OBED - Hyperosmolar Hyperglycemic State

7/30/2019 OBED - Hyperosmolar Hyperglycemic State

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Hyperosmolar Hyperglicemic State Obed Yosia (406127068)

Hyperosmolar Hyperglycemic State

Author

Robin R Hemphill, MD, MPH Associate Professor, Director, Quality andSafety, Department of Emergency Medicine, Emory University School ofMedicine

Robin R Hemphill, MD, MPH is a member of the following medical societies:American College of Emergency Physicians and Society for AcademicEmergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates


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 Collegeof Emergency Physicians


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 medicalsocieties: American Association of Clinical Endocrinologists, Association of ClinicalResearchers and Educators (ACRE), and Minnesota Medical Association


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: AmericanAssociation for the Advancement of Science, American College of Medical PracticeExecutives, American College of Physician Executives, American College of Physicians,American Diabetes Association, American Federation for Medical Research, AmericanHeart Association, Central Society for Clinical Research, Endocrine Society,InternationalSocietyfor Clinical Densitometry, and Southern Society for ClinicalInvestigation


KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 1
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Lewis S Nelson, MD, FACEP, FAACT, FACMT Associate Professor, Department ofEmergency Medicine, New York University School of Medicine; Attending Physician,Department of Emergency Medicine, Bellevue Hospital Center, New York UniversityMedical 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 EmergencyPhysicians, American College of Medical Toxicology, and Society for AcademicEmergency Medicine


David S Schade, MD Chief, Division of Endocrinology and Metabolism, Professor,Department of Internal Medicine, University of New Mexico School of Medicine andHealth Sciences Center

David S Schade, MD is a member of the following medical societies: American College ofPhysicians, American Diabetes Association, American Federation for Medical Research,

Endocrine Society, New Mexico Medical Society, New York Academy of Sciences, andSociety for Experimental Biology and Medicine


Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division ofEndocrinology, University of Wisconsin Hospitals and Clinics

Don S Schalch, MD is a member of the following medical societies: American DiabetesAssociation, American Federation for Medical Research, Central Society for ClinicalResearch, and Endocrine Society


Paulina B Sergot, MD Staff Physician, Department of Emergency Medicine, New YorkUniversity/Bellevue Hospital Center

Paulina B Sergot, MD is a member of the following medical societies: American MedicalAssociation


Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University ofNebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug

Reference

http://www.clintox.org/http://www.acep.org/http://www.acep.org/http://www.acmt.net/http://www.saem.org/http://www.saem.org/http://www.acponline.org/http://www.acponline.org/http://www.diabetes.org/http://www.afmr.org/http://www.endo-society.org/http://www.nmms.org/http://www.nyas.org/http://www.sebm.org/http://www.diabetes.org/http://www.diabetes.org/http://www.afmr.org/http://www.cscr.com/index.phphttp://www.cscr.com/index.phphttp://www.endo-society.org/http://www.ama-assn.org/http://www.ama-assn.org/http://www.clintox.org/http://www.acep.org/http://www.acep.org/http://www.acmt.net/http://www.saem.org/http://www.saem.org/http://www.acponline.org/http://www.acponline.org/http://www.diabetes.org/http://www.afmr.org/http://www.endo-society.org/http://www.nmms.org/http://www.nyas.org/http://www.sebm.org/http://www.diabetes.org/http://www.diabetes.org/http://www.afmr.org/http://www.cscr.com/index.phphttp://www.cscr.com/index.phphttp://www.endo-society.org/http://www.ama-assn.org/http://www.ama-assn.org/


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Background

Hyperosmolar hyperglycemic state (HHS) is 1 of 2 serious metabolicderangements that occurs in patients with diabetes mellitus (DM) andcan be a life-threatening emergency. It is less common than the otheracute complication of diabetes, diabetic ketoacidosis (DKA). HHS waspreviously 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 someconcomitant illness that leads to reduced fluid intake. Infection is themost common preceding illness, but many other conditions can causealtered mentation, dehydration, or both. Once HHS has developed, it maybe difficult to differentiate it from the antecedent illness. Theconcomitant illness may not be identifiable. (See Etiology.) HHS has alsobeen 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 ahigher mortality than DKA, estimated at approximately 10-20%. (SeeEpidemiology.)

HHS is characterized by hyperglycemia, hyperosmolarity, anddehydration without significant ketoacidosis. Most patients present withsevere dehydration and focal or global neurologic deficits.[2, 1, 3] In asmany as one third of cases, the clinical features of HHS and DKA overlapand are observed simultaneously (overlap cases); this suggests thatthese 2 states of uncontrolled DM differ only with respect to themagnitude of dehydration and the severity of acidosis. (See

Presentation.)

According to the consensus statement published by the AmericanDiabetes Association, diagnostic features of HHS may include thefollowing (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 7.30KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 3
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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. Standardcare for dehydration and altered mental status is appropriate, includingairway management, intravenous (IV) access, crystalloid administration,and any medications routinely given to coma patients. Although manypatients with HHS respond to fluids alone, IV insulin in dosages similar tothose used in DKA can facilitate correction of hyperglycemia. Insulin usedwithout concomitant vigorous fluid replacement increases the risk ofshock

Pathophysiology

Insulin-sensitive tissues normally take up glucose during meals, when theglycemic rise of ingested carbohydrates stimulates insulin secretion. Theincreased insulin levels inhibit glucagon release from the pancreaticislets, and the ratio of plasma insulin to glucagon becomes relativelyhigh.

A high insulin-to-glucagon ratio favors storage of glucose as glycogen inliver and muscle and lipogenesis in adipocytes. Insulin-dependenttransport of glucose across the cell membranes of insulin-sensitivetissues drives potassium into these cells. A high insulin-to-glucagon ratioduring meals also favors amino acid uptake by muscle.

