| Diabetes Mellitus, Type 2 - A Review |
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Coauthored by Anne L Peters, MD, Director of Clinical Diabetes Program, Associate Professor, Department of Internal Medicine, University of California at Los Angeles Medical Center
Edited by William Lober, MD, Instructor, Department of Medical Education, Division of Biomedical and Health Informatics, University of Washington School of Medicine; Francisco Talavera, PharmD, PhD, Department of Pharmacy, Creighton University; Howard A Bessen, MD, Program Director, Professor, Department of Emergency Medicine, Harbor-University of California at Los Angeles Medical Center; John Halamka, MD, chief Information Officer/CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; and Barry Brenner, MD, PhD, Vice-Chair, Director, Associate Clinical Professor, Department of Emergency Medicine, Division of Research, Cornell University, The Brooklyn Hospital Center
| Author's Email: | Scott R Votey, MD | Topic Last Updated: |
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| Editor's Email: | William Lober, MD | 09/12/2000 17:38:27 |
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Background: Diabetes is a chronic disease that requires long-term medical attention to both limit the development of its devastating complications and manage them when they do occur. It is a disproportionately expensive disease; patients diagnosed with diabetes accounted for 4.6% of the US population, yet were responsible for 14.6% of all direct care expenditures in 1994. This chapter focuses on the ED evaluation and treatment of the acute and chronic complications of diabetes other than those directly associated with hypoglycemia and severe metabolic disturbances such as diabetic ketoacidosis (DKA) and hyperosmolar nonketotic syndrome(HNKS).
Pathophysiology: Two basic types of diabetes are type 1 and type 2.
Type 1 diabetes generally occurs in younger, lean patients and is characterized by the marked inability of the pancreas to secrete insulin primarily due to auto immune destruction of the beta-cells. The distinguishing characteristic of a patient with type 1 diabetes is that if insulin is withdrawn, ketosis and eventually ketoacidosis develop. These patients are, therefore, insulin-dependent (ie, insulin is life-sustaining) since they produce no endogenous insulin.
Type 2 diabetes typically occurs in individuals older than 40 years who have a family history of diabetes. Type 2 diabetes is characterized by peripheral insulin resistance with an insulin secretory defect, which varies in severity. In addition, these defects lead to increased hepatic gluconeogenesis, which produces fasting hyperglycemia. Most patients (90%) who develop type 2 diabetes are obese and obesity itself is associated with insulin resistance which further worsens the diabetic state. Since patients with type 2 diabetes retain the ability to secrete some endogenous insulin, those who are taking insulin do not develop DKA without it. Therefore, they are considered insulin-requiring, not insulin-dependent. Moreover, patients with type 2 diabetes often do not need treatment with oral antidiabetic medication or insulin if they lose weight or do not eat.
A variety of other types of diabetes exist, previously called secondary diabetes, caused by other illnesses or medications. Depending on the primary process involved (ie, destruction of pancreatic beta-cells or development of peripheral insulin resistance), patients with these types of diabetes behave similarly to patients with type 1 or type 2 diabetes. The most common are diseases of the pancreas that destroy the pancreatic beta-cell (eg, hemochromatosis, pancreatitis, cystic fibrosis, pancreatic cancer); hormonal syndromes that interfere with insulin secretion (eg, pheochromocytoma) and/or cause peripheral insulin resistance (eg, acromegaly, Cushing syndrome, pheochromocytoma) and drug-induced diabetes (eg, phenytoin, glucocorticoids, estrogens).
Maturity onset diabetes of the young (MODY) is a form of type 2 diabetes that affects many generations in the same family with onset in an individual younger than age 25 years. Several types exist.
Gestational diabetes (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. GDM complicates approximately 4% of all pregnancies in the US, although this ranges from 1-14% depending on the population studied. Untreated GDM can lead to fetal macrosomia, hypoglycemia, hypocalcemia and/or hyperbilirubinemia. In addition, mothers have a higher rate of caesarean delivery and chronic hypertension. To diagnose GDM, a 50-g screening test should be done at 24-28 weeks of gestation. This is followed by a 100-g, 3-h oral glucose tolerance test if the 1-hour postscreen plasma glucose concentration is greater than 140 mg/dl.
Frequency:
Mortality/Morbidity: The morbidity and mortality of diabetes are related to the short- and long-term complications. These complications include those of hypo- and hyperglycemia, an increased risk of infections, microvascular (ie, retinopathy and nephropathy) complications, neuropathic complications and macrovascular disease. Diabetes is the major cause of adult blindness in those aged 20-74 years, as well as the leading cause of nontraumatic lower extremity amputation and endstage renal disease.
Race: Type 2 diabetes mellitus is more prevalent among Hispanic, Native American, and African American racial groups.
Sex: Female > Male in white populations
Age: Type 2 diabetes is becoming increasingly common because more people are living longer (diabetes increases with age). It also is being seen more frequently in younger people in association with the rising prevalence of childhood obesity. Typically, diabetes occurs after the age of 40.
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History:
Physical:
Causes:
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Diabetes
Mellitus, Type 1 - A Review
Other Problems to be Considered:
Differentiating type 1 and type 2 diabetes:
It is important to
determine whether a patient has type 1 diabetes and is dependent on a continuous
source of exogenous insulin and carbohydrate for survival or if they have type 2
diabetes and may not need any treatment for hyperglycemia during periods of
fasting or decreased oral intake.
