Document 6429783
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Document 6429783
EMERGENCY MEDICINE PRACTICE . EMPRACTICE NET A N E V I D E N C E - B A S E D A P P ROAC H T O E M E RG E N C Y M E D I C I N E February 2004 Diabetic Emergencies: Diagnosis And Management Of Hyperglycemic Disorders Volume 6, Number 2 Author Charles Stewart, MD, FACEP Colorado Springs, CO. 2:20 a.m.: Prehospital personnel call with a case of vomiting and altered mental status in a 9-year-old girl. The child’s mother found her unconscious in bed in a pool of vomit. The child’s mother notes that the child had been vomiting earlier but had consumed clear liquids for supper. She also notes that her child had recently started a diet and was doing exceptionally well at her planned weight loss; she also comments that for the past two days, her daughter kept a pitcher of water at the bedside and would wake frequently and drink. The child felt that the extra water was helping her weight loss program. The paramedics note that the child’s respiratory rate is 50, she has a heart rate of 128, and her bedside glucose test measures “HHH” on their glucometer. They’ve been unable to obtain intravenous access in this child. D Peer Reviewers Catherine A. Marco, MD, FACEP Associate Professor, Department of Surgery, Medical College of Ohio; Attending Physician, St. Vincent Mercy Medical Center, Toledo, OH. Amal Mattu, MD Director, Emergency Medicine Residency, University of Maryland School of Medicine, Baltimore, MD. IABETES is a chronic disease that requires long-term medical attention. As many as 5%-6% of the United States population have either diagnosed or undiagnosed diabetes.1 Diabetic emergencies are common in patients with diabetes, and the effects can be devastating. Hypoglycemia and hyperglycemia represent two extremes in the emergency presentations of the diabetic patient. This edition of Emergency Medicine Practice reviews the acute management of two of the most serious hyperglycemic disorders—diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS)—and the controversy that surrounds the management of these diseases. Over 100,000 cases of DKA, 5000 cases of diabetic coma, and 10,000 cases of hyperosmolar coma were recorded in the United States between 1989 and 1991.2 DKA is the most common cause of diabetes-related death in childhood and is a significant cause of mortality in adults.101 There is considerable overlap—about one-fifth to one-third of patients with otherwise classic DKA will also have hyperosmolarity. About one-half to three-fourths of patients with uncontrolled diabetes will have an osmolarity of 320 mOsm or more.3 Despite the plethora of guidelines and protocols, all with meticulous details of fluid and electrolyte replacement and insulin therapy, the mortality of diabetic emergencies has remained unchanged for the past 10 years.111 However, Associate Editor San Gabriel Valley Medical Center, San Gabriel, CA. Andy Jagoda, MD, FACEP, ViceChair of Academic Affairs, Department of Emergency Medicine; Residency Program Director; Director, International Studies Program, Mount Sinai School of Medicine, New York, NY. Francis M. Fesmire, MD, FACEP, Director, Heart-Stroke Center, Erlanger Medical Center; Assistant Professor of Medicine, UT College of Medicine, Chattanooga, TN. Editorial Board Valerio Gai, MD, Professor and Chair, Department of Emergency Medicine, University of Turin, Italy. Judith C. Brillman, MD, Associate Professor, Department of Emergency Medicine, The University of New Mexico Health Sciences Center School of Medicine, Albuquerque, NM. W. Richard Bukata, MD, Clinical Professor, Emergency Medicine, Los Angeles County/USC Medical Center, Los Angeles, CA; Medical Director, Emergency Department, Michael J. Gerardi, MD, FAAP, FACEP, Clinical Assistant Professor, Medicine, University of Medicine and Dentistry of New Jersey; Director, Pediatric Emergency Medicine, Children’s Medical Center, Atlantic Health System; Department of Emergency Medicine, Morristown Memorial Hospital. Michael A. Gibbs, MD, FACEP, Chief, Department of Emergency Medicine, Maine Medical Center, Portland, ME. Gregory L. Henry, MD, FACEP, CEO, Medical Practice Risk Assessment, Inc., Ann Arbor, MI; Clinical Professor, Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI; Past President, ACEP. Jerome R. Hoffman, MA, MD, FACEP, Professor of Medicine/ Emergency Medicine, UCLA School of Medicine; Attending Physician, UCLA Emergency Medicine Center; Co-Director, The Doctoring Program, UCLA School of Medicine, Los Angeles, CA. Francis P. Kohrs, MD, MSPH, Lifelong Medical Care, Berkeley, CA. CME Objectives Upon completing this article, you should be able to: 1. discuss the pathophysiology and risk factors for diabetes and related hyperglycemic complications; 2. describe the signs and symptoms of hyperglycemic emergencies such as diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome; 3. explain ways to target the history, physical examination, and laboratory studies in order to identify potentially lethal complications of diabetes such as diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome; and 4. discuss complications of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome, such as coexisting infection and/or other illnesses, including cerebral edema. Date of original release: February 1, 2004. Date of most recent review: January 9, 2004. See “Physician CME Information” on back page. Michael S. Radeos, MD, MPH, Attending Physician, Department of Emergency Medicine, Lincoln Medical and Mental Health Center, Bronx, NY; Assistant Professor in Emergency Medicine, Weill College of Medicine, Cornell University, New York, NY. Steven G. Rothrock, MD, FACEP, FAAP, Associate Professor of Emergency Medicine, University of Florida; Orlando Regional Medical Center; Medical Director of Orange County Emergency Medical Service, Orlando, FL. Alfred Sacchetti, MD, FACEP, Research Director, Our Lady of Lourdes Medical Center, Camden, NJ; Assistant Clinical Professor of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA. Corey M. Slovis, MD, FACP, FACEP, Professor of Emergency Medicine and Chairman, Department of Emergency Medicine, Vanderbilt University Medical Center; Medical Director, Metro Nashville EMS, Nashville, TN. Mark Smith, MD, Chairman, Department of Emergency Medicine, Washington Hospital Center and Georgetown University School of Medicine, Washington, DC. Charles Stewart, MD, FACEP, Colorado Springs, CO. Thomas E. Terndrup, MD, Professor and Chair, Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL. COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC level greater than 140 mg/dL (7.8 mmol/L) or an oral glucose tolerance test greater than 200 mg/dL (11.1 mmol/L). As a practical point to emergency physicians, any measured glucose > 200 mg/dL should be considered diagnostic of diabetes (unless it has been drawn from the same venous runoff as currently infusing glucose solutions!). with continued emphasis on the timely and appropriate identification and management of diabetic emergencies, hopefully this trend may change. Critical Appraisal Of The Literature Since the literature on diabetic hyperglycemic emergencies is fairly mature, there are a number of review articles that cover basic management of hyperglycemic emergencies.4 The 2003 American Diabetes Association review presents that group’s latest consensus recommendations.4 The substance of these recommendations has been covered in detail in this article. The state of the literature concerning some key discussions made in this article is summarized as follows. Use of insulin by intravenous infusion is well-supported by appropriately conducted randomized, controlled trials that have adequate power. Meta-analysis of the data further supports this conclusion. Use of insulin by other routes has supportive evidence from well-conducted studies. These studies are older, but nonetheless valid. Use of fluid replacement in DKA in both adults and children, use of fluid replacement in HHS in adults, and use of electrolyte replacement in both DKA and HHS in adults and DKA in children, as noted in this text and in the clinical pathways, are well-supported by well-designed trials that have adequate power. Meta-analysis of the data further supports the conclusions. Bicarbonate therapy is not well-supported, and there is conflicting evidence in the literature. The weight of the evidence appears to support use of bicarbonate in patients with pH levels less than 7.0, but this recommendation may change with better evidence. Use of phosphate replacement has shown no evidence of clinical benefit to the vast majority of patients with DKA and is not recommended. Replacement of phosphate may be of some benefit in patients who have cardiac dysfunction or respiratory depression. Replacement of phosphate when phosphate is lower than 1.0 is indicated and is wellsupported by appropriately conducted randomized, controlled trials that have adequate power. Cerebral edema associated with DKA has only a limited number of studies that present somewhat conflicting results, resulting in different recommendations for therapy. Currently, the strength of evidence cannot conclusively support one recommendation over another. The best advice for the emergency practitioner is to be wary of this condition in all diabetic patients who have an alteration of consciousness and hyperglycemia. Normal Glucose Physiology Maintenance of blood glucose homeostasis is of paramount importance to the survival of the human body. The brain requires 75% of the glucose circulating in the blood. Both elevated and reduced levels of blood glucose trigger hormonal responses to restore glucose homeostasis. Low blood glucose triggers the release of glucagon from pancreatic alpha cells. High blood glucose triggers the release of insulin from pancreatic beta cells. Additional signals, adrenocorticotropic hormone (ACTH) and growth hormone released from the pituitary, increase blood glucose levels by inhibition of glucose uptake by extrahepatic tissues. Glucocorticoids also act to increase blood glucose levels by inhibition of glucose uptake. Cortisol is secreted by the adrenal cortex in response to the increased ACTH levels. The adrenal medullary hormone, epinephrine, stimulates the production of glucose by activation of glycogenolysis in response to stress. Insulin Pathophysiology Insulin is initially synthesized in the form of proinsulin. In this form, the alpha and beta chains of active insulin are linked by a third polypeptide chain, called the connecting peptide (c-peptide for short). For every molecule of insulin produced, one molecule of c-peptide is also produced. Levels of c-peptide can be measured and used as an indicator of insulin production in cases where insulin has been injected and mixed with insulin produced by the body. The c-peptide test can also be used to assess if high blood sugar is due to reduced insulin production (as in type I diabetes) or to reduced glucose intake by the cells (as in type II diabetes). There is little or no c-peptide in the blood of type I diabetics, and c-peptide levels in type II diabetics can be reduced or normal. Normal serum concentrations of cpeptide range from 0.5-3.0 nanograms per milliliter. Insulin levels can also be measured. The primary clinical utility of insulin measurement is in the evaluation of patients with fasting hypoglycemia, rather than diabetes. Insulin levels are inappropriately elevated by insulinsecreting tumors.9 They may also be useful in predicting susceptibility to the development of type II diabetes, although c-peptide has largely supplanted direct insulin measurements for this role. Diabetes Epidemiology And Etiology The broad, sweeping term “diabetes” is used to describe a group of diseases consisting of different errors or faults in metabolic processes that culminate in high blood sugar. While the implications, treatment, and short-term complications seen with these various diseases can be quite different, they are all classified as diabetes. The current definition of diabetes is a fasting glucose Previously, diabetes was classified as either insulindependent or non-insulin-dependent. The disease was often further separated into juvenile onset or adult onset. However, these terms are not only passé, but they may be quite inaccurate. Knowledge about diabetes mellitus and its management has steadily increased since the discovery of insulin in 1921. The emergency physician should be aware Emergency Medicine Practice 2 www.empractice.net • February 2004 Latent Autoimmune Diabetes Of Adults To further complicate the picture, in older people, type I diabetes does not present as it does in childhood. When clinical type I diabetes develops in people over the age of 15, beta cell function is preserved much longer. This translates into about 70% of the older type I diabetics having relatively high c-peptide levels after two years of the disease.11 When diabetes is diagnosed before age 15, only about 10% of the patients will have normal c-peptide levels after two years.113 The process is much slower and may be, in the early phases, indistinguishable from type II diabetes.12 The clinical presentation is often not catastrophic and may occur over years or months. These older patients with type I diabetes may have more insulin secretory capacity and may do well on oral agents at first. While the various autoantibody measurements that can define a type I diabetic are beyond the scope of this article, about 5% of adults diagnosed with type II diabetes have positive autoantibodies.12 This puts them into a group known as latent autoimmune diabetes of adults (LADA). LADA patients all require insulin therapy eventually, and this therapy is often started early in the disease process. In the older literature, LADA cases were described as type II diabetes that “converted” to type I diabetes—when, in fact, the LADA patients had type I diabetes all along. Type I Diabetes Type I diabetes is due to absolute insulin deficiency. These patients will have a lifetime dependence on exogenous insulin. The overall incidence of insulin-dependent diabetes is about 15 cases per 100,000 people per year. (About 50,000 are diagnosed with type I diabetes each year.) An estimated three of every 1000 children will develop insulin-dependent diabetes by the age of 20.112 Type I diabetes is primarily a disease of Caucasians. The worldwide incidence is highest in Finland and Sardinia and lowest in Asians and blacks. Type I diabetes is more frequently diagnosed in the winter months. (The reason for this is not known.) Interestingly, twins affected by type I diabetes are often discordant in the development of the disease.10 One of the most exciting findings of the past 10 years about diabetes is that most (about 95%) of type I diabetes is the result of a genetic defect of the immune system, exacerbated by environmental factors.10 The autoimmune destruction of the beta cells of the pancreas results in the inability to produce insulin. Inheritance of type I diabetes is carried in genes of the major histocompatibility complex (the human leukocyte antigen system). Eventually, this line of research may make it possible to identify all patients who are susceptible to diabetes by a simple blood test. Indeed, this research may lead to a vaccine using the insulin B chain 8-24 peptides to prevent type I diabetes.10 It is currently thought that islet cells damaged by a virus produce a membrane antigen that may stimulate a response by T killer cells of the immune system in the genetically susceptible patient. The T killer cells misidentify the beta cell as foreign and destroy it. As the beta cells in the pancreas are destroyed, the remaining beta cells must increase their metabolism and, thus, the turnover of membrane antigen in order to keep up with insulin demands. More membrane antigen means that more T killer cells are activated and, hence, more islet cell destruction. This sets up a vicious cycle that ends in the destruction of the entire beta cell mass and the symptoms of clinical diabetes. This chronic destructive process involves humoral and cellular components that are detectable in the peripheral blood months, or even years, before the onset of clinical diabetes. Throughout this long “pre-diabetic” period, metabolic changes including a decrease in insulin secretion with altered glucose tolerance develop at variable rates, leading to full-blown diabetes. Early recognition of diabetes and adequate supplemental insulin may reverse this process and prevent the immune response.10 This preservation and possible recovery of the beta cell mass is thought to be the basis of the “honeymoon” period seen after insulin is started in the patient with newonset type I diabetes. Early identification and adequate treatment with insulin may initiate, sustain, and even February 2004 • www.empractice.net Medications For Type I Diabetes The FDA approved insulin in 1939.13 Early insulin preparations were crude extractions from the pancreases of pigs or cows. These