Between meals, insulin secretion is not stimulated, and the insulin-mediated glucagon inhibition in the pancreatic islets stops. The glucagonlevels rise in the plasma, leading to a decrease in the plasma insulin-to-glucagon ratio. The consequence of this decrease is the breakdown ofglycogen in the liver and muscle and gluconeogenesis by the liver, bothof which maintain the plasma glucose concentration in the normal range.A fall in the insulin-to-glucagon ratio also favors lipolysis and theformation 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 andthe kidneys.

In patients with a preexisting lack of or resistance to insulin, aphysiologic stress such as an acute illness can cause further netreduction in circulating insulin. The basic underlying mechanism of HHSis a relative or absolute reduction in effective circulating insulin with aconcomitant elevation of counterregulatory hormones.[1, 2]

Decreased renal clearance and decreased peripheral utilization of



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glucose lead to hyperglycemia. Hyperglycemia and hyperosmolarityresult in an osmotic diuresis and an osmotic shift of fluid to theintravascular space, resulting in further intracellular dehydration. Thisdiuresis also leads to loss of electrolytes, such as sodium and potassium.[1, 2, 3]

Unlike patients with DKA, patients with HHS do not develop significantketoacidosis, but the reason for this is not known. Contributing factorslikely include the availability of insulin in amounts sufficient to inhibitketogenesis but insufficient to prevent hyperglycemia. Additionally,hyperosmolarity itself may decrease lipolysis, limiting the amount of freefatty acids available for ketogenesis. In addition, levels ofcounterregulatory hormones are found to be lower in patients with HHSthan in those with DKA.[1, 2, 3]

Obesity is the most prevalent cause of insulin resistance. Pregnancy is astate of insulin resistance largely due to the action of placental hormoneson 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 thesecounterregulatory 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] andcyclosporine and other immunosuppressive agents) cause insulinresistance.

Insulin deficiency is due to autoimmune destruction of the beta cells intype 1 DM. In type 2 DM, a defect in the first-phase release of insulinoccurs, which leads to relative insulinopenia. The defective insulinsecretion in persons with type 2 DM is due to the direct toxic effect ofglucose on beta cells. Many patients with diabetes treated with insulinbecome 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 adipocytesand muscles; glucose cannot be stored as glycogen in muscle and livertissue; and hepatocytes, under the influence of glucagon, stimulategluconeogenesis.

The resulting elevation in plasma glucose concentration leads to furtherimpairment of insulin release by pancreatic beta cells. In this setting of

inadequate insulin action, the magnitude of the rise in plasma glucoseKEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 5


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concentration also depends, in part, on the level of hydration and oralcarbohydrate (or glucose) loading.

Under normal circumstances, all of the glucose filtered by the kidneys isreabsorbed. When glycemia reaches approximately 180 mg/dL, proximal

tubular transport of glucose from the tubular lumen into the renalinterstitium becomes saturated, and further glucose reabsorption is nolonger possible. The glucose that remains in the renal tubules continuesto travel into the distal nephron and, eventually, the urine, carrying waterand electrolytes with it.

Osmotic diuresis then results. The direct consequence of this osmoticdiuresis is a decrease in total body water. Within the vascular space, inwhich gluconeogenesis and dietary intake continue to add glucose, theloss of water results in further hyperglycemia and loss of circulatingvolume.

Hyperglycemia and the rise in the plasma protein concentration afterintravascular water loss cause a hyperosmolar state. Thehyperosmolarity of the plasma triggers release of antidiuretic hormone,which ameliorates renal water loss. Hyperosmolarity also stimulatesthirst, a defense mechanism that is impaired in people dependent onothers for care.

In the presence of HHS, if the renal water loss is not compensated for byoral water intake, dehydration leads to hypovolemia. Hypovolemia, in

turn, leads to hypotension, and hypotension results in impaired tissueperfusion. Coma is the end stage of this hyperglycemic process, whensevere electrolyte disturbances occur in association with hypotension.

Any process that accelerates water loss, such as diarrhea or severeburns, accelerates the development of hyperosmolarity and hypotension.In this severely dehydrated and hyperosmolar state, hypotension causesa massive stimulation of the renin-angiotensin-aldosterone system and,eventually, renal shutdown. Oliguria precludes further excretion ofglucose from the kidneys, which conserves circulating volume butexacerbates hyperglycemia.

EtiologyHHS most commonly occurs in patients with type 2 DM who have someconcomitant illness that leads to reduced fluid intake. In general, anyillness that predisposes to dehydration or to reduced insulin activity maylead to HHS.[1, 3] A wide variety of major illnesses may trigger HHS bylimiting patient mobility and free access to water.

When considering treatment of a patient with HHS, assess for andaddress any acute illness and contributions from medications.



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Acute febrile illnesses, including infections, account for the largestproportion of HHS cases. A preceding or intercurrent infection (inparticular, pneumonia or urinary tract infection [UTI][1] ) is the single mostcommon cause, but in a number of patients, the concomitant illness isnot identifiable.

The stress response to any acute illness tends to increase hormones thatfavor elevated glucose levels. Cortisol, catecholamines, glucagon, andmany 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 causedehydration 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 inHHS.

Other conditions and illnesses associated with HHS include the following:

Acromegaly Anesthesia Burns Cerebrovascular accident

Cushing syndrome (eg, endogenous, exogenous, ectopic)KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 7
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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.

