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1424 SECTION 17: Endocrine Disorders administered in the ED. Insulin can be given even if it is not known at the time whether the patient has T1DM or T2DM. Patients with severe or symptomatic hyperglycemia should be admitted or placed in an observation unit for further glucose control and education. For patients with hyperglycemia but without ketoacidosis, a low dose of regular or rapid-acting insulin (1 unit subcutaneously for every 30 to 50 milligrams/dL above glucose of 250 to 300 milligrams/dL) may be given to reduce hyperglycemia, and a long-acting insulin (e.g., 0.1 to 0.2 units/kg of insulin glargine) should be given in the ED to prevent diabetic ketoacidosis. For patients without severe and symptomatic hyperglycemia, regular or rapid-acting insulin can be given to reduce the glucose to about 250 milligrams/dL. Then, most patients may be discharged with a pre scription for metformin and referral to their physician or clinic within 24 hours for further evaluation and care. 19,43 For further discussion of T2DM care and noninsulin antidiabetic agents such as metformin, see Chapter 224.  GLUCOCORTICOID THERAPY Patients with T1DM who are started on glucocorticoids before dis charge from the ED will likely develop hyperglycemia. They should be informed about warning signs of hyperglycemia and advised to seek close follow-up with their primary physician, with frequent monitoring of blood glucose at home and additional bolus doses of insulin. Routine increase in long-acting basal insulin dosage is not advised, as both the duration of action of the insulin as well as the steroid must be carefully considered. Although previously undiagnosed patients with diabetes may develop hyperglycemia while on glucocorticoid therapy, the hyperglycemia will often resolve spontaneously once the glucocorticoid course is completed. If hyperglycemia is persistent or symptomatic, medication may be required after failure of dietary modification and exercise.  PRAMLINTIDE Patients with T1DM who are unable to achieve optimal glucose control may also be treated with injections of prandial pramlintide in addition to prandial or continuous SC insulin. Pramlintide, a synthetic form of the hormone amylin, is produced by β-cells. Amylin promotes satiety, slows gastric emptying, aids in suppressing postprandial glucagon secretion, and reduces hemoglobin A1C levels. 5,44,45 Despite these benefits, the necessity for injection of a second prandial medication, incidence of nausea, and severe hypoglycemia, especially during dose titration, prevent the great majority of patients with T1DM from using this medication. 46,47  TRANSPLANTATION There are three methods of pancreas transplantation: simultaneous pancreas and kidney (75% of transplants), pancreas after kidney (18%), and pancreas transplant alone (7%). 48 In 2016, 215 pancreas transplants and 798 combined kidney/pancreas transplants were performed in the United States. 49 Life-long immunosuppression is required. One-year graft survival with insulin independence approaches 86% (simultaneous pancreas and kidney), 80% (pancreas after kidney), and 78% (pancreas transplant alone); 10-year graft survival is 68% (simultaneous pancreas and kidney), 46% (pancreas after kidney), and 39% (pancreas transplant alone). 48,50 Another promising modality is islet cell transplantation. The Edmonton protocol has led to insulin independence in T1DM.

(pancreas after kidney), and 78% (pancreas transplant alone); 10-year graft survival is 68% (simultaneous pancreas and kidney), 46% (pancreas after kidney), and 39% (pancreas transplant alone). 48,50 Another promising modality is islet cell transplantation. The Edmonton protocol has led to insulin independence in T1DM. 51 Insulin independence is short lived, however; 2 years after transplantation, 76% of patients again required the use of exogenous insulin. Some longitudinal studies have demonstrated insulin independence 12 years after Edmonton protocol islet cell transplant. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Type 2 Diabetes Mellitus Mohammad Jalili Mahtab Niroomand  TYPE 2 DIABETES MELLITUS EPIDEMIOLOGY Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic dis order. It is a major public health issue and an important contributor to morbidity and mortality all over the world. 1,2 Diabetes reduces the life expectancy of its victims by approximately 10 years. Mortality and morbidity increase because of increased risk of cardiovascular disease, stroke, visual impairment, renal disease, and amputations. According to the Centers for Disease Control and Prevention report on ED visits of ≥18-year-old adults in 2014, 14.2 million were reported with diabetes as any listed diagnosis. These included 245,000 visits for hypoglycemia and 207,000 for hyperglycemic crisis. PATHOPHYSIOLOGY T2DM is a complex heterogeneous metabolic disorder, characterized by chronic elevation of plasma glucose levels. The pathogenesis is complex and involves interaction of genetic and environmental factors. The most important pathophysiologic features of T2DM are decreased insulin sensitivity (insulin resistance) and impaired insulin secretion It is generally believed that, in T2DM, fasting hyperglycemia is caused by increased production of glucose by liver, which is not suppressed because of hepatic resistance to insulin action. Normally, after meals, glucose uptake in peripheral tissues increases and glucose production by gluconeogenesis and glycogenolysis decreases. Insulin acts both directly and indirectly to inhibit gluconeogenesis and glycogenolysis. In T2DM, owing to hepatic resistance to insulin, the liver is programmed to both overproduce and underuse glucose. However, postprandial hyperglycemia results from several mecha nisms: abnormal insulin secretion by pancreatic β cells in response to a meal, impaired regulation of hepatic glucose production, and reduced glucose uptake by peripheral tissues, particularly the skeletal muscle, that are insulin sensitive. Insulin resistance is the diminished tissue response to insulin at one or more sites in the complex pathways of hormone action and requires higher than normal plasma insulin levels to maintain normoglycemia. The major sites of insulin resistance in T2DM are the liver, skeletal muscle, and adipose tissue. Insulin secretion is usually impaired and generally insufficient to compensate for insulin resistance. 5 The mechanism behind impaired insulin release in T2DM is complicated and includes glucotoxic and lipotoxic effects, as well as deposition of amyloid within islet cells. Glu cotoxicity is the negative effect of prolonged and excessive glucose on β-cell function. Lipotoxicity is the exposure to increased levels of free fatty acid, which also impairs β-cell function. The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide , secreted by intestinal L cells following glucose intake, stimulate pancreatic β cells and are responsible for 50% to 70% of total insulin secretion. In people with T2DM, the incretin system is functionally impaired, 7,8 leading to hyperglycemia.

-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide , secreted by intestinal L cells following glucose intake, stimulate pancreatic β cells and are responsible for 50% to 70% of total insulin secretion. In people with T2DM, the incretin system is functionally impaired, 7,8 leading to hyperglycemia. Chronic hyperglycemia is the cornerstone of microvascular complications. Dyslipidemia and hypertension that often accompany T2DM play an important part in macrovascular complications. 9,10 The increased prevalence of infection is primarily attributed to phagocyte dysfunction, including impaired adherence, chemotaxis, phagocytosis, bacterial killing, and respiratory burst. 11 Other abnormalities include nonenzymatic glycation of immunoglobulins and reduced T-lymphocyte populations. CHAPTER Tintinalli_Sec17_p1419-1460.indd 1424 8/2/19 12:23 PM