preparations were purified, but they still contained a number of additional substances such as proinsulin, insulin derivatives, and other active peptides found in the pancreas. Since then, purer forms of insulin with various time profiles of action have been developed.14 (See Table 1 on page 4.) Type II Diabetes Typical type II diabetes is a heterogeneous glucose disorder found most often in patients over 40 years of age and associated with a family history of diabetes. Type II diabetes is usually characterized by a resistance to the patient’s own insulin that may or may not be coupled with a defect in insulin secretion of varying severity. These defects lead to an increase in the liver’s production of glucose and subsequent fasting hyperglycemia. Type II diabetes is increasing in incidence as the population ages and becomes more affluent. The major risk factor for type II diabetes appears to be obesity—and obesity has become an epidemic in the United States for all ethnic subtypes.15 Obesity is associated with insulin resistance, which worsens diabetes in any case. If the type II diabetic loses weight and adheres to a strict diet, often no medication at all is required. DKA is uncommon in the type II diabetic, since the majority of these patients have some insulin secretion. The type II diabetic patient is often considered to require insulin for control but not to be “insulin-dependent.” Although type II diabetes was formerly considered to 3 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC extend this partial remission. that some of the recent developments in diabetes care include further separation and identification of these disparate disease processes that can cause a high blood sugar. COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC seen by the emergency physician. (See Table 2 on page 5.) Oral medications work by causing the pancreas to make more insulin, by making the tissues more sensitive to the effects of insulin, by decreasing hepatic output of glucose, or by decreasing absorption of glucose from the gut. No single medication uses all four mechanisms, but most will have one or more effects. A new, cutting-edge drug, exenatide, actually causes the pancreas to produce more islet cells and hence produce more natural insulin.32 be a disease of people older than 40, emergency physicians are seeing increasing numbers of patients in their 20s or 30s with type II diabetes. It is seen more frequently in younger people in association with childhood obesity.16,17 Type II diabetes is even found in adolescents. (These patients have the slow clinical course of type II diabetics without the development of DKA.) High blood sugars in type II diabetics can be associated with obesity, high blood pressure, renal failure, and accelerated coronary artery disease. Prolonged hyperglycemia will increase the rate of development of all of these diseases.18 Prolonged high blood sugars will also reduce the effect of insulin (insulin resistance) and decrease the secretion of insulin (glucose toxicity).19 When the pancreas quits making insulin, then the type II diabetic needs insulin as much as the type I diabetic.20 (As noted, these patients often will secrete enough insulin to stave off ketoacidosis, but not enough to prevent profound hyperglycemia.) Secondary Diabetes Severe pancreatic disorders, including pancreatic cancer, chronic pancreatitis, hemachromatosis, and cystic fibrosis, can lead to insulin deficiency and subsequent diabetes. Since the pancreatic tissue in these individuals is destroyed, these patients clinically resemble type I diabetics and require insulin. Other patients may have diseases or hormonal syndromes that interfere with insulin secretion (such as pheochromocytoma) or insulin use (such as acromegaly, Cushing’s syndrome, and pheochromocytoma). These cases more closely resemble type II diabetes. Several common medications can impair the body’s use of insulin and produce diabetes. The most commonly seen is probably associated with glucocorticosteroids such as methylprednisolone or prednisone. Treatment for high blood pressure (furosemide, clonidine, and thiazide diuretics), other drugs with hormonal activity (oral contraceptives, thyroid hormone, and progestins), and the antiinflammatory drug indomethacin can also cause or exacerbate diabetes. Numerous other drugs can impair glucose absorption, such as haloperidol, lithium, phenothiazines, tricyclic antidepressants, isoniazid, nicotinic acid, heparin, and cimetidine. Drug-induced diabetes may or may not require insulin and may simply resolve after the drug is stopped. Drug-induced diabetes may resemble either type I or type II diabetes. Maturity Onset Diabetes Of The Young Maturity onset diabetes of the young (MODY) is a familial form of type II diabetes that was described as a separate entity from type II diabetes by many researchers.21-24 MODY represents a very small subset of type II diabetes. It is estimated that only 1%-5% of all type II diabetics may have MODY.21-24 A typical MODY patient has a diagnosis of diabetes that is not type I diabetes, is less than 25 years old, and has a positive family history with a dominant mode of inheritance. These patients are often lean and do not appear to be insulin-resistant. There are several types that have been identified and classified by the type of genetic defect involved. A monogenic defect in insulin secretion is responsible for all forms of MODY, and genetic tests can confirm the clinical suspicion.25-31 Medications For Type II Diabetes Oral medications for the treatment of type II diabetes have been around since the 1950s. Recently, there has been a marked increase in the number and kinds of drugs that are Continued on page 6 Table 1. Types Of Insulin And Times Of Onset/Peak. Insulin Onset Of Action Peak Action Duration Of Action Humalog 10 minutes 1 hour 4 hours Regular 30 minutes 2-5 hours 8 hours NPH 90 minutes 4-12 hours 22-24 hours Lente 2.5 hours 6-12 hours 24 hours Ultralente 4 hours 8-18 hours 30 hours 70/30 blend (70% NPH, 30% regular) 30 minutes 2-12 hours 24 hours 50/50 blend (50% regular, 50% NPH) 30 minutes 2-6 hours 24 hours • While Humalog, Regular, and 50/50 blend have sharp and definable peaks, the long-acting Lente insulins have a slow onset, long flat peaks, and a very slow rate of decline. • Lente insulins should never be combined with NPH insulin. (The chemicals in the NPH insulin turn the Lente insulin into an approximation of fast-acting Regular insulin.) Emergency Medicine Practice • There are several insulins not charted above. Buffered insulins from Lilly and Novo Nordisk and a special U-400 insulin from Hoechst of Germany are designed for use in insulin pumps. Source: Derived from data furnished by Eli Lilly and Novo Nordisk Pharmaceuticals in their product information. 4 www.empractice.net • February 2004 Sulfonylureas Sulfonylureas have been available in the United States for 40 years. They lower blood glucose mainly by stimulating the pancreas to produce more insulin. To a lesser degree, this action increases the use of glucose in the peripheral tissues and reduces the hepatic glucose output. For these pills to work, the patient’s pancreas must still be making insulin. Acetohexamide Available generically? Yes Brand name: Dymelor Duration of action: Intermediate Dosage: 1 or 2 times a day Chlorpropamide Available generically? Yes Brand name: Diabinese Duration of action: Long Dosage: Daily Comments: With this sulfonylurea in particular: Patient who drink alcohol may develop a tingling in the neck and arms, red eyes, and flushed face. Hypoglycemia is a real problem with overdoses, as this drug is eliminated slowly. In children, a single pill may be lethal. Glimepiride Available generically? No Brand name: Amaryl Duration of action: Long Dosage: Daily Comments: Similar to other sulfonylureas, but may have fewer side effects. Glipizide Available generically? Yes Brand name: Glucotrol, Glucotrol XL Duration of action: Intermediate-and longacting formulas Dosage: 1 or 2 times a day Comments: Appears to be more effective when taken before meals. Glyburide Available generically? Yes Brand names: Diabeta, Micronase, Glynase PresTab Duration of action: Intermediate Dosage: 1 or 2 times a day Comments: Intermediate in duration, but effects may last entire day. Glynase PresTab is new and more readily absorbed than the other preparations. Tolazamide Available generically? Yes Brand name: Tolinase Duration of action: Intermediate Dosage: 1 or 2 times a day Tolbutamide Available generically? Yes Brand name: Orinase Duration of action: Short Dosage: 2 or 3 times a day Comments: May be a good choice if the February 2004 • www.empractice.net patient has kidney problems. Relatively short half-life, so the risk of hypoglycemia is lower than with some of the other sulfonylureas. Repaglinide Available generically? No Duration of action: Short Dosage: Three times a day Comments: Repaglinide is chemically not a sulfonylurea, but has a similar action. This drug causes a rapid and short-lived release of insulin. The effects go away quickly. Biguanides Metformin lowers blood glucose mainly by keeping the liver from releasing too much glucose. It also increases the glucose use in peripheral tissues by a small amount. Metformin may also decrease intestinal glucose absorption somewhat. In contrast to sulfonylureas, metformin doesn’t raise insulin levels, so under ordinary circumstances, it doesn’t cause hypoglycemia. Hypoglycemia may occur if metformin is taken with insulin, a sulfonylurea, or an excessive amount of alcohol. Metformin Available generically? Yes Brand name: Glucophage Duration of action: Intermediate Dosage: 2 or 3 times a day Comments: Under usual circumstances, doesn’t cause hypoglycemia. Doesn’t promote weight gain. May cause low B12 levels. Patients will often complain of gastrointestinal side-effects. In very rare cases, especially if kidney disease is present, can produce lactic acidosis, a serious complication. Can be used alone or with a sulfonylurea. This is the preferred agent for the obese patient. Alpha-Glucosidase Inhibitors Acarbose is an alpha-glucosidase inhibitor that blocks the digestion of starches. This slows down the rise of glucose in the blood after eating. It may also prove useful for people who have insulin-dependent diabetes, when they use it with their usual insulin doses. This drug doesn’t have any other effects on sugar metabolism. Acarbose Available generically? No Brand name: Precose Duration of action: Short Dosage: 3 times a day, with main meals Comments: Doesn’t cause hypoglycemia or weight gain. Side effects include gas, bloating, and diarrhea. Causes no serious side effects. May cause rise in liver function tests. This drug should be taken with the first mouthful of each meal. If a dose is missed, there is no advantage to taking it later. 5 Miglitol Available generically? No Brand name: Glyset Duration of action: Short Dosage: 3 times a day with meals Comments: Gastrointestinal side-effects are quite common. Thiazolidinediones These drugs reduce resistance to insulin in the tissues. The drugs have no effect on the secretion of insulin. They are often known as “insulin sensitizers.” Thiazolidinediones also decrease the production of glucose by the liver, but only modestly. As an added beneficial effect, thiazolidinediones will lower triglycerides and HDL levels. Troglitazone Available generically? No Brand name: Rezulin Duration of action: No longer available Dosage: n/a Comments: Associated with liver abnormalities that caused several fatalities. This drug is no longer available. Rosiglitazone Available generically? No Brand name: Avandia Comments: Lowers insulin resistance. Pioglitazone Available generically? No Brand name: Actos Comments: Lowers insulin resistance. Exenatide This new and experimental drug can improve blood sugar control in type II diabetes. These actions include stimulating the body’s ability to produce insulin in response to elevated levels of blood glucose, inhibiting the release of glucagon following meals and slowing the rate at which nutrients are absorbed into the bloodstream. It has the added benefit of not affecting body weight or cholesterol. (Kolterman, O, Buse J, Fineman M, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting glucose in subjects with type II diabetes. J Clin Endocrinol Metab 2003;88(7):3082-3089.) Exenatide Available generically? No Brand name: Investigative new drug only Comments: Increases the number of insulinproducing cells in the pancreas in animal studies. Increases the secretion of insulin resulting from elevated sugars. Inhibits the release of glucagon following meals and slows the rate at which nutrients are absorbed into the bloodstream. Adapted from: Stewart CE. New trends in diabetes management. EMS Magazine 2001 Nov;30:80. Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Table 2. Oral Medications For The Treatment Of Type II Diabetes. COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Continued from page 4 very long differential for altered mental status. Since these patients may have complex medical histories and comorbidities, this evaluation should not stop at the first disease encountered. Not all patients with ketoacidosis have DKA. The differential diagnosis for the patient who has a known history of diabetes and presents with the findings of DKA includes: • HHS • Alcoholic ketoacidosis • Starvation • Sepsis • Lactic acidosis • Uremia Gestational Diabetes Gestational diabetes is glucose intolerance during pregnancy. About 4% of all pregnancies are complicated by gestational diabetes.114 Mothers with gestational diabetes have higher rates of cesarean delivery and chronic hypertension.114 Their children may have macrosomia, hypoglycemia, hypocalcemia, and hyperbilirubinemia. (A complete discussion of gestational diabetes is beyond the scope of this review.) Impaired Glucose Tolerance An impaired glucose tolerance is defined as a fasting glucose of greater than 110 mg/dL (6.1 mmol/L) but less than 140 mg/dL.115,116 It is also defined as a patient who has a glucose tolerance test with ranges between 140 mg/dL (7.8 mmol/L) and 199 mg/dL.115,116 Impaired glucose tolerance was formerly known as borderline, chemical, or latent diabetes.115,116 (Impaired glucose tolerance and its implications are not covered in this review.) Starvation ketosis and alcoholic ketoacidosis are excluded by the clinical history and by a plasma glucose that ranges from mildly elevated (rarely ≥ 250 mg/dL) to frank hypoglycemia. In addition, although alcoholic ketoacidosis can result in profound acidosis, the serum bicarbonate concentration in starvation ketosis is usually less pronounced than in DKA. Differential Diagnosis: Hyperglycemic Complications Of Diabetes Diabetic Ketoacidosis DKA and HHS are the most lethal hyperglycemic complications of diabetes. Patients may present with some combination of hyperglycemia, altered mental status, and dehydration. Significantly, both can be associated with coexisting medical conditions that may obfuscate the clinical encounter, and both can be associated with a patient’s initial presentation of diabetes. The history, physical examination, and laboratory studies must therefore be tailored to detect DKA, HHS, and any possible coexisting illnesses. (See also Table 3 and Table 4 on page 7.) The basic underlying mechanism for both DKA and HHS is a reduction in the net effective action of circulating insulin coupled with a concomitant elevation of counterregulatory hormones, such as glucagon, catecholamines, cortisol, and growth hormone. The differential diagnosis for the patient who has no history of diabetes and is found in a coma starts with the The pathology of DKA is due to the inability of the cells to take up and use glucose when insulin is not present. Insulin is the most significant hormone of blood glucose regulation. It increases the ability of the cell to take in glucose and stimulates the manufacture of glycogen. DKA can be caused by either an absolute or relative deficiency of insulin and is exacerbated by the concomitant increase in the insulin counter-regulatory hormones: glucagon, epinephrine, cortisol, and growth hormone. In DKA, the classic triad of hyperglycemia, ketosis, and acidosis is present. The counter-regulatory hormones further shift metabolism toward hyperglycemia, acidosis, and ketosis. DKA is characterized by hyperglycemia with glucose over 250 mg/dL, although it has been recently recognized that some patients may present with only mild hyperglycemia, but with marked ketoacidosis (notably pregnant Table 3. Comparison Of Diabetic Ketoacidosis And Hyperglycemic Hyperosmolar Syndrome. Ketoacidosis Diabetic Ketoacidosis Hyperglycemic Hyperosmolar Syndrome Profound Minimal or none Glucose ~250-600 mg/dL Often >900 mg/dL HCO3 < 15 mEq/L > 15 mEq/L Osmolarity 300-325 mOsm Often > 350 mOsm Age Young Elderly Onset Acute; over hours to days Chronic; over days to weeks Associated diseases Common Common Seizures Very rare Common Coma Rare Common