EpidemiologyUnited States statistics

No population-based studies of HHS have been conducted. According tothe US National Hospital Discharge Survey funded by the National Centerfor Health Statistics, there were 10,800 annual discharges for HNS in theUnited States from 1989 to 1991. HHS affects approximately 1 of 500patients with DM. The overall incidence of HHS is less than 1 case per1000 person-years, making it significantly less common than DKA. As the

prevalence of type 2 DM increases, the incidence of HHS will likelyincrease as well.[1]

Age-related demographicsHHS has a mean age of onset early in the seventh decade of life. Theaverage age of patients with HHS is 60 years. Most published seriesreport an average age of 57-69 years at diagnosis.[1, 3, 7] In contrast, themean age of onset for DKA is early in the fourth decade of life. HHS mayalso occur in younger people. In particular, as rates of obesity increase inchildren, the prevalence of type 2 DM is also rising in this age group andmay lead to an increased incidence of HHS in this population.[8, 9, 10]

Nursing home populations are at risk for HHS. Underlying comorbiditiesthat prevent adequate hydration, including immobility, advanced age,debility, dementia, agitation, and restraint use, place these patients atrisk. Impaired senses, such as deafness and blindness, may lead to socialisolation and also increase the risk of HHS.

Sex-related demographicsNo sex predilection is noted in most published series of HHS. However,some data suggest that the prevalence is slightly higher in females than

in males. In the US National Hospital Discharge Survey (see above), 3700KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 8
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persons were male and 7100 were female.

Race-related demographicsAfrican Americans, Hispanics, and Native Americans aredisproportionately affected by HHS as a consequence of an increased

prevalence of type 2 DM.[1] In the US National Hospital Discharge Surveyof 10,800 hospital discharges listing HHS in the United States between1989 and 1991, there were 6300 white patients and 2900 AfricanAmerican patients; the remainder of the discharges were people of otherraces or of unknown race.

PrognosisOverall mortality for HHS is typically 10-20%, though figures as high as58% have been reported. Older age, the presence of concurrentillnesses, and severity of the metabolic derangements (especiallydehydration) contribute to this high mortality, as do delay in establishingthe diagnosis and failure to treat HHS aggressively from the outset alsomay contribute to this high mortality rate. In children, mortality from HHSalso appears to be higher than mortality from DKA, but too few caseshave been reported to allow accurate calculation of pediatric mortality.

Patient EducationDiabetic teaching, provided both in the hospital and after discharge bythe primary care physician, a visiting home nurse, or both, is essential formodifying behavior and enhancing compliance. A certified diabeteseducator should instruct all patients on management of sick days and

provide a thorough review of self-care. A home evaluation by a visitingnurse may help identify factors limiting adequate access to water.

Having had HHS places patients at risk for further episodes. Diabeticteaching is vital for preventing a recurrence of HHS. Warn patients toavoid poor glycemic control and dehydration.

HistoryMost patients with hyperosmolar hyperglycemic state (HHS) have aknown history of diabetes mellitus (DM), which is usually type 2. In 30-40% of cases, HHS is the patients initial presentation of diabetes.[3]

HHS usually develops over a course of days to weeks, unlike diabeticketoacidosis (DKA), which develops more rapidly, over the course of afew days. Often, a preceding illness results in several days of increasingdehydration. Adequate oral hydration may be impaired by concurrentacute illness (eg, vomiting) or chronic comorbidity (eg, dementia,immobility).

Patients may complain of increasing thirst, polydipsia, polyuria, weightloss, and weakness. They do not typically report abdominal pain, a

complaint that is often noted in patients with DKA.KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 9


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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 rapiddetermination of their level of glycemia. Both hypoglycemia anddecompensated hyperglycemia may manifest as mental status changes.

A blood sugar level outside the range of 65-250 mg/dL suggests an acutediabetic problem. In this case, obtain a complete history from the patientor a companion, with an emphasis on recent illnesses or other conditionsleading to altered insulin requirements, lack of compliance withhypoglycemic medications (including insulin), and dietary indiscretion.Emphasize identification of potential causes of HHS. Prior hospitalizationsfor management of hyperglycemia are important to note and indicate apatient at risk for future episodes.

To quench the thirst they experience, many HHS patients consumebeverages containing glucose, including juices and soda. Attempt to

quantitate the volume ingested over the preceding 24 hours to try toestimate the degree of osmotic diuresis with which the patient ispresenting.

Physical ExaminationExamine the patient for evidence of HHS, focusing on hydration status,mentation, and signs of possible underlying causes, such as a source ofinfection. General appearance and hygiene may provide clues to thestate of hydration, the presence of chronic illness, and the level ofmentation. 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 systemsTachycardia is an early indicator of dehydration; hypotension is a latersign suggestive of profound dehydration due to volume loss secondary toosmotic diuresis. Tachypnea may result from respiratory compensationfor metabolic acidosis in overlap cases.

Assess core temperature rectally. Abnormally high or low temperaturessuggest sepsis as an underlying cause. Lack of fever does not rule out

infection. Hypothermia is a poor prognostic factor.KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 10


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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 tohydration status.

Examine the head, eyes, ears, nose, and throat. Examination may revealsigns indicating altered hydration status (eg, sunken eyes or dry mouth).Cranial neuropathies, visual field losses, and nystagmus may beappreciated, which are symptoms of HHS. They are usually reversiblewith therapy.

HHS may be associated with several neurologic findings, includingseizures, hemianopsia, aphasia, paresis, a positive Babinski sign,myoclonic jerks, change in muscle tone, nystagmus, eye deviation, andgastroparesis. For many patients, these neurologic symptoms and signscould be the manifestation of an underlying cerebrovascular accident.Cerebral dehydration, neurotransmitter level changes in the centralnervous system (CNS), and microvascular ischemia may contribute tothese findings.

When HHS causes neurologic dysfunction, treatment results in resolutionof signs and symptoms. When neurologic events cause HHS, signs andsymptoms fail to improve with correction of the metabolic derangements.