is primarily attributed to phagocyte dysfunction, including impaired adherence, chemotaxis, phagocytosis, bacterial killing, and respiratory burst. 11 Other abnormalities include nonenzymatic glycation of immunoglobulins and reduced T-lymphocyte populations. CHAPTER Tintinalli_Sec17_p1419-1460.indd 1424 8/2/19 12:23 PM CHAPTER 224: Type 2 Diabetes Mellitus 1425 CLINICAL FEATURES The classic symptoms, which are usually mild and nonspecific, include fatigue, weakness, polyuria, polydipsia, polyphagia, and blurred vision. Most patients with T2DM are overweight, beyond their 30s, and suffer from other comorbid conditions such as hypertension, cardiovascu lar disease, dyslipidemia, or polycystic ovary syndrome. Clues in the patient’s past medical history that are suggestive of diabetes mellitus include frequent superficial infections and slow healing of skin lesions after minor trauma. Acute complications include diabetic ketoacidosis, hyperosmolar hypertonic nonketotic state, and hypoglycemia. Diabetic ketoacidosis and hyperosmolar hypertonic nonketotic state are covered elsewhere in this book (see Chapters 225 and 227), and hypoglycemia, which in most cases is actually a complication of the treatment of diabetes, is discussed separately at the end of this chapter in the “Hypoglycemia” section. Chronic complications are categorized as microvascular (retinopathy, neuropathy, and nephropathy), macrovascular (coronary artery disease, cerebrovascular disease, peripheral vascular disease), and nonvascular (including infectious) complications. One of the chronic complications of diabetes may be the reason for the ED visit or may be found dur ing review of systems and physical examination. A brief review of the manifestations of the involvement of various organ systems by diabetes is presented in Table 224-1.  CARDIOVASCULAR COMPLICATIONS “Silent ischemia” (the absence of chest pain despite myocardial isch emia) is common in diabetic patients. It is also common for myocar dial infarction to present with atypical or less impressive symptoms such as weakness, fatigue, and confusion. Patients may suffer from pain in unusual locations or with lower than expected severity. This may explain the increased incidence of medically unrecognized acute myocardial infarction in diabetics compared with nondiabetics (40% vs 25%).  NEUROLOGIC COMPLICATIONS Diabetic neuropathy is a diagnosis of exclusion and should be labeled as such only after other forms of neuropathy, such as chronic inflammatory demyelinating polyneuropathy, vitamin B 12 deficiency, hypothyroidism, and uremia, have been excluded. The most significant morbidity associated with diabetic neuropathy is foot ulceration. It may be difficult in the ED to differentiate the signs and symptoms of diabetic mononeuropathy from a transient ischemic attack or stroke, and imaging and other modalities are needed for diagnosis.  FOOT AND LOWER EXTREMITY COMPLICATIONS Diabetic foot ulceration results from interaction of many factors, including peripheral neuropathy, excessive plantar pressure, repetitive trauma, peripheral vascular disease, and wound-healing disturbances. 12-14 Ulcers act as a portal of entry for bacteria, resulting in cellulitis and abscess formation. Aerobic gram-positive cocci (especially Staphylococcus aureus) are the predominant pathogens. Gram-negative rods may be encountered in patients with chronic wounds or those who have recently received antibiotic therapy. Those with foot ischemia or gangrene may be infected with obligate anaerobic microorganisms. 14,15 Foot complaints in a diabetic require a thorough foot examination. Ulcer characteristics, including dimensions, depth, appearance (erythema, swelling, and purulence), and location, should be described.

antibiotic therapy. Those with foot ischemia or gangrene may be infected with obligate anaerobic microorganisms. 14,15 Foot complaints in a diabetic require a thorough foot examination. Ulcer characteristics, including dimensions, depth, appearance (erythema, swelling, and purulence), and location, should be described. Hair and nail growth, calluses, corns, foot deformities, sensation, and vascular status (palpation of pedal and popliteal pulses) should be assessed. It is sometimes difficult to distinguish between lower extremity ulcers resulting from vascular insufficiency and those due to diabetes. Venous ulcers are typically present above the malleoli with irregular borders. Arterial ulcers are often found on the toes or the shins, with pale, “punched-out” borders. These ulcers are typically painful in the absence of coexisting neuropathy. Diabetic ulcers, on the other hand, usually occur at areas of increased pressure (e.g., sole of the foot) or friction (due to footwear). Any ulceration found should be unroofed and probed using a blunt-ended rigid sterile probe to determine the depth. The ability to probe to bone through the ulcer suggests the strong possibility of osteomyelitis and deep-space soft tissue infection. Purulence or inflammation suggests infection, and both aerobic and anaerobic cultures should be taken from purulent drainage or material curetted from the base of the wound. Such specimens are preferable to wound swab specimens, which are often contaminated with colonizing bacteria and often do not identify the infected organism(s). The diagnosis of osteomyelitis in patients with diabetic foot ulcer remains a challenge. When the wound can be probed to the underlying bone, presence of osteomyelitis is almost certain. Radiographs, although not very sensitive, should be obtained in patients with deep or long-standing ulcers to exclude osteomyelitis, subcutaneous gas, foreign bodies, and Charcot joints. MRI can identify osteomyelitis if radiographs are negative but clinical suspicion is high. 16,17 Table 224-2 shows the diagnostic utility of physical examination, laboratory, and basic radiographic testing in the diagnosis of osteomyelitis in patients with diabetic foot ulcer.  OPHTHALMIC COMPLICATIONS Although there are case reports of ocular hemorrhage after throm bolysis with streptokinase,18,19 the risk of intraocular bleeding following thrombolytic therapy in patients with retinopathy is thought to be very low (0.05%). TABLE 224-1 Chronic Complications of Type 2 Diabetes Mellitus Organ Complications Disorders Comments Cardiovascular complications Coronary artery disease 2- to 4-fold increase in risk and worse prognosis than in nondiabetics Atypical acute coronary syndrome symptoms Heart failure 2–5 times increased risk in diabetics Risk factor–adjusted hazard ratio of 1.82 in men and 3.73 in women Diabetic cardiomyopathy Myocardium more susceptible to ischemia and less able to recover after an ischemic insult Peripheral vascular disease 2–4 times increased in diabetics Limb claudication, limb ischemia and tissue loss, and amputation Affects tibial and peroneal arteries, as well as femoral and popliteal arteries Renal complications Diabetic nephropathy Affects 5%–40% of patients with type 2 diabetes Present in approximately 7% of the cases at the time of diagnosis Triad of hypertension, albuminuria, and progressive renal failure Renal papillary necrosis Asymptomatic or symptoms similar to renal colic or acute pyelonephritis Urinalysis: necrotic fragments of renal papilla, red and white blood cells, bacteria (Continued) Tintinalli_Sec17_p1419-1460.indd 1425 8/2/19 12:23 PM