A patient who is controlled with diet
or an oral anti-diabetic agent clearly has type 2 diabetes. A lean patient with
diabetes since childhood, who has always been insulin-dependent and has a
history of DKA, is almost certainly a patient with type 1
diabetes.
Distinguishing the type of diabetes becomes harder in patients
treated with insulin who are younger and clinically appear to have type 2
diabetes as well as or older, late-onset patients taking insulin who seem more
like patients with type 1 diabetes. When in doubt, treat with insulin and follow
glucose levels closely. There are reports, however, of many patients (mostly
Hispanic or African American) who present as an adolescent or young adult with
classic DKA who subsequently are found to have type 2
diabetes.
Measurement of islet-cell and antiinsulin autoantibodies,
present in early type 1 but not type 2 diabetes, within 6 months of diagnosis
can help differentiate patients with type 1 and type 2 diabetes (the antibodies
fade after 6 months). Additionally, a fasting C-peptide level above 1 ng/dl in a
patient who has had diabetes for more than 1-2 years is suggestive of type 2
diabetes (that is, residual beta-cell function).
Additional differential:
Secondary diabetes and gestational diabetes (See Pathophysiology).
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Lab Studies:
Other Tests:
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Emergency Department Care:
Most patients with diabetes have type 2 diabetes, and most of those are asymptomatic at diagnosis. The initial treatment for patients with newly discovered asymptomatic diabetes is a trial of diet therapy. Therefore, if an asymptomatic patient is noted incidentally to have an elevated blood glucose level in the ED, this can be followed-up by the patient's outpatient physician. Patients who have mild symptoms of poorly controlled diabetes but have not previously been diagnosed, can usually be treated on an outpatient basis, often with the initiation of low-dose sulfonylurea agent therapy.
Controversy exists over the management of markedly symptomatic patients with newly discovered type 2 diabetes and blood glucose levels over 400 mg/dl. If close follow-up can be arranged, these patients can be started on maximal doses of a sulfonylurea agent and treated as outpatients. Generally, the patient feels better within 1-2 days, and within a week the blood glucose levels are markedly lower.These patients can often have their sulfonylurea agent dose tapered as they comply with diet therapy, and in some cases, diabetes can subsequently be controlled by diet alone. Patients who cannot drink adequate amounts of fluid, who have serious coexisting medical conditions (eg, myocardial infarction or systemic infection) or who do not have reliable follow-up generally should be hospitalized for initiation of therapy.
Acute hyperglycemia, even when not associated with DKA or the hyperglycemic HNKS, is harmful for a number of reasons. If the blood glucose level exceeds the renal threshold for glucose, an osmotic diuresis ensues, with loss of glucose, electrolytes and water. Hyperglycemia impairs leukocyte function through a variety of mechanisms. Patients with diabetes have an increased rate of wound infection and hyperglycemia may also independently impair wound healing.
In patients with known type 2 diabetes that is poorly controlled, there is no absolute level of blood glucose elevation that necessitates admission to the hospital or the ED administration of insulin. If the patient is severely symptomatic or if the precipitating cause of hyperglycemia cannot be adequately treated in the ED, the patient may need to be admitted. Generally, lowering the blood glucose level in the ED does not correct the underlying cause of hyperglycemia and has no long-term impact on the patient's blood glucose levels. Therefore, a plan must be formulated as to how the patient's blood glucose level will be lowered and how it will subsequently be monitored. The adequacy of follow-up is an extremely important consideration. Whether to give insulin in the ED is of lesser consequence and can be decided on an individual basis.
Serious medical illness and surgery produce a state of increased insulin resistance and relative insulin deficiency. Hyperglycemia can occur, even in nondiabetic patients, because of stress-induced insulin resistance plus the administration of dextrose-containing IV fluids. Increases of glucagon, catecholamines, cortisol, and growth hormone antagonize the effects of insulin and insulin secretion is itself inhibited by the alpha-adrenergic effect of increased catecholamine levels. The counterregulatory hormones also directly increase hepatic gluconeogenesis.
To maintain normal blood glucose levels, treatment regimens must be modified to compensate for both the decreased caloric intake and increased physiologic stress. Near-normal blood glucose levels should be maintained in medical and surgical patients with diabetes in order to do the following:
1. Prevent the development of ketosis in patients with type 1 diabetes.
2. Prevent electrolyte abnormalities and volume depletion secondary to osmotic diuresis.
3. Prevent the development of impaired leukocyte function that occurs when blood glucose levels are elevated.
4. Prevent the impaired wound healing that occurs when blood glucose levels are elevated.
A variety of approaches have been described for the management of patients with diabetes who undergo surgery, or are otherwise unable to maintain oral caloric intake. Patients with type 1 diabetes must have insulin and carbohydrate given at all times to prevent the development of ketosis. For seriously ill patients and those undergoing general anesthesia, the optimal regimen involves continuous intravenous infusions of dextrose and insulin. This technique requires that the blood glucose level be measured with a glucose meter every hour, and that the insulin and dextrose infusion rates be adjusted accordingly to prevent hypoglycemia or persistent hyperglycemia.
