type 2 diabetes mellitus...type 2 diabetes mellitus (t2dm) is a complex, chronic metabolic disorder....

Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 9e

Chapter 224: Type 2 Diabetes Mellitus Mohammad Jalili; Mahtab Niroomand

TYPE 2 DIABETES MELLITUS

EPIDEMIOLOGY

Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic disorder. 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 increasebecause 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.3

PATHOPHYSIOLOGY

T2DM is a complex heterogeneous metabolic disorder, characterized by chronic elevation of plasma glucose levels. The pathogenesis is complex andinvolves 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 becauseof hepatic resistance to insulin action. Normally, a�er meals, glucose uptake in peripheral tissues increases and glucose production bygluconeogenesis 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 mechanisms: 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.4

Insulin resistance is the diminished tissue response to insulin at one or more sites in the complex pathways of hormone action and requires higherthan normal plasma insulin levels to maintain normoglycemia. The major sites of insulin resistance in T2DM are the liver, skeletal muscle, andadipose tissue.

Insulin secretion is usually impaired and generally insu�icient to compensate for insulin resistance.5 The mechanism behind impaired insulinrelease in T2DM is complicated and includes glucotoxic and lipotoxic e�ects, as well as deposition of amyloid within islet cells. Glucotoxicity is thenegative e�ect 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.6

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, secreted by intestinal L cells followingglucose 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 o�en 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-lymphocytepopulations.

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The classic symptoms, which are usually mild and nonspecific, include fatigue, weakness, polyuria, polydipsia, polyphagia, and blurred vision. Mostpatients with T2DM are overweight, beyond their 30s, and su�er from other comorbid conditions such as hypertension, cardiovascular disease,dyslipidemia, or polycystic ovary syndrome. Clues in the patient’s past medical history that are suggestive of diabetes mellitus include frequentsuperficial infections and slow healing of skin lesions a�er minor trauma.

Acute complications include diabetic ketoacidosis, hyperosmolar hypertonic nonketotic state, and hypoglycemia. Diabetic ketoacidosis andhyperosmolar hypertonic nonketotic state are covered elsewhere in this book (see Chapters 225 and 227), and hypoglycemia, which in most cases isactually 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 ofdiabetes may be the reason for the ED visit or may be found during review of systems and physical examination. A brief review of the manifestationsof the involvement of various organ systems by diabetes is presented in Table 224-1.

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TABLE 224-1

Chronic Complications of Type 2 Diabetes Mellitus

Organ

ComplicationsDisorders 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 a�er an ischemic insult

Peripheral vascular disease 2–4 times increased in diabetics

Limb claudication, limb ischemia and tissue loss, and amputation

A�ects tibial and peroneal arteries, as well as femoral and popliteal arteries

Renal

complications

Diabetic nephropathy A�ects 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

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 a�ect 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,

so� 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)


Organ


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)

So� 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, neurotropic ulcers, and di�iculties 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


Organ


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

CARDIOVASCULAR COMPLICATIONS

“Silent ischemia” (the absence of chest pain despite myocardial ischemia) is common in diabetic patients. It is also common for myocardialinfarction to present with atypical or less impressive symptoms such as weakness, fatigue, and confusion. Patients may su�er from pain in unusuallocations or with lower than expected severity. This may explain the increased incidence of medically unrecognized acute myocardial infarction indiabetics compared with nondiabetics (40% vs 25%).

NEUROLOGIC COMPLICATIONS

Diabetic neuropathy is a diagnosis of exclusion and should be labeled as such only a�er other forms of neuropathy, such as chronic inflammatorydemyelinating polyneuropathy, vitamin B12 deficiency, hypothyroidism, and uremia, have been excluded. The most significant morbidity associated

with diabetic neuropathy is foot ulceration.

It may be di�icult in the ED to di�erentiate the signs and symptoms of diabetic mononeuropathy from a transient ischemic attack or stroke, andimaging 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 abscessformation. Aerobic gram-positive cocci (especially Staphylococcus aureus) are the predominant pathogens. Gram-negative rods may beencountered 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. Hair and nail growth, calluses, corns, foot deformities, sensation, and vascular status(palpation of pedal and popliteal pulses) should be assessed. It is sometimes di�icult to distinguish between lower extremity ulcers resulting fromvascular insu�iciency and those due to diabetes. Venous ulcers are typically present above the malleoli with irregular borders. Arterial ulcers areo�en 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 ulcerationfound should be unroofed and probed using a blunt-ended rigid sterile probe to determine the depth. The ability to probe to bone through the ulcersuggests the strong possibility of osteomyelitis and deep-space so� tissue infection. Purulence or inflammation suggests infection, and both aerobicand anaerobic cultures should be taken from purulent drainage or material curetted from the base of the wound. Such specimens are preferable towound swab specimens, which are o�en contaminated with colonizing bacteria and o�en 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-standingulcers 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 thediagnosis of osteomyelitis in patients with diabetic foot ulcer.