gnosis Triad of hypertension, albuminuria, and progressive renal failure Renal papillary necrosis Asymptomatic or symptoms similar to renal colic or acute pyelonephritis Urinalysis: necrotic fragments of renal papilla, red and white blood cells, bacteria (Continued) Tintinalli_Sec17_p1419-1460.indd 1425 8/2/19 12:23 PM 1426 SECTION 17: Endocrine Disorders Neurologic complications Stroke 3 times increased risk of stroke Increased risk of recurrent stroke and stroke-related dementia Chronic sensorimotor distal symmetric polyneuropathy Burning pain, electrical or stabbing sensations, paresthesia, hyperesthesia, and deep aching pain Loss of vibration, pressure, pain, and temperature sense; commonly in the legs and feet with a symmetric stocking and glove pattern Proximal motor neuropathy Weakness of the proximal muscles of the lower limbs Spontaneous or percussion-provoked muscle fasciculation Onset may be gradual or abrupt Mononeuropathies May affect a large peripheral nerve or an isolated cranial nerve Usually sudden onset with pain Due to entrapment or microvascular infarct Increased incidence of carpal tunnel syndrome Autonomic neuropathy May cause dysfunction of every part of the body Signs include resting tachycardia, orthostatic hypotension, gastroparesis, autonomic diarrhea (at least 3 weeks of increased stool frequency and/or liquidity), constipation, erectile dysfunction, neurogenic bladder Infectious complications Common infections (pneumonia, soft tissue infections, and urinary tract infections) Infectious agents usually similar to nondiabetics Some organisms more common (Staphylococcus aureus and Mycobacterium tuberculosis in pneumonia, and Candida species in urinary tract infections) Malignant otitis externa Frequently due to Pseudomonas aeruginosa, but staphylococci, fungi, and other gram-negative organisms also have been isolated Unilateral otalgia, decreased hearing, purulent ear discharge, tenderness of the pinna and periauricular area, swollen external auditory canal, and sometimes fever Tender, inflamed external auditory canal with a mass of granular-appearing tissue Can lead to osteomyelitis, meningitis, venous sinus thrombosis, or subdural empyema Emphysematous cholecystitis Fever and abdominal pain Gas within the gallbladder and biliary tree on imaging Most frequently Clostridium species in addition to streptococci, Escherichia coli, and Pseudomonas Emphysematous pyelonephritis Rare, life-threatening infection with gas production in renal parenchyma and around the kidney Fever, clinical toxicity, flank pain, and sometimes a palpable mass Rhinocerebral mucormycosis Almost exclusively occurs in diabetics Invasive fungal infection of the nasal and paranasal sinuses, sometimes involving the palate and adjacent tissues Sudden and rapidly progressive onset Periorbital or perinasal pain, blood-tinged nasal discharge, unilateral headache, increased tearing, swelling of eyelids and conjunctiva, and decreased vision Signs can include black eschar on the nasal mucosa or hard palate due to ischemia, proptosis, and, if the infection progresses, cranial nerve involvement or seizures Ophthalmologic complications Retinopathy Nonproliferative stage: • Hard exudates (accumulation of lipid in the outer plexiform layer) • Retinal hemorrhage (flame-shaped hemorrhage in the nerve fiber layer; dot-and-blot hemorrhage in deeper layers of the retina) • Soft exudates (cotton wool spots due to microinfarctions of the retina) • Venous tortuosity and beading Proliferative stage: • Neovascularization • Vitreous hemorrhage • Rubeosis iridis and the resultant glaucoma • Traction retinal detachment Eyelids and conjunctiva Recurrent styes, blepharoconjunctivitis, and xanthelasma; fatty deposits in the subcutaneous tissue of the lids Cornea Bacterial corneal ulcers,

and beading Proliferative stage: • Neovascularization • Vitreous hemorrhage • Rubeosis iridis and the resultant glaucoma • Traction retinal detachment Eyelids and conjunctiva Recurrent styes, blepharoconjunctivitis, and xanthelasma; fatty deposits in the subcutaneous tissue of the lids Cornea Bacterial corneal ulcers,  neurotropic ulcers, and difficulties with contact lenses Other Cataracts and open- and narrow-angle glaucoma Dermatologic complications Noninfectious Protracted wound healing, acanthosis nigricans, necrobiosis lipoidica, diabetic dermopathy, scleredema, and granuloma annulare Infectious Cellulitis, furuncles and carbuncles, and candidiasis Necrotizing fasciitis: typically of mixed bacterial origin, most common organisms: Streptococcus pyogenes, S. aureus, anaerobic streptococci, and Bacteroides. Fournier's gangrene Erythrasma: pruritic red-brown patch in the axilla or groin; Corynebacterium minutissimum TABLE 224-1 Chronic Complications of Type 2 Diabetes Mellitus ( Continued) Organ Complications Disorders Comments Tintinalli_Sec17_p1419-1460.indd 1426 8/2/19 12:23 PM

, anaerobic streptococci, and Bacteroides. Fournier's gangrene Erythrasma: pruritic red-brown patch in the axilla or groin; Corynebacterium minutissimum TABLE 224-1 Chronic Complications of Type 2 Diabetes Mellitus ( Continued) Organ Complications Disorders Comments Tintinalli_Sec17_p1419-1460.indd 1426 8/2/19 12:23 PM CHAPTER 224: Type 2 Diabetes Mellitus 1427 In neither the American College of Cardiology/American Heart Association21 nor the European Society of Cardiology guidelines 22 for the management of patients with ST-segment elevation myocardial infarction has retinopathy been mentioned as the absolute or relative contraindications to intravenous fibrinolytic therapy. Therefore, reti nopathy should not be considered a contraindication. The indications and potential complications of thrombolytic therapy should be dis cussed with the patient before its administration.  RENAL , DERMATOLOGIC, AND INFECTIOUS COMPLICATIONS Renal, dermatologic, and infectious complications are listed in Table 224-1. DIAGNOSIS Look for diabetes in the presence of symptoms suggestive of hypergly cemia in the undiagnosed diabetic. It is reasonable to check the glucose level in patients with certain presentations such as unexplained cellulitis, foot ulcers, frequent candidal infections, and unexplained neuropathy. When evaluating a patient with established diabetes mellitus in the ED, in addition to complaint-directed history and physical examination, give special attention to diabetes-related aspects. Assessment can include questions about prior diabetes care, presence or absence of diabetes complications and diabetes-related comorbidities, and assessment of the patient’s knowledge about the disease. Elements of the history and physical examination relative to T2DM are presented in Tables 224-3 and 224-4. Diagnosis of diabetes can be done in four ways: fasting plasma glucose level; random glucose level; hemoglobin A 1c (HbA 1c) level; or 2-hour oral glucose tolerance test. An oral glucose tolerance test is reserved for patients in whom diabetes is strongly suspected despite a normal or impaired fasting glucose. 23 HbA1c is often used to monitor the effective ness of treatment. Current criteria for the diagnosis of diabetes are summarized in Table 224-5. Impaired fasting glucose, impaired glucose tolerance, or an HbA 1c level between 5.7% and 6.4% is usually referred to as prediabetes and denotes hyperglycemia not sufficient to meet diagnostic criteria for diabetes but significant for being a risk factor for future diabetes and for cardiovascular disease. TREATMENT Treatment of T2DM can be discussed under three topics: the day-to-day prevention of hyperglycemia (long-term management of hyperglycemia); prevention and management of chronic complications; and acute therapy of severe hyperglycemia and life-threatening metabolic decompensation (i.e., hyperosmolar hypertonic nonketotic state and diabetic ketoacidosis). Diabetic ketoacidosis and hyperosmolar hypertonic non ketotic state are discussed elsewhere in this book (see Chapters 225 and 227, respectively). TABLE 224-2 Diagnostic Accuracy of Physical Examination, Laboratory, and Imaging Investigations for Lower Extremity Osteomyelitis in Patients with Diabetic Foot Ulcers * Finding Positive LR (95% CI) Negative LR (95% CI) Ulcer area >2 cm2 7.2 (1.1–49) 0.48 (0.31–0.76) Positive “probe-to-bone” test 6.4 (3.6–11) 0.39 (0.20–0.76) Erythrocyte sedimentation rate (with a cutoff of 70 mm/h) 11 (1.6–79) 0.34 (0.06–1.90) † Plain radiograph 2.3 (1.6–3.3) 0.63 (0.51–0.78) MRI 3.8 (2.5–5.8) 0.14 (0.08–0.26) Abbreviations: CI = confidence interval; LR = likelihood ratio. *Bone biopsy is considered the gold standard. †95% CI crosses 1.0.