Frequent blood glucose monitoring is not always possible for every patient, and patients with less serious illness or those undergoing minor surgery may do just as well with subcutaneously injected insulin. In patients going to surgery who have not received a dose of intermediate-acting insulin that day, an injection of half of the patient's total daily dose as NPH insulin before surgery is often effective. At the same time, an IV infusion containing 5% dextrose should be started at a rate of 125 ml/hr. Blood glucose levels should be checked every 2 hours, and small doses of regular insulin given if values are greater than 250 mg/dl.
The same principles of providing a constant source of insulin and carbohydrate apply to patients with type 1 diabetes who are not going to surgery, but who must remain NPO due to other medical reasons. One approach is to give sliding-scale regular or lispro insulin; the dose is based on the patient's blood glucose level. To avoid hypoglycemia, the regular insulin should not be given more frequently than every 3-4 hours, since the previous doselasts up to 6 hours. Lispro insulin can be given every 3 hours.
The presence of cardiovascular disease and renal dysfunction increases surgical morbidity and mortality in patients with and without diabetes. In addition, diabetic autonomic neuropathy increases the likelihood of cardiovascular instability. The emergency physician caring for the diabetic patient who requires emergent surgery must notify the surgeon and the anesthesiologist of the patient's condition, obtain medical consultation when appropriate and promptly initiate a thorough medical evaluation so as not to delay surgery.
Infections cause considerable morbidity and mortality in patients with diabetes. Infections may precipitate metabolic derangements and, conversely, the metabolic derangements of diabetes may facilitate infection. Depending on the population studied, infections have been identified as the precipitant in 26-77% of cases of DKA.
A few infections such as malignant otitis externa, rhinocerebral mucormycosis, and emphysematous pyelonephritis occur almost exclusively in patients with diabetes. Certain infections, such as staphylococcal sepsis, occur more frequently and result in greater mortality in patients with diabetes. Others, such as pneumococcal pneumonia, affect diabetic patients no differently than the general population.
Although diabetes can compromise all aspects of host defenses against infection, not all diabetic patients are equally susceptible to infection. Impairments in humoral immunity and polymorphonuclear leukocyte and lymphocyte function are exacerbated by hyperglycemia and acidemia, but are substantially, if not entirely, reversed by normalization of pH and blood glucose levels. Although the exact level above which impaired leukocyte function occurs has not been well defined, in vitro evidence suggests that glucose levels above 250 mg/dl impair leukocyte function.
Patients with long-standing diabetes also tend to develop microvascular and macrovascular disease with resulting poor tissue perfusion and an increased risk of infection. The ability of skin to act as a barrier to infection may also be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury.
- Ear, nose and throat infections -
Two head and neck infections that are associated with high morbidity and mortality, malignant otitis externa and rhinocerebral mucormycosis, are seen almost exclusively in diabetic patients.
Malignant or necrotizing otitis externa principally occurs in diabetic patients older aged 35 years and is almost always caused by Pseudomonas aeruginosa. The infection starts in the external auditory canal and spreads to the adjacent soft tissue, cartilage and bone. Patients typically present with severe ear pain and otorrhea. Although they often have a preexisting otitis externa, the progression to invasive disease is usually rapid.
Examination of the auditory canal may reveal granulation tissue, but spread of infection to the pinna, the preauricular tissue and the mastoid often make the diagnosis apparent. Involvement of cranial nerves, particularly the facial nerve, is common; when there is extension to the meninges, the outcome is often fatal. Computed tomography (CT) scan is useful to define the extent of disease.
Prompt surgical consultation is mandatory for malignant otitis externa, since surgical debridement is often an essential part of therapy. IV antipseudomonal antibiotic therapy should be started at once in patients with invasive disease.
Diabetic patients with severe otitis externa but no evidence of invasive disease can be treated with an otic antibiotic drop and oral ciprofloxacin, but require close follow-up.
Mucormycosis is the name given collectively to the infections caused by various ubiquitous molds. Invasive disease occurs in poorly controlled diabetic patients, especially in conjunction with DKA. In these patients, the organism colonizes the nose and paranasal sinuses, spreading into adjacent tissues by invading blood vessels and causing soft tissue necrosis and bony erosion. Patients usually present with periorbital or perinasal pain and various degrees of swelling and induration. There may be a bloody nasal discharge. Involvement of the orbits with lid swelling, proptosis and diplopia is common. The nasal turbinates may appear dusky red or frankly necrotic. The appearance of black necrotic tissue is an important visual clue.
As the illness progresses, there is invasion of the cranial vault through the cribriform plate, which may result in cerebral abscess, cavernous sinus thrombosis or internal carotid artery thrombosis. Wet smears of the necrotic tissue often reveal broad hyphae and distinguish mucormycosis from a severe facial cellulitis.
CT scan helps to delineate the extent of disease. Treatment consists of control of the predisposing hyperglycemia and acidemia, IV amphotericin B and immediate surgical debridement. Until the diagnosis is confirmed, treatment with antistaphylococcal antibiotics is appropriate.
- Urinary tract infections -
Patients with diabetes have an increased risk for cystitis and, more importantly, for serious upper urinary tract infection. Intrarenal bacterial infection should be considered in the differential diagnosis of any patient with diabetes who presents with flank or abdominal pain.