Abbreviations: CI = confidence interval; LR = likelihood ratio.

*Bone biopsy is considered the gold standard.

†95% CI crosses 1.0.

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 cuto� 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)

OPHTHALMIC COMPLICATIONS

Although there are case reports of ocular hemorrhage a�er thrombolysis with streptokinase,18,19 the risk of intraocular bleeding following

thrombolytic therapy in patients with retinopathy is thought to be very low (0.05%).20

In neither the American College of Cardiology/American Heart Association21 nor the European Society of Cardiology guidelines22 for themanagement of patients with ST-segment elevation myocardial infarction has retinopathy been mentioned as the absolute or relativecontraindications to intravenous fibrinolytic therapy. Therefore, retinopathy should not be considered a contraindication. The indications andpotential complications of thrombolytic therapy should be discussed 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 hyperglycemia in the undiagnosed diabetic. It is reasonable to check the glucose levelin 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, givespecial attention to diabetes-related aspects. Assessment can include questions about prior diabetes care, presence or absence of diabetescomplications and diabetes-related comorbidities, and assessment of the patient’s knowledge about the disease. Elements of the history andphysical examination relative to T2DM are presented in Tables 224-3 and 224-4.


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 hypoglycemic 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

Diagnosis of diabetes can be done in four ways: fasting plasma glucose level; random glucose level; hemoglobin A1c (HbA1c) 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 o�en used to monitor the e�ectiveness of treatment.




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.

Current criteria for the diagnosis of diabetes are summarized in Table 224-5. Impaired fasting glucose, impaired glucose tolerance, or an HbA1c level

between 5.7% and 6.4% is usually referred to as prediabetes and denotes hyperglycemia not su�icient to meet diagnostic criteria for diabetes butsignificant for being a risk factor for future diabetes and for cardiovascular disease.

TABLE 224-5

Diagnostic Criteria for Diabetes

TestImpaired 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%

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 nonketotic state arediscussed elsewhere in this book (see Chapters 225 and 227, respectively).

The American Diabetes Association recommends that the goal of treatment in nonpregnant adults should be an HbA1c 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 224-6.25

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 A1c <7.0%

NEWLY DIAGNOSED DIABETIC IN THE EDLoading [Contrib]/a11y/accessibility-menu.js



The consensus statement on management of T2DM by the American Diabetes Association and the European Association for the Study of Diabetesrecommends metformin in combination with lifestyle changes, as well as timely augmentation of therapy with additional agents (including otheroral antidiabetic agents and insulin) to achieve recommended levels of glycemic control. This should be done in conjunction with the control of thesymptoms of acute hyperglycemia and treatment of the underlying or exacerbating conditions. Metformin can be safely initiated at a dose of 500milligrams 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 m2.24 The dose can be increased as needed in 500-milligram increments each week to a maximum of 2 grams per day. If admission isnot warranted and exacerbating factors have been sought and e�ectively addressed, however, the initiation of pharmacotherapy can also be le� tothe 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 urineoutput, weight loss, fatigue, blurred vision, or prominent neuropathic symptoms. Older patients may develop volume depletion, with acute mentalstatus changes, hypovolemic shock, and acute renal insu�iciency. Common precipitants include drug interaction with glucose-altering medications(most commonly, corticosteroids, sympathomimetics, diuretics, anticonvulsants, salicylates, and β-adrenergic receptor agonists), infections, acuteillnesses such as acute coronary syndrome or CNS ischemia, or changes in or noncompliance with the prescribed drug regimen. Volume repletion, IVregular insulin, correction of electrolyte imbalance, and specific therapies directed toward any identified underlying cause of hyperglycemia are thecomponents of treatment.