Insulin levels Very low to none May be normal Mortality 0%-10% (depends on underlying conditions) 20%-40% Dehydration Severe Profound Emergency Medicine Practice 6 www.empractice.net • February 2004 hypertriglyceridemia (found in as many as 50% of patients with DKA).34,35 This extreme hypertriglyceridemia can cause the blood sugar, sodium, and bicarbonate to be factitiously lowered.36 Blood glucose levels will rise above the renal threshold for glucose reabsorption, so an osmotic diuresis occurs, as discussed below. Acidosis Insulin inhibits the lipolytic action of cortisol and growth hormone. A deficiency of insulin will increase the circulating levels of fatty acids. These fatty acids are metabolized by alternative metabolic pathways. The breakdown products of the alternative metabolic pathways cause the characteristic acetone byproducts and a resultant metabolic acidosis. The acidosis of DKA is mostly due to the ketoacids, although excess fatty acids and lactic acid (produced by poor tissue perfusion) also contribute to the lowered pH. These increased ketoacids include acetone, beta-hydroxybutyric acid, and acetoacetic acid, although the major derangement in DKA is an increased level of beta-hydroxybutyric acid rather than acetone or acetoacetate (on the order of 10:1).115 Hyperglycemia The main counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormones) are increased because the cells can’t use the available glucose. Increased hepatic glucose production and decreased peripheral uptake of glucose are major causes of the hyperglycemia seen in diabetes. In the absence of insulin, glucagon becomes the primary driving hormone for hepatic carbohydrate metabolism. Glucagon stimulates the release of glucose from the liver by gluconeogenesis and glycogenolysis. Liver glycogen stores are broken down into sugar and released into the bloodstream. Deficiency of insulin and concomitant increases in glucagon will enhance the liver production of glucose by breakdown of fat and protein. The fatty acid oxidation leads to ketone body formation and inhibits the conversion of acetyl CoA, by acetyl CoA carboxylase, to malonyl CoA, which is the first intermediate in the lipogenesis pathway. This inhibition means that fatty acids are unable to enter the citric acid cycle and move instead into the mitochondria, where they are oxidized and further ketone bodies (acetoacetate and betahydroxybutyrate) are formed.33 At the same time, peripheral uptake of glucose is impaired by both lack of insulin and excess of glucagon, so the excess glucose accumulates in the bloodstream. Insulin deficiency alone, or in combination with the insulin counter-regulatory hormone increases will increase protein breakdown, providing amino acids for increased gluconeogenesis. Poorly controlled diabetes may result in Volume Depletion The kidney plays an important role in the development of DKA. The normal renal threshold for glucose reabsorption is greater than 240 mg/dL.37 When the patient is wellhydrated and normal kidney function is maintained, the serum glucose level is maintained at about 240 mg/dL by spillage into the urine. The osmotic diuresis results in significant volume depletion unless the patient drinks copious amounts of fluids. When hypovolemia occurs, the glomerular filtration rate falls and the hyperglycemia is exacerbated. The diuresis also leads to significant urinary losses of potassium, sodium, phosphate, chloride, and magnesium ions. Hyperglycemic Hyperosmolar Syndrome Epidemiology HHS has a mean age of onset in the seventh decade of life.115 Males are affected slightly less often than females.115 Residents of nursing facilities who are both elderly and Table 4. Diagnostic Criteria For Diabetic Ketoacidosis And Hyperglycemic Hyperosmolar Syndrome. Mild DKA Moderate DKA Severe DKA HHS Plasma glucose (mg/dL) >250 >250 >250 >600 Arterial pH 7.25–7.30 7.00–7.24 <7.00 >7.30 15–18 10 to <15 <10 >15 Urine ketones Positive Positive Positive Small Serum ketones* Positive Positive Positive Small Variable Variable Variable >320 >10 >12 >12 <12 Alert Alert/drowsy Stupor/coma Stupor/coma Serum bicarbonate (mEq/L) * Effective serum osmolality (mOsm/kg) Anion gap † ‡ Alteration in sensoria or mental obtundation * Nitroprusside reaction method † Calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18 ‡ Calculation: (Na+) - (Cl- + HCO3-) (mEq/L)—see text for details February 2004 • www.empractice.net 7 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC women).115 Typically, patients will be overtly acidotic with pH levels less than 7.35, low serum bicarbonate (commonly under 15 mmol/L), and positive serum ketones. (If a patient presents with a marked ketosis, but a glucose under 250 mg/dL, the physician should consider the possibility that the ketosis is related to another cause such as alcoholic ketosis, rather than DKA.) Insulin must be administered to correct the underlying metabolic abnormalities. COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC demented are at the highest risk.115 (Oral hydration may be impaired by dementia and immobility.) Estimates of incidence are 1 out of every 1000 hospital admissions and a frequency of 17.5 per 100,000.38 This is a very lethal disease; mortality rates as high as 12%-46% have been recorded.39,40 Wachtel et al found an increasing mortality associated with increasing age—10% among those less than 75 years, 19% in those 75-84 years old, and 35% among those older than 85 years.41 The mortality rate also increases with higher levels of serum osmolality. Most deaths caused by HHS occur within the first 1-2 days.39-41 the kidney is unable to excrete the increased sugar load. If the patient is unable to drink due to either incapacity or confusion, the patient also will develop hyperosmolar hyperglycemia. The patient may be unable to ingest liquids due to restraints, chemical sedation, coma, nausea or vomiting, diarrhea, or because they are not given fluids by a caretaker. The patient may also have been given inadequate free water from hyperosmolar feedings such as Ensure. Metabolic abnormalities leading to the pathogenesis of HHS are similar to those that occur in DKA. Lack of ketosis in HHS is thought to represent the combination of three major effects: 1) insulin is available—even if not in sufficient quantities to prevent hypoglycemia; 2) lower levels of insulin counter-regulatory hormone levels; and 3) relative inhibition of lipolysis that result in lower levels of free fatty acids for the body to process to ketone bodies.38,42,43 Pathogenesis The initiating event in HHS is an osmotic diuresis due to a high glucose level. The presence of glucose in the urine impairs the kidneys’ ability to concentrate the urine and thus causes increased water losses. If these losses are not replaced, hypovolemia, intra- and extracellular dehydration, and hyperosmolarity develop. Fluid losses in HHS are considerable and may be as much as 10% of the patient’s body weight.115 If the fluid intake is adequate and glomerular filtration is maintained, the renal loss of sugar prevents further rise in osmolarity. When the patient has kidney disease or develops renal insufficiency due to intravascular volume depletion and subsequent decreased glomerular filtration, Prehospital Care Prehospital care of the patient with a hyperglycemic diabetic emergency is primarily supportive. Ideally, providers should have access to blood glucose measurement devices. These strips or meters will frequently measure as “high” and not give an accurate number when attempting to measure the serum glucose of a patient with a glucose over 400 mg/dL. Depending on transport time, an intravenous line should be started and normal saline given as a bolus of up to 1 liter in the average-sized adult. All of the patient’s medications should be identified and brought to the ED. Table 5. Signs And Symptoms Of Hyperglycemic Emergencies. Hyperglycemia Emergency Department Management Acidosis Initial Stabilization • Polyuria—This may be • Hyperventilation—This is seen as nocturia or due to the metabolic enuresis in a previously acidosis. The patient may continent child. have peri-oral and limb • Polydipsia—This may be paresthesias. Acidosis may quite extreme; the be mistaken for hypervenpatient may report that tilation syndrome. he or she will set a large • Altered mental status— glass of water or other This can vary from lethargy liquid at the bedside to coma. when going to bed. Cerebral Edema • Polyphagia • Decreasing sensoria • Weight loss—This may be quite dramatic due to • Sudden and severe headache the breakdown of • Incontinence protein and fat stores. • Vomiting • Fatigue and weakness— • Combativeness, disorientaThese are common tion, agitation presenting symptoms. • Change in vital signs • Abdominal pain—The (hypothermia, hypotension, abdominal pain is of hypertension, tachycardia, uncertain cause or may bradycardia, gasping be due to pancreatitis or respirations, periods of another disease that apnea) precipitated the DKA. • Ophthalmoplegia Note that DKA is often • Pupillary changes mistaken for gastroen• Papilledema teritis. • Posturing, seizures • Nausea and vomiting Emergency Medicine Practice Initial stabilization of the patient with a hyperglycemic diabetic emergency consists of ensuring that an appropriate airway is secured and/or protected, ensuring that the patient has an intravenous line, and verifying the serum glucose concentration. Following these initial stabilizations, the patient evaluation should commence with history, examination, and laboratory evaluation. History A thorough history should be obtained, documenting the patient’s chief complaint, duration, and associated symptoms. In the review of systems, be sure to focus on possible precipitants—particularly ones which may complicate the treatment and/or increase mortality, such as infection, stroke, and myocardial infarction. Some high-yield questions that may help streamline the history include the following: 1. Are any symptoms consistent with hyperglycemia, acidosis, or cerebral edema present? See Table 5. 2. Does the patient have diabetes? If so, has the patient had prior episodes of DKA or HHS? The most common association with hyperglycemic emergencies is, of course, a prior history of diabetes. Unfortunately, as many as 20%-30% of cases of DKA may be the initial presentation of previously undiagnosed diabetes.117 8 www.empractice.net • February 2004 3. Is there an associated infection? An infection—including pneumonia, urinary tract infection, or sepsis—is the most common precipitating factor of both DKA and HHS.44-47 The physician must search diligently in these patients for a focus of infection such as sinusitis, middle ear infections, prostatitis, perirectal abscess, or infected decubiti. Rectal and pelvic examinations are important parts of the evaluation if the patient has no obvious focus of infection identified. 4. Is there another associated illness? Associated medical illnesses are commonly present in HHS. These may include: • Cerebrovascular accidents (both stroke and intracranial hemorrhage) • Myocardial infarction • Acute pancreatitis • Pulmonary embolus • Mesenteric thrombosis • Renal failure • Heat stroke and heat stress • Gastrointestinal hemorrhage • Hypothermia • Alcohol consumption or cocaine use 6. What other medications has the patient been taking? Drugs such as sympathomimetics, pentamidine, thiazides, phenytoin, and calcium-channel blocker agents can precipitate diabetes and DKA.48 As noted earlier, corticosteroids can not only precipitate diabetes, they can alter the glucose tolerance of normal patients. The use of drugs and therapies that are known to cause hyperglycemia may precipitate HHS. These include azathioprine, beta-blocking agents, cimetidine, diazoxide, diuretics, glycerol, phenothiazines, calcium-channel blocking agents, phenytoin, and steroids.50-56 Initiation of total parenteral nutrition (parenteral hyperalimentation) is commonly implicated as a precipitating factor, but this is not usually seen in the ED.57 Furthermore, trauma, febrile illnesses, or even psychological turmoil may elevate the counter-regulatory hormones (glucagon, epinephrine, growth hormone, and cortisol) and precipitate DKA. Other precipitating diseases include alcohol abuse and pancreatitis. In older patients, the stress of myocardial infarction or stroke can precipitate DKA. The stress of pregnancy may also precipitate DKA in diabetic patients. Steroid excess due to exogenous steroid administration or endogenous production of steroids (Cushing’s syndrome) is a common precipitating factor of DKA. Excess of counterregulatory hormones, such as is found in pheochromocytoma, may cause DKA. Thyrotoxicosis and hyperthyroidism can precipitate DKA. Physical Examination The physical examination for cases of suspected DKA or HHS is essentially the same. In such cases, be sure to carefully assess vital signs. Also, check and document the patient’s weight, extent of dehydration, level of consciousness, whether Kussmaul respirations are present, and be sure to evaluate for the possibility of infection. Certain physical findings can help determine whether the patient has DKA, HHS, or both. 5. Has the patient been receiving adequate insulin? Thorough questioning may be necessary in order to evaluate this issue adequately. Failure to take insulin is the most common cause of recurrent DKA, particularly in February 2004 • www.empractice.net Physical Findings In Both Diabetic Ketoacidosis And Hyperglycemic Hyperosmolar Syndrome Uniformly, the patient will be dehydrated. The typical 9 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC adolescents.5 The patient may also run out of insulin, have a calibration error in the injection device, use the wrong concentration or type of insulin, or inadvertently inject an inadequate dose of insulin. Underinsurance may mean that the patient can’t afford insulin or that funds were diverted to other uses (e.g., syringes).5 A change of diet or exercise may also mean that the insulin administered is inadequate. In young patients with type I diabetes, psychological problems complicated by eating disorders may be a contributing factor in up to 20% of cases of recurrent ketoacidosis.5,48 Factors that decrease compliance in the young include fear of weight gain, fear of hypoglycemia, rebellion, and the stress of chronic disease.48 Noncompliance with insulin or other drugs is one of the most commonly cited precipitating factors for HHS.38 The noncompliant adult diabetic may have repeated episodes of HHS. Noncompliance may be due to psychiatric disorders, neglect/abuse, onset of dementia, or inability to purchase medications or obtain refills.38 Each of these causes should be explored in the patient who presents with recurrent HHS and considered carefully in a patient with new HHS. It is also important to note that patients may skip insulin when ill. Insulin must always be administered during illness, even when eating is markedly diminished. Infection induces insulin resistance and may require increased or supplemental doses of insulin. Failing to increase insulin during periods of illness may contribute to an increased incidence of DKA during this period of stress.49 The blood sugar level and the presence of ketones help to determine the optimal supplemental insulin dosage. When DKA occurs as the initial presentation in the new diabetic, the symptoms are often gradual in onset with progressive dehydration and slowly developing ketosis. The stress and symptoms of another illness may both mask the onset of the DKA and precipitate the entire process. In the established diabetic, DKA can develop quite rapidly. This may occur during an illness or when insulin therapy has been forgotten, deliberately omitted, or disrupted. When this happens, the ketoacidosis may predominate, and DKA may present with only a modest elevation of the blood glucose (250 mg/dL). DKA most often occurs in patients with type I diabetes, although it may occur in patients with type II diabetes.118 In one series, 13% of cases of DKA occurred in patients over 60 years of age and 31% of mixed DKA and HHS cases were in patients over the age of 60.44 COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC are generated in adipose tissue, are increased during DKA.59 These prostaglandins decrease peripheral vascular resistance and may cause tachycardia, hypotension, nausea, vomiting, and abdominal pain. The same symptoms occur when PGI2 is infused over several hours into normal humans. The abdominal pain associated with diabetes is disconcerting, since it may be from either DKA or from a pathologic process that caused the crisis, such as pyelonephritis, appendicitis, or pancreatitis.48 Indeed, in some patients with DKA, surgeons have been asked to evaluate the patient for intra-abdominal pathology before the diagnosis of DKA is made. The respiratory rate may be normal or somewhat rapid. If the patient is carefully examined, the rapid, deep breathing typical of Kussmaul respirations is often found. If