Evaluation for underlying diabetes mellitusThe presence of needle pricks or calluses on the fingertips (from home

glucose monitoring) indicates glycemic derangement as the cause of achange in mental status. Similarly, ecchymoses on the abdomen, thighs,and arms may be signs of insulin injection. Many patients carry cards intheir wallets or purses or wear bracelets or chains with a metallic plateidentifying them as having DM.

Obesity, acanthosis nigricans, diabetic dermopathy, necrobiosis on thepretibial 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 associatedwith underlying DM and should indicate consideration of HHS.

A funduscopic examination showing findings of retinopathy, prematurecataracts, and xanthelasmas are also clues suggestive of underlying DM.

Assessment of degree of dehydrationBody weight is the single most important measurement in assessing thedegree of hydration. For every 1 L of body fluids lost, 1 kg of body weightis lost. Unfortunately, recently recorded weights are usually not availablewhen patients with HHS are being assessed, and the weight reported bypatients may not be accurate.



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In the early stages of dehydration, cardiac stroke volume decreases. Thebody is able to maintain constant cardiac output by increasing the heartrate. 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 bemaintained by increasing the peripheral resistance. This is most apparentwhen the patient is sitting or standing; therefore, documentation oforthostatic changes in blood pressure and heart rate are very importantin the assessment of volume status. With profound dehydration,hypotension occurs even in the supine position.

With moderate-to-severe dehydration, urine output falls because thebody engages the renin-angiotensin-aldosterone system and antidiuretichormone to preserve volume. Dryness of the mucous membranes,anhidrosis, poor skin turgor, and sunken eyes indicate significantdehydration.

A careful cardiovascular examination is indicated in all patients withhypotension. 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 ofsevere 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 infectiousprocess, especially one in the thorax, abdomen, or soft tissues, must beincluded in the physical examination of patients with HHS. Documentbody temperature. Low-grade fever is usually present in patients withHHS, secondary to a reduction in sweating. High-grade fever suggestsinfection.

ComplicationsCerebral edema

Cerebral edema is rare in HHS and is usually observed in patients muchyounger than the average age of 60 years. However, it may occur fromrapid lowering of glucose levels and an ensuing rapid drop in plasmaosmolarity. Brain cells, which trap osmotically active particles,preferentially absorb water and swell during rapid rehydration. Cerebraledema follows, and, given the constraints of the cranium, uncalherniation may be the cause of death in persons with HHS.

However, death from cerebral edema due to HHS is rare, presumablybecause the older population that it affects has underlying cerebral

atrophy. Thus, even with the edema of rehydration, the intracranialKEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 12


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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. Adrop in the partial pressure of alveolar oxygen during therapy for HHSmay signal acute respiratory distress syndrome (ARDS), PE, MI, or apneumonitis that has worsened with rehydration. ARDS may develop inassociation with underlying diseases, such as pancreatitis and MI.

Although the precise mechanism by which ARDS develops in personswith HHS remains unclear, a likely scenario is that rapid correction ofhyperglycemia and hyperosmolarity gives rise to pulmonary edema inmuch the same manner as it gives rise to cerebral edema. Tocompensate for hypoxia and mild acidosis, an increase in the minuteventilation with tachypnea develops. Continuing pulmonary disease maylead to acute respiratory failure that necessitates full respiratory support,including mechanical ventilation.

Vascular complicationsThe severe dehydration of HHS leads to hypotension and hyperviscosityof the blood, both of which predispose patients to thromboembolicdisease 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 allpatients without a contraindication

Diagnostic ConsiderationsIn addition to the conditions listed in the differential diagnosis, anycondition 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)KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 13


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Polyuria Excessive diuretic use

Differential Diagnoses Diabetes Insipidus Diabetic Ketoacidosis Myocardial Infarction Pulmonary Embolism

Approach ConsiderationsOn the basis of the consensus statement published by the AmericanDiabetes Association, diagnostic features of hyperosmolar hyperglycemicstate (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 andhyperosmolarity without significant ketoacidosis. It is particularlyimportant 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 inpatients who are intubated or require admission to the intensive care unit(ICU).

Blood StudiesHemoglobin and hematocrit values are usually elevated because ofvolume contraction. Leukocytosis is frequently present, with white bloodcell (WBC) counts often exceeding 20,000/L. Stress, dehydration, anddemargination of leukocytes contribute to leukocytosis. Given that

infections commonly precipitate HHS, consider leukocytosis secondary toan infectious process until proven otherwise. Obtain a chest radiographand urine and blood cultures from all patients with leukocytosis.

Serum glucoseA fingerstick blood sugar measurement with a reflectance meter is thesimplest first step in the evaluation. The serum glucose level usually iselevated dramatically, often to greater than 800 mg/dL. Many patientspresent with glucose concentrations greater than 1000 mg/dL. Bloodsugar levels of 65-250 mg/dL exclude significant glycemic derangement

and should prompt a search for other causes of mental status changes.KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 14
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The concentration of glucose in the plasma is directly proportional to thedegree of dehydration. Higher concentrations of glucose relate to higherdegrees of dehydration, higher plasma osmolality, and a worseprognosis.

Monitor the plasma glucose concentration hourly during the first 24-48hours of treatment.

Hemoglobin A1cAlthough hemoglobin A1c (glycosylated hemoglobin) levels are not usefulin the acute phase of therapy, they may be obtained as an indicator ofthe patients glucose control over the previous several weeks.

Serum osmolarity or osmolalityNormal serum osmolality ranges from 280 to 290 mOsm/kg. A serumosmolality of 320 mOsm/kg or higher defines HHS. Rarely, serumosmolality may exceed 400 mOsm/kg. In HHS, higher serum osmolalityrelates to greater impairment of the level of consciousness. Osmolalitycan be measured directly by means of freezing point depression orosmometry. Alternatively, serum osmolality may be calculated fromsodium, 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 notcreate an osmotic gradient between the intracellular and extracellular

fluids. The last term of the serum osmolality equation above thus may bedropped, giving the effective serum osmolality. The effective serumosmolality may be used to calculate a patients osmolality quickly at thebedside but should be confirmed by a measured value.