Regular human insulin is administered IV because absorption of SC insulin in a volume-depleted patient can be erratic. SC administration of insulinin non–volume-depleted patients is acceptable. Insulin lispro is an excellent alternative to regular human insulin. However, insulin lispro does notcurrently have U.S. Food and Drug Administration approval for IV administration, although many clinicians do use it. Typically, an initial bolus doseof 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 notfallen 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 tooral therapies and may be able to switch to oral agents alone a�er using insulin initially. When initial therapy with insulin can be discontinuedbecause 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 (7.8mmol/L) or higher on routine lab tests. The patient may or may not be a known diabetic. Stress and decompensation of diabetes may contribute tothe pathophysiology of this problem, or it may be iatrogenic, resulting from either inadvertent cessation of antihyperglycemic medications oradministration of hyperglycemia-inducing drugs such as glucocorticoids or vasopressors. Whatever the mechanism, emergency physicians may becalled upon to control the patient’s blood glucose. There is some evidence that in patients who are later admitted, paying careful attention to highblood 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 randomblood glucose of less than 180 mg/dL (10 mmol/L) is recommended. In most patients with T2DM admitted for an acute illness, oral hypoglycemicagents should be discontinued and insulin substituted. However, writing orders for sliding scale insulin for admitted patients can lead toundesirable levels of hypoglycemia and hyperglycemia. Sliding scale insulin should not be used for more than 12 to 24 hours, and scheduledsubcutaneous insulin therapy, consisting of basal (long- or 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 thisdose 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 current regimen should be adjusted based on the patient glycemic control status; the 0.2 to 0.5 unit/kg/day dose calculation may notbe su�icient 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 areusually treated on an outpatient basis.Loading [Contrib]/a11y/accessibility-menu.js

























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

Patients who present with new-onset T2DM without evidence of metabolic decompensation, acute hypoglycemia, or hyperglycemia and do notmeet 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 appropriate 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 sensitizationprimarily in the liver, agents that cause insulin sensitization primarily in peripheral tissues, agents that promote secretion of insulin, agents thatblock reabsorption of glucose by the kidney, and agents that slow the absorption of carbohydrates (Table 224-8). Combined formulations areavailable that mix drugs from di�erent classes of antihyperglycemic agents (metformin plus a thiazolidinedione or a secretagogue).





Abbreviation: DKA = diabetic ketoacidosis; DPP4 = dipeptidyl peptidase 4; GLP1 = glucagon-like peptide-1; SGLT2 = sodium-glucose cotransporter 2; TZD =

thiazolidinediones.

TABLE 224-8

Some Properties of Classes of Antihyperglycemic Agents

Parameter Biguanides Sulfonylureas GlinidesGlitazones

(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

E�icacy High High Modest High Modest High Intermediate Intermediate Modest

Adverse

e�ects

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

e�ects

Limits

weight

gain

None None None None Weight

loss

Weight loss,

blood

pressure

reduction

None Weight loss

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 e�ect is decreased gluconeogenesis and glucose production in the liver.29,30 Some e�ect onimproving insulin sensitivity in peripheral tissues has inconsistently been suggested. Metformin is usually started at a dose of 500 milligrams oncedaily (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 margin31; the most common adverse e�ects include nausea, diarrhea, crampyabdominal pain, metallic taste, and dysgeusia. Another rare side e�ect of metformin is lactic acidosis, which almost exclusively occurs in patientswith renal insu�iciency. Metformin is eliminated by the kidney in unchanged form and so is contraindicated in patients with an estimatedglomerular filtration rate of <30 mL/min. Because metformin does not increase insulin levels, it is not associated with a significant risk ofhypoglycemia. Other contraindications include hepatic insu�iciency, any form of acidosis, severe hypoxemia, and alcohol abuse. Take care whenadministering metformin simultaneously with nephrotoxic agents such as contrast dye. Withhold metformin for 48 hours a�er IV contrastadministration.Loading [Contrib]/a11y/accessibility-menu.js
