0.39 (0.20–0.76) Erythrocyte sedimentation rate (with a cutoff of 70 mm/h) 11 (1.6–79) 0.34 (0.06–1.90) † Plain radiograph 2.3 (1.6–3.3) 0.63 (0.51–0.78) MRI 3.8 (2.5–5.8) 0.14 (0.08–0.26) Abbreviations: CI = confidence interval; LR = likelihood ratio. *Bone biopsy is considered the gold standard. †95% CI crosses 1.0. TABLE 224-3 Elements of the Medical History in Patients with Type 2 Diabetes Mellitus Key Elements of Medical History Past medical history Cardiovascular disease, hypertension, dyslipidemia, foot lesions, ophthalmologic diseases, nephropathy, neuropathy, cerebrovascular disease Prior diabetes care Type of treatment and recent changes in the regimen; prior glycated hemoglobin A1c levels; blood sugar self-monitoring results; frequency, severity, and cause of hyper- or hypoglycemi c episodes; diet and exercise history Drug history Oral antidiabetic drugs, insulin, diuretics, β-adrenergic agonists, β-adrenergic blockers, aspirin, statins Social history Smoking, substance abuse Review of systems Skin: dryness, pruritus, color changes, ulcers Weight loss GI: constipation, diarrhea, nausea, gastric fullness GU: urine, and sexual dysfunction (impotence) Visual changes Numbness, dizziness, and weakness Chest pain TABLE 224-4 Elements of the Physical Examination in Patients with Type 2 Diabetes Mellitus Key Elements of Physical Examination General Height, weight, and body mass index Vital signs Blood pressure (including orthostatic measurement) Head, eye, ear, nose, and throat examination Funduscopy (to look for hemorrhage or proliferative retinopathy); visual acuity; intraocular pressure; thyroid palpation Skin Intertriginous areas (to look for acanthosis nigricans), insulin injection sites, lancet puncture sites, nonhealing wounds, cellulitis, tinea Cardiovascular Auscultation of the carotid arteries and abdomen for bruits; assessment of peripheral pulses (especially dorsalis pedis and posterior tibial pulses) Foot examination Signs of skin breakdown on the feet, signs of infection, determination of proprioception and vibration, monofilament sensation, presence/absence of patellar and ankle reflexes, pinprick or temperature sensation TABLE 224-5 Diagnostic Criteria for Diabetes Test Impaired Fasting Glucose (milligrams/dL) Impaired Glucose Tolerance (milligrams/dL) Diabetes * (milligrams/dL) Fasting plasma glucose † 100–125 (5.5–6.9 mmol/L) — ≥126 (≥6.9 mmol/L) 2-h OGTT — 140–199 (7.8–11 mmol/L) ≥200 (≥11 mmol/L) Random ‡ plasma glucose concentration — — ≥200 (≥11 mmol/L) plus symptoms of diabetes # HgbA1c 5.7–6.4% ≥6.5% Abbreviations: HgbA1c = hemoglobin A1c; OGTT = oral glucose tolerance test (75-gram glucose load). *In the absence of unequivocal symptoms of hyperglycemia, these criteria should be confirmed on a subsequent day. †Fasting is defined as no caloric intake for at least 8 hours. ‡Random is defined as any time of the day without regard to time since last meal. #The classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss. Tintinalli_Sec17_p1419-1460.indd 1427 8/2/19 12:23 PM

ed on a subsequent day. †Fasting is defined as no caloric intake for at least 8 hours. ‡Random is defined as any time of the day without regard to time since last meal. #The classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss. Tintinalli_Sec17_p1419-1460.indd 1427 8/2/19 12:23 PM 1428 SECTION 17: Endocrine Disorders The American Diabetes Association recommends that the goal of treatment in nonpregnant adults should be an HbA 1c value <7%. Other guidelines, such as that of the American College of Endocrinology, have recommended lower levels.24 With respect to fasting, premeal, and postprandial targets, the American Diabetes Association suggestions are summarized in Table 224-6.  NEWLY DIAGNOSED DIABETIC IN THE ED The consensus statement on management of T2DM by the American Diabetes Association and the European Association for the Study of Diabetes recommends metformin in combination with lifestyle changes, as well as timely augmentation of therapy with additional agents (including other oral antidiabetic agents and insulin) to achieve recommended levels of glycemic control. This should be done in conjunction with the control of the symptoms of acute hyperglycemia and treatment of the underlying or exacerbating conditions. Metformin can be safely initiated at a dose of 500 milligrams per day for patients whose T2DM has been newly diagnosed in the ED, provided that the estimated glomerular filtration rate is ≥30 mL/min/1.73 m 2.24 The dose can be increased as needed in 500-milligram increments each week to a maxi mum of 2 grams per day. If admission is not warranted and exacerbating factors have been sought and effectively addressed, however, the initia tion of pharmacotherapy can also be left to the primary care physician at 24- to 48-hour follow-up.  ACUTE THERAPY OF SEVERE HYPERGLYCEMIA Acute hyperglycemia is defined as a blood glucose level of >300 milligrams/dL (>16.7 mmol/L). In this situation, the patient may have excessive urine output, weight loss, fatigue, blurred vision, or prominent neuropathic symptoms. Older patients may develop volume depletion, with acute mental status changes, hypovolemic shock, and acute renal insufficiency. Common precipitants include drug interac tion with glucose-altering medications (most commonly, corticoste roids, sympathomimetics, diuretics, anticonvulsants, salicylates, and β-adrenergic receptor agonists), infections, acute illnesses such as acute coronary syndrome or CNS ischemia, or changes in or noncompliance with the prescribed drug regimen. Volume repletion, IV regular insu lin, correction of electrolyte imbalance, and specific therapies directed toward any identified underlying cause of hyperglycemia are the com ponents of treatment. Regular human insulin is administered IV because absorption of SC insulin in a volume-depleted patient can be erratic. SC admin istration of insulin in non–volume-depleted patients is acceptable. Insulin lispro is an excellent alternative to regular human insulin. However, insulin lispro does not currently have U.S. Food and Drug Administration approval for IV administration, although many clini cians do use it. Typically, an initial bolus dose of 0.1 to 0.15 unit/kg IV or SC of regular human insulin or insulin lispro is given, which may be repeated in 1 to 2 hours if glucose levels have not fallen at least 50 milligrams/dL (2.8 mmol/L). Patients should have a rapid therapeutic response to insulin, and with improved glycemic control, many patients may become more responsive to oral therapies and may be able to switch to oral agents alone after using insulin initially.

to 2 hours if glucose levels have not fallen at least 50 milligrams/dL (2.8 mmol/L). Patients should have a rapid therapeutic response to insulin, and with improved glycemic control, many patients may become more responsive to oral therapies and may be able to switch to oral agents alone after using insulin initially. When initial therapy with insulin can be discontinued because of recovery from an acute illness or marked improvement of metabolic control, a standard oral therapy approach may be instituted.  MANAGEMENT OF HYPERGLYCEMIA IN ED OBSERVATION OR ED BOARDING With many admitted patients boarding in the ED for longer periods, EPs frequently encounter patients with random blood glucose of 140 mg/dL (7.8 mmol/L) or higher on routine lab tests. The patient may or may not be a known diabetic. Stress and decompensation of diabetes may contribute to the pathophysiology of this problem, or it may be iatro genic, resulting from either inadvertent cessation of antihyperglycemic medications or administration of hyperglycemia-inducing drugs such as glucocorticoids or vasopressors. Whatever the mechanism, emergency physicians may be called upon to control the patient’s blood glucose. There is some evidence that in patients who are later admitted, paying careful attention to high blood glucose levels in the ED leads to better glycemic control in the hospital. In critically ill patients, insulin infusion is usually required. The goal is to maintain blood glucose in the range of 140 to 180 mg/dL (7.8 to 10 mmol/L). More stringent control (with blood glucose <110 mg/dL [<6 mmol/L]) may actually increase mortality and is not recommended. In patients who are not in a critical condition, subcutaneous insulin with a premeal glucose target of less than 140 mg/dL (7.8 mmol/L) and random blood glucose of less than 180 mg/dL (10 mmol/L) is recom mended. In most patients with T2DM admitted for an acute illness, oral hypoglycemic agents should be discontinued and insulin substituted. However, writing orders for sliding scale insulin for admitted patients can lead to undesirable levels of hypoglycemia and hyperglycemia. Sliding scale insulin should not be used for more than 12 to 24 hours, and scheduled subcutaneous insulin therapy, consisting of basal (longor intermediate-acting) insulin, in combination with bolus/prandial (rapid- or short-acting) insulin, should be substituted. A total dose of 0.2 to 0.5 unit/kg/day is usually required based on the age and renal function of the patient. Half of this dose is administered as basal once or twice a day, and the remaining is given as prandial doses in three equally divided doses before each meal (only if the patient is eating) or every 4 to 6 hours (in patients on enteral or parenteral nutrition). If the desired target blood glucose is not achieved, correction insulin should also be added to the scheduled insulin regimen. 26-28 In noncritical diabetic patients who are already on insulin therapy, the patient’s cur rent regimen should be adjusted based on the patient glycemic control status; the 0.2 to 0.5 unit/kg/day dose calculation may not be sufficient in these cases. DISPOSITION AND FOLLOW-UP Guidelines for admission considerations are listed in Table 224-7. Diabetic patients may need admission for conditions that in nondiabetics are usually treated on an outpatient basis.