The treatment of cystitis is essentially the same as in nondiabetic patients, although individuals with a neurogenic bladder due to diabetic neuropathy may not empty the bladder well and may require urologic referral. Sulfonamide antibiotics can cause hypoglycemia in patients taking sulfonylurea agents by displacing the sulfonylurea agents from their binding sites and increasing their hypoglycemic effect.
The principles of treatment of pyelonephritis do not differ for diabetic patients, but a lower threshold for hospital admission is appropriate for at least two reasons. First, pyelonephritis makes control of diabetes more difficult by causing insulin resistance; in addition, nausea may limit the patient's ability to maintain normal hydration. The ensuing hyperglycemia further compromises the immune response. Second, diabetic patients are more susceptible to the complications of pyelonephritis, including renal abscess, emphysematous pyelonephritis, renal papillary necrosis and gram-negative sepsis.
In one series, 36 of 52 patients with renal abscess had diabetes, and over 70% of cases of emphysematous pyelonephritis occur in patients with diabetes. The latter is an uncommon necrotizing infection of the kidney caused by Escherichia coli, Klebsiella pneumoniae, or other organisms capable of fermenting glucose to carbon dioxide. The presentation is usually similar to that of uncomplicated pyelonephritis.
The diagnosis is established by identifying renal gas on plain radiography or ultrasonography, and surgical intervention is indicated once the diagnosis is made.
- Skin and soft tissue infection -
Sensory neuropathy, atherosclerotic vascular disease, and hyperglycemia all predispose diabetic patients to skin and soft tissue infections. These can affect any skin surface, but most commonly involve the feet.
Even the smallest wound can be complicated by cellulitis, lymphangitis and, more ominously, staphylococcal sepsis. Minor wound infections and cellulitis are typically caused by Staphylococcus aureus or hemolytic streptococci and can be treated with a penicillinase-resistant synthetic penicillin or a first-generation cephalosporin.
Outpatient treatment of minor infections is appropriate if the patient is reliable, performs self-monitoring of blood glucose levels (and urine ketones for type 1 diabetic patients) and has close follow-up available.
Wounds and, in particular, cutaneous ulcers, can also be complicated by necrotizing infections of the skin, subcutaneous tissues, fascia, or muscle. These infections are typically polymicrobial, involving group A streptococci, enterococci, Staphylococcus aureus, Enterobacteriaceae, and various anaerobes. Radiographs should be taken of any spreading soft tissue infection in a diabetic patient to look for the soft tissue gas that characterizes these infections. Surgical debridement is necessary for necrotizing infections. Gram stains and surface cultures are not helpful; antibiotic coverage should reflect the range of potential pathogens.
- Osteomyelitis - Contiguous spread of a polymicrobial infection from skin ulcer to adjacent bone is common in diabetic patients. In one study, osteomyelitis was found underlying 68% of diabetic foot ulcers and physical examination and plain radiographs each failed to make the diagnosis in one half of patients. Unfortunately, these are typically the only diagnostic modalities available in the ED, and often the diagnosis is suspected but cannot be established.
If osteomyelitis is apparent by radiograph or physical examination (eg, if wounds are deep enough to expose tendons or bone), the patient should be admitted for IV administration of antibiotics. If osteomyelitis is suspected, but admission is not necessitated by the soft tissue infection or metabolic disturbances, the patient can be discharged to have an outpatient work-up.
- Other infections -
Although cholecystitis is probably no more common in patients with diabetes than in the general population, severe fulminating infection, especially with gas-forming organisms, is. The early clinical manifestations of emphysematous cholecystitis are indistinguishable from those of usual cholecystitis. The diagnosis can be made by finding gas in the gallbladder lumen, wall or surrounding tissues.Even with immediate surgery, mortality is high. Clostridial species are found in over 50% of cases.
Diabetic patients have a greater incidence of staphylococcal and Klebsiella pneumoniae than persons without diabetes. Diabetes is also a risk factor for reactivation of tuberculosis. Cryptococcal infections and coccidioidomycoses are more virulent in diabetic patients.
Diabetes can affect the lens, the vitreous, and the retina, causing visual symptoms that may prompt the patient to come to the ED. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations. This effect, which is caused by osmotic fluxes of water into and out of the lens as the blood glucose concentration varies, usually occurs as hyperglycemia increases but may also be seen when high blood glucose levels are lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month and some patients are almost completely unable to read small print or do close work during this period.
Patients with diabetes also tend to develop senile cataracts at a younger age than do persons without diabetes, although this is not related to the degree of glycemic control.