GLITAZONES

Glitazones (thiazolidinediones) work through binding and modulation of the activity of peroxisome proliferator–activated receptors. This nuclearreceptor influences the di�erentiation of fibroblasts into adipocytes and lowers free fatty acid levels. Thus, thiazolidinediones improve insulinsensitivity and reduce free fatty acid levels. Pioglitazone and rosiglitazone have replaced the first drug of this class, troglitazone, because they arebelieved to be safer. Thiazolidinediones are well tolerated, and their only significant adverse e�ects are weight gain and fluid retention. This class ofdrugs 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(exocytosis of insulin granules). Drugs in this class can be divided into first- and second-generation agents. First-generation sulfonylureas includechlorpropamide, tolbutamide, tolazamide, and acetohexamide. The second generation of this class includes drugs with higher potency and feweradverse e�ects and drug–drug interactions (namely, glipizide, glyburide, gliclazide, and glimepiride). Hypoglycemia and weight gain are the majoradverse e�ects of sulfonylureas (highest risk of hypoglycemia seen with glyburide), and other side e�ects 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 e�ect onfasting glucose. The maximum dose of this drug is 2 milligrams taken with each meal. Repaglinide has an almost completely biliary elimination, andtherefore, can be used safely in patients with renal insu�iciency.

Nateglinide, a phenylalanine derivative, has an even shorter duration of action than repaglinide. It has a specific e�ect on postprandial glucose andalmost no e�ect 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 ofα-glucosidases. This action delays the absorption of carbohydrates and consequently decreases the postprandial glucose peak and insulin responseto the meal. They have only a modest e�ect on blood glucose reduction and commonly cause flatulence and diarrhea. Their advantage is loweringpostprandial 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 e�ect on endogenous insulinsecretion than parenteral glucose (the so-called incretin e�ect). GLP-1 analogues (also referred to as incretin analogues or incretin mimetics) areavailable in several formulations and exert their HbA1c-lowering and weight reduction e�ects 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 presence of hyperglycemia resulting fromoral intake, leading to a low risk of hypoglycemia. Exenatide (Byetta®) is a synthetic peptide with 53% amino acid similarity to GLP-1. Exenatide isadministered at a dose of 5 to 10 micrograms twice daily as SC injection in the abdomen, thigh, or arm. Dose adjustment is necessary in patientswith 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 to1.2 milligrams once a day, so some prefer it over exenatide. This class of drug is contraindicated in the presence of medullary thyroid cancer or inthose with multiple endocrine neoplasia. Pancreatitis is a reported adverse e�ect, but the evidence is questionable. They should be withheld if thepatient 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 areadministered orally. Saxagliptin, sitagliptin, linagliptin, and vildagliptin are some of available preparations. Dipeptidyl peptidase 4 inhibitors (exceptlinagliptin) need dose adjustment in renal dysfunction. A safety alert was issued for saxagliptin in February 2014 due to possible association withheart failure. This class should be used cautiously in patients with history of pancreatitis.Loading [Contrib]/a11y/accessibility-menu.js

























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 inregulating plasma glucose. In T2DM, secretion of amylin diminishes and is delayed in advanced stages of the disease. Pramlintide is the syntheticanalogue of amylin with several metabolic e�ects: It (1) suppresses endogenous secretion of glucagon, especially in the postprandial state, therebydecreasing postprandial hepatic glucose production; (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 aspatients with T2DM who are treated with insulin but who are very vigilant with insulin dosage and blood glucose monitoring. It carries a U.S. Foodand Drug Administration black box warning; if given with insulin therapy, it can induce severe hypoglycemia, especially within 3 hours of insulinadministration.

SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS

This group of drugs, through a mechanism that is independent of insulin, inhibits sodium-glucose cotransporter 2 in the proximal nephron, therebydecreasing reabsorption of glucose and increasing glucose and sodium excretion in the urine. This leads to the reduction of HbA1c as well as systolic

and diastolic blood pressure. Due to their mechanism of action, their e�ectiveness decreases at the estimated glomerular filtration rate of less than

45 to 60 mL/min/1.73 m2. 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 taking sodium-glucose cotransporter 2inhibitors, the presence of nausea, vomiting, malaise, or metabolic acidosis should prompt the clinician to look for the presence of urine and/orserum ketones.

INSULIN

Decreased secretion of insulin due to declining β-cell function eventually makes oral antidiabetic agents ine�ective in achieving glycemic controland leads to the need for insulin therapy. Insulin can be used to supplement endogenous production of insulin both in the basal and postprandialstate. Traditionally, insulin has been used for the treatment of T2DM when nutritional therapy and oral agents have failed to control blood glucoselevels. There is, however, an increasing trend toward the initiation of insulin at an earlier stage of the disease. Besides when therapy with oral agentsfails to achieve the glycemic target, insulin may be used in the treatment of T2DM in several other situations: during the perioperative period in adiabetic patient, for treatment of acute hyperglycemic crises, and even as the initial therapy in severe hyperglycemia (blood glucose ≥300milligrams/dL or HbA1c ≥10%). There are several formulations of insulin available, with di�erent 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 initiatedor augmented in the ED for chronic complications are presented in Table 224-9, 224-10, and 224-11 and are briefly discussed below.























Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; PCSK9 = proprotein convertase subtilisin/kexin type 9.

*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.

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 a�er thrombolytic therapy felt to be very low (0.05%); discuss risks/benefits before administration

Neuropathy Improved glycemic control

Pharmacologic treatment

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



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



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 so�ener

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

LOWER EXTREMITY AND FOOT COMPLICATIONS

From a clinical standpoint, foot ulcers can be classified as non–limb-threatening, 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, andis the result of recent injury to a well-perfused limb. The patient has no signs of systemic toxicity or leukocytosis. Limb-threatening infections arecharacterized by the presence of >2 cm of surrounding cellulitis or inflammation, with associated ascending lymphangitis, deep full-thicknessulceration or abscess, a large area of necrotic tissue, involvement of deep structures or bone, gangrene adjacent to the ulcer, or critical lowerextremity ischemia (i.e., absence of palpable pulses). Life-threatening infection has clinical signs of sepsis, including fever, leukocytosis,hypotension, tachycardia, tachypnea, altered mental status, and metabolic abnormalities ranging from hypoglycemia to diabetic ketoacidosis andhyperosmolar hypertonic nonketotic state (Table 224-12).






Abbreviation: ESR = erythrocyte sedimentation rate.

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 di�erential

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 o�-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 limb-

threatening

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 di�erential

ESR

Comprehensive metabolic panel

Blood cultures

Hospital admission

Surgical debridement with resection of all

necrotic bone and so� 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

Management of foot ulcers requires a multidisciplinary approach. Principles of management include debridement of necrotic tissues, avoidance ofpressure points, management of infection (Table 224-13) and/or ischemia, management of hyperglycemia and other medical comorbidities, properwound handling, and surgery.


Abbreviation: MRSA = methicillin-resistant Staphylococcus aureus.

Note: Adjust all dosages for renal/hepatic function and monitor blood levels where appropriate.

*See the section “Lower Extremity and Foot Complications” for definitions.

†This approach is acceptable under special circumstances with close follow-up.

TABLE 224-13

Antimicrobial Therapy in Infected Diabetes-Related Lower Extremity Ulcers

Non–limb-threatening*

Cephalexin, 500 milligrams PO every 6 h, 10-d course

Or

Clindamycin, 300–450 milligrams PO every 6–8 h, 10-d course

Or

Dicloxacillin, 500 milligrams PO every 6 h, 10-d course

Or

Amoxicillin-clavulanate, 875/125 milligrams PO every 12 h, 10-d course

Or

Clarithromycin 500 milligrams PO every 12 h (in severe penicillin allergy)

Limb-threatening*

Oral regimen†:

(Ciprofloxacin or levofloxacin or moxifloxacin) plus clindamycin

Or

Trimethoprim-sulfamethoxazole plus amoxicillin-clavulanate

IV regimens:

Ampicillin-sulbactam, 3 grams every 6 h

Or

Piperacillin-tazobactam 4.5 grams every 6–8 h

Or

Clindamycin, 900 milligrams every 6 h plus

(ciprofloxacin, 400 milligrams every 8–12 h

Or

Ce�riaxone, 1 gram every 12 h)

Life-threatening*

IV regimens:

Imipenem-cilastatin, 500 milligrams every 6 h

Or

Meropenem 1 gram every 8 h

Or

Vancomycin, 15–20 milligram/kg every 12 h, plus metronidazole, 500 milligrams every 8 h, plus (aztreonam, 2 grams every 6–8 h

Or

Ciprofloxacin 400 milligrams every 8–12 h)

(if MRSA coverage is warranted)

Treatment of noninfected chronic wounds mostly relies on avoidance of weight bearing and nonadherent padded dressings. Prophylacticantibiotics are not recommended. Refer to a specialist in diabetes-related foot care within a few days to consider the need for debridement, totalcontact 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 outpatient setting with appropriate minor debridement and administration of oralantibiotic therapy (Table 224-13). Application of well-padded dressing and avoidance of pressure to the a�ected area are necessary for adequatewound healing.