Kussmaul respirations are present, serum CO2 is likely to be less than 10 mEq/L. A fruity odor to the breath, due to the acetone and ketone bodies associated with DKA, is often reported.60 Lethargy is common, and some patients will present in a coma. Mental status changes may occur in DKA and may be the result of DKA or may be due to an underlying process that caused the patient to develop DKA. If a mental status change is present, it is imperative to find the cause. Coma may result from the hyperosmolality associated with DKA. A calculated osmolality greater than 320 mOsm/L is often associated with coma.61,62 Calculated or measured values below this level would not explain a coma, and another cause such as meningitis or stroke should be pursued. The clinician should also be wary of cerebral edema associated with DKA, as described later in this article. Up to 25% of patients with DKA have emesis, which may be coffee-ground in appearance and guaiacpositive.47 Endoscopy has shown this to be the result of hemorrhagic gastritis.48 deficit in body water is 20%-25%, which is about 12% of the patient’s total body weight.58 The physical examination may reflect this profound dehydration. The mucous membranes may be quite dry. Skin turgor may be decreased, but this may be difficult to evaluate in the elderly patient. The patient’s eyes may be sunken. Tachycardia and hypotension may be present. The pulse may be weak and thready. Use of beta-blockers must be taken into consideration when evaluating the vital signs. If infection is present, the patient may be febrile; however, those patients who are immunocompromised or septic may be normothermic or even hypothermic.48 Abdominal pain or tenderness, nausea and vomiting, lack of bowel sounds, and ileus may be found in many patients with uncontrolled diabetes. These same findings may also be due to an intra-abdominal process that caused the patient to decompensate. This is not uncommon in the elderly. The development of findings due to decompensation of the diabetes follows the onset of symptoms rather than precedes it. The symptoms should improve markedly after the patient’s elevated blood sugar and dehydration are properly treated. Physical Findings In Diabetic Ketoacidosis The physical signs of DKA can be quite variable. Typical signs include fatigue, malaise, thirst, polyuria, reduced skin elasticity (poor skin turgor), dry mucous membranes, hypotension, and tachycardia from the volume deficits. Protracted vomiting may markedly increase the water loss. Some water loss may also occur due to the compensatory hyperventilation from the metabolic acidosis (Kussmaul respiration). The patient may note weight loss if there is a long onset. As the patient becomes more ill, he or she will begin to vomit and may complain of abdominal pain. The exact cause of the abdominal pain associated with DKA is not known. Prostaglandins I2 and E2, which Cost- And Time-Effective Strategies For Hyperglycemic Disorders 1. Check the glucose in children, even if the chief complaint does not appear to relate to diabetes. A major impact that the emergency physician can make is to ensure that no child with new-onset diabetes is missed. Since the original presenting symptom often masquerades as gastroenteritis, abdominal pain, or is concomitant with another illness, the emergency physician’s best strategy is to ensure that a glucose measurement is always obtained. other samples can both save time and costs. Use of a bedside glucose measurement on all patients who require an IV for hydration can both rapidly and inexpensively ensure that the vast majority of DKA patients will not be missed. Use of bedside glucose measurements on all patients with alteration of consciousness is both appropriate and will rapidly identify those who have hypoor hyperglycemia as either contributing or primary causes of the alteration of consciousness. 2. Dipstick the urine in all patients with vomiting. Since glucose is spilled into the urine when the blood sugar exceeds about 200 mg/dL, the easiest cost- and time-saving measure is to simply dipstick the urine and ensure that there is no significant sugar in the urine in patients with vomiting. 4. In many cases, phosphate replacement is unnecessary and can be potentially harmful. Use of phosphate replacement in diabetes has shown no benefit on clinical outcome in the majority of patients with DKA. Overzealous use of phosphate can cause severe hypocalcemia. Unless the patient has a phosphate of less than 1.0 mg/dL, the clinician can decrease costs by omitting this mineral in intravenous fluids used in DKA. ▲ 3. Bedside glucose measurements are fast, inexpensive, and relay clinically relevant information. Bedside glucose measurements done from fingerstick or Emergency Medicine Practice 10 www.empractice.net • February 2004 DKA. The findings are somewhat different, however. On presentation, the patient with HHS has glucosuria and no or minimal ketonuria and ketonemia. A mild metabolic acidosis may be present in these patients. Laboratory criteria used to diagnose DKA include a glucose level greater than 250 mg/dL, a pH less than 7.35, a serum bicarbonate of 12-15 mEq/dL, a high anion gap, and positive ketones. (Occasionally DKA can occur with a normal glucose level when there is vomiting, reduced intake of carbohydrate, and continued insulin therapy.) (See also Table 6.) HHS is characterized by a marked hyperglycemia (plasma glucose is often greater than 600 mg/dL with hyperosmolarity (serum osmolarity is often greater than 350 mOsm, dehydration, and a relative lack of insulin. Ketosis may be present but is not a significant feature. The presence of some ketonuria or mild ketonemia does not preclude the diagnosis. This syndrome may also be called hyperosmolar hyperglycemic nonketotic coma or hyperosmolar nonacidotic diabetes. The patient may have one of several presentations, each of which should prompt the clinician’s consideration of the possibility of HHS. The onset of HHS is more insidious than that of DKA. The patient with hyperosmolar syndrome often has no history of diabetes or may have a mild type II disease, treated with diet or oral antidiabetic agents. Rarely will HHS present in a young patient with type I diabetes. As in other endocrine emergencies, patients with HHS often do not present with specific signs and symptoms suggesting a metabolic disorder. Initial features of HHS include fatigue, blurred vision, polydipsia, muscle cramps, and weight loss. The increased osmotic load of the high glucose may lead to decreased visual acuity with distance vision and paradoxical improvement of near vision. The patient may also complain of muscle cramps, nausea, vomiting, or abdominal pain. Unfortunately, many patients with HHS present with more advanced symptoms. The typical patient is elderly, volumedepleted, and comatose or with an altered mental status.115 While the patient with HHS often has an altered mental status, he or she may be alert.3,46 Indeed, the name was changed from hyperosmolar nonketotic coma to HHS because frank coma is present in less than 10% of cases.113 Patients with HHS often present with neurologic abnormalities that are rarely seen in the patient with DKA.63 In HHS, mental obtundation and coma are more frequent because the majority of patients, by definition, are hyperosmolar. These abnormalities include seizures, transient hemiparesis, movement disorders, and other focal neurologic findings. Seizures are seen in up to 25% of patients and can be either generalized or focal.64-66 The unwary examiner may erroneously pin the diagnosis of stroke on the patient with HHS due to the obtundation associated with hyperosmolarity. Likewise, of course, coma should not be attributed to hyperosmolality when the osmolality is less than 320 mOsm/kg. Others who may develop HHS include patients who have been given massive glucose loads—such as in hyperalimentation, patients with significant renal disease and diabetes, and elderly patients who have been newly started on oral antidiabetic drugs. The patient often has another disease process to confuse the initial picture. Meticulous attention will be needed to treat both the metabolic disturbance and the precipitating factors. Serum Glucose A serum glucose determination should always be obtained, but most management can be done with bedside glucose testing. Suspect DKA when the glucose is greater than 250 mg/dL.48 However, normoglycemia may be seen in patients who received insulin before being seen in the ED, were fasting, or who have impaired gluconeogenesis from liver failure. Electrolytes The massive diuresis may contribute significantly to the electrolyte abnormalities seen in DKA. Free water, sodium, potassium, magnesium, and phosphate are excreted into the urine along with the glucose. Ketoacids act as nonresorbable ions in the kidney and are excreted as potassium and sodium salts. Because urine contains about 70-80 mEq/L of cations, most of which are sodium and potassium, massive total body deficiencies in sodium and potassium may result. Despite this urinary potassium loss and total body deficits of potassium, most patients will have an elevated potassium at initial laboratory evaluation.47 This is due to the lack of insulin, acidosis, and the increased osmolality. Loss of insulin will cause a shift in intracellular potassium into the serum. Acidosis and movement of water from the intracellular space to the extracellular space will further move potassium into the extracellular fluid. The sodium should be corrected for the high glucose seen in the patient with HHS. The effects of a very elevated glucose on the sodium may be greater than the usual correction. There is some controversy about the method of correction to be used.113 See Table 6 for the usually accepted correction. When the patient has severe acidosis, the differential diagnosis should consider DKA, lactic acidosis, and other Continued on page 15 Table 6. Useful Calculations In Diabetic Ketoacidosis. The anion gap: Na+ -(Cl- + HCO3-) Correction of serum sodium: Corrected Na+ = Na+ + 1.6 * [(glucose in mg/dL) – 100] / 100 Calculation of effective serum osmolality: 2[Na+ + K+ ] + [glucose in mg/dL]/18 Diagnostic Studies Total body water deficit: 0.6 x weight x [1-140/serum sodium] The diagnostic work-up for HHS is identical to that for February 2004 • www.empractice.net 11 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Physical Findings In Hyperglycemic Hyperosmolar Syndrome Presumptive diagnosis of diabetic ketoacidosis ED encounter: Laboratory findings: • ECG if age greater than 20 • Chest radiograph and cultures as appropriate • Start IV fluids 15-20 mL/kg/hour • History and physical examination • Laboratory tests, serum pH, CBC, UA, BUN, creatinine, electrolytes • • • • Blood glucose > 250 mg/dL pH < 7.3 Serum HCO3 < 15 mEq/L Moderate ketonuria and ketonemia Evaluate volume status and potassium (Class I) ➤ ➤ ➤ Insulin IV fluids Potassium ➤ ➤ • Administer regular insulin IV 0.15 U/ kg as IV bolus (this is controversial) (Class indeterminate) • Administer regular insulin IV 0.1 U/ kg/hour as IV drip (Class I) Hypovolemic shock? YES ➤ ➤ ➤ ➤ ➤ Switch to 0.45% sodium chloride solution (Class II) Continue 0.9% sodium chloride solution (Class II) ➤ ➤ K < 3.3 mEq/L • Hold insulin • Give K (40 mEq in adults) per hour until K > 3.3 mEq/L (Class II) ➤ * ICU bed may not be necessary if adequate monitoring is available in a lesser unit—depends on hospital capabilities ➤ ➤ ➤ ➤ • Continue insulin infusion (Class I) • Add glucose 5% to IV (Class I) • Continue to monitor electrolytes or glucose every 2 hours until patient is stable (Class I) • Search diligently for precipitating cause (Class indeterminate) • Admit to ICU* (Class indeterminate) Continue insulin infusion (Class I) ➤ ➤ ➤ Low sodium NO K 3.3-5.5 mEq/L • Give 20-30 mEq to keep serum potassium at about 4-5 mEq/L (Class II) Normal or elevated sodium Continue insulin infusion until serum glucose reaches 250 mg/dL (Class I) YES ➤ Evaluate corrected sodium Double insulin infusion hourly until serum glucose drops 50-70 mg/dL (Class indeterminate) Serum glucose under 250 mg/dL? NO ➤ NO K > 5.5 mEq/L • Hold K • Check K every 2 hours (Class II) ➤ ➤ YES ➤ • Hemodynamic monitoring (Class I) • Administer 0.9% sodium chloride 20-40 mL/kg (Class I) • Re-evaluate volume status Did the blood glucose fall by 50-70 mg/dL in the first hour? ➤ COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Clinical Pathway: Treatment Of Diabetic Ketoacidosis Monitor serum glucose, potassium, sodium, and bicarbonate every 1-2 hours for at least 18 hours (Class II) If serum glucose falls under 250 mg/dL: • • • • • Continue insulin infusion (Class I) Add glucose 5% to IV (Class I) Continue to monitor chem 7 every 2 hours until patient is stable (Class II) Search diligently for precipitating cause (Class indeterminate) Admit to ICU* (Class indeterminate) The evidence for recommendations is graded using the following scale. For complete definitions, see back page. Class I: Definitely recommended. Definitive, excellent evidence provides support. Class II: Acceptable and useful. Good evidence provides support. Class III: May be acceptable, possibly useful. Fair-to-good evidence provides support. Indeterminate: Continuing area of research. This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual needs. Failure to comply with this pathway does not represent a breach of the standard of care. Copyright ©2004 EB Practice, LLC. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Practice, LLC. Emergency Medicine Practice 12 www.empractice.net • February 2004 Presumptive diagnosis of hyerpglycemic hyperosmolar syndrome Continued from previous column YES ➤ NO ➤ • Add glucose 5% to IV (Class I) • Lower serum glucose slowly to normal, decreasing the insulin infusion as needed (Class I) • Replace remaining estimated fluid deficit over the next 24-48 hours (Class II) Establish invasive monitoring (Class I) ➤ ➤ Administer normal saline at 250 mL/hour (Class II) ➤ Adequate urine output established?* YES Monitor serum glucose, potassium, bicarbonate every 1-2 hours for at least 18 hours (Class II) NO ➤ ➤ • Add KCl (40 mEq/L) and potassium phosphate (Class II) • Administer insulin bolus 5-10 units IV regular and then insulin infusion at 5-10 units per hour (Class II) • Monitor serum glucose, potassium, bicarbonate every 1-2 hours for at least 18 hours (Class I) Continue insulin infusion (Class I) ➤ ➤ YES ➤ Evidence of cardiac decompensation? Continue insulin infusion (Class I) NO ➤ ➤ Administer 1-2 liters of normal saline solution (Class I) ➤ ➤ Serum glucose under 300 mg/dL? Reassess volume status of patient (Class I) ➤ Go to top of next column * Note: If the patient continues to have inadequate urine output despite adequate volume replenishment, assume that renal failure is present: Use insulin and decrease the IV fluid rates (Class indeterminate) The evidence for recommendations is graded using the following scale. For complete definitions, see back page. Class I: Definitely recommended. Definitive, excellent evidence provides support. Class II: Acceptable and useful. Good evidence provides support. Class III: May be acceptable, possibly useful. Fair-to-good evidence provides support. Indeterminate: Continuing area of research. This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual needs. Failure to comply with this pathway does not represent a breach of the standard of care. Copyright ©2004 EB Practice, LLC. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Practice, LLC. February 2004 • www.empractice.net 13 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Clinical Pathway: Treatment Of Hyperglycemic Hyperosmolar Syndrome COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Ten Pitfalls To Avoid 1. “The little girl did really well during therapy for DKA, and the glucose returned to normal before I could arrange a bed in the ICU. I arranged for a floor admission for overnight. How could I predict that she’d develop cerebral edema?” The patient with DKA always deserves to be admitted and carefully watched. The responsible clinician should admit the patient with DKA to a unit where neurologic status and vital signs can be monitored frequently and the blood or fingerstick glucose can be measured hourly. A diabetic flow sheet is quite helpful in the management of these patients. ketones may become positive later in the disease process. In this patient, the development of “positive ketones” could signify improvement if other laboratory values and clinical signs are improving. 6. “The blood sugar dropped to 30 while the patient was waiting for a bed in the ICU. The ED was too busy for serial examinations.” The patient in DKA is a critical patient who deserves high priority. By any method of administration, insulin may produce hypoglycemia. With low-dose insulin therapy and adequate volume replenishment, the drop in blood glucose is predictable and may be easily observed with adequate monitoring. This complication should not occur. As the blood glucose approaches 300 mg/dL, exogenous glucose should be added, either intravenously or orally (if the patient is awake). As exogenous sugar is added, insulin will still need to be given, but the dosage and rate of administration may have to be adjusted. 