The osmole gap is the difference between the measured osmolality andthe calculated osmolality (at low solute concentrations, they are nearlyequivalent measures). Although the measured osmolality is very high inpatients with HHS, the osmole gap should be unimpressive, because thecalculated osmolality includes the elevated serum glucose concentration.If the osmole gap is very large, consider toxic alcohol ingestion.

Blood gasesDocument arterial plasma pH early in the treatment of patients withhyperglycemia presenting with an altered level of consciousness. Arterialblood gas (ABG) values are obtained to measure serum pH. In most casesof HHS, the blood pH is greater than 7.30.

Venous blood gas (VBG) values may be substituted in patients withnormal oxygen saturation on room air. Venous blood gases providecomparable information, are easier to draw, and are less painful to the

patient. The pH measured by a VBG assessment is 0.03 pH units lessKEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 15


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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 pulmonarydiseases. Hypocarbia may be due to respiratory alkalosis as a

compensatory mechanism to a primary metabolic acidosis. Hypocarbiaalso may be due to tachypnea in response to an elevated alveolar-arterial oxygen gradient from pulmonary disease. A low plasmabicarbonate level is commonly observed in persons with HHS, but verylow levels (< 15 mEq/L) indicate DKA.

Serum electrolytesEarly in the course of HHS, before significant osmotic diuresis hasoccurred, the elevated plasma glucose level exerts an osmotic drag. Thisresults in the movement of water from the intracellular to theextracellular space, with dilution of all electrolytes in the plasma.Patients with renal insufficiency who may not establish an osmoticdiuresis may effectively present with hyponatremia and hypochloremia.

As HHS progresses and osmotic diuresis occurs, electrolytes are lost inthe urine. All electrolytes are extremely deficient at the time ofpresentation, at which time the relative deficiencies of water andelectrolytes determine their plasma concentrations. Additionally, thepresence of hypertriglyceridemia affects the concentration ofelectrolytes. Triglycerides also exert an osmotic drag and displaceelectrolytes in the plasma.

Hyponatremia or hypernatremia may be present. In the setting ofhyperglycemia, pseudo-hyponatremia is common as a result of theosmotic effect of glucose drawing water into the vascular space. Themeasured serum sodium concentration can be corrected upward inproportion to increases in serum glucose to yield an estimate of what theserum sodium level would be in the absence of hyperglycemia and itsassociated osmotic effect.

Bartoli et al described a mathematical model and formulas designed toimprove estimation of the plasma sodium concentrations that patients

will have after treatment of hyperosmolar coma.[12, 13] Such estimationsare important for avoiding sodium imbalances after coma treatment. Themodel estimates the amount of glucose added to the plasma, along withassociated water loss, but excludes concomitant sodium loss.

Hypokalemia or hyperkalemia may be present. Serum potassium may beelevated 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 dilutesKEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 16
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potassium in the circulation. Aggressively replace potassium to maintainplasma levels in the normal range during treatment.

Serum magnesium levels are also a poor indicator of true total bodymagnesium. In the presence of hypokalemia, concomitant

hypomagnesemia should be presumed and treated.

The bicarbonate concentration in a patient with HHS may be greater than15 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 aniongap is observed in most patients with HHS, reflecting mild metabolicacidosis. The mild acidosis in HHS is often multifactorial and results, inpart, from the accumulation of ketoacids in the absence of effectiveinsulin activity. Some patients with profound dehydration may have highanion gaps, reflecting the additional contribution of lactic acid producedby hypoperfusion of tissues. Underlying renal disease with uremia alsomay contribute to a high anion gap.

Monitor plasma electrolyte levels at least every 4 hours during the first24-48 hours of treatment.

Serum ketonesA mild degree of ketosis is usually observed in any patient who isdehydrated. In those with HHS, despite the significant degree ofdehydration, ketosis is mild and responds readily to treatment. Profoundketosis that does not respond readily to IV rehydration is the norm inpersons with DKA. Mild-to-moderate ketosis can be present when thedisease has features of both HHS and DKA (overlap cases).

BUN and creatininePatients with HNS present with prerenal azotemia. Initially, BUN andcreatinine concentrations are likely to be elevated, and the BUN-to-

creatinine ratio may exceed 30:1. When possible, these values should becompared with previous values; many patients with diabetes havebaseline renal insufficiency. The renal function of many patients does notnormalize after treatment; this indicates irreversible or underlying renaldamage.

Serum enzymesDehydration 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 andKEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 17


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isoenzymes should be measured routinely because both MI andrhabdomyolysis can trigger HHS and both can be secondarycomplications of HHS.[14]

Avoid the assumption that enzyme level elevation is due to dehydration.

Exclude underlying disease associated with each of these abnormal bloodlevels in patients with HHS. This is especially true in the case of CKelevations.

Blood cultureBlood cultures should be obtained to search for bacteremia.

Urine StudiesUrinalysis 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 dehydratedpatient with HHS. Catheterization of the urinary bladder may benecessary.

Urinalysis may provide further information about the patients metabolicstate. Ketones are rarely present in persons with HHS, mostly because ofdehydration. Gross proteinuria suggests underlying renal disease. Urinaryosmolality and the urine specific gravity should be very high in patientswith HHS. Occasionally, a patient presents with a low urine specificgravity. This is diagnostic of coexisting diabetes insipidus, prompts amore 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 fluidtherapy.

Urine cultures are useful because UTIs may be underdetected byurinalysis alone, particularly in patients with diabetes mellitus (DM). Sendcultures as clinically indicated.