Treatment of limb-threatening infections requires hospitalization, IV antibiotics (Table 224-13), and surgical debridement. Direct empiric antibioticsagainst the predominant pathogens, Staphylococcus and Streptococcus species. Include coverage for aerobic gram-negative and anaerobic bacteriafor 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 oxygentension. Immediate surgical consultation is indicated for incision and debridement, possible revascularization, or amputation.

HYPOGLYCEMIA

Hypoglycemia is o�en a complication of the treatment of diabetes mellitus. However, some cases of hypoglycemia encountered in the ED arespontaneous. 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.40

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 ofhypoglycemia in diabetics is more complex. Generally speaking, a plasma glucose concentration of ≤70 milligrams/dL (3.9 mmol/L) is o�en

considered as a reasonable threshold to alert the patient to the possibility of developing hypoglycemia.44

PATHOPHYSIOLOGY

Although the human brain depends on glucose as its primary source of energy, it is unable to synthesize or store glucose, accounting for thecommon manifestation of hypoglycemia as altered mental status. Physiologic response to low blood glucose includes suppression of insulinsecretion and release of the counterregulatory hormones (e.g., glucagon and epinephrine). These responses are modified with increasing age. Renalclearance 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 glucose 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 bloodglucose level threshold for the counterregulatory response and o�sets this protective e�ect of diabetes.

Hypoglycemia occurs most frequently with insulin and sulfonylureas. Hypoglycemia is not a common side e�ect of treatment with glitazones,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 ofhypoglycemia. Hypoglycemia is rarely, if ever, encountered in patients using only metformin. Risk factors for severe hypoglycemia in patients withT2DM include age, past history of vascular disease, renal failure, decreased food ingestion, alcohol consumption, and drug interactions. Innondiabetics, other causes such as adverse e�ects of drugs (and alcohol), factitious hypoglycemia, tumors (insulinoma or non–islet cell), criticalillness (e.g., sepsis or liver failure), and hormone deficiencies (adrenal insu�iciency or hypopituitarism) should be considered.

CLINICAL FEATURES

The clinical manifestations of hypoglycemia are divided into two broad categories: neuroglycopenic and autonomic. Autonomic findings consist ofadrenergic 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 alteredmental status. Table 224-14 lists various medical conditions that may be mistaken for hypoglycemia.










TABLE 224-14

Di�erential Diagnosis of Hypoglycemia

Stroke

Transient ischemic attack

Seizure disorder

Traumatic head injury

Brain tumor

Narcolepsy

Multiple sclerosis

Psychosis

Sympathomimetic drug ingestion

Hysteria

Altered sleep patterns and nightmares

Depression

DIAGNOSIS

Always consider hypoglycemia (in both the ED and the prehospital setting) as a potential cause of altered mental status. Failure to determine theblood glucose level early in the evaluation can result in a delayed or missed diagnosis with associated morbidity because of CNS injury orunnecessary invasive procedures and therapies. Confirm hypoglycemia with bedside glucose testing. The accuracy of bedside reflectance tests isacceptable although less reliable at extremely low and high glucose levels. Glucose values of whole blood are approximately 15% less than that ofserum or plasma. This discrepancy is a result of the relatively low glucose concentration in red blood cells. Whenever possible, send a serum sampleto the laboratory for confirmation. In diabetic patients who develop hypoglycemia while taking the usual dose of sulfonylurea, suspect anunderlying cause. Drug interactions, decreased drug metabolism, and decreased drug excretion are common precipitating causes. In nondiabeticpatients, without history of inadvertent or deliberate use of blood sugar–lowering agents, obtain a serum sample before initiation of dextrosetherapy. This sample can later be sent to the laboratory for measuring serum insulin, pro-insulin, and C-peptide, at the discretion of the consultantendocrinologist. 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 metabolizedcarbohydrates (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 a�er 15 minutes if hypoglycemia persists. When blood glucose reaches 70milligrams/dL and the patient regains consciousness, continue carbohydrates to prevent recurrence of hypoglycemia. This can be accomplishedthrough PO administration of long-acting carbohydrates. If blood glucose is normalized but the patient is still unconscious or receiving nothing bymouth, provide a continuous IV infusion of dextrose (5% dextrose in water at a rate to maintain the serum glucose >100 milligrams/dL [5.55mmol/L]). Check blood glucose every 30 minutes for the first 2 hours, looking for rebound hypoglycemia. If hyperglycemia is maintained by slowadministration 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 insu�iciency. Hypoglycemia resulting from sulfonylureas is much more challenging than insulin-inducedhypoglycemia. Hemodialysis and charcoal hemoperfusion, although mentioned in case reports, are not routinely recommended for sulfonylureaoverdose.