2. “I told the family that that their elderly grandmother had another stroke! She had two prior strokes by the medical records and was a stable, diet-controlled diabetic. How was I to know that this time was different?” HHS often presents as an alteration of consciousness, and a cerebrovascular accident may precipitate the illness. Unfortunately, bedridden patients may also not be able to get adequate fluids, which also can precipitate the syndrome. 7. “She really looked quite dehydrated, her BUN was 45, and her CO2 was 12, so I just let a couple of liters of normal saline with bicarbonate run in wide open.” The incidence of cerebral edema in DKA may be related to the administration of bicarbonate rather than the speed of fluid replenishment, so bicarbonate should be avoided if at all possible. 3. “The patient was admitted in DKA; there was no reason to suspect that he had an MI.” Myocardial infarction elevates catecholamines, which can precipitate DKA. Any patient with DKA who is clinically at risk for a myocardial infarction should be evaluated for myocardial ischemia. Patients with an infarction or congestive heart failure may require a central line. 8. “I thought that 8-year-old boy only had gastroenteritis.” DKA often presents initially as an upset stomach. You don’t have to look for acetone in every patient with gastroenteritis, but you should check serum glucose. Many previously undiagnosed patients are seen in physicians’ offices or EDs before they become critically ill. Checking the sugar may be life-saving in these patients. 4. “I knew that the patient’s renal status was marginal, but she still appeared quite dehydrated. How was I to predict the rapid onset of congestive heart failure in this patient?” The patient with DKA and renal failure may be very difficult to manage. Fluid losses will have been smaller than those seen in DKA patients with normal renal function, and fluid replacement must be done much more slowly. Therapeutic emphasis is on insulin per se, careful monitoring of potassium, and consideration of dialysis. Rapid fluid administration may lead to congestive heart failure. The patient with both renal failure and DKA may require central monitoring to prevent pulmonary edema. 9. “She was an elderly type II diabetic who recovered quite promptly from the blood sugar of 32, so I gave her a meal and let her go home.” The diabetic patient on oral hypoglycemic agents who becomes hypoglycemic should be evaluated carefully. The half-life of the oral hypoglycemic agents is often long and may be unpredictable. Admission is generally recommended for these patients, since hypoglycemia is likely to recur. 5. “I knew that the patient had diabetes, and I found a urinary tract infection. The blood sugar was 450 and I didn’t think to get an arterial blood gas when the serum ketones were negative. How was I to know that this was DKA?” Sepsis, accumulation of lactate, and poor tissue perfusion prevent the formation of acetoacetate. Betahydroxybutyrate—a ketoacid that does not react in the nitroprusside test—is preferentially formed. The very ill diabetic with hyperglycemia and an anion gap acidosis should be treated for DKA. A nitroprusside test for Emergency Medicine Practice 10. “The blood sugar was only 240—how could he have had DKA?” Most patients with DKA present with glucose levels greater than 300 mg/dL, but occasionally patients may have lower glucose levels or even normal glucose levels. Normal glucose may be seen when the patient has had insulin before presentation, reduced food intake, or impaired gluconeogenesis (as with liver failure or severe alcohol abuse). Markedly increased triglycerides may foil the lab, so be wary if the serum is very lipemic. ▲ 14 www.empractice.net • February 2004 The forces governing the movement of water are both hydrostatic and osmotic pressures. The osmotic pressures greatly exceed hydrostatic pressures in the body. Osmotic pressure is a property of solutions that depends on the number of osmotically active molecules in solution. It does not depend on the ionic charge, the size of the molecule, or the chemical properties of the molecule. One gram-molecular weight (1 mole) of a compound is also termed 1 osmole (osmol or Osm). Most biological concentrations are expressed in milliosmolar (mOsm) or microosmolar (µOsm) concentrations. Ionized molecules such as sodium chloride will dissociate in solution, and each ion exerts its own osmotic force. (This means that 1 mOsm of NaCl exerts 2 mOsm of osmotic pressure.) Osmolality is the expression of this quantity of osmotically active particles per 1000 grams of water or solvent. The more common term, osmolarity, expresses the number of osmotically active particles per liter of solvent. The difference between osmolarity and osmolality is due to protein and fat, which comprise about 6%-8% of the solutes in plasma. Hyperosmolality in diabetes is largely due to hyperglycemia. non-HHS disease processes. Vomiting or the concomitant use of a thiazide diuretic can cause a metabolic alkalosis that can mask the severity of the acidosis. This situation might be found if the combined anion gap and the measured HCO3 are greater than expected. Complete Blood Count The complete blood count often shows a leukocytosis. This may be in part due to the hemoconcentration from dehydration. White blood cell counts of 20,000 cells/mm3 are not uncommon. If the patient has an elevated band count (bandemia) on peripheral smear, then an infectious process is likely.67 Serum pH An arterial blood gas or venous gas should be sent early in the evaluation of the patient considered to have DKA.68,69 (The correlation between arterial and venous pH is quite close, and the two can be used interchangably for the evaluation of DKA patients.) This will help determine the degree of acidosis and bicarbonate loss. When the pH is less than 7.35 and a low HCO3- is found, then the diagnosis of DKA should be seriously considered. Lumbar Puncture Lumbar puncture is indicated in patients with an acute alteration of consciousness and clinical features suggestive of possible central nervous system infection. Blood Urea Nitrogen And Creatinine The patient will often have some elevation of the blood urea nitrogen due to dehydration. The clinician should carefully consider the possibility of chronic renal failure. The patient with both diabetes and renal failure may be quite difficult to manage. Fluid losses may be smaller than when the patient has normal renal function, and fluid replacement must be much more conservative. Therapeutic emphasis will switch to insulin, careful monitoring of potassium, and consideration of dialysis. Hemoglobin A1c Determination Glycosylated hemoglobin measurement is not needed for the emergent management of the patient’s diabetes. The hemoglobin A1c will give the clinician some idea of the duration or degree of control of the patient’s diabetes prior to the emergency. Treatment Urinalysis And Urine Culture Successful treatment of both DKA and HHS includes correction of the dehydration and hyperglycemia, resolution and anticipation of the electrolyte abnormalities, identification of precipitating or comorbid illnesses. (See also the Clinical Pathways on page 12 and page 13.) Infection is quite common as a precipitating factor. Pneumonia, urinary infections, and sepsis are the most common etiologies. This high incidence of infection in HHS patients has led to a recommendation for early empiric antibiotic therapy, even if no source is identified.41,70 This is controversial; others recommend waiting for definitive evidence since both fever and leukocytosis can also be precipitated by other factors.71 The current mortality rate of DKA is about 2%-5%.72 Without insulin therapy, the mortality rate of DKA is 100%. Remember that the underlying pathology may be the reason for mortality in the patient with HHS. Re-evaluate the patient for infection, myocardial infarction, and underlying diseases. Early mortality in HHS is more likely to be caused by sepsis, shock, or an underlying illness. The most common complications of DKA and HHS include hypoglycemia due to overtreatment with insulin, hypokalemia due to insulin administration in the potas- Check the urine on every patient who presents with a possible diagnosis of DKA in order to identify possible urosepsis causing the DKA. Likewise, in females of childbearing age, a urine pregnancy test is equally important. Serum Ketones Serum ketone testing may not correlate with the degree of ketoacidosis. Beta-hydroxybutyric acid is the major ketoacid produced in DKA. It does not react with nitroprusside, so urine or blood testing for ketones may be negative or only slightly positive. During the treatment of DKA, beta-hydroxybutyric acid will be converted to acetoacetic acid. The resultant increase in acetoacetic acid may make the serum or urine testing for ketones more positive, despite clinical improvement and an increasing pH and decreasing anion gap. While some literature has suggested that urine ketones can be used to rule out DKA, serum ketones are more accurate and should be used instead. Serum Osmolality Because biological membranes are readily permeable to water molecules, there is a continuing movement or exchange of water between various fluid compartments. February 2004 • www.empractice.net 15 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Continued from page 11 COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC monitoring of mental status, which may be the first indication of cerebral edema in the diabetic patient. sium-depleted patient and treatment of acidosis with bicarbonate, and hyperglycemia due to interruption of intravenous insulin before coverage with other forms of insulin has been established. Insulin Replacing insulin reverses the mobilization of free fatty acid and the hepatic production of glucose and ketoacids. Insulin treats the ketosis and the acidosis as well as the hyperglycemia. Insulin can be given intravenously or intramuscularly. Some physicians advocate preceding the infusion with a bolus of insulin; however, this has no physiologic advantage. Continuous intravenous insulin infusion has several advantages over intramuscular insulin.113 Smaller insulin doses are needed for clinical efficacy when given intravenously. An insulin drip gives therapeutic plasma insulin levels with a smooth correction and flexibility to increase or decrease the dose easily. A common intravenous insulin administration regimen is continuous infusion of 0.1 units per kilogram per hour (about 6-8 units per hour in the average adult). If the insulin infusion is connected through a separate line or through a “piggy-back” connection, the infusion can be regulated separately from the rate of fluid administration. An alternative method of dosing would be to give an equivalent dose of rapid-acting insulin intramuscularly every hour. Since vasoconstriction decreases medication absorption in hypotensive patients, this method is less than optimal in the critically ill patient. Subcutaneous insulin is not recommended during the treatment of any critically ill patient. In these potentially hypotensive and/or dehydrated patients, the absorption from subcutaneous tissues may be inadequate or unpredictable. Research indicates that bolus administration of insulin may not be the best possible therapy for the patient.113 Bolus insulin causes plasma insulin levels to rise within minutes to over 3000 microunits per milliliter. This level far exceeds physiological levels of insulin. Potassium levels are significantly reduced when these boluses of insulin are used. This could be a clinical problem if the patient is hypokalemic before insulin is given. The endpoint for continuous insulin infusion should be resolution of hyperketonemia (3-hydroxybutyrate < 0.5 mmol/L) rather than the normalization of blood sugar.73 To prevent the recurrence of DKA, the patient should resume his or her usual subcutaneous dose of insulin before the insulin infusion is stopped. The insulin drip should not be considered as part of fluid replacement calculations. The glucose level can be anticipated to fall by 50-100 mg/dL (2.5-5.0 mmol/L) per hour.74 The initial rate of decrease may be more rapid as the renal function improves with improved hydration. When the glucose level reaches 250 mg/dL (12.5 mmol/L), the possibility of hypoglycemia should be anticipated. When the patient’s glucose level reaches 250 mg/dL, the rate of infusion of insulin should be cut in half to decrease the possibility of hypoglycemia. In some patients, D5 normal saline or even D10 normal sailine may be used to prevent hypoglycemia and allow intrave- Diabetic Ketoacidosis The specific treatment goals of the patient with DKA are: 1. Improve tissue perfusion and correct hypovolemia 2. Decrease the serum glucose 3. Reverse acidosis and ketonemia 4. Correct electrolyte imbalances 5. Treat the disease process that precipitated the patient’s DKA (if present) This is not a rigid treatment protocol but a guideline. Each aspect of each case must be assessed individually and reassessed frequently. Fluids Rehydration is the most important intervention in the therapy of DKA; however, the optimal fluid management for DKA is uncertain. The practitioner is faced with a patient who is often dehydrated, yet rapid fluid administration may predispose the patient to lethal complications. If the patient is hypotensive, administer a bolus of 1-2 liters of normal saline (0.9%) over the first hour (pediatric dose, 20-40 mL/kg). If hypotension persists, then give another bolus. If the patient is normotensive, then use 0.9% saline at 1000 cc per hour. Subsequent choice of fluids depends on the state of hydration, serum electrolytes, and the urinary output. When giving this much fluid to older patients, pulmonary edema is a real possibility. The patient’s lung sounds should be carefully monitored. If the patient has renal failure or has a history of congestive heart failure, then invasive monitoring with Swan catheters may be an appropriate step. This is a clinical judgment. In general, normal saline (0.9%) infused at 4-14 mL/ kg/hour is appropriate if the corrected serum sodium is normal or elevated.113 Once renal function is ensured, the infusion should include 20-30 mEq/L of potassium until the patient is stable and can tolerate oral intake. Provide maintenance fluids and electrolytes evenly over the first 24 hours. Deficit fluids are usually replaced in a bi-level fashion: One half of the deficit is replaced over the first eight hours, and the other half of the deficit is replaced over the next 16 hours.113 Successful fluid replacement is judged by hemodynamic stability, measurement of fluid input/output, and clinical examination of the patient. Overhydration is a concern when treating children with DKA, adults with compromised renal or cardiac function, and elderly patients with incipient congestive heart failure. In patients with renal or cardiac insufficiency, monitoring of cardiac, renal, and mental status must be diligently performed during the fluid resuscitation to avoid an iatrogenic fluid overload. In pediatric patients, the need for volume expansion must be balanced with the risk of cerebral edema, as discussed later in this article. Therapy must include Emergency Medicine Practice 16 www.empractice.net • February 2004 disappearance of the P wave, and widening of the QRS complex. (Remember that the T waves usually peak if the serum potassium is over 6 mEq/L.) Hypertonicity, deficit of insulin, and acidosis can combine to cause extracellular hyperkalemia. In reality, the patient has lost total body potassium, but the lack of insulin and acidosis can mobilize remaining intracellular potassium into the extracellular fluid. An ECG may show these signs of hyper- or hypokalemia before the electrolyte determination has returned. Multiple algorithms are described in the literature for the replacement of potassium during therapy of DKA. The most important part of any such algorithm is adequate monitoring of the electrolytes during the process. If the serum potassium is less than 5.0 mEq/L and there is a recent history of urination, and/or the ECG has no peaked T waves, then potassium can be started safely. Before any potassium is given, kidney function and adequate urine output must be established. Bicarbonate In DKA, calcium, magnesium, and phosphate are also deficient. The prevalence and clinical need for replacement of these electrolytes are not universally accepted. Phosphate, Magnesium, And Calcium The use of bicarbonate is not recommended for DKA. Bicarbonate is used to treat metabolic acidosis. The rationale for the use of bicarbonate in DKA is based on the assumption that the acidosis may contribute to morbidity in these patients.75,76 This