Cerebrospinal Fluid StudiesCerebrospinal fluid (CSF) cell count, glucose, protein, and culture areindicated in patients with an acute alteration of consciousness andclinical features suggestive of possible central nervous system (CNS)infection. Patients who are immunocompromised may require additionalstudies of the CSF, such as polymerase chain reaction (PCR) for herpessimplex virus (HSV) and cryptococcal antigen.

When meningitis or subarachnoid hemorrhage is suspected, lumbarpuncture (LP) is indicated. If meningitis is suspected clinically, do not

withhold antibiotics while waiting for the LP to be completed.KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 18
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Radiography of Chest and AbdomenIn the initial evaluation of patients with HHS, a chest radiograph is almostalways advisable to exclude pneumonitis. Radiographic findings may befalsely negative at first because of the profound dehydration in somepatients, and serial studies may document the pneumonitis process as

rehydration proceeds. Cardiomegaly in the presence of dehydrationimplies a severely compromised heart, which is probably affected bycardiomyopathy.

Abdominal radiographs are indicated if the patient has abdominal pain oris vomiting.

Computed Tomography of HeadPatients with HHS who present with altered mental status may have anunderlying CNS disease. Computed tomography (CT) of the head isindicated in many patients with focal or global neurologic changes tohelp exclude hemorrhagic strokes, subdural hematoma, subarachnoidbleeding, intracranial abscesses, and intracranial masses. It may beuseful for patients who show no clinical improvement after several hoursof treatment, even in the absence of clinical signs of intracranialpathology.

Repeat CT scanning is indicated if cerebral edema is a concern during thetreatment of HHS.

Electrocardiography

Electrocardiography (ECG) is indicated in all patients with HHS becausemyocardial infarction (MI) and pulmonary embolism (PE) frequentlyprecipitate HHS.

The height of the T waves in the ECG tracings may point to a potassiumderangement. The duration of the QT interval may be abnormal as aconsequence of calcium abnormalities.

Approach ConsiderationsDiagnosis and management guidelines for hyperglycemic crises areavailable 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 electrolytehomeostasis

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 receivingfacility while en route to ensure preparation for a comatose, dehydrated,or hyperglycemic patient. When appropriate, notify the facility of apossible cerebrovascular accident. Initiation of insulin therapy in theemergency 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 whomairway protection is of concern, endotracheal intubation may beindicated. Cervical spine immobilization is necessary if head or neckinjury is a possibility. In patients with HHS, consider other procedures,including nasogastric tube placement, thoracentesis, paracentesis, andspinal tap, as appropriate.

Rapid and aggressive intravascular volume replacement is alwaysindicated as the first line of therapy for patients with HHS. Isotonicsodium chloride solution is the fluid of choice for initial treatmentbecause sodium and water must be replaced in these severelydehydrated patients.

Although many patients with HHS respond to fluids alone, IV insulin indosages similar to those used in diabetic ketoacidosis (DKA) can facilitatecorrection of hyperglycemia.[18] Insulin used without concomitant vigorousfluid replacement increases the risk of shock. Adjust insulin or oralhypoglycemic therapy on the basis of the patients insulin requirementonce serum glucose level has been relatively stabilized.

All patients diagnosed with HHS require hospitalization; virtually all needadmission to a monitored unit managed by medicine, pediatrics, or theintensive care unit (ICU) for close monitoring. When available, anendocrinologist should direct the care of these patients.

Frequent reevaluation of the patients clinical and laboratory parametersis necessary. Recheck glucose concentrations every hour. Electrolytesand venous blood gases should be monitored every 2-4 hours or asclinically indicated.

When an underlying disease is responsible for HHS, it must be promptlyidentified and treated. Resolution of HHS often lags while the underlyingprocess remains to be resolved. Some authors advocate prophylacticheparin treatment and broad-spectrum antibiotic coverage, but thesemeasures have not yet been studied thoroughly enough to allowrecommendation of their use.

Standard Care for Dehydration and Altered Mental StatusStandard 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.KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 20


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Airway managementProtection of the airway is mandatory in patients with obtundation orunconsciousness. Many patients present with respiratory failure andcirculatory collapse and must be ventilated mechanically.

Because of the underlying metabolic acidosis that is frequently present,take care to hyperventilate patients when mechanical ventilation isinstituted. Hyperventilation generates respiratory alkalosis, whichcompensates for the metabolic acidosis and also decreases the risk ofcerebral edema.

Intravenous accessIV access, large bore if possible, or central venous access is useful,provided attempts to obtain it do not significantly delay transfer to thenearest ED. Insertion of a central venous catheter is the only procedurethat should be considered routinely in patients with HHS. A centrallyplaced catheter offers an avenue for vigorous rehydration. Findings frommonitoring of the pulmonary capillary wedge pressure or the centralvenous pressure may help guide intravenous rehydration therapy.

Large-bore IV or central venous access may be especially helpful in casesin which hemorrhage is a precipitant and blood products are likely to berequired or when inotropic agents may be necessary.

Fluid resuscitationFluid 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 forcomparison, the difference between the admission weight and thepreadmission weight may provide a rough estimate of the degree ofdehydration.

Infuse enough volume to allow the perfusion of vital organs and thekidneys. A reasonable goal of treatment is to replace half of theestimated volume deficit in the first 12 hours of therapy. The remainderof the volume deficit may then be replaced over the second 12-hourperiod.

A 500-mL bolus of 0.9% isotonic saline is appropriate for nearly all adultswho are clinically dehydrated. Administer 1-2 L of isotonic saline in thefirst 2 hours. A higher initial volume may be necessary in patients withsevere volume depletion. Slower initial rates may be appropriate inpatients with significant cardiac or renal disease. Caution should betaken to not correct hypernatremia too quickly, as this could lead tocerebral edema. As much as 2 L of 0.9% isotonic saline may be infusedsafely over the first hour of treatment.