ent glycemic control status; the 0.2 to 0.5 unit/kg/day dose calculation may not be sufficient in these cases. DISPOSITION AND FOLLOW-UP Guidelines for admission considerations are listed in Table 224-7. Diabetic patients may need admission for conditions that in nondiabetics are usually treated on an outpatient basis. Patients who present with new-onset T2DM without evidence of metabolic decompensation, acute hypoglycemia, or hyperglycemia and TABLE 224-6 Glycemic Goals Parameter American Diabetes Association Recommended Target Premeal plasma glucose 80–130 milligrams/dL (4.4–7.2 mmol/L) Postprandial plasma glucose <180 milligrams/dL (<10 mmol/L) Hemoglobin A 1c <7.0% TABLE 224-7 Disposition/Guidelines for Hospital Admission Inpatient care for type 2 diabetes mellitus is generally appropriate for the following clinical situations: •   Life-threatening metabolic decompensation such as diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic state •   Severe chronic complications of diabetes, acute comorbidities, or inadequate social situation •   Hyperglycemia (>400 milligrams/dL [>22 mmol/L]) associated with severe volume depletion or refractory to appropriate interventions •   Hypoglycemia with neuroglycopenia (altered level of consciousness, altered behavior, coma, seizure) that does not rapidly resolve with correction of hypoglycemia •   Hypoglycemia resulting from long-acting oral hypoglycemic agents or hypoglycemia of unknown cause •  Fever  without an obvious source in patients with poorly controlled diabetes Tintinalli_Sec17_p1419-1460.indd 1428 8/2/19 12:23 PM

havior, coma, seizure) that does not rapidly resolve with correction of hypoglycemia •   Hypoglycemia resulting from long-acting oral hypoglycemic agents or hypoglycemia of unknown cause •  Fever  without an obvious source in patients with poorly controlled diabetes Tintinalli_Sec17_p1419-1460.indd 1428 8/2/19 12:23 PM CHAPTER 224: Type 2 Diabetes Mellitus 1429 do not meet the aforementioned criteria for admission should see their primary care provider within the week, as a general rule, to arrange for education, dietary evaluation, and initiation or refinement of appropri ate therapy for glycemic control.  ANTIDIABETIC PHARMACOTHERAPY There are several classes of antidiabetic agents. Their classification is based on mechanism of action: agents that cause insulin sensitization primarily in the liver, agents that cause insulin sensitization primar ily in peripheral tissues, agents that promote secretion of insulin, agents that block reabsorption of glucose by the kidney, and agents that slow the absorption of carbohydrates (Table 224-8). Combined formulations are available that mix drugs from different classes of antihyperglycemic agents (metformin plus a thiazolidinedione or a secretagogue). METFORMIN Metformin is the only biguanide available in the United States. Metformin activates adenosine monophosphate–activated protein kinase and hence reduces hepatic insulin resistance. The resulting effect is decreased gluconeogenesis and glucose production in the liver. 29,30 Some effect on improving insulin sensitivity in peripheral tis sues has inconsistently been suggested. Metformin is usually started at a dose of 500 milligrams once daily (with a meal) and can be titrated upward slowly to a maximum dose of 2 grams per day. Due to its short duration of action, metformin is generally taken at least twice daily. Metformin bears a wide safety margin 31; the most common adverse effects include nausea, diarrhea, crampy abdominal pain, metallic taste, and dysgeusia. Another rare side effect of metformin is lactic acidosis, which almost exclusively occurs in patients with renal insufficiency. Metformin is eliminated by the kidney in unchanged form and so is contraindicated in patients with an estimated glo merular filtration rate of <30 mL/min. Because metformin does not increase insulin levels, it is not associated with a significant risk of hypoglycemia. Other contraindications include hepatic insufficiency, any form of acidosis, severe hypoxemia, and alcohol abuse. Take care when administering metformin simultaneously with nephrotoxic agents such as contrast dye. Withhold metformin for 48 hours after IV contrast administration. GLITAZONES Glitazones (thiazolidinediones) work through binding and modula tion of the activity of peroxisome proliferator–activated receptors. This nuclear receptor influences the differentiation of fibroblasts into adipocytes and lowers free fatty acid levels. Thus, thiazolidinediones improve insulin sensitivity and reduce free fatty acid levels. Pioglitazone and rosiglitazone have replaced the first drug of this class, troglitazone, because they are believed to be safer. Thiazolidinediones are well toler ated, and their only significant adverse effects are weight gain and fluid retention. This class of drugs is contraindicated in the presence of active hepatocellular disease. Thiazolidinediones can increase the risk of bone fractures in postmenopausal women and older males. 24,32 SULFONYLUREAS Sulfonylureas are the oldest class of oral antidiabetic agents. They bind to the sulfonylurea receptor, a subunit of the adenosine triphosphate– sensitive potassium channel on plasma membrane of pancreatic β cells, causing a series of reactions, thereby leading to insulin secretion (exo cytosis of insulin granules).

AS Sulfonylureas are the oldest class of oral antidiabetic agents. They bind to the sulfonylurea receptor, a subunit of the adenosine triphosphate– sensitive potassium channel on plasma membrane of pancreatic β cells, causing a series of reactions, thereby leading to insulin secretion (exo cytosis of insulin granules). Drugs in this class can be divided into first- and second-generation agents. First-generation sulfonylureas include chlorpropamide, tolbutamide, tolazamide, and acetohexamide. The second generation of this class includes drugs with higher potency and fewer adverse effects and drug–drug interactions (namely, glipizide, glyburide, gliclazide, and glimepiride). Hypoglycemia and weight gain are the major adverse effects of sulfonylureas (highest risk of hypogly cemia seen with glyburide), and other side effects like allergic reactions, GI intolerance, hyponatremia, or alcohol flushing are very rare and drug dependent. GLINIDES Repaglinide is an insulin secretagogue, structurally distinct from the sulfonylureas. It binds to pancreatic β cells and stimulates insulin release. Repaglinide is absorbed more rapidly and thus produces faster and briefer stimulus to insulin secretion. However, it has a prolonged effect on fasting glucose. The maximum dose of this drug is 2 milligrams taken with each meal. Repaglinide has an almost completely biliary elimination, and therefore, can be used safely in patients with renal insufficiency. TABLE 224-8 Some Properties of Classes of Antihyperglycemic Agents Parameter Biguanides Sulfonylureas Glinides Glitazones (TZDs) α-Glucosidase Inhibitors GLP1 Receptor Agonists SGLT2 Inhibitors DPP4 Inhibitors Amylin Mimetics Mechanism of action Suppress liver glucose production Potentiate insulin secretion Potentiate insulin secretion Improve insulin sensitivity (fat, liver, and muscle) Delay intestinal carbohydrate absorption Potentiate insulin secretion, decrease glucagon secretion, and slow gastric emptying Block glucose reabsorption by the kidney Potentiate insulin secretion and decrease glucagon secretion Decrease glucagon secretion, slow gastric emptying Examples Metformin Glyburide, glipizide, glimepiride Repaglinide, nateglinide Pioglitazone, rosiglitazone Acarbose, miglitol Exenatide, liraglutide Canaglifiozin, dapaglifiozin Sitagliptin Pramlintide Efficacy High High Modest High Modest High Intermediate Intermediate Modest Adverse effects Nausea, diarrhea, lactic acidosis (rare), vitamin B12 deficiency Hypoglycemia, weight gain Weight gain Edema, congestive heart failure, weight gain Flatulence, diarrhea Nausea, vomiting, diarrhea Genitourinary infections, euglycemic DKA Angioedema, urticaria, pancreatitis Nausea, vomiting Nonglycemic effects Limits weight gain None None None None Weight loss Weight loss, blood pressure reduction None Weight loss Abbreviation: DKA = diabetic ketoacidosis; DPP4 = dipeptidyl peptidase 4; GLP1 = glucagon-like peptide-1; SGLT2 = sodium-glucose cotransporter 2; TZD = thiazolidinediones. Tintinalli_Sec17_p1419-1460.indd 1429 8/2/19 12:23 PM

ht gain None None None None Weight loss Weight loss, blood pressure reduction None Weight loss Abbreviation: DKA = diabetic ketoacidosis; DPP4 = dipeptidyl peptidase 4; GLP1 = glucagon-like peptide-1; SGLT2 = sodium-glucose cotransporter 2; TZD = thiazolidinediones. Tintinalli_Sec17_p1419-1460.indd 1429 8/2/19 12:23 PM 1430 SECTION 17: Endocrine Disorders Nateglinide, a phenylalanine derivative, has an even shorter duration of action than repaglinide. It has a specific effect on postprandial glucose and almost no effect on fasting glucose. This drug is used as 120-milligram tablets taken with each meal. ALPHA-GLUCOSIDASE INHIBITORS Acarbose and miglitol inhibit the final step of carbohydrate digestion at the brush border of intestinal epithelium through competitive inhibition of α-glucosidases. This action delays the absorption of carbohydrates and consequently decreases the postprandial glucose peak and insulin response to the meal. They have only a modest effect on blood glucose reduction and commonly cause flatulence and diarrhea. Their advantage is lowering postprandial glucose without increasing weight or hypoglycemic risk. They should be used cautiously in patients with chronic renal disease. GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONISTS In humans, glucagon-like peptide 1 (GLP-1) mediates the process by which oral glucose has a greater stimulatory effect on endogenous insulin secretion than parenteral glucose (the so-called incretin effect). GLP-1 analogues (also referred to as incretin analogues or incretin mimetics) are available in several formulations and exert their HbA 1clowering and weight reduction effects through several mechanisms: they suppress glucagon secretion, slow gastric emptying, reduce food intake, and promote β-cell proliferation and secretion. GLP-1 analogues are used in the treatment of T2DM patients who do not achieve adequate glycemic control on metformin or the combination of metformin and another antidiabetic agent. 33-35 An important feature of GLP-1 analogues is that this class of drugs increases insulin secretion only in the pres ence of hyperglycemia resulting from oral intake, leading to a low risk of hypoglycemia. Exenatide (Byetta ® ) is a synthetic peptide with 53% amino acid similarity to GLP-1. Exenatide is administered at a dose of 5 to 10 micrograms twice daily as SC injection in the abdomen, thigh, or arm. Dose adjustment is necessary in patients with end-stage renal failure (creatinine clearance of <30 mL/min). Liraglutide (Victoza ® ) is a GLP-1 receptor agonist that is injected at a dose of 0.6 to 1.2 milligrams once a day, so some prefer it over exenatide. This class of drug is contraindicated in the presence of medullary thyroid cancer or in those with multiple endocrine neoplasia. Pancreatitis is a reported adverse effect, but the evidence is questionable. They should be withheld if the patient develops acute pancreatitis. DIPEPTIDYL PEPTIDASE 4 INHIBITORS Dipeptidyl peptidase 4 inhibitors prolong the action of native GLP-1 through inhibiting its metabolism by dipeptidyl peptidase 4. They are administered orally. Saxagliptin, sitagliptin, linagliptin, and vildagliptin are some of available preparations. Dipeptidyl peptidase 4 inhibitors (except linagliptin) need dose adjustment in renal dysfunction. A safety alert was issued for saxagliptin in February 2014 due to possible association with heart failure. This class should be used cautiously in patients with history of pancreatitis. AMYLIN ANALOGUES Amylin is a neuroendocrine peptide that is normally cosecreted with insulin from the pancreatic β cells. It has a complementary action for insulin in regulating plasma glucose. In T2DM, secretion of amylin diminishes and is delayed in advanced stages of the disease.

tients with history of pancreatitis. AMYLIN ANALOGUES Amylin is a neuroendocrine peptide that is normally cosecreted with insulin from the pancreatic β cells. It has a complementary action for insulin in regulating plasma glucose. In T2DM, secretion of amylin diminishes and is delayed in advanced stages of the disease. Pramlintide is the synthetic analogue of amylin with several metabolic effects: It (1) suppresses endogenous secretion of glucagon, especially in the post prandial state, thereby decreasing postprandial hepatic glucose produc tion; (2) reduces the rate of gastric emptying; (3) decreases appetite and induces satiety; and (4) reduces postprandial glucose levels. 36-38 Pramlintide is used as a 120-microgram SC injection at mealtime in patients with type 1 diabetes as well as patients with T2DM who are treated with insulin but who are very vigilant with insulin dosage and blood glucose monitoring. It carries a U.S. Food and Drug Administration black box warning; if given with insulin therapy, it can induce severe hypoglyce mia, especially within 3 hours of insulin administration. SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS This group of drugs, through a mechanism that is independent of insu lin, inhibits sodium-glucose cotransporter 2 in the proximal nephron, thereby decreasing reabsorption of glucose and increasing glucose and sodium excretion in the urine. This leads to the reduction of HbA 1c as well as systolic and diastolic blood pressure. Due to their mechanism of action, their effectiveness decreases at the estimated glomerular filtra tion rate of less than 45 to 60 mL/min/1.73 m 2. Canagliflozin, dapagliflozin, and empagliflozin are the available formularies in this group. Sodium-glucose cotransporter 2 inhibitors have been reported to be associated with euglycemic DKA. 39 Therefore, in diabetic patients tak ing sodium-glucose cotransporter 2 inhibitors, the presence of nausea, vomiting, malaise, or metabolic acidosis should prompt the clinician to look for the presence of urine and/or serum ketones. INSULIN Decreased secretion of insulin due to declining β-cell function eventu ally makes oral antidiabetic agents ineffective in achieving glycemic control and leads to the need for insulin therapy. Insulin can be used to supplement endogenous production of insulin both in the basal and postprandial state. Traditionally, insulin has been used for the treatment of T2DM when nutritional therapy and oral agents have failed to con trol blood glucose levels. There is, however, an increasing trend toward the initiation of insulin at an earlier stage of the disease. Besides when therapy with oral agents fails to achieve the glycemic target, insulin may be used in the treatment of T2DM in several other situations: during the perioperative period in a diabetic patient, for treatment of acute hyper glycemic crises, and even as the initial therapy in severe hyperglycemia (blood glucose ≥300 milligrams/dL or HbA 1c ≥10%). There are several formulations of insulin available, with different pharmacokinetics. See Chapter 223, “Type 1 Diabetes Mellitus, ” for detailed discussion of insulins.  PREVENTION AND MANAGEMENT OF CHRONIC COMPLICATIONS Emergency physicians can reinforce patient education and provide access to additional resources as necessary. Interventions that may be initiated or augmented in the ED for chronic complications are pre sented in Table 224-9, 224-10, and 224-11 and are briefly discussed below. LOWER EXTREMITY AND FOOT COMPLICATIONS From a clinical standpoint, foot ulcers can be classified as non–limbthreatening, limb-threatening, or life-threatening infections.