Since sulfonylureas cause glucose-stimulated insulin secretion, glucose administration may potentially aggravate hypoglycemia in these cases.Octreotide is a somatostatin analog and is able to suppress insulin secretion immediately and negates the e�ects of the sulfonylurea. It can be usedsuccessfully for the treatment of sulfonylurea-induced hypoglycemia and is believed to be superior to glucose and diazoxide in preventing recurrenthypoglycemia. The ideal dosage and interval of octreotide are not well defined. Recommendations vary from a single 50- to 100-microgram SCinjection a�er a single hypoglycemic episode, to serial SC injections (50 to 100 micrograms every 6 to 8 hours) or constant IV infusion (125micrograms/h) a�er a second hypoglycemic episode. Some suggest that the addition of octreotide, 50 micrograms SC, to standard therapy may

result in a decrease in frequency of hypoglycemic episodes and an increase in mean plasma glucose.45,46 Octreotide is only recommended a�erLoading [Contrib]/a11y/accessibility-menu.js




1.

2.

3.

4.

5.

6.

7.

8.

9.

initial glucose therapy has been initiated for sulfonylurea-induced hypoglycemia and can be considered when the response to dextrose isinadequate. It is primarily used to reduce the risk of recurrent hypoglycemia.

Glucagon is a U.S. Food and Drug Administration–approved alternative that may be used SC or IM in the absence of IV access. SC injection of thispolypeptide hormone can cause an approximate 100 milligram/dL (5.55 mmol/L) increase in serum glucose of hypoglycemic patients. Response toglucagon therapy is generally slower when compared with IV dextrose, requiring 7 to 10 minutes for normalization of mental status. Additionally, theresponse to glucagon administration may be short lived. In adults, glucagon is administered at the dose of 1 milligram as an SC or IM injection.

Intranasal glucagon has also been used safely in some studies for the treatment of hypoglycemia.46 In patients who are thought to be glycogen-depleted (such as heavy alcohol users or marathon runners a�er the race), glucagon therapy is not recommended. Glucagon is not recommendedfor sulfonylurea-induced hypoglycemia.

Diazoxide has also been used in the treatment of refractory sulfonylurea-induced hypoglycemia. It acts by directly inhibiting insulin secretion frompancreatic β cells. Diazoxide may cause hypotension and so should be administered as a slow IV infusion (300 milligrams over 30 minutes every 4hours).

DISPOSITION AND FOLLOW-UP

Patients who experience hypoglycemia due to sulfonylureas, non–short-acting insulins, or meglitinides should be admitted for serial glucosemonitoring and treatment. A patient with an isolated episode of accidental hypoglycemia not resulting from oral hypoglycemic agents of long-

acting insulins, who has reliable follow-up, may be discharged from the ED upon completion of an uneventful 4-hour observation period.46

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http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf (World Health Organization: Global Report on Diabetes, 2016.)Accessed on February 9, 2018.

https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf (Centers for Disease Control and Prevention: NationalDiabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2017.) AccessedNovember 25, 2017.

Forst T, Heise T, Plum-Morschel L: Pharmacological intervention in type 2 diabetes mellitus: a pathophysiologically reasoned approach? CurrDiabetes Rev 12: 429, 2016. [PubMed: 27296043]

American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 32(Suppl 1): S62, 2009. [PubMed: PMC2613584]

Cerf ME: Beta cell dysfunction and insulin resistance. Front Endocrinol 4: 37, 2013. [PubMed: PMC3608918]

Bagger JI, Knop FK, Lund A, et al: Impaired regulation of the incretin e�ect in patients with type 2 diabetes. J Clin Endocrinol Metab 96: 737,2011. [PubMed: 21252240]

Petrie JR: The cardiovascular safety of incretin-based therapies: a review of the evidence. Cardiovasc Diabetol 12: 130, 2013. [PubMed: 24011363]

Paneni F, Beckman JA, Creager MA, Cosentino F: Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy:part I. Eur Heart J 34(31): 2436, 2013. [PubMed: 23641007]




http://www.ncbi.nlm.nih.gov/pubmed/21705069

http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf

https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf


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