After the initial bolus, some clinicians recommend changing to half-

normal saline, whereas others continue with isotonic saline. Either fluidKEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 21


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likely will replenish intravascular volume and correct hyperosmolarity; agood standard is to switch to half-normal saline once blood pressure andurine 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. Thishelps prevent a precipitous fall of glucose, which may be associated withcerebral edema.[2] In pediatric patients with suspected HHS, correctingfluid deficits over a longer period (48 h) may help reduce the risk ofcerebral edema.[8]

In most patients, adequately monitoring volume status entails the use ofa urinary catheter. In patients with preexisting or acute cardiac diseaseor with diseases in which third-spacing is a problem, use findings frompulmonary capillary wedge pressure monitoring to guide rehydrationtherapy. Patients with hypotension may require pressor support in theICU while rehydration is being accomplished.

Medications for coma patientsBasic medications given to coma patients in the field may includedextrose (50 mL of % dextrose in water [D50]). This is of benefit to manycomatose patients with few adverse effects.

When possible, fingerstick glucose measurement is obtained before

dextrose administration. Whenever fingerstick glucose measurement isunavailable or is likely to be delayed, D50 must be administered tocomatose patients on an empiric basis without delay. Undiagnosed anduntreated hypoglycemia, which may present with signs and symptomsvery similar to those of HHS, is readily reversible but can be rapidly lethalif not treated promptly.

Insulin Therapy for Correction of HyperglycemiaAll patients with HHS require IV insulin therapy; however, immediatetreatment with insulin is contraindicated in the initial management ofpatients with HHS. The osmotic pressure that glucose exerts within the

vascular space contributes to the maintenance of circulating volume inthese severely dehydrated patients. Institution of insulin therapy drivesglucose, potassium, and water into cells. This results in circulatorycollapse if fluid has not been replaced first.

After the kidneys show evidence of being perfused, initiating insulintherapy is safe. This is accomplished most effectively in the ICU, wherecardiovascular and respiratory support is available if needed. Infuseinsulin separately from other fluids, and do not interrupt or suspend theinfusion 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 insulininfusion rate

When the glucose level has been between 200 and 300 mg/dL for at least1 day and the patients level of consciousness has improved, glycemiccontrol may be tightened. The recommended level of glycemia for mostpatients with type 2 diabetes mellitus (DM) is 80-120 mg/dL. Thiscorrelates to the hemoglobin A1c value of 7% recommended by the

American Diabetes Association.

All patients who have experienced HHS will probably require intensivemanagement of their diabetes initially, and this includes insulin therapy.The severe hyperglycemia with which these patients present impliesprofound beta cell dysfunction. In most instances, sufficient recovery ofendogenous insulin production is a reasonable expectation, with safedismissal of the patient from the hospital on oral therapy. Aftermaintaining adequate glycemic control with insulin for several weeksafter HHS, consider switching patients to an oral regimen.

Initiation of insulin therapy in the ED via subcutaneous insulin pump maybe an alternative to intravenous insulin infusion.[17]

Electrolyte ReplacementProfound potassium depletion necessitates careful replacement. Withrehydration, the potassium concentration is diluted. With the institutionof insulin therapy, potassium is driven into cells, exacerbatinghypokalemia. A precipitous drop in the potassium concentration may leadto cardiac arrhythmia.

Potassium may be added to the infusion fluid and should be started at aKEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 23


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level of 5 mEq/L or less. Hypokalemia at the onset of rehydration requiresup to 60 mEq/L to correct the serum potassium concentration. Check thepotassium level at least every 4 hours until the blood glucoseconcentration is stabilized.

Phosphate, magnesium, and calcium are not replaced routinely, but apatient who is symptomatic with tetany requires replacement therapy.

Monitoring During TreatmentThe mortality associated with HHS remains high. The profoundelectrolyte and metabolic abnormalities present during treatmentwarrant careful cardiorespiratory monitoring. When gas exchange hasbeen compromised, endotracheal intubation and mechanical ventilationare indicated.

Neurologic monitoring is indicated in all patients with HHS who presentwith altered mental status. Hyperosmolarity may trigger many neurologicsyndromes. If a patient has seizures, phenytoin is not the agent ofchoice, because it inhibits endogenous insulin secretion and because, ingeneral, it is ineffective in persons with HHS.

DietProvide adequate nutritional support for all patients. Most HHS patientswith HNS are unable to eat for several days as a consequence of thecomorbidities with which they present.

Patients in the ICU who require prolonged mechanical ventilation,patients with impaired airway defenses, and all patients with prolongedMS changes are candidates for enteral or parenteral nutrition. The use ofparenteral nutrition often induces insulin resistance and leads toincreased insulin requirements.

Once HHS is resolved, provide dietary counseling for all patients. Thisprobably is most effectively delivered by a registered dietitian who hasexpertise in counseling patients with diabetes.

Consultations

Generally, no consultation is absolutely required to manage HHS in theED; 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 alteredmental status. A neurologist should monitor the cases of any patientswith underlying neurologic disease (eg, cerebrovascular accident or ahistory of seizures). A pulmonologist or critical care specialist shouldmonitor the cases of patients requiring intubation and mechanicalventilation. Other consultations (eg, with infectious disease or psychiatry)

may be obtained as appropriate.KEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 24


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Long-Term MonitoringPrimary care follow-up is necessary for additional diabetic teaching andany appropriate immunizations. Visiting home nurse referral may benecessary to enhance compliance.