Whether or not patients develop diabetic retinopathy depends on the duration of their diabetes as well as the level of glycemic control maintained.Importantly, since the diagnosis of diabetes is often delayed in patients with type 2 diabetes, 20% have some degree of retinopathy at the time of diagnosis. The following are 5 stages in the progression of diabetic retinopathy:
1. Dilation of the retinal venules and formation of retinal capillary microaneurysms
2. Increased vascular permeability
3. Vascular occlusion and retinal ischemia
4. Proliferation of new blood vessels on the surface of the retina
5. Hemorrhage and contraction of the fibrovascular proliferation and the vitreous
The first 2 stages of diabetic retinopathy are known as "background" or nonproliferative retinopathy. Initially, there is dilatation of the retinal venules, followed by the appearance of microaneurysms, which appear as tiny red dots on the retina and cause no visual impairment. As the microaneurysms or retinal capillaries become more permeable, however, hard exudates appear, reflecting the leakage of plasma. Rupture of intraretinal capillaries results in hemorrhage. If a more superficial capillary ruptures, a flame-shaped hemorrhage appears. Hard exudates are often found in partial or complete rings (circinate pattern), which usually includes multiple microaneurysms. These rings usually mark an area of edematous retina. No change in visual acuity may be noted by the patient unless the center of the macula is involved. Macular edema can cause visual loss, however, so it is extremely important to refer patients with suspected macular edema to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective at decreasing macular edema and preserving vision, but is less effective in restoring vision once it is lost.
Preproliferative and proliferative diabetic retinopathy are the next stages in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts due to capillary occlusion and are off-white to gray patches with poorly defined margins.
Proliferative retinopathy is characterized by neovascularization, the development of networks of fragile new vessels that are often seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. Contraction also tears the fragile new vessels, which hemorrhage into the vitreous. Patients may notice a small hemorrhage as a "floater," although a larger hemorrhage may result in marked visual loss. Patients with reproliferative or proliferative retinopathy must be referred immediately for ophthalmologic evaluation, since laser therapy is also effective for these conditions, hopefully prior to actual hemorrhage. Patients with retinal hemorrhage should be advised to limit their activity and keep their head upright (even while sleeping) so that the blood settles to the inferior portion of the retina, thus obscuring less central vision.
Patients with active proliferative diabetic retinopathy are at increased risk for retinal hemorrhage if they receive thrombolytic therapy, so this is a relative contraindication to the use of thrombolytic agents.
End-stage renal disease (ESRD) affects 30-35% of patients with type 1 diabetes diagnosed prior to 1965 (10-15% of patients diagnosed after 1965). Since type 2 diabetes is much more common, patients with type 2 diabetes constitute the majority of diabetic patients with ESRD. All patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. Thus, extreme care should be exercised when using any nephrotoxic agent in a patient with diabetes.
The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy and although most recover within 10 days, some develop irreversible renal failure. Patients with diabetes who must undergo contrast medium-enhanced studies should be well hydrated before, during and after the procedure and should have careful monitoring of renal function. A better solution is to seek equivalent clinical information using an alternative study that does not require contrast medium administration (eg, ultrasonography).
Potentially nephrotoxic drugs should be avoided whenever possible. Renally excreted or potentially nephrotoxic drugs should be given at reduced dosage as appropriate to the patient's serum creatinine level. Since chronic blood pressure elevation contributes to the decline in renal function, it is extremely important that patients with diabetes who are found to be hypertensive be referred for chronic blood pressure management. If antihypertensive therapy is to be started in the ED, an angiotensin-converting enzyme (ACE) inhibitor is a good choice since these agents have been found to decrease proteinuria and reduce the rate of decline in renal function, independent of their effect on blood pressure. ACE inhibitors tend to increase the serum potassium level and should, thus, be used with caution in patients with renal serum insufficiency or somewhat elevated serum potassium levels.
There are many types of diabetic neuropathy, both peripheral and autonomic. Distal symmetric sensorimotor polyneuropathy (in a "glove and stocking" distribution) is the most frequent. In addition to the pain often experienced in its early stages, this type of neuropathy eventually results in the loss of peripheral sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation.
Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies, mononeuropathy multiplex, focal lesions of the brachial or lumbosacral plexus and radiculopathies. Of the cranial neuropathies, the third nerve (oculomotor) is the most commonly affected, followed by the sixth (abducens) and finally the fourth (trochlear). All can present with diplopia and eye pain. In diabetic third nerve palsy, the pupil is usually spared; whereas in third nerve palsy due to intracranial aneurysm or tumor, the pupil is affected in 80-90% of cases. It is important to consider nondiabetic causes for cranial nerve palsies because 42% have been found to be due to causes other than diabetes. Evaluation should therefore include either nonenhanced and contrast medium-enhanced CT scan or magnetic resonance imaging. Neurologic consultation is recommended. Acute cranial nerve mononeuropathies usually resolve within 2-9 months. These neuropathies are thought to be caused by acute thrombosis or ischemia of the blood vessels supplying the nervous system structure involved.
Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains and produce myriad manifestations. Patients likely to seek care in the ED include those with diabetic gastroparesis and vomiting, those with severe diarrhea and those with bladder dysfunction and urinary retention. Treatment is symptomatic and symptoms tend to wax and wane over time. Patients with gastroparesis may benefit from the use of metoclopramide, cisapride or erythromycin. Patients with disabling orthostatic hypotension may be treated with salt tablets, support stockings or 9a-fluorohydrocortiosone. Alleviating the functional abnormalities associated with the autonomic neuropathy is often difficult and frustrating for both doctor and patient. The patient's primary physician, and often an appropriate subspecialist, should be involved in devising a long-term treatment plan.
Between 50-70% of all nontraumatic lower extremity amputations occur in diabetic patients. The insensate, poorly perfused foot is at risk for ulcers from pressure necrosis or inflammation from repeated skin stress and unnoticed minor trauma. Either can evolve into cellulitis, osteomyelitis or nonclostridial gangrene and end in amputation.