may be initiated or augmented in the ED for chronic complications are pre sented in Table 224-9, 224-10, and 224-11 and are briefly discussed below. LOWER EXTREMITY AND FOOT COMPLICATIONS From a clinical standpoint, foot ulcers can be classified as non–limbthreatening, limb-threatening, or life-threatening infections. Non– limb-threatening infection is defined as one that is small (<2 cm of surrounding cellulitis or inflammation), does not involve deep structures or bone, and is the result of recent injury to a well-perfused limb. The patient has no signs of systemic toxicity or leukocytosis. Limb-threatening infections are characterized by the presence of >2 cm of surrounding cellulitis or inflammation, with associated ascending lymphangitis, deep full-thickness ulceration or abscess, a large area of necrotic tissue, involvement of deep structures or bone, gangrene adjacent to the ulcer, or critical lower extremity ischemia (i.e., absence of palpable pulses). Life-threatening infection has clinical signs of sep sis, including fever, leukocytosis, hypotension, tachycardia, tachypnea, altered mental status, and metabolic abnormalities ranging from hypo glycemia to diabetic ketoacidosis and hyperosmolar hypertonic nonke totic state (Table 224-12). Tintinalli_Sec17_p1419-1460.indd 1430 8/2/19 12:23 PM

on has clinical signs of sep sis, including fever, leukocytosis, hypotension, tachycardia, tachypnea, altered mental status, and metabolic abnormalities ranging from hypo glycemia to diabetic ketoacidosis and hyperosmolar hypertonic nonke totic state (Table 224-12). Tintinalli_Sec17_p1419-1460.indd 1430 8/2/19 12:23 PM CHAPTER 224: Type 2 Diabetes Mellitus 1431 TABLE 224-9 Management of Diabetes Complications Complication Treatment Hypertension Lifestyle modification ACEI and ARB are the preferred agents if albuminuria is present Thiazide-like diuretics or dihydropyridine calcium channel blockers can also be used Dyslipidemia Lifestyle modifications Moderate to high-intensity statin therapy PCSK9 inhibitors in refractory cases Fibrates for extreme hypertriglyceridemia Acute coronary syndrome Same as in nondiabetic patients Nephropathy ACEI or ARB (if hypertensive) Retinopathy Optimize glucose and blood pressure control Prompt referral of patients with any level of macular edema, severe nonproliferative diabetic retinopathy, or any proliferative diabetic retinopathy Bleeding after thrombolytic therapy felt to be very low (0.05%); discuss risks/benefits before administration Neuropathy Improved glycemic control Pharmacologic treatment Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; PCSK9 = proprotein convertase subtilisin/kexin type 9. TABLE 224-11 Symptomatic Treatment of Selected Autonomic Neuropathies in Diabetic Patients Manifestation of Autonomic Neuropathy Treatment Gastroparesis Frequent small meals, prokinetic agents (e.g., metoclopramide), dietary modification Diarrhea Soluble fiber, anticholinergic agents, cholestyramine Constipation Dietary fiber supplementation, bulking agents, stool softener Neurogenic bladder Bethanechol, intermittent catheterization Erectile dysfunction Psychological counseling, phosphodiesterase inhibitors (e.g., sildenafil) Postural hypotension Increasing salt intake (in the absence of hypertension), elastic stockings, midodrine, or droxidopa Anhydrosis Scopolamine, emollients, skin lubricants TABLE 224-10 Drugs Used in the Treatment of Symptomatic Diabetic Autonomic Neuropathy Class Examples Typical Dosages* Tricyclic drugs Amitriptyline Nortriptyline Imipramine 10–75 milligrams at bedtime 25–75 milligrams at bedtime 25–75 milligrams at bedtime Anticonvulsants Gabapentin Carbamazepine Pregabalin † 300–1200 milligrams twice a day 200–400 milligrams twice a day 100 milligrams twice a day 5-Hydroxytryptamine and norepinephrine uptake inhibitor Duloxetine† 60–120 milligrams daily Substance P inhibitor Capsaicin cream 0.025%–0.075% applied twice a day or four times a day Opioids Tapentadol (extended release)† 50–250 milligrams orally twice a day *Dose response may vary; initial doses need to be low and titrated up. †Has U.S. Food and Drug Administration indication for treatment of painful diabetic neuropathy. Management of foot ulcers requires a multidisciplinary approach. Principles of management include debridement of necrotic tissues, avoidance of pressure points, management of infection ( Table 224-13) and/or ischemia, management of hyperglycemia and other medical comorbidities, proper wound handling, and surgery. Treatment of noninfected chronic wounds mostly relies on avoidance of weight bearing and nonadherent padded dressings. Prophylactic antibiotics are not recommended. Refer to a specialist in diabetes-related foot care within a few days to consider the need for debridement, total contact casting, further evaluation of any bony deformity or neuropathy, and evaluation for peripheral vascular disease.

aring and nonadherent padded dressings. Prophylactic antibiotics are not recommended. Refer to a specialist in diabetes-related foot care within a few days to consider the need for debridement, total contact casting, further evaluation of any bony deformity or neuropathy, and evaluation for peripheral vascular disease. Non–limb-threatening infections can usually be managed in the out patient setting with appropriate minor debridement and administration of oral antibiotic therapy (Table 224-13). Application of well-padded dressing and avoidance of pressure to the affected area are necessary for adequate wound healing. Treatment of limb-threatening infections requires hospitalization, IV antibiotics (Table 224-13), and surgical debridement. Direct empiric antibiotics against the predominant pathogens, Staphylococcus and Streptococcus species. Include coverage for aerobic gram-negative and anaerobic bacteria for gangrenous, ischemic, or malodorous wounds. Topical antibiotics are generally not recommended. In the absence of palpable pedal pulses, vascular ultrasonography is needed. Further studies can include the ankle-brachial index, toe pressures, or measurement of transcutaneous oxygen tension. Immediate surgical consultation is indicated for incision and debridement, possible revascularization, or amputation.  HYPOGLYCEMIA Hypoglycemia is often a complication of the treatment of diabetes mellitus. However, some cases of hypoglycemia encountered in the ED are spontaneous. Timely recognition of this diagnosis and prompt intervention, as well as initiating the workup for the etiology of the spontaneous hypoglycemic event, are important yet sometimes challenging tasks. Although there is no fixed laboratory definition of hypoglycemia, in a nondiabetic patient, it is clinically defined as follows: (1) symptoms consistent with the diagnosis; (2) symptoms associated with a low glucose level; and (3) symptoms resolve with glucose administration .41-43 The definition of hypoglycemia in diabetics is more complex. Gener ally speaking, a plasma glucose concentration of ≤70 milligrams/dL (3.9 mmol/L) is often considered as a reasonable threshold to alert the patient to the possibility of developing hypoglycemia. PATHOPHYSIOLOGY Although the human brain depends on glucose as its primary source of energy, it is unable to synthesize or store glucose, accounting for the common manifestation of hypoglycemia as altered mental status. Physiologic response to low blood glucose includes suppression of insulin secretion and release of the counterregulatory hormones (e.g., glucagon and epinephrine). These responses are modified with increasing age. Renal clearance of insulin decreases with age, and this may enhance the risk of hypoglycemia in the elderly. On the other hand, in subjects with T2DM, counterregulatory hormones are secreted at higher blood glu cose levels (compared with nondiabetics and those with type 1 diabetes mellitus), resulting in some protection against hypoglycemia in patients with T2DM. Improved glycemic control through insulin therapy lowers the blood glucose level threshold for the counterregulatory response and offsets this protective effect of diabetes. Hypoglycemia occurs most frequently with insulin and sulfonylureas. Hypoglycemia is not a common side effect of treatment with gli tazones, glinides, or α-glucosidase inhibitors. Among sulfonylureas, the risk of hypoglycemia depends on the pharmacokinetic properties of each agent. Chlorpropamide, glyburide (glibenclamide), and long-acting glipizide are long-acting sulfonylureas and are associated with more episodes of hypoglycemia. Hypoglycemia is rarely, if ever, encountered in patients using only metformin.