After any episode of HHS, enroll patients in a program of routine diabetescare. Adhere to American Diabetes Association guidelines for the care ofpeople with diabetes. For patients with diabetes that was unrecognizedbefore HHS, perform a dilated eye examination. Advise patients treatedwith insulin to wear a bracelet or chain identifying them as havingdiabetes.

Medication SummaryAggressive rehydration with intravenous (IV) fluids, including 0.9%isotonic saline, is indicated in every patient with hyperosmolarhyperglycemic state (HHS). Insulin therapy and repletion of electrolytes(especially potassium) are the other cornerstones of management.Antipyretics, antiemetics, and antibiotics are added when appropriate tocontrol fever and vomiting and to treat an underlying infection if one issuspected.

Frequent monitoring of electrolyte concentrations is indicated whenpatients are treated with IV fluids. Volume overload is the only otherpotential problem associated with IV fluid replacement; therefore, regularassessment of the hydration state is indicated.

Antidiabetics, InsulinsClass Summary

Although many patients with hyperosmolar hyperglycemic state (HHS)respond to fluids alone, intravenous (IV) insulin in dosages similar tothose used in diabetic ketoacidosis (DKA) can facilitate correction ofhyperglycemia. Insulin used without concomitant vigorous fluidreplacement 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 ashort 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 rationalethat fluids are the cornerstone of therapy and that HHS is more adisorder of insulin resistance than it is one of insulin deficiency.Furthermore, lowering serum glucose and serum osmolarity overlyrapidly can result in complications.

Insulin aspart (NovoLog)Insulin aspart has a rapid onset of action (5-15 minutes) and a shortduration of action (3-5 hours). Peak effects occurs within 30-90 minutes.

http://reference.medscape.com/drug/humulin-r-novolin-r-insulin-regular-human-999007http://reference.medscape.com/drug/novolog-insulin-aspart-999001http://reference.medscape.com/drug/humulin-r-novolin-r-insulin-regular-human-999007http://reference.medscape.com/drug/novolog-insulin-aspart-999001


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Insulin glulisine (Apidra)Insulin glulisine has a rapid onset of action (5-15 minutes) and a shortduration of action (3-5 hours).

Insulin lispro (Humalog)Insulin lispro has a rapid onset of action (5-15 minutes) and a shortduration of action (4 hours).

Alkalizing agentsClass Summary

No evidence is found that sodium bicarbonate provides any benefit topatients with HHS. It may be considered if a patient has significantacidosis (pH < 7.0), particularly if inotropic agents are required tomaintain blood pressure.

Sodium bicarbonate (NaHCO3)Sodium bicarbonate neutralizes hydrogen ions and raises urinary andblood pH.

Electrolytes Supplements, ParenteralClass Summary

Electrolytes are given to replenish electrolyte supplies depleted by thepresence of a high blood glucose level.

Potassium chloride (Klor-Con, K-Tab, Micro-K)

In virtually all cases of HHS, supplemental potassium is necessarybecause the serum level drops secondary to insulin therapy andcorrection of metabolic acidosis. Do not start IV potassium until the initialserum level is ascertained, as the initial level may be high related tohemoconcentration. Administer it cautiously, with attention to properdosing and concentration. If the patient can tolerate oral medications orhas a gastric tube in place, potassium chloride can be given orally indoses of up to 60 mEq, with dosing based on frequently obtainedlaboratory values.

http://reference.medscape.com/drug/apidra-insulin-glulisine-999004http://reference.medscape.com/drug/humalog-insulin-lispro-999005http://reference.medscape.com/drug/sodium-bicarbonate-342305http://reference.medscape.com/drug/kdur-slow-k-potassium-chloride-344450http://reference.medscape.com/drug/apidra-insulin-glulisine-999004http://reference.medscape.com/drug/humalog-insulin-lispro-999005http://reference.medscape.com/drug/sodium-bicarbonate-342305http://reference.medscape.com/drug/kdur-slow-k-potassium-chloride-344450


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2. Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA,Malone JI, et al. Management of hyperglycemic crises in patientswith diabetes. Diabetes Care. Jan 2001;24(1):131-53. [Medline].

3. Trence DL, Hirsch IB. Hyperglycemic crises in diabetes mellitustype 2. Endocrinol Metab Clin North Am. Dec 2001;30(4):817-31.[Medline].

4. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA.Hyperglycemic crises in adult patients with diabetes: a consensusstatement from the American Diabetes Association. Diabetes Care.Dec 2006;29(12):2739-48. [Medline].

5. Campanella LM, Lartey R, Shih R. Severe hyperglycemichyperosmolar nonketotic coma in a nondiabetic patient receivingaripiprazole.Ann Emerg Med. Feb 2009;53(2):264-6. [Medline].

6. Ahuja N, Palanichamy N, Mackin P, Lloyd A. Olanzapine-inducedhyperglycaemic coma and neuroleptic malignant syndrome: casereport and review of literature.J Psychopharmacol. Jan2010;24(1):125-30. [Medline].

7. MacIsaac RJ, Lee LY, McNeil KJ, Tsalamandris C, Jerums G. Influence

of age on the presentation and outcome of acidotic andhyperosmolar diabetic emergencies. Intern Med J. Aug2002;32(8):379-85. [Medline].

8. Kershaw MJ, Newton T, Barrett TG, Berry K, Kirk J. Childhooddiabetes presenting with hyperosmolar dehydration but withoutketoacidosis: a report of three cases. Diabet Med. May2005;22(5):645-7. [Medline].

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crisis: an acute life-threatening event in children and adolescentsKEPANITERAAN KLINIK ILMU PENYAKIT DALAMFakultas Kedokteran Universitas TarumanagaraRumah Sakit Umum Daerah Kota SemarangPeriode 13 Mei 2013 20 Juli 2013 Page 27
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OBED - Hyperosmolar Hyperglycemic State