Diabetic patients presenting with wounds, infections or ulcers of the foot should be treated intensively. In addition to appropriate use of antibiotics, it is mandatory to avoid further trauma to the healing foot through use of crutches, wheel chairs or bed rest. Patients should be treated by a podiatrist or an orthopedist with experience in the care of a diabetic foot. If bone or tendon is visible, osteomyelitis is present and hospitalization for IV antibiotics is often necessary. Many patients need a vascular evaluation in conjunction with local treatment of the foot ulcer, since in some cases a revascularization procedure may be required to provide adequate blood flow for wound healing.
Since curing ulcers and foot infections is so difficult, it is better to prevent them. At one clinic, the rate of amputation was halved after patients were required to remove their shoes and socks at every visit. The emergency physician can facilitate this by briefly inspecting the feet of each patient with diabetes and educating the patient about the need for proper foot care. Patients with distal sensory neuropathy to pinprick or light touch, decreased peripheral pulses, moderate to severe onychomycosis or impending skin breakdown deserve referral to a podiatrist for foot care.
Macrovascular disease is the leading cause of death in patients with diabetes, causing 75% of the deaths in this population, compared to approximately 35% of deaths in patients without diabetes. The presence of diabetes causes a two-fold increase in males and a four-fold increase in females in myocardial infarction, in addition to the other known risk factors. The risk of stroke is doubled and the risk of developing peripheral vascular disease is increased four-fold. Although the disease process itself is the same as in patients without diabetes, atherosclerosis develops earlier and follows a more malignant course in patients with diabetes.
Hypertension is twice as common in patients with type 2 diabetes, which also increases the risk of atherosclerosis. Patients with diabetes must, therefore, have their hypertension and measurable lipid abnormalities treated aggressively to lessen their risk of developing serious atherosclerosis.
Patients with diabetes have been said to have increased incidence of silent ischemia. Silent ischemia, however, is common in many patients with coronary artery disease and the apparent higher incidence in patients with diabetes may simply be related to the fact that they are more likely to have coronary artery disease to begin with. Nevertheless, it is prudent to order an electrocardiogram on patients with diabetes who have a serious illness or who present with generalized weakness, malaise or other nonspecific symptoms that generally are not expected to be due to myocardial ischemia.
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Chronic hyperglycemia is associated with an increased risk for the development of the microvascular complications of diabetes, as elegantly demonstrated in the Diabetes Control and Complications Trial (DCCT) for type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes. In the DCCT intensive therapy designed to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, microalbuminuria, proteinuria and neuropathy as assessed over a 7-year period. Intensive therapy was not associated with increased mortality or major macrovascular events and did not decrease the quality of life, although it did increase the likelihood of severe hypoglycemic episodes.
In the UKPDS trial more than 5000 patients with type 2 diabetes were studied for up to 15 years. Those in the intensively treated group had a significantly lower rate of progression of microvascular complications compared to those receiving standard care. Moreover, in the UKPDS severe hypoglycemia occurred much less often than in patients with type 1 diabetes in the DCCT.
The goal of treatment with oral antidiabetic agents is to lower blood glucose levels into the near normal range (i.e. pre-prandial blood glucoses levels of 80-140 mg/dl; glycosylated hemoglobin levels less than 8% and maintain them in this range throughout most of the patient's life. Patients with no or mild symptoms should be treated initially with diet, and diet therapy should be encouraged throughout the course of a patient's treatment. In the ED, drugs are started when a patient presents with moderate to marked symptoms of diabetes.
Some patients should not aim for near-normal blood glucose levels. In elderly patients who have a life expectancy of less than 5 years or any patient with a terminal disease, tight control is unnecessary. Patients with known coronary artery disease or cerebrovascular disease should also have higher preprandial blood glucose targets (eg, 100-180 mg/dl) in order to prevent excessive hypoglycemia. Some patients have advanced microvascular and neuropathic diabetic complications and may not particularly benefit from maintenance of near-euglycemia. Finally, patients with hypoglycemia unawareness (the lack of adrenergic warning signs of hypoglycemia) or those with recurrent episodes of severe hypoglycemia (meaning hypoglycemia requiring treatment by another) should also have higher target levels.
Throughout the treatment of a patient with type 2 diabetes, adherence to diet and exercise should be stressed, since behavior modification can have a large impact on the degree of diabetic control reached.
Although most emergency physicians rarely start diabetics on new therapy, it
is useful to be acquainted with the medications used and their side effects and
contraindications.
Drug Category: Oral anti-diabeticaAgents -- sulfonylurea agents
| Drug Name | Oral anti-diabetic agents -- sulfonylurea agents-
These agents increase insulin secretion from pancreatic beta-cells. All
sulfonylurea agents are well absorbed; half life and duration of action
vary by agent. Agents 1st generation: chlorpropamide, tolbutamide, tolazamide, acetohexamide 2nd generation: glyburide, glipizide 3rd generation: glimepiride Dosing regimens vary. |
|---|---|
| Adult Dose | Varies by agent. There is no fixed dosing regimen.