reas, the risk of hypoglycemia depends on the pharmacokinetic properties of each agent. Chlorpropamide, glyburide (glibenclamide), and long-acting glipizide are long-acting sulfonylureas and are associated with more episodes of hypoglycemia. Hypoglycemia is rarely, if ever, encountered in patients using only metformin. Risk factors for severe hypoglycemia in patients with T2DM include age, past history of vascular disease, renal Tintinalli_Sec17_p1419-1460.indd 1431 8/2/19 12:23 PM

reas, the risk of hypoglycemia depends on the pharmacokinetic properties of each agent. Chlorpropamide, glyburide (glibenclamide), and long-acting glipizide are long-acting sulfonylureas and are associated with more episodes of hypoglycemia. Hypoglycemia is rarely, if ever, encountered in patients using only metformin. Risk factors for severe hypoglycemia in patients with T2DM include age, past history of vascular disease, renal Tintinalli_Sec17_p1419-1460.indd 1431 8/2/19 12:23 PM 1432 SECTION 17: Endocrine Disorders failure, decreased food ingestion, alcohol consumption, and drug inter actions. In nondiabetics, other causes such as adverse effects of drugs (and alcohol), factitious hypoglycemia, tumors (insulinoma or non–islet cell), critical illness (e.g., sepsis or liver failure), and hormone deficien cies (adrenal insufficiency or hypopituitarism) should be considered. CLINICAL FEATURES The clinical manifestations of hypoglycemia are divided into two broad categories: neuroglycopenic and autonomic. Autonomic find ings consist of adrenergic symptoms (including anxiety, nervousness, irritability, nausea, vomiting, palpitations, and tremor) and cholinergic symptoms (e.g., sweating, hunger, paresthesias, and sweating). Neuroglycopenic manifestations include alterations in consciousness, lethargy, confusion, combativeness, agitation, seizures, and focal neurologic deficits. The patient is commonly found pale and diaphoretic, with some levels of altered mental status. Table 224-14 lists various medical conditions that may be mistaken for hypoglycemia. DIAGNOSIS Always consider hypoglycemia (in both the ED and the prehospi tal setting) as a potential cause of altered mental status. Failure to determine the blood glucose level early in the evaluation can result in a delayed or missed diagnosis with associated morbidity because of CNS injury or unnecessary invasive procedures and therapies. Confirm hypoglycemia with bedside glucose testing. The accuracy of bedside reflectance tests is acceptable although less reliable at extremely low and high glucose levels. Glucose values of whole blood are approximately 15% less than that of serum or plasma. This discrepancy is a result of the relatively low glucose concentration in red blood cells. Whenever possible, send a serum sample to the laboratory for confirmation. In diabetic patients who develop hypoglycemia while taking the usual dose of sulfonylurea, suspect an underlying cause. Drug interactions, decreased drug metabolism, and decreased drug excretion are com mon precipitating causes. In nondiabetic patients, without history of inadvertent or deliberate use of blood sugar–lowering agents, obtain a serum sample before initiation of dextrose therapy. This sample can later be sent to the laboratory for measuring serum insulin, pro-insulin, and C-peptide, at the discretion of the consultant endocrinologist. This simple measure obviates the need to perform a fasting test in order to diagnose the cause of hypoglycemia. TREATMENT Regardless of the cause, management of hypoglycemia in the ED includes prompt diagnosis and PO or IV administration of rapidly metabolized carbohydrates (i.e., glucose or dextrose). In patients with altered mental status, 50% dextrose in water is administered IV as a bolus dose of 50 mL, which provides 25 grams of glucose. This dose may be repeated after 15 minutes if hypoglycemia persists. When blood glucose reaches 70 milligrams/dL and the patient regains consciousness, continue carbohydrates to prevent recurrence of hypoglycemia. This can be accomplished through PO administration of long-acting carbohy drates. If blood glucose is normalized but the patient is still unconscious or receiving nothing by mouth, provide a continuous IV infusion of dextrose (5% dextrose in water at a rate to maintain the serum glu cose >100 milligrams/dL [5.55 mmol/L]). Check blood glucose every 30 minutes for the first 2 hours, looking for rebound hypoglycemia.

e is normalized but the patient is still unconscious or receiving nothing by mouth, provide a continuous IV infusion of dextrose (5% dextrose in water at a rate to maintain the serum glu cose >100 milligrams/dL [5.55 mmol/L]). Check blood glucose every 30 minutes for the first 2 hours, looking for rebound hypoglycemia. If hyperglycemia is maintained by slow administration of dextrose, the infusion may be reduced and eventually withdrawn. Failure to respond to parenteral glucose administration should prompt consideration of other causes of hypoglycemia, such as sepsis, toxin, insulinoma, hepatic failure, or adrenal insufficiency. Hypoglycemia resulting from sulfonylureas is much more challenging than insulin-induced hypoglycemia. Hemodialysis and charcoal hemoperfusion, although mentioned in case reports, are not routinely recommended for sulfonylurea overdose. Since sulfonylureas cause glucose-stimulated insulin secretion, glu cose administration may potentially aggravate hypoglycemia in these cases. Octreotide is a somatostatin analog and is able to suppress insu lin secretion immediately and negates the effects of the sulfonylurea. It can be used successfully for the treatment of sulfonylurea-induced hypoglycemia and is believed to be superior to glucose and diazoxide TABLE 224-12 Clinical Practice Pathways for Diabetic Foot Ulcer and Infection Extent of Infection Characteristics Diagnostic Procedures Treatment Non–limb-threatening infection <2 cm cellulitis Superficial ulcer Mild infection No systemic toxicity No ischemic changes No bone or joint involvement Does not probe to bone Cultures from base of ulcer (with tissue specimen if possible) Diagnostic imaging (radiography, MRI, nuclear scans as indicated) Serologic testing CBC with differential ESR Comprehensive metabolic panel Outpatient management with follow-up in 24–72 h Debridement of all necrotic tissue and callus Wound care/dressing Empiric antibiotic coverage, modified by culture findings Appropriate off-loading of weight bearing Wound care continued with packs, dressings, and debridement as needed Hospital admission if infection progresses or systemic signs or symptoms develop Refer to podiatrist for follow-up care, special shoes, and prostheses as needed Life- or limbthreatening infection >2 cm cellulitis Deep ulcer Odor or purulent drainage from wound Fever Ischemic changes Lymphangitis, edema Sepsis or septic shock Deep culture from base of ulcer/wound with tissue specimen if possible Diagnostic imaging (radiography, MRI, nuclear scan, bone scan, leukocyte scan, arteriography) Serologic testing CBC with differential ESR Comprehensive metabolic panel Blood cultures Hospital admission Surgical debridement with resection of all necrotic bone and soft tissue Exploration and drainage of deep abscess Empiric antibiotic coverage, modified by culture findings Surgical resection of osteomyelitis Wound care continued with packs, dressings, debridement as needed Foot-sparing reconstructive procedures Refer to podiatrist for follow-up care, special shoes, and prostheses as needed Abbreviation: ESR = erythrocyte sedimentation rate. Tintinalli_Sec17_p1419-1460.indd 1432 8/2/19 12:23 PM