenteric beds. Disseminated intravascular coagulation (DIC) also may complicate HHS. Together, these vascular syndromes account for much of the morbidity and mortality in HHS. Low-dose subcutaneous heparin is advisable for all patients without a contraindication Diagnostic Considerations In addition to the conditions listed in the differential diagnosis, any condition that can cause altered mental status should be considered, including the following[1] :

Central nervous system infection Hypoglycemia Hyponatremia Severe dehydration Uremia Hyperammonemia Intoxication (eg, with ethanol, narcotics, other drugs) Sepsis Change in mental status or level of consciousness Postictal state Arrhythmia Hypotension Other causes of dehydration Acute blood loss (gastrointestinal or other)

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Polyuria Excessive diuretic use

Differential Diagnoses Diabetes Insipidus Diabetic Ketoacidosis Myocardial Infarction Pulmonary Embolism Approach Considerations On the basis of the consensus statement published by the American Diabetes Association, diagnostic features of hyperosmolar hyperglycemic state (HHS) may include the following[2, 4] :

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 9 L Serum pH greater than 7.30 Bicarbonate concentration greater than 15 mEq/L Small ketonuria and absent-to-low ketonemia Some alteration in consciousness

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. An arterial line provides access for repeated blood draws, particularly in patients who are intubated or require admission to the intensive care unit (ICU). Blood Studies Hemoglobin and hematocrit values are usually elevated because of volume contraction. Leukocytosis is frequently present, with white blood cell (WBC) counts often exceeding 20,000/L. Stress, dehydration, and demargination of leukocytes contribute to leukocytosis. Given that infections commonly precipitate HHS, consider leukocytosis secondary to an infectious process until proven otherwise. Obtain a chest radiograph and urine and blood cultures from all patients with leukocytosis. Serum glucose A fingerstick blood sugar measurement with a reflectance meter is the simplest first step in the evaluation. The serum glucose level usually is elevated dramatically, often to greater than 800 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 mental status changes.
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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. Hemoglobin A1c Although hemoglobin A1c (glycosylated hemoglobin) levels are not useful in the acute phase of therapy, they may be obtained as an indicator of the patients glucose control over the previous several weeks. Serum osmolarity or osmolality 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. Osmolality can be measured directly by means of freezing point depression or osmometry. Alternatively, serum osmolality may be calculated from sodium, blood urea nitrogen (BUN), and glucose values, as follows: Osm = (2 Na) + (glucose/18) + (BUN/2.8) Urea is freely permeable across cell membranes and therefore does not create an osmotic gradient between the intracellular and extracellular fluids. The last term of the serum osmolality equation above thus may be dropped, giving the effective serum osmolality. The effective serum osmolality may be used to calculate a patients osmolality quickly at the bedside but should be confirmed by a measured value. 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. Blood gases Document arterial plasma pH early in the treatment of patients with hyperglycemia presenting with an altered level of consciousness. Arterial blood gas (ABG) values are obtained to measure serum pH. In most cases of HHS, the blood pH is greater than 7.30. Venous blood gas (VBG) values may be substituted in patients with normal oxygen saturation on room air. Venous blood gases 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
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than the pH measured by ABG assessment.[11] 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 alveolararterial oxygen gradient from pulmonary disease. A low plasma bicarbonate level is commonly observed in persons with HHS, but very low levels (< 15 mEq/L) indicate DKA. Serum electrolytes Early in the course of HHS, before significant osmotic diuresis has occurred, the elevated plasma glucose level exerts an osmotic drag. This results in the movement of water from the intracellular to the extracellular space, with dilution of all electrolytes in the plasma. Patients with renal insufficiency who may not establish an osmotic diuresis may effectively present with hyponatremia and hypochloremia. 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 also exert an osmotic drag and displace electrolytes in the plasma. Hyponatremia or hypernatremia may be present. In the setting of hyperglycemia, pseudo-hyponatremia 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. Bartoli et al described a mathematical model and formulas designed to improve estimation of the plasma sodium concentrations that patients will have after treatment of hyperosmolar coma.[12, 13] Such estimations are important for avoiding sodium imbalances after coma treatment. The model estimates the amount of glucose added to the plasma, along with associated water loss, but excludes concomitant sodium loss. Hypokalemia or hyperkalemia may be present. 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; 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
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potassium in the circulation. Aggressively replace potassium to maintain plasma levels in the normal range during treatment. 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. The bicarbonate concentration in a patient with HHS may be greater than 15 mEq/L. The anion gap is calculated according to the following formula: (Na+ + K+) (Cl + HCO3) The calculated anion gap is usually less than 12 mmol/L. A wide anion gap is observed in most patients with HHS, reflecting mild metabolic acidosis. The mild acidosis in HHS is often multifactorial and results, in part, from the accumulation of 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. Serum ketones 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). BUN and creatinine Patients with HNS present with prerenal azotemia. Initially, BUN and creatinine concentrations are likely to be elevated, and the BUN-tocreatinine ratio may exceed 30:1. When possible, these values should be compared with previous values; many patients with diabetes have baseline renal insufficiency. The renal function of many patients does not normalize after treatment; this indicates irreversible or underlying renal damage. Serum enzymes Dehydration causes a rise in the plasma levels of albumin, amylase, bilirubin, calcium, total protein, lactate dehydrogenase, transaminases, and creatine kinase (CK). Up to two thirds of patients with HHS have elevated serum enzyme levels. Accordingly, serum levels of CK and
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isoenzymes should be measured routinely because both MI and rhabdomyolysis can trigger HHS and both can be secondary complications of HHS.[14] 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. Blood culture Blood cultures should be obtained to search for bacteremia. Urine Studies Urinalysis can reveal elevated specific gravity (evidence of dehydration), glycosuria, small ketonuria, and evidence of urinary tract infection (UTI). 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 patients metabolic state. Ketones are rarely present in persons with HHS, mostly because of dehydration. Gross proteinuria suggests underlying renal disease. Urinary osmolality and the urine specific gravity should be very high in patients with HHS. Occasionally, a patient presents with a low urine specific gravity. This is diagnostic of coexisting diabetes insipidus, prompts a more thorough evaluation of pituitary and renal function, and warrants aggressive fluid resuscitation and central pressure monitoring. Urethral catheterization is useful for obtaining a clean urine specimen. This is especially important if the urine dipstick shows signs of infection. An indwelling Foley catheter indicates urine output and response to fluid therapy. Urine cultures are useful because UTIs may be underdetected by urinalysis alone, particularly in patients with diabetes mellitus (DM). Send cultures as clinically indicated. Cerebrospinal Fluid Studies 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. Patients who are immunocompromised may require additional studies of the CSF, such as polymerase chain reaction (PCR) 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.
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Radiography of Chest and Abdomen In the initial evaluation of patients with HHS, a chest radiograph is almost always advisable to exclude pneumonitis. Radiographic findings may be falsely negative at first because of the profound dehydration in some patients, and serial studies may document the pneumonitis process as rehydration proceeds. Cardiomegaly in the presence of dehydration implies a severely compromised heart, which is probably affected by cardiomyopathy. Abdominal radiographs are indicated if the patient has abdominal pain or is vomiting. Computed Tomography of Head 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 Electrocardiography (ECG) is indicated in all patients with HHS because myocardial infarction (MI) and pulmonary embolism (PE) frequently 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. Approach Considerations Diagnosis and management guidelines for hyperglycemic crises are available from the American Diabetes Association.[15, 16, 4] The main goals in the treatment of hyperosmolar hyperglycemic state (HHS) are as follows:

To vigorously rehydrate the patient while maintaining electrolyte homeostasis To correct hyperglycemia To treat underlying diseases To monitor and assist cardiovascular, pulmonary, renal, and central nervous system (CNS) function

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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. Initiation of insulin therapy in the emergency department (ED) through a subcutaneous insulin pump may be an alternative to intravenous (IV) insulin infusion.[17] Airway management is the top priority. In comatose patients in whom airway protection is of concern, endotracheal intubation may be indicated. Cervical spine immobilization is necessary if head or neck injury is a possibility. In patients with HHS, consider other procedures, including nasogastric tube placement, thoracentesis, paracentesis, and spinal tap, as appropriate. 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.[18] Insulin used without concomitant vigorous fluid replacement increases the risk of shock. Adjust insulin or oral hypoglycemic therapy on the basis of the patients 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 patients 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 to be resolved. 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 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.
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Airway management Protection of the airway is mandatory in patients with obtundation or unconsciousness. Many patients present with respiratory failure and circulatory collapse and must be ventilated mechanically. Because of the underlying metabolic acidosis that is frequently present, take care to hyperventilate patients when mechanical ventilation is instituted. Hyperventilation generates respiratory alkalosis, which compensates for the metabolic acidosis and also decreases the risk of cerebral edema. Intravenous access 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 ED. Insertion of a central venous catheter is the only procedure that should be considered routinely in patients with HHS. A centrally placed catheter offers an avenue for vigorous rehydration. Findings from monitoring of the pulmonary capillary wedge pressure or the central venous pressure may help guide intravenous rehydration therapy. Large-bore IV or central venous access may be especially helpful in cases in which hemorrhage is a precipitant and blood products are likely to be required or when inotropic agents may be necessary. Fluid resuscitation Fluid deficits in HHS are large; the fluid deficit of an adult may be 10 L or more. If a recent record of the patients weight is available for comparison, the difference between the admission weight and the preadmission weight may provide a rough estimate of the degree of dehydration. Infuse enough volume to allow the perfusion of vital organs and the kidneys. A reasonable goal of treatment is to replace half of the estimated volume deficit in the first 12 hours of therapy. The remainder of the volume deficit may then be replaced over the second 12-hour period. A 500-mL bolus of 0.9% isotonic saline is appropriate for nearly all adults who are clinically dehydrated. Administer 1-2 L of isotonic saline in the first 2 hours. A higher initial volume may be necessary in patients with severe volume depletion. Slower initial rates may be appropriate in patients with significant cardiac or renal disease. Caution should be taken to not correct hypernatremia too quickly, as this could lead to cerebral edema. As much as 2 L of 0.9% isotonic saline may be infused safely over the first hour of treatment. After the initial bolus, some clinicians recommend changing to halfnormal saline, whereas others continue with isotonic saline. Either fluid
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likely will replenish intravascular volume and correct hyperosmolarity; a good standard is to switch to half-normal saline once blood pressure and urine output are adequate. At a serum osmolality below 320 mOsm/kg, the IV fluids may again be switched to 0.9% isotonic saline. When the blood glucose concentration, initially checked hourly, reaches 300 (or, as some prefer, 250) mg/dL, change the infusion to 5% dextrose in 0.9% isotonic saline again. This helps prevent a precipitous fall of glucose, which may be associated with cerebral edema.[2] In pediatric patients with suspected HHS, correcting fluid deficits over a longer period (48 h) may help reduce the risk of cerebral edema.[8] In most patients, adequately monitoring volume status entails the use of a urinary catheter. In patients with preexisting or acute cardiac disease or with diseases in which third-spacing is a problem, use findings from pulmonary capillary wedge pressure monitoring to guide rehydration therapy. Patients with hypotension may require pressor support in the ICU while rehydration is being accomplished. Medications for coma patients 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. Insulin Therapy for Correction of Hyperglycemia 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. After the kidneys show evidence of being perfused, initiating insulin therapy is safe. This 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 is started.
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The following steps may be used as a guideline for insulin infusion:


Begin a continuous insulin infusion of 0.1 U/kg/h Monitor blood glucose by means of bedside testing every hour; if glucose levels are stable for 3 hours, decrease the frequency of testing to every 2 hours Set the target blood glucose level at 250-300 mg/dL; this target level may be adjusted downward after the patient is stabilized For a blood glucose concentration lower than 250 mg/dL, decrease the insulin infusion rate by 0.5 U/h For a blood glucose concentration of 250-300 mg/dL, do not change the insulin infusion rate. For a blood glucose concentration of 301-350 mg/dL, increase the insulin infusion rate by 0.5 U/h For a blood glucose concentration higher than 350 mg/dL, increase the insulin infusion rate by 1 U/h Do not discontinue the insulin drip If the blood glucose concentration decreases by more than 100 mg/dL between consecutive readings, wait to increase the insulin infusion rate

When the glucose level has been between 200 and 300 mg/dL for at least 1 day and the patients 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. Initiation of insulin therapy in the ED via subcutaneous insulin pump may be an alternative to intravenous insulin infusion.[17] Electrolyte Replacement Profound potassium depletion necessitates careful replacement. 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
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level of 5 mEq/L or less. Hypokalemia at the onset of rehydration requires up to 60 mEq/L to correct the serum potassium concentration. Check the potassium level at least every 4 hours until the blood glucose concentration is stabilized. Phosphate, magnesium, and calcium are not replaced routinely, but a patient who is symptomatic with tetany requires replacement therapy. Monitoring During Treatment 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. Diet Provide adequate nutritional support for all patients. Most HHS patients with HNS 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 MS 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. Consultations 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 HNS. 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.
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Long-Term Monitoring 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 dilated eye examination. Advise patients treated with insulin to wear a bracelet or chain identifying them as having diabetes. Medication Summary 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. Antipyretics, antiemetics, 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 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 state is indicated. Antidiabetics, Insulins Class Summary 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. Regular insulin (Humulin R, Novolin R) 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. Insulin aspart (NovoLog) 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.
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Insulin glulisine (Apidra) Insulin glulisine has a rapid onset of action (5-15 minutes) and a short duration of action (3-5 hours). Insulin lispro (Humalog) Insulin lispro has a rapid onset of action (5-15 minutes) and a short duration of action (4 hours). Alkalizing agents Class Summary 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. Sodium bicarbonate (NaHCO3) Sodium bicarbonate neutralizes hydrogen ions and raises urinary and blood pH. Electrolytes Supplements, Parenteral Class Summary Electrolytes are given to replenish electrolyte supplies depleted by the presence of a high blood glucose level. Potassium chloride (Klor-Con, K-Tab, Micro-K) 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.

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