Untreated type 2 diabetes patients with symptomatic hyperglycemia may have therapy initiated with glyburide (5.0mg qd) or glipizide (5.0mg qd). Lower starting doses (2.5mg qd) are appropriate for elderly patients and those with hepatic or renal disease. Higher starting doses (eg, glyburide to a maximum of 20mg qd) are occasionally appropriate for patients with severe hyperglycemia for whom home glucose monitering and close follow up can be arranged. |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Sulfonamides and chloramphenicol will displace the sulfonylurea agents from their protein binding sites, which leads to more free drug and an increased risk of hypoglycemia. |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | The following side effects occur in approximately 5%
of patients and 2% cause patients to discontinue treatment: Skin: rash Gastrointestinal: nausea, vomiting Hematological: leukopenia, agranulocytosis, aplastic anemia (very rare) Intrahepatic cholestasis (very rare), primarily with chlorpropamide Disulfiram reaction: flushing, headache, nausea and vomiting after alcohol ingestion with chlorpropamide only (10-20%) Syndrome of inappropriate ADH secretion (SIADH) causing hyponatremia, principally with chlorpropamide (rarely with tolbutamide) Hypoglycemia is most common with glyburide and chlorpropamide (up to 33% in some studies). It is less common with glipizide (2-4%) and least common with others (approximately 1%). Risk factors include elderly patients, malnutrition, irregular eating, impaired renal function and possibly hepatic dysfunction. Hypoglycemia resulting from sulfonylurea agents may be prolonged or recurrent, and hospital admission should be strongly considered in these patients. |
| Drug Name | Repaglinide (Prandin) |
|---|---|
| Pediatric Dose | Not established |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Drug Name | Metformin (Glucophage)- Decreases hepatic
gluconeogenesis (primary effect) and increases peripheral insulin
sensitivity (secondary effect). Does not increase insulin levels or
cause weight gain. Metformin is absorbed from the small intestine and its bioavailability is 50-60%. It is not bound to plasma proteins and not metabolized, although it is rapidly eliminated by the kidneys. The renal clearance is greater than the GFR, suggesting secretion by the proximal convoluted tubules. Therefore, serum metformin levels are markedly increased during any state of renal insufficiency. Metformin accumulates in the small intestine and may cause a local decrease in glucose absorption, which may explain some of the gastrointestinal side effects. At higher concentrations (such as those occurring in renal failure) mitochondrial accumulation occurs, which inhibits oxidative phosphorylation and produces lactic acidosis. Ingestion of alcohol can potentiate the development of lactic acidosis. |
|---|---|
| Adult Dose | The drug should be started at a low dose (500 or 850
mg with dinner) and increased no more often than every 2 weeks until the
desired therapeutic endpoint is reached, GI side effects prevent further
increases, or the maximal dose is reached. Metformin can be used as monotherapy or combined with a sulfonylurea agent, troglitazone, or insulin. The combination of acarbose and metformin can be difficult because of additive GI side effects. Metformin should be taken with food to minimize GI side effects. It is important to note that metformin alone does not cause hypoglycemia. |
| Pediatric Dose | Not established |
| Contraindications | Metformin cannot be used if any of the following are
present: Serum creatinine level >1.5 mg/dl (males) or >1.4 mg/dl (females) Abnormal hepatic function Presence of acute or chronic acidosis Evidence of local or systemic tissue hypoxia Excessive alcohol intake Pharmacologic therapy for congestive heart failure |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Side effects: Gastrointestinal: These side effects, especially diarrhea, occur in 30% of patients. They lead to discontinuation of the drug in approximately 5% of patients. Lactic acidosis: This is essentially nonexistent in patients without contraindications to metformin use. Precautions for use include the following: Stop metformin before the patient undergoes any procedure using IV contrast material. Do not re-start until a normal creatinine has been documented. Hold metformin during any acute periods of hypoxia. Check renal function and stop metformin if it is abnormal. |
| Drug Name | Acarbose and miglitol- AGIs delay the digestion and
absorption of carbohydrates. They do not increase insulin levels or
cause weight gain. Lactase is not inhibited, and their major effect is
to lower postprandial blood glucose levels. <2% is absorbed as the active drug. AGIs inhibit the breakdown of carbohydrates in the small intestine, which causes delivery of undigested sugars to the colon where they are fermented by bacteria into short-chain fatty acids, methane, carbon dioxide and hydrogen. |
|---|---|
| Adult Dose | AGIs are given tid, immediately before meals. These drugs should be started at a low dose (25 mg ac dinner) and increased every 1-2 wk until desired therapeutic effect is reached, GI side effects prevent further increases or the maximal dose is reached. The fall in postprandial blood glucose levels will be greater than the fall in fasting levels. AGIs can be used as monotherapy or combined with a sulfonylurea agent, troglitazone or insulin. The combination of AGIs and metformin can be difficult because of additive GI side effects. AGIs alone do not cause hypoglycemia; however, if used in combination with insulin or sulfonylurea agents and hypoglycemia occurs, glucose (dextrose) must be administered since the absorption of longer chain carbohydrates is delayed. |
| Pediatric Dose | Not established |
| Contraindications | Serum creatinine level >2 Elevated liver function tests Presence of Crohn disease or inflammatory bowel disease History of recurrent small bowel obstruction |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Side effects Flatulence, diarrhea, and abdominal discomfort occur commonly because of undigested carbohydrate in the lower GI tract. In clinical trials, approximately 17% of patients discontinued acarbose due to side effects. At higher doses and in patients with abnormal renal function, some systemic accumulation occurs, which can lead to drug-induced hepatitis. |