ignores the issue in the patient with DKA that the appropriate treatment for ketoacidosis is not bicarbonate, but insulin. Use of bicarbonate merely masks the ketoacidosis. Studies of cerebral edema (outlined later in this article) show that there is an increased risk of cerebral edema when bicarbonate is used. Given all of these factors, bicarbonate can’t be recommended for patients in DKA. The American Diabetes Association guidelines suggest the use of bicarbonate when the pH is below 6.9.6 There are no prospective, randomized studies concerning the use of bicarbonate in DKA in either children or adults. The support for this part of these American Diabetes Association guidelines, therefore, is incredibly weak. Phosphate Whole body phosphate deficits in DKA are substantial. Despite this, several small studies have not shown any clear benefit to phosphate replacement in DKA.78-80 Excessive phosphate replacement may cause hypocalcemia and softtissue metastatic calcifications. The clinical manifestations of severe hypophosphatemia are diverse. Alterations in the function of skeletal and smooth muscles can lead to rhabdomyolysis, ileus, respiratory failure, and cardiac dysfunction. Decrease in intracellular adenosine triphosphate can result in hemolysis, thrombocytopenia, and impaired phagocytosis. Patients also may demonstrate metabolic encephalopathy, progressing from irritability to coma. Indications for the clinical repletion of phosphate include left ventricular dysfunction or failure to clear mental confusion despite improvement in circulating volume, hyperosmolarity, and acidosis. If the patient’s phosphate level is less than 1.0 mg/dL or if one of the above indications for phosphate therapy is present, then give 30-60 mM of phosphate over a 24-hour period. Obtain phosphate levels before the start of treatment, after an infusion, and at 24 and 48 hours into treatment. Potassium The major electrolyte lost during DKA is potassium. The total body potassium deficit ranges from 300-1000 mEq total body deficit for an adult.77 Hypokalemia is a potentially lethal complication of DKA. The patient may have a mildly elevated potassium level upon initial evaluation and still have a tremendous total potassium deficit. Much potassium is lost as the potassium salts of ketoacidosis. Continued potassium losses are the rule during the treatment of the patient with normal renal function and DKA. Resolution of acidosis and concomitant administration of insulin will force the remaining extracellular potassium into the cells. The clinician should anticipate the massive shift of potassium carried into the cells with insulin and the endogenous glucose loading. Insulin therapy should not be started until the potassium level is known, in order to prevent lethal hypokalemia.113 The electrocardiogram should be evaluated for the signs of hyperkalemia, such as tall peaked T waves, February 2004 • www.empractice.net Magnesium The kidney is the primary organ responsible for magnesium homeostasis. Under normal conditions, 15% of filtered magnesium is reabsorbed in the proximal tubule through an active transcellular process, 60%-70% is reabsorbed passively in the thick ascending limb of the loop of Henle driven by transepithelial voltage, and 10% is reabsorbed in the distal tubule.119 Because magnesium reabsorption is proportional to urine volume and flow, volume expansion or osmotic diuresis can lead to magnesium wasting. 17 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC nous infusion of insulin until the subcutaneous administration of insulin is resumed.113 If the patient’s glucose is falling steadily, the anion gap is decreasing, and the pH is improving, then the insulin infusion is appropriate. If the glucose level does not fall in the presence of adequate hydration and urine output, then the patient may have insulin resistance. In this case, the insulin dose can be doubled each hour where there is no decrease. This insulin resistance should remind the clinician that the patient may have sepsis, occult infection (e.g., endocarditis, perirectal abscess, prostatitis, or sinusitis, to name a few), myocardial infarction, or an intra-abdominal illness that precipitated the crisis. A few patients may have a primary insulin resistance. The serum glucose level may decline more rapidly in the older patient, so carefully monitor glucose levels in these patients. This insulin administration regimen is only a guideline. Consider the patient’s previously injected long-acting insulin, concurrent stress (such as a myocardial infarction), or the concurrent administration of steroids. COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC may accompany the administration of insulin as potassium is forced into the cells with insulin and sugar. (This is now quite rare since patients are now treated with lower-dose continuous insulin infusion rather than large boluses of insulin.113) The clinician must follow serum potassium levels frequently and administer a minimum of 10 mEq per hour of potassium chloride. Severe hypokalemia is often correlated with frequent emesis, nasogastric suction, or the use of thiazide diuretic agents. As with DKA, do not initiate potassium replacement until it has been confirmed by the laboratory and adequate urine output has been established. Hypokalemia is often accompanied by hypomagnesemia. Again, the initial serum levels of magnesium and phosphate are typically normal or elevated when the disease process is diagnosed and may fall with insulin administration. Significant magnesium depletion usually is associated with hypocalcemia and hypokalemia, since they have the similar mechanisms. Clinical manifestations of hypomagnesemia are nonspecific and include weakness, dizziness, tremors, cramps, paresthesias, and seizures.81 Severe hypomagnesemia can lead to both atrial and ventricular arrhythmias. If the patient has a magnesium level of less than 1.8 mEq/L or has tetany, then magnesium sulfate may be started as 5 grams in 500 mL of normal saline administered over five hours. Calcium If the patient has symptomatic hypocalcemia, then 10-20 mL (1-2 grams) of 10% calcium gluconate may be given intravenously over 10 minutes. Hyperosmolar Hyperglycemic Syndrome Careful Monitoring Adequate management of HHS requires fluid replacement; this is the first priority of treatment. HHS patients are often about 25% dehydrated and may require 9-12 liters of fluid replenishment. Unfortunately, many patients with this disease cannot tolerate either the disease or the treatment required. Careful monitoring during this fluid therapy is crucial, because people with hyperosmolar coma may have compromised cardiovascular function. Most patients can be treated with normal saline at 5001000 cc per hour until the blood pressure is normal and the patient has good urine output. The clinician should plan on replacing about 50% of the fluid deficit in the first 12 hours and the remaining 50% in the subsequent 24-36 hours.113 Controversy also abounds about the proper choice of rehydration fluid in HHS. Normal saline replaces the intracellular volume more quickly but also increases the possibility of fluid overload. It may provoke adult respiratory distress syndrome, particularly in patients with potential cardiac and respiratory compromise. Hypotonic fluids such as half-normal saline (0.45%) may be more effective in replacing the lost free water, but risk too rapid correction of hyponatremia with subsequent pontine myelinonecrolysis. (Severe hypertonicity is associated with large sodium deficits and hypovolemic shock.40,82) An appropriate compromise is an initial fluid replacement of one liter of normal saline and then switching to half normal saline when urine output is adequate. Insulin, while not present in quantities sufficient to prevent hyperglycemia, is usually present in patients with HHS and may serve to prevent the formation of ketone bodies. Relative insulin deficiency is exacerbated by the patient’s dehydration. Insulin therapy is not as important as it is in DKA. Indeed, the use of too much insulin, given too rapidly, may cause vascular collapse as glucose and water are moved into the cells and out of the volume-depleted intravascular space. As in the patient with DKA, once the glucose drops to 250 mg/dL, the patient must receive dextrose in the intravenous fluids. Although patients are generally not hypokalemic by initial measurement of serum potassium, the total body deficit may be quite high as in DKA. Lethal hypokalemia Emergency Medicine Practice The sicker the patient, the more frequently he or she should be monitored. Do not wait for results to come back before sending the next set of tests. The following parameters should be monitored and recorded on a flow sheet: • Glucose—every 1-2 hours by fingerstick (confirmed by laboratory correlation when indicated) • Basic metabolic profile for anion gap and serum potassium—at the onset of treatment, at one and two hours after the onset of treatment, and at two- to fourhour intervals until the patient is substantially better • Arterial or venous pH—follow as indicated to monitor clinical status • Insulin dose and route of administration—every hour • IV fluids—every hour • Urine output—every hour Special Circumstances Pulmonary Edema And Adult Respiratory Distress Syndrome Cardiogenic and non-cardiogenic pulmonary edema can occur in association with the treatment of DKA. These complications more often are noted during the ICU stay, but they may be found by the emergency physician. Excessive fluid replacement may cause pulmonary edema even when the cardiac function is normal. These patients should have continuous pulse oximeter monitoring. Avoiding overzealous fluid administration should prevent cases related to decreased colloid osmotic pressure. Adult respiratory distress syndrome is a rare but potentially fatal complication of the treatment of DKA.83,84 A patient who has an increased alveolar-to-arterial oxygen gradient on arterial blood gas or who presents with rales may have an increased risk of adult respiratory distress syndrome. This rare complication appears to result from an increased capillary membrane permeability and is consequently more difficult to prevent. Treatment requires a delicate balance between adequate rehydration and fluid restriction needed for the treatment of the pulmonary edema. These patients require invasive hemodynamic monitoring and intensive pulmonary therapy. 18 www.empractice.net • February 2004 diabetic patients.88,89 It is almost always a disease of children; over 95% of cases in the largest reported series occurred under the age of 20, and one-third of cases occurred under the age of 5 years.88 One-fourth of the children affected die from this complication. When cerebral edema does occur in adults, it is quite similar in presentation to the pediatric disease. After initial improvement of clinical, biochemical, and central nervous system signs in a patient with DKA, the patient develops increasing irritability, central nervous system depression, seizures, and coma. Cerebral edema complicating DKA generally occurs in children who seem to be metabolically returning to normal about 3-12 hours after the onset of therapy.6,7 The risk factors for cerebral edema are incompletely defined. Recent work shows that children who have a low CO2 and a high blood urea nitrogen and then are treated with bicarbonate are at increased risk for cerebral edema.8,90 Children who had a smaller increase in serum sodium during therapy were also at more risk of cerebral edema. The highest risk was found with the use of bicarbonate and a low CO2. The initial serum glucose and the rate of change in the serum glucose were not associated with the development of cerebral edema in this study. The traditional dogma has been that these values are related to cerebral edema; however, this appears to be completely unsubstantiated by this study. Previous investigations of cerebral edema in children with DKA implicated a younger age, a new onset of the disease,91 and a rapid rate of fluid administration as factors associated with cerebral edema.88,92 In these studies, children with cerebral edema were not compared with controls. Why does it occur in children and not adults? There is no clear answer. Some speculate that it may relate to relatively greater brain volume, more rapid changes in plasma osmolarity, lack of sex steroids, less developed mechanisms for brain cell volume regulation, a difference in taurine or other osmolyte metabolism, a difference in bloodbrain barrier efficiency, or unidentified causes.89 Why does cerebral edema with the treatment of DKA occur at all? The pathogenesis remains an enigma. There are a number of hypotheses attempting to explain the development of cerebral edema, none of which are entirely satisfactory and have remained unproven.8,93-106 The mechanisms that lead to the development of cerebral edema in DKA probably involve a complex interaction of many of these hypothetical mechanisms. How they relate to fluid and electrolyte balance during the treatment of DKA is also not known. Much more study is needed to answer these questions. DKA is a hypercoagulable state. The factors that precipitate thrombosis include the hypercoagulability in the DKA patient, stasis, and endothelial damage.85,86 The severe dehydration and immobility that occur in DKA also decrease perfusion of vital organs and promote stasis and hypercoagulability. Vascular occlusions (such as myocardial infarction, cerebrovascular accidents, and mesenteric artery occlusions) are important complications of both DKA and HHS.113 Predisposing factors include dehydration with resultant increased viscosity, and preexisting coagulation abnormalities. With aggressive rehydration of the patient, the expected incidence of these complications can be reduced to about 2%.113 Rhabdomyolysis Subclinical rhabdomyolysis, possibly owing to shrinkage of muscle cells and impaired glucose use, is a common finding in patients with HHS (and to a lesser degree with DKA), but secondary acute renal failure is extremely rare.113 Many patients do not develop myoglobinuria; thus, monitoring serum creatinine phosphokinase levels is the most sensitive way to screen for this potentially serious complication. Acute Gastric Dilatation Acute gastric dilatation is a relatively uncommon but potentially lethal problem. If the patient is distended, then other causes of intra-abdominal pathology must be sought first. A nasogastric tube will make the diagnosis and serve as therapy if the patient continues to vomit. Electrolyte Disorders Treatment for DKA can cause life-threatening, predictable, and avoidable acute complications such as hypokalemia, hyponatremia, and fluid overload. These are common yet preventable complications of the treatment of diabetic emergencies. Hyperchloremic Metabolic Acidosis Hyperchloremic metabolic acidosis with a normal anion gap often persists after the resolution of ketonemia. This acidosis has no adverse clinical effects and is gradually corrected over the subsequent 24-48 hours by enhanced renal acid excretion.87 Hyperchloremia can be aggravated by excessive chloride administration during the rehydration phase. Seizures Seizures associated with HHS are often resistant to typical antiseizure medications.120 Phenytoin may further exacerbate the HHS.120 The emergency physician should be aware of this problem with seizure control and proceed to alternative agents such as barbiturates if benzodiazepines are not effective. Management Of Cerebral Edema Cerebral Edema—A Pediatric Problem Children with the biochemical features of cerebral edema should be monitored carefully during therapy. If any sign of neurologic deterioration is noted, hyperosmolar therapy should be readily available and neurologic consultation sought. Two of the risk factors identified in the study by Cerebral edema is the most feared complication of DKA and may have driven many of the changes in the management of DKA over the past few decades. Cerebral edema occurs in about 1% of DKA cases and is the most common cause of diabetes-related death in young February 2004 • www.empractice.net 19 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Vascular Complications COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Summary Glaser et al were blood urea nitrogen and CO2 at presentation, which can’t be altered by ED therapy. However, the third risk factor—bicarbonate administration—is directly within the realm of ED care. Bicarbonate is associated with several risks, including cerebral edema, and should be avoided if possible. Initial therapy of cerebral edema should be the use of mannitol as an osmotic diuretic to lower the intracranial pressure. Recent studies show that for maximum effect, mannitol should be given within 5-10 minutes of the initial deterioration in neurologic function.107,108 A more favorable outcome has been reported when intracranial pressure monitoring is used in addition to mannitol.109 The role of dexamethasone and diuretics has not been established. DKA and HHS are among the most lethal complications of diabetes. Furthermore, they can occur with other serious comorbid illnesses or infection—or as the patient’s initial presentation of diabetes. With the growing incidence diabetes, it is all the more necessary for the prompt identification and effective management of these complications to be a part of every emergency physician’s armamentarium. The major complications related to the treatment of DKA and HHS include hypoglycemia, hypokalemia, and, rarely, cerebral edema. The use of low-dose insulin regimens, potassium replacement early in management, the addition of glucose to intravenous solutions, and attentive monitoring of therapeutic response should significantly reduce these complications. ▲ HHS And Cerebral Edema References Cerebral edema is generally not seen in adults with HHS. Because undertreatment of HHS carries an increased risk for mortality, rapid correction of hyperosmolarity to an effective serum osmolarity under 320 mOsm/L and correction of the glucose to about 250-300 mg/dL is the goal of early therapy.110 This approach differs from the one used to correct hyperosmolarity in DKA. Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report. To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study, will be included in bold type following the reference, where available. In addition, the most informative references cited in the paper, as determined by the authors, will be noted by an asterisk (*) next to the number of the reference. Cutting Edge There are many exciting developments in the management of the diabetic patient that have not been covered in this article. Inhaled delivery of insulin is in the final stages of field testing.121 Gene therapy for some of the variants of diabetes is in planning stages.122 Insulin pumps that measure the glucose and deliver the exact dose—an artificial pancreas—are under development.123 This device would make DKA much less common, as the patient would not be able to forget or misread the delivered dose of insulin. Sick days and exercise doses of insulin would be automatically compensated. 1. 2. 3.* Disposition 4. The patient with DKA or HHS requires hospital admission to a unit where the patient’s neurologic status and vital signs can be monitored frequently and blood glucose (or fingerstick glucose) can be measured hourly. Severely decompensated diabetes should be managed in the ICU. Admit the patient to the ICU if: • the patient has hemodynamic instability; • the patient is unable to defend the airway (this patient should be promptly intubated); • the patient is obtunded (this patient should also be promptly intubated); • abdominal distention, acute abdominal signs, or symptoms suggestive of acute gastric dilatation are present (surgical consultation should be considered for these patients); • insulin infusions cannot be administered on the ward; • monitoring cannot be provided on the ward; or • the patient has a co-morbid disease such as sepsis, myocardial infarction, or trauma. Emergency Medicine Practice 5.* 6. 7. 8. 9. 10. 11. 20 No authors listed. Diabetes: 1991 vital statistics. Alexandria, VA: American Diabetes Association; 1991. (Statistical compilation) Fishbein H, Palumbo PJ. Acute metabolic complications in diabetes. In: Diabetes in America. Washington, DC, NIH Publication No. 95-1468, 283-291. (Statistical compilation) Carroll P, Matz R. Uncontrolled diabetes mellitus in adults: experience in treating diabetic ketoacidosis and hyperosmolar nonketotic coma with low-dose insulin and a uniform treatment regimen. Diabetes Care 1983 Nov-Dec;6(6):579-585. (Retrospective; 275 cases) Kitabchi AE, Umpierrez GE, Murphy MB; American Diabetes Association. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care 2003 Jan;26 Suppl 1:S109-S117. (Review) Rewers A, Chase HP, Mackenzie T, et al. Predictors of acute complications in children with type I diabetes. JAMA 2002 May 15;287(19):25112518. (Prospective cohort over four years; 1243 patients) Bratton SL, Krane EJ. Diabetic ketoacidosis: pathophysiology, management and complications. J Intensive Care Med 1992;7:199-211. (Review) Krane EJ, Rockoff MA, Wallman JK, et al. Subclinical brain swelling in children during treatment of diabetic ketoacidosis. N Engl J Med 1985 May 2;312(18):1147-1151. (Convenience sampling; 6 children—shows that even asymptomatic children may have signs of cerebral edema on CT scan) Glaser N, Barnett P, McCaslin I, et al; Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. N Engl J Med 2001 Jan 25;344(4):264-269. (Retrospective, case-control; 61 children) Boden G. Glucagonomas and insulinomas. Gastroenterol Clin North Am 1989 Dec;18(4):831-845. (Review) Kukreja A, Maclaren NK. Autoimmunity and diabetes. J Clin Endocrinol Metab 1999 Dec;84(12):4371-4378. (Review) Decochez K, Keymeulen B, Somers G, et al; Belgian Diabetes Registry. Use of an islet cell antibody assay to identify type I diabetic patients with rapid decrease in C-peptide levels after clinical onset. Belgian www.empractice.net • February 2004 13. 14. 15. 16.* 17. 18. 19.* 20. 21. 22. 23. 24. 25. 26. 27.* 28. 29. 30. 31. 32. 33. 34.* 35. 36. 37. 38. February 2004 • www.empractice.net 39. 21 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC 12. North Am 1995 Jan;79(1):39-52. (Review) Khardori R, Soler NG. Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22 cases and brief review. Am J Med 1984 Nov;77(5):899-904. (Review, case report) 40. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine (Baltimore) 1972 Mar;51(2):73-94. (Retrospective; 37 cases) 41. Wachtel TJ, Silliman RA, Lamberton P. Prognostic factors in the diabetic hyperosmolar state. J Am Geriatr Soc 1987 Aug;35(8):737-741. (Retrospective; 135 patients) 42. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995 Jan;79(1):39-52. (Review) 43. Umpierrez GE, Khajavi M, Kitabchi AE. Review: diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Am J Med Sci 1996 May;311(5):225-233. (Review) 44. Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, et al. Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med 1991 Nov-Dec;6(6):495-502. (Retrospective; 613 patients) 45. Ellemann K, Soerensen JN, Pedersen L, et al. Epidemiology and treatment of diabetic ketoacidosis in a community population. Diabetes Care 1984 Nov-Dec;7(6):528-532. (Epidemiological statistical review) 46. Umpierrez GE, Kelly JP, Navarrete JE, et al. Hyperglycemic crises in urban blacks. Arch Intern Med 1997 Mar 24;157(6):669-675. (Prospective; 144 patients) 47. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001 Jan;24(1):131-153. (Review) 48.* No authors listed. American Diabetes Association. Position statement: hyperglycemic crises in patients with diabetes mellitus. Diabetes Care 2002;25:S100-S108. (Consensus statement, review) 49. Laffel L. Sick-day management in type I diabetes. Endocrinol Metab Clin North Am 2000 Dec;29(4):707-723. (Review) 50. Bress P, DeFronzo RA. Drugs and diabetes. Diabetes Rev 1994;2:53-84. (Review) 51. Harrison BD, Rutter TW, Taylor RT. Severe non-ketotic hyperglycaemic pre-coma in a hypertensive patient receiving diazoxide. Lancet 1972 Sep 16;2(7777):599-600. (Review, case report) 52. Ahmad S. Diltiazem and hyperglycemia-coma. J Am Coll Cardiol 1985 Aug;6(2):494. (Letter, case report) 53. Fonseca V, Phear DN. Hyperosmolar non-ketotic diabetic syndrome precipitated by treatment with diuretics. Br Med J (Clin Res Ed) 1982 Jan 2;284(6308):36-37. (Case report) 54. Hollis WC. Aggravation of diabetes mellitus during treatment with chlorothiazide. JAMA 1961 Jun 17;176:947-949. (Case report) 55. Podolsky S, Pattavina CG. Hyperosmolar nonketotic diabetic coma: a complication of propranolol therapy. Metabolism 1973 May;22(5):685693. (Case report) 56. Hiler B. Hyperglycemia and glycosuria following chlorpromazine therapy. JAMA 1956;162:1651-1652. (Case report) 57. Sypniewski E Jr, Mirtallo JM, Schneider PJ. Hyperosmolar, hyperglycemic, nonketotic coma in a patient receiving home total parenteral nutrient therapy. Clin Pharm 1987 Jan;6(1):69-73. (Case report) 58. Ennis ED, Stachl EJ, Kreisberg RA. The hyperosmolar hyperglycemic syndrome. Diabetes Rev 1994;2:115-126. (Review) 59. Axelrod L. Insulin, prostaglandins, and the pathogenesis of hypertension. Diabetes 1991 Oct;40(10):1223-1227. (Review) 60. Axelrod L. Diabetic ketoacidosis. Endocrinologist 1992;2:375-383. (Review) 61. Fulop M, Tannenbaum H, Dreyer N. Ketotic hyperosmolar coma. Lancet 1973 Sep 22;2(7830):635-639. (Retrospective; 70 cases) 62. Arieff AI, Carroll HJ. Cerebral edema and depression of sensorium in nonketotic hyperosmolar coma. Diabetes 1974 Jun;23(6):525-531. (Retrospective; 53 cases) 63. Morres CA, Dire DJ. Movement disorders as a manifestation of nonketotic hyperglycemia. J Emerg Med 1989 Jul-Aug;7(4):359-364. (Review, case report; 2 patients) 64. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995 Jan;79(1):39-52. (Review) 65. Harden CL, Rosenbaum DH, Daras M. Hyperglycemia presenting with occipital seizures. Epilepsia 1991 Mar-Apr;32(2):215-220. (Case report) 66. Duncan MB, Jabbari B, Rosenberg ML. Gaze-evoked visual seizures in nonketotic hyperglycemia. Epilepsia 1991 Mar-Apr;32(2):221-224. (Case report) 67. Slovis CM, Mork VG, Slovis RJ, et al. Diabetic ketoacidosis and Diabetes Registry. Diabetes Care 2000 Aug;23(8):1072-1078. (Case series; 172 patients) Leslie RD, Pozzilli P. Type I diabetes masquerading as type II diabetes. Possible implications for prevention and treatment. Diabetes Care 1994 Oct;17(10):1214-1219. (Review) Bliss M. The Discovery of Insulin. Chicago: University of Chicago Press; 1982:112-113. (Historical reference) White JR Jr, Campbell RK, Hirsch I. Insulin analogues: new agents for improving glycemic control. Postgrad Med 1997 Feb;101(2):58-60, 63-65, 70. (Review) Crawford PB, Story M, Wang MC, et al. Ethnic issues in the epidemiology of childhood obesity. Pediatr Clin North Am 2001 Aug;48(4):855878. (Review) No authors listed. Type II diabetes in children and adolescents. American Diabetes Association. Diabetes Care 2000 Mar;23(3):381-389. (Practice guideline, consensus statement) Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type II diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr 2000 May;136(5):664672. (Multicase review) Edelman SV. Importance of glucose control. Med Clin North Am 1998 Jul;82(4):665-687. (Review) Le Roith D, Zick Y. Recent advances in our understanding of insulin action and insulin resistance. Diabetes Care 2001 Mar;24(3):588-597. (Review) Buse JB. The use of insulin alone and in combination with oral agents in type II diabetes. Prim Care 1999 Dec;26(4):931-950. (Review) Fajans SS, Floyd JC Jr, Pek S, et al. The course of asymptomatic diabetes in young people, as determined by levels of blood glucose and plasma insulin. Trans Assoc Am Physicians 1969;82:211-224. (Historical review) Fajans SS, Floyd JC Jr, Conn JW, et al. The course of asymptomatic diabetes of children, adolescents, and young adults. Adv Metab Disord 1970;1:Suppl 1:377. (Historical review) Tattersall RB, Fajans SS. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes 1975 Jan;24(1):44-53. (Historical review) Tattersall RB. Mild familial diabetes with dominant inheritance. Q J Med 1974 Apr;43(170):339-357. (Historical review) Fajans SS. Scope and heterogeneous nature of MODY. Diabetes Care 1990 Jan;13(1):49-64. (Review) Hattersley AT. Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diabet Med 1998 Jan;15(1):15-24. (Review) Froguel P. Glucokinase and MODY: from the gene to the disease. Diabet Med 1996 Sep;13(9 Suppl 6):S96-S97. (Review) Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 2001 Sep 27;345(13):971-980. (Review) Byrne MM, Sturis J, Fajans SS, et al. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 1995 Jun;44(6):699-704. (Case-control; 10 patients) Byrne MM, Sturis J, Clement K, et al. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest 1994 Mar;93(3):1120-1130. (Case control; 6 patients) Byrne MM, Sturis J, Menzel S, et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes 1996 Nov;45(11):1503-1510. (Case control; 18 patients) Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type II diabetes. J Clin Endocrinol Metab 2003 Jul;88(7):3082-3089. (Controlled clinical trial [Phase III]; 37 patients) Fleckman AM. Diabetic ketoacidosis. Endocrinol Metab Clin North Am 1993 Jun;22(2):181-207. (Review) Kitabchi AE, Murphy MB. Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma. Med Clin North Am 1988 Nov;72(6):1545-1563. (Review) Bagdade JD, Porte D Jr, Bierman EL. Diabetic lipemia. A form of acquired fat-induced lipemia. N Engl J Med 1967 Feb 23;276(8):427-433. (Review, case report) Rumbak MJ, Hughes TA, Kitabchi AE. Pseudonormoglycemia in diabetic ketoacidosis with elevated triglycerides. Am J Emerg Med 1991 Jan;9(1):61-63. (Case report) Rose BD. Proximal tubule. In: Rose BD. Clinical Physiology of Acid-Base and Electrolyte Disorders. New York: McGraw-Hill; 1989:102. (Review) Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC infection: leukocyte count and differential as early predictors of serious infection. Am J Emerg Med 1987 Jan;5(1):1-5. (Retrospective; 153 patients) 68. Brandenburg MA, Dire DJ. Comparison of arterial and venous blood gas values in the initial emergency department evaluation of patients with diabetic ketoacidosis. Ann Emerg Med 1998 Apr;31(4):459-465. (Retrospective; 38 patients with 44 episodes of DKA) 69. Gokel Y, Paydas S, Koseoglu Z, et al. Comparison of blood gas and acid-base measurements in arterial and venous blood samples in patients with uremic acidosis and diabetic ketoacidosis in the emergency room. Am J Nephrol 2000 Jul-Aug;20(4):319-323. (Retrospective; 100 uremic patients, 21 diabetic patients, and 31 normal controls with a total of 152 venous and arterial samples) 70. Small M, Alzaid A, MacCuish AC. Diabetic hyperosmolar non-ketotic decompensation. Q J Med 1988 Mar;66(251):251-257. (Retrospective; 22 patients) 71. Levine SN, Sanson TH. Treatment of hyperglycaemic hyperosmolar non-ketotic syndrome. Drugs 1989 Sep;38(3):462-472. (Review) 72. Scibilia J, Finegold D, Dorman J, et al. Why do children with diabetes die? Acta Endocrinol Suppl (Copenh) 1986;279:326-333. (Retrospective; 55 cases) 73.* Wiggam MI, O’Kane MJ, Harper R, et al. Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management. A randomized controlled study. Diabetes Care 1997 Sep;20(9):1347-1352. (Randomized, controlled trial; 22 adult patients [11 in each study arm]) 74. Kitabchi AE, Young R, Sacks H, et al. Diabetic ketoacidosis: reappraisal of therapeutic approach. Annu Rev Med 1979;30:339-357. (Review) 75. Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med 1986 Dec;105(6):836-840. (Randomized, controlled trial; 21 adult patients) 76. Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999 Dec;27(12):2690-2693. (Retrospective; 39 patients) 77. Van Gaal L, De Leeuwen I, Beaker J. Serum potassium levels in untreated diabetic ketoacidosis. Diabetoliga 1981;21:338A. (Retrospective; 22 cases) 78. Fisher JN, Kitabchi AE. A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab 1983 Jul;57(1):177-180. (Randomized, controlled trial; 30 patients) 79. Wilson HK, Keuer SP, Lea AS, et al. Phosphate therapy in diabetic ketoacidosis. Arch Intern Med 1982 Mar;142(3):517-520. (Randomized, controlled trial; 44 patients) 80. Zipf WB, Bacon GE, Spencer ML, et al. Hypocalcemia, hypomagnesemia, and transient hypoparathyroidism during therapy with potassium phosphate in diabetic ketoacidosis. Diabetes Care 1979 MayJun;2(3):265-268. (Case report) 81. Bell DR, Woods RL, Levi JA. cis-Diamminedichloroplatinum-induced hypomagnesemia and renal magnesium wasting. Eur J Cancer Clin Oncol 1985 Mar;21(3):287-290. (Prospective; 50 patients; describes symptoms of hypomagnesemia well) 82. Pinies JA, Cairo G, Gaztambide S, et al. Course and prognosis of 132 patients with diabetic non ketotic hyperosmolar state. Diabetes Metab 1994 Jan-Feb;20(1):43-48. (Retrospective; 132 cases) 83. Carroll P, Matz R. Adult respiratory distress syndrome complicating severely uncontrolled diabetes mellitus: report of nine cases and a review of the literature. Diabetes Care 1982 Nov-Dec;5(6):574-580. (Case report; 9 patients) 84. Oh MS, Carroll HJ, Uribarri J. Mechanism of normochloremic and hyperchloremic acidosis in diabetic ketoacidosis. Nephron 1990;54(1):16. (Review) 85. Kitches CS. Concepts of hypercoagulability: A review of its development, clinical application, and recent progress. Semin Thromb Hemostas 1985;11:293-315. (Review) 86. Lavis VR, D’Souza D, Brown SD. Decompensated diabetes. New features of an old problem. Circulation 1994 Dec;90(6):3108-3112. (Review, clinical conference) 87. DeFronzo RA, Matsuda M, Barret EJ. Diabetic ketoacidosis A combined metabolic-nephrologic approach to therapy. Diabetes Rev 1994;2:209-238. (Review) 88. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 1990 Jan;13(1):22-33. (Retrospective; 69 cases) 89. Edge JA. Cerebral oedema during treatment of diabetic ketoacidosis: are we any nearer finding a cause? Diabetes Metab Res Rev 2000 SepOct;16(5):316-324. (Review) 90. Mahoney CP, Vlcek BW, DelAguila M. Risk factors for developing Emergency Medicine Practice 91.* 92. 93. 94. 95. 96. 97. 98.* 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113.* 114. 115. 22 brain herniation during diabetic ketoacidosis. Pediatr Neurol 1999 Oct;21(4):721-727. (Retrospective; 153 children) Edge JA, Hawkins MM, Winter DL, et al. The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Arch Dis Child 2001 Jul;85(1):16-22. (Prospective, population-based statistical study; 20 children with DKA and cerebral edema) Duck SC, Wyatt DT. Factors associated with brain herniation in the treatment of diabetic ketoacidosis. J Pediatr 1988 Jul;113(1 Pt 1):10-14. (Retrospective [33 cases]; case report [9 cases]) Arieff AI, Kleeman CR. Studies on mechanisms of cerebral edema in diabetic comas. Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits. J Clin Invest 1973 Mar;52(3):571-583. (Animal study) Arieff AI, Kleeman CR. Cerebral edema in diabetic comas. II. Effects of hyperosmolality, hyperglycemia and insulin in diabetic rabbits. J Clin Endocrinol Metab 1974 Jun;38(6):1057-1067. (Animal study) Rother KI, Schwenk WF 2nd. Effect of rehydration fluid with 75 mmol/L of sodium on serum sodium concentration and serum osmolality in young patients with diabetic ketoacidosis. Mayo Clin Proc 1994 Dec;69(12):1149-1153. (Retrospective; 18 episodes) Felner EI, White PC. Improving management of diabetic ketoacidosis in children. Pediatrics 2001 Sep;108(3):735-740. (Retrospective; 520 patients) Rosenbloom AL. Cerebral edema in diabetic ketoacidosis. J Clin Endocrinol Metab 2000;85:508-509. (Editorial, case report; 2 cases) Rutledge J, Couch R. Initial fluid management of diabetic ketoacidosis in children. Am J Emerg Med 2000 Oct;18(6):658-660. (Retrospective; 49 cases of DKA in 37 patients) Glasgow AM. Devastating cerebral edema in diabetic ketoacidosis before therapy. Diabetes Care 1991 Jan;14(1):77-78. (Letter, case report) Couch RM, Acott PD, Wong GW. Early onset fatal cerebral edema in diabetic ketoacidosis. Diabetes Care 1991 Jan;14(1):78-79. (Letter, case report) Edge JA, Ford-Adams ME, Dunger DB. Causes of death in children with insulin dependent diabetes 1990-96. Arch Dis Child 1999 Oct;81(4):318-323. (Retrospective; 83 deaths caused by diabetes) Clements RS Jr, Blumenthal SA, Morrison AD, et al. Increased cerebrospinal fluid pressure during therapy for diabetic acidosis. Trans Assoc Am Physicians 1971;84:102-112. (Case report) Fein IA, Rachow EC, Sprung CL, et al. Relation of colloid osmotic pressure to arterial hypoxemia and cerebral edema during crystalloid volume loading of patients with diabetic ketoacidosis. Ann Intern Med 1982 May;96(5):570-575. (Prospective; 18 patients) Hoffman WH, Pluta RM, Fisher AQ, et al. Transcranial Doppler ultrasound assessment of intracranial hemodynamics in children with diabetic ketoacidosis. J Clin Ultrasound 1995 Nov-Dec;23(9):517-523. (Convenience sample) Hoffman WH, Steinhart CM, el Gammal T, et al. Cranial CT in children and adolescents with diabetic ketoacidosis. AJNR Am J Neuroradiol 1988 Jul-Aug;9(4):733-739. (Convenience sample; 9 patients) Hoffman WH, Casanova MF, Bauza JA, et al. Computer analysis of magnetic resonance imaging of the brain in children and adolescents after treatment of diabetic ketoacidosis. J Diabetes Complications 1999 Jul-Aug;13(4):176-181. (Convenience sample; 6 patients) Duck SC, Kohler E. Cerebral edema in diabetic ketoacidosis. J Pediatr 1981 Apr;98(4):674-676. (Letter) Franklin B, Liu J, Ginsberg-Fellner F. Cerebral edema and ophthalmoplegia reversed by mannitol in a new case of insulin-dependent diabetes mellitus. Pediatrics 1982 Jan;69(1):87-90. (Case report) Wood EG, Go-Wingkun J, Luisiri A, et al. Symptomatic cerebral swelling complicating diabetic ketoacidosis documented by intraventricular pressure monitoring: survival without neurologic sequela. Pediatr Emerg Care 1990 Dec;6(4):285-288. (Case report) Matz R. Management of the hyperosmolar hyperglycemic syndrome. Am Fam Physician 1999 Oct 1;60(5):1468-1476. (Review) Inward CD, Chambers TL. Fluid management in diabetic ketoacidosis. Arch Dis Child 2002 Jun;86(6):443-444. (Review) LaPorte RE, Matsushima M, Chang Y-F. Prevalence and incidence of insulin dependent diabetes. http://diabetes.niddk.nih.gov/dm/ pubs/America/pdf/chapter3.pdf. (Statistical analysis) Magee MF, Bhatt BA. Management of decompensated diabetes. Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Crit Care Clin 2001 Jan;17(1):75-106. (Review) U.S. preventative services task force. Screening for gestational diabetes: Recommendations and rationale. http://www.ahcpr.gov/clinic/ 3rduspstf/gdmrr.pdf. (Consensus practice guidelines) Delaney MF, Zisman A, Kettyle WM. Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Endocrinol Metab www.empractice.net • February 2004 23. Ketoacidosis: a. is profound in DKA but is minimal in HHS. b. is profound in HHS but is minimal in DKA. c. is profound in both DKA and HHS. d. rarely occurs except in severe cases of DKA. 24. Dehydration: a. is severe in DKA but is minimal in HHS. b. is severe in HHS but is minimal in DKA. c. is severe in both DKA and HHS. d. rarely occurs in hyperglycemic disorders. 25. Neurologic symptoms such as seizures and coma: a. are common in DKA but rare in HHS. b. are common in HHS but rare in DKA. c. are common in both DKA and HHS. d. rarely occur in hyperglycemic disorders. Physician CME Questions 26. Which of the following is not a common sign/ symptom of hyperglycemia? a. Nervousness/perspiration b. Polyuria c. Polydipsia d. Fatigue and weakness 17. Type I diabetes results from a decreased secretion of insulin, and type II diabetes results from insulin resistance. a. True b. False 18. Latent autoimmune diabetes of adults: a. presents very similarly to the way diabetes presents in children. b. has a rapid onset. c. can often be managed on oral agents at first, but all patients will eventually require insulin therapy. d. is a form of type II diabetes. 27. Hyperglycemic emergencies: a. rarely occur in patients with previously undiagnosed diabetes. b. are associated with very low morbidity. c. often occur in conjunction with other illnesses or infection. d. rarely require hospital admission. 19. Prolonged hyperglycemia in the type II diabetic can cause all of the following except: a. obesity. b. type I diabetes. c. high blood pressure. d. renal failure. 28. Which of the following medications is not known to cause or complicate diabetes? a. Glucocorticosteroids (methylprednisolone, prednisone) b. NSAIDs c. High blood pressure medications (furosemide, clonidine, and thiazide diuretics) d. Drugs with hormonal activity (oral contraceptives, thyroid hormone, and progestins) 20. Oral medications for type II diabetes work by: a. causing the pancreas to make more insulin. b. making the tissues more sensitive to the effects of insulin. c. decreasing hepatic output of glucose. d. decreasing absorption of glucose from the gut. e. any of the above. 29. Which of the following factors may prevent a patient from receiving adequate insulin? a. Lack of funds to buy insulin, syringes, etc. b. Psychological problems, including eating disorders or dementia c. Recent changes in diet or exercise d. Recent illness, especially if the patient is unable to eat normally e. Any of the above 21. Which of the following is not known to cause diabetes? a. Pancreatic disorders, including pancreatic cancer, chronic pancreatitis, hemachromatosis, and cystic fibrosis b. Pregnancy c. Use of glucocorticosteroids such as methylprednisolone or prednisone d. Vegetarianism 30. Laboratory findings of a glucose level greater than 250 mg/dL, a pH less than 7.35, a serum bicarbonate of 12-15 mEq/L, a high anion gap, and positive ketones suggest: a. DKA. b. HHS. c. both DKA and HHS. d. neither DKA nor HHS. 22. DKA most frequently occurs in the elderly, while HHS most frequently occurs in children. a. True b. False February 2004 • www.empractice.net 23 Emergency Medicine Practice COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Clin North Am 2000 Dec;29(4):683-705, V. (Review) 116.* No authors listed. Standards of medical care in diabetes. Diabetes Care 2004 Jan;27(Suppl 1):S15-S35. (Position statement, clinical guideline) 117. White NH. Diabetic ketoacidosis in children. Endocrinol Metab Clin North Am 2000 Dec;29(4):657-682. (Review) 118.* Adler E, Paauw D. Medical myths involving diabetes. Prim Care 2003 Sep;30(3):607-618. (Review) 119. Kapoor M, Chan GZ. Fluid and electrolyte abnormalities. Crit Care Clin 2001 Jul;17(3):503-529. (Review) 120. Trence DL, Hirsch IB. Hyperglycemic crises in diabetes mellitus type 2. Endocrinol Metab Clin North Am 2001 Dec;30(4):817-831. (Review) 121. No authors listed. Inhaled insulin could become a reality soon. Diabetes Monitor http://www.diabetesmonitor.com/inhaledi.htm. (News release of phase III trials) 122. No authors listed. VA researchers develop potential gene therapy for diabetes. VA Research and Development http://www1.va.gov/resdev/ highlights/diabetes.htm. (News release of animal studies) 123. Gano S. Artificial pancreas. Energy Science News http://www.pnl.gov/ energyscience/06-01/ws.htm. (News release) COPYRIGHTED MATERIAL—DO NOT PHOTOCOPY OR DISTRIBUTE ELECTRONICALLY WITHOUT WRITTEN CONSENT OF EB PRACTICE, LLC Physician CME Information 31. DKA treatment goals are to improve tissue perfusion and correct hypovolemia; decrease the serum glucose; reverse acidosis and ketonemia; correct electrolyte imbalances; and treat coexisting disease. a. True b. False This CME enduring material is sponsored by Mount Sinai School of Medicine and has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education. Credit may be obtained by reading each issue and completing the printed post-tests administered in December and June or online single-issue post-tests administered at www.empractice.net. Target Audience: This enduring material is designed for emergency medicine physicians. 32. Cerebral edema: a. is almost always a disease of adults and rarely occurs in children. b. is more common in patients who have a low CO2, a high blood urea nitrogen, and who are then treated with bicarbonate. c. rarely requires a neurologic consult. d. is common among adults with HHS. Needs Assessment: The need for this educational activity was determined by a survey of medical staff, including the editorial board of this publication; review of morbidity and mortality data from the CDC, AHA, NCHS, and ACEP; and evaluation of prior activities for emergency physicians. Date of Original Release: This issue of Emergency Medicine Practice was published February 1, 2004. This activity is eligible for CME credit through February 1, 2007. The latest review of this material was January 9, 2004. Discussion of Investigational Information: As part of the newsletter, faculty may be presenting investigational information about pharmaceutical products that is outside Food and Drug Administration approved labeling. Information presented as part of this activity is intended solely as continuing medical education and is not intended to promote off-label use of any pharmaceutical product. Disclosure of Off-Label Usage: This issue of Emergency Medicine Practice discusses no off-label use of any pharmaceutical product. Coming in Future Issues: Acute Coronary Syndromes • Gastrointestinal Hemorrhage • Deep Venous Thrombosis Faculty Disclosure: In compliance with all ACCME Essentials, Standards, and Guidelines, all faculty for this CME activity were asked to complete a full disclosure statement. The information received is as follows: Dr. Stewart, Dr. Marco, and Dr. Mattu report no significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) discussed in this educational presentation. Class Of Evidence Definitions Each action in the clinical pathways section of Emergency Medicine Practice receives an alpha-numerical score based on the following definitions. Class I • Always acceptable, safe • Definitely useful • Proven in both efficacy and effectiveness Level of Evidence: • One or more large prospective studies are present (with rare exceptions) • High-quality meta-analyses • Study results consistently positive and compelling Class II • Safe, acceptable • Probably useful Level of Evidence: • Generally higher levels of evidence • Non-randomized or retrospective studies: historic, cohort, or case-control studies • Less robust RCTs • Results consistently positive Class III • May be acceptable • Possibly useful • Considered optional or alternative treatments Level of Evidence: • Generally lower or intermediate levels of evidence • Case series, animal studies, consensus panels • Occasionally positive results Accreditation: Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. Indeterminate • Continuing area of research • No recommendations until further research Credit Designation: Mount Sinai School of Medicine designates this educational activity for up to 4 hours of Category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit actually spent in the educational activity. Emergency Medicine Practice is approved by the American College of Emergency Physicians for 48 hours of ACEP Category 1 credit (per annual subscription). Emergency Medicine Practice has been reviewed and is acceptable for up to 48 Prescribed credit hours by the American Academy of Family Physicians. Emergency Medicine Practice has been approved for 48 Category 2-B credit hours by the American Osteopathic Association. Level of Evidence: • Evidence not available • Higher studies in progress • Results inconsistent, contradictory • Results not compelling Earning Credit: Two Convenient Methods Significantly modified from: The Emergency Cardiovascular Care Committees of the American Heart Association and representatives from the resuscitation councils of ILCOR: How to Develop EvidenceBased Guidelines for Emergency Cardiac Care: Quality of Evidence and Classes of Recommendations; also: Anonymous. Guidelines for cardiopulmonary resuscitation and emergency cardiac care. Emergency Cardiac Care Committee and Subcommittees, American Heart Association. Part IX. Ensuring effectiveness of community-wide emergency cardiac care. JAMA 1992;268(16):2289-2295. • Print Subscription Semester Program: Paid subscribers with current and valid licenses in the United States who read all CME articles during each Emergency Medicine Practice six-month testing period, complete the posttest and the CME Evaluation Form distributed with the December and June issues, and return it according to the published instructions are eligible for up to 4 hours of Category 1 credit toward the AMA Physician’s Recognition Award (PRA) for each issue. You must complete both the post-test and CME Evaluation Form to receive credit. Results will be kept confidential. CME certificates will be delivered to each participant scoring higher than 70%. • Online Single-Issue Program: Paid subscribers with current and valid licenses in the United States who read this Emergency Medicine Practice CME article and complete the online post-test and CME Evaluation Form at www.empractice.net are eligible for up to 4 hours of Category 1 credit toward the AMA Physician’s Recognition Award (PRA). You must complete both the post-test and CME Evaluation Form to receive credit. Results will be kept confidential. CME certificates may be printed directly from the Web site to each participant scoring higher than 70%. Emergency Medicine Practice is not affiliated with any pharmaceutical firm or medical device manufacturer. President and CEO: Robert Williford. Publisher: Heidi Frost. Research Editors: Ben Abella, MD, University of Chicago; Richard Kwun, MD, Mount Sinai School of Medicine. Direct all editorial or subscription-related questions to EB Practice, LLC: 1-800-249-5770 • Fax: 1-770-500-1316 • Non-U.S. subscribers, call: 1-678-366-7933 EB Practice, LLC • 305 Windlake Court • Alpharetta, GA 30022 E-mail: [email protected] • Web Site: http://www.empractice.net Emergency Medicine Practice (ISSN 1524-1971) is published monthly (12 times per year) by EB Practice, LLC, 305 Windlake Court, Alpharetta, GA 30022. Opinions expressed are not necessarily those of this publication. Mention of products or services does not constitute endorsement. This publication is intended as a general guide and is intended to supplement, rather than substitute, professional judgment. It covers a highly technical and complex subject and should not be used for making specific medical decisions. The materials contained herein are not intended to establish policy, procedure, or standard of care. Emergency Medicine Practice is a trademark of EB Practice, LLC. Copyright 2004 EB Practice, LLC. All rights reserved. No part of this publication may be reproduced in any format without written consent of EB Practice, LLC. Subscription price: $299, U.S. funds. (Call for international shipping prices.) Emergency Medicine Practice 24 www.empractice.net • February 2004