| Drug Name | Troglitazone, rosiglitazone, pioglitazone- The
glitazones increase peripheral insulin sensitivity via increasing
transcription of nuclear proteins that help increase uptake of
glucose. Bioavailability is increased when given with food. Pills should not be broken in half since the drug will oxidize and lose effectiveness. Metabolism is hepatic and elimination unaffected by renal failure. |
|---|---|
| Adult Dose | Use of each drug varies. All can be used in combination with other oral agents. With all of the drugs it takes 12-16 wk to achieve maximal effect. |
| Pediatric Dose | Not established |
| Contraindications | NYHA Class III or IV congestive heart failure Known liver disease and/or ALT 1.5 times the upper limits of normal. In March 1999, the FDA advisory panel voted that the benefits of troglitazone outweighed its risks of hepatotoxicity. However, this spring and summer, rosiglitazone and pioglitazone were approved as similar agents with hepatic monitoring recommended, though no hepatic toxicity was observed prior to approval. |
| Precautions | All require liver function monitoring -- monthly for
the first year with troglitazone, every other month for rosiglitazone
and pioglitazone. Side effects: With troglitazone idiosyncratic hepatitis occurs in 1-2% of patients. It is largely reversible if the drug is stopped; hepatic failure has occurred. Rates of hepatitis appear to be much lower with the other agents; edema (4-10%); GI symptoms (7.5% in women, 2% in men); anemia (dilutional); may cause dilutional anemia by expanding plasma volume Precautions include the following: LFTs must be monitored; troglitazone may increase metabolism of immunosuppressive agents and birth control pills. |
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Further Inpatient Care:
Further Outpatient Care:
Deterrence/Prevention:
Complications:
Prognosis:
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Medical/Legal Pitfalls:
Special Concerns:
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CME Question 1: Which of the following head and neck infections are seen almost exclusively in diabetic patients?
A: Retropharyngeal abscess
B:
Mucormycosis
C: Malignant otitis
externa
D: Otitis media
E: B and
C
The correct answer is E: Mucormycosis and malignant otitis
externa are seen almost exclusively in diabetics. Hyperglycemia predisposes
patients to both conditions.
CME Question 2: Metformin, when given to diabetics with contraindications, is associated with what life-threatening side effect?
A: DKA
B: Prolonged
hypoglycemia
C: Drug-induced
hepatitis
D: Lactic acidosis
E:
Explosive flatulence
The correct answer is D: Metformin when given
to diabetics with contraindications can cause fatal lactic acidosis.
Pearl Question 1 (T/F): Blood glucose level in diabetics does not correlate with an increased risk for skin and soft tissue infections in diabetics.
The correct answer is False: Although diabetes-related macrovascular disease and neuropathy may predispose diabetics to skin and soft tissue infections, their risk escalates when blood glucoses exceed 250 mg/dl. Above this level, neutrophil function declines markedly.
Pearl Question 2 (T/F): Specific historical data may be helpful in distinguishing between type 1 and type 2 diabetes in a patient newly discovered to have a serum glucose of greater than 200 mg/dl.
The correct answer is True: Type 2 diabetes typically occurs in those patients older than age 40 years. Most have one or more of the following risk factors: (1) Obesity: 90% of type 2 diabetics are >120% of ideal body weight; (2) Family history of type 2 diabetes in a first-degree relative; (3) Hispanic, Native American, or African descent; (4) History of prior impaired glucose tolerance (IGT) or impaired fasting glucose (IFG); (5) Hypertension (>140/90) or significant hyperlipidemia (HDL cholesterol <35 mg/dl or triglyceride level >250 mg/dl); (6) History of GDM or a history of the delivery of a baby >9 pounds in weight, which suggests a history of GDM.
Pearl Question 3 (T/F): No additional workup for a diabetic patient presenting with a cranial nerve III palsy is required.
The correct answer is False: Although cranial nerve palsies are a well known form of diabetic neuropathy, other etiologies must be considered. In one series, 42% of diabetic patients presenting with a cranial nerve palsy ultimately had an etiologic diagnosis other than diabetic neuropathy. From the standpoint of the emergency physician, neuroimaging with CT scan (preferably MRI, if available) is the important diagnostic study. Neurologic consultation is warranted.
Pearl Question 4 (T/F): Sulfonylurea agents are appropriate therapy for a symptomatic patient newly diagnosed in the ED as having type 2 diabetes.
The correct answer is True: Sulfonylurea agents are the most rapidly effective oral anti-diabetic agents and, therefore, are the standard therapy in this setting. Starting a newly diagnosed type 2 diabetic on medication is best done in consultation with the physician who will be assuming responsibility for the patient`s ongoing care. Although there is evidence that symptomatic patients with glucoses in excess of 400 mg/dl can be successfully started on maximal doses and discharged home, this approach is only feasible if close outpatient follow-up can be arranged.
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| NOTE: |
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| Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this textbook have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this text do not warrant the information in this text is accurate or complete, nor are they responsible for omissions or errors in the text or for the results of using this information. The reader should confirm the information in this text from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER |