Scott R. Votey and Anne L. Peters
Diabetes affects an estimated 8.3% of the US population, or approximately 25.8 million people (1), and this is expected to rise to 33.5 million by 2050 (2). Management of diabetes and its complications is disproportionately resource-intensive. In 2012, the per-capita cost of health care was $13,741 for people with diabetes as compared to $3,495 for those without the disease. The emergency department (ED) utilization rate by people with diabetes is twice that of the unaffected population (3). 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.
Approximately 90% of patients with diabetes have type 2 (or ketosis-resistant) diabetes (T2DM), and the remainder have type 1 (ketosis-prone) diabetes (T1DM). Although the pathophysiology of the disease differs between the types of diabetes, most of the complications, including microvascular, macrovascular, and neuropathic, are similar regardless of the type of diabetes.
Microvascular complications of diabetes include retinopathy and nephropathy. Macrovascular complications are peripheral vascular, cerebrovascular, and coronary artery disease (CAD). Hypertension eventually occurs in approximately 50% of patients with diabetes. Chronic, poorly controlled hyperglycemia, in addition to the metabolic consequences associated with glycosuria, can lead to impaired immune function and delayed wound healing. The development of complications is related to the duration of diabetes and the degree of glycemic control.
ED EVALUATION
In addition to the history and physical examination related to the presenting complaint, the assessment of patients with diabetes includes the following.
History
Type of Diabetes
Type 1 diabetes mellitus (T1DM) generally occurs in younger, lean patients and is characterized by an autoimmune process that leads to the marked inability of the pancreas to secrete insulin (Table 204.1). The distinguishing characteristic of a patient with T1DM is that if insulin is withdrawn, ketosis, and eventually ketoacidosis, develops. These patients are therefore insulin-dependent (i.e., insulin is life-sustaining), because they produce no endogenous insulin. Although the onset of T1DM often occurs in childhood, 30% of patients with new-onset T1DM are older than 18 years of age. In adults, T1DM tends to have a slower course to total islet-cell failure than it does in children. In addition, rates of obesity in individuals with type 1 diabetes are similar to that in the general population, which means that among adults, one-third is normal weight, one-third is overweight, and one-third obese. Newer antibody tests have allowed for the identification of more people with this slower-onset adult form of T1DM, which has been called latent autoimmune diabetes of the adult (LADA).
TABLE 204.1
Metabolic and Clinical Characteristics of the Two Major Types of Diabetes Mellitus
Type 2 diabetes mellitus (T2DM) typically occurs in older (>40 years of age) patients who have a family history of diabetes. However, T2DM is occurring in younger and younger individuals. Children as young as 2 years old have been diagnosed with T2DM, and increasingly teenagers of Hispanic, Native American, and African American descent are developing prediabetes and diabetes (4). Patients who develop T2DM have a genetic predisposition to do so and develop insulin resistance along with insufficient pancreatic β-cell secretion of insulin. Most patients (90%) who develop T2DM are obese, and obesity itself is associated with insulin resistance, which further worsens the diabetic state. Because patients with T2DM retain the ability to secrete some endogenous insulin, those who take insulin rarely develop diabetic ketoacidosis (DKA) when insulin is stopped. Therefore, they are considered insulin-requiring, not insulin-dependent. Moreover, patients with T2DM often do not require treatment with oral or injectable antidiabetic medication if they lose weight.
Differentiating between the two types of diabetes on the basis of age has become less reliable and cannot always be done in the ED, but a good clinical history often allows the distinction to be made. A strong family history of T2DM, obesity, and Hispanic, African American, or Native American heritage all make the diagnosis of type 2 diabetes more likely, regardless of age.
The presence of anti-GAD65 antibodies confirms the diagnosis of T1DM, and the presence of an elevated or even normal C-peptide level in patients who have been treated with insulin for several years confirms a diagnosis of T2DM. The presence of measurable C-peptide levels at the time of diagnosis is not usually helpful as C-peptide levels can be elevated or absent in both new-onset type 1 and type 2 diabetes, depending on the level of hyperglycemia and other clinical circumstances. Although neither of these tests is likely to be available on a stat basis in the ED, an understanding of their results may be useful to emergency physicians. When in doubt, use insulin therapy as needed in the ED and defer to the patient’s primary care provider to follow up on testing and diagnosis.
Duration of the Diagnosis of Diabetes
The chronic complications of diabetes are related to the length of time the patient has had the disease. Patients with T2DM have often had diabetes for 5 to 7 years before the diagnosis is made and can present with the complications of diabetes at the time of diagnosis (5).
Blood Glucose Levels
Patients should be asked if they self-monitor their blood glucose levels and what their usual and recent blood glucose levels have been. Recent changes in the frequency of high and low blood sugar levels should be noted.
Diabetes Medications
Patients should be asked the names and doses of their diabetes medications. A sense of patients’ level of knowledge about managing their diabetes is useful, as it may indicate their degree of adherence with their treatment plan.
Hemoglobin A1c Level
The date and value of the most recent level is a useful indicator of both the quality of glycemic control and the patients’ monitoring of their disease.
Symptoms of Diabetes
Symptoms of hyperglycemia (polyuria, polydipsia, nocturia, weight loss) and hypoglycemia (see Chapter 206) should be elicited, with their time course and severity.
Complication of Diabetes
Although complications are often diagnosed by physical examination or by laboratory testing, the presence of known complications of diabetes should also be sought in the history: retinopathy, nephropathy, vasculopathy (hypertension and coronary, peripheral, and cerebrovascular disease), neuropathy, or diabetic foot complications (ulcers and amputations).
Physical Examination
Vital Signs
Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy. If the respiratory rate and pattern suggest Kussmaul breathing, DKA must be immediately considered and appropriate tests ordered.
Fundoscopy
Include a careful view of the retina, visualizing both the optic disc and the macula. If hemorrhages or exudates are seen, the patient should be seen by an ophthalmologist as soon as possible. Nonophthalmologists tend to underestimate the severity of retinopathy, especially if the pupils have not been dilated. In general, if patients have not been seen by an ophthalmologist within the past year, they should be encouraged to follow up for an annual retinal examination.
Foot Examination
Foot deformity and abnormal nails can be a sign that follow-up with a podiatrist is needed and attention given to foot care. The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important among patients with foot infection, because poor lower-extremity blood flow can delay healing and increase the risk of amputation. Documenting lower-extremity sensory neuropathy is also useful, because decreased sensation limits the patient’s ability to protect the feet and ankles. If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examinations) is very important for the prevention of foot ulcers and possible subsequent lower-extremity amputation.
DIABETES MEDICATIONS
The number and variety of medications available for the treatment of diabetes, particularly T2DM, continues to increase (Table 204.2). These drugs allow for the use of combination oral therapy, including the combination oral agents plus a noninsulin injectable and the combinations of nearly any oral or noninsulin injectable with insulin (6,7).
TABLE 204.2
Properties of Currently Available Glucose Lowering Agents Used in the Treatment of Patients with Type 2 Diabetes Mellitus
The biguanides (e.g., metformin) primarily decrease hepatic glucose production and may also slightly lower insulin resistance. These drugs commonly cause nausea, abdominal cramping, and diarrhea. Rarely, they can cause severe lactic acidosis, especially among patients with renal insufficiency.
The sulfonylurea agents (e.g., glyburide, glipizide, glimepiride) and meglitinides (e.g., repaglinide and nateglinide) increase insulin secretion and are considered long- and short-acting insulin secretagogues, respectively. Their most common serious adverse reaction is hypoglycemia, which can be severe and may limit use of these agents.
The thiazolidinediones (rosiglitazone and pioglitazone) act as insulin sensitizers. Both increase plasma volume and can cause fluid retention. The most common side effect is mild-to-moderate pedal edema. Both can result in congestive heart failure (CHF) in patients who are at risk. The thiazolidinediones should not be used in patients with CHF and in patients who have a baseline alanine aminotransferase three times the upper limit of normal. Pioglitazone and rosiglitazone differ in terms of their effect on lipids (pioglitazone decreases triglyceride levels and raises high-density lipoprotein (HDL) levels; rosiglitazone causes a lesser increase in HDL cholesterol levels and has no effect on triglyceride levels). Rosiglitazone may cause an increased risk of myocardial infarction (MI) and heart-related deaths (8) and is only available as a restricted use agent. Pioglitazone appears to be safe from a cardiovascular event perspective (9). Finally, thiazolidinediones increase the risk of bone fracture and should be used with caution in individuals with advanced osteoporosis.
The α-glucosidase inhibitors (e.g., acarbose and miglitol) decrease intestinal absorption of carbohydrate, often producing flatulence and, rarely, causing small bowel obstruction. These agents produce a relatively small fall in A1c (approximately 0.5% compared to 1% to 2% for most other agents). They are most effective in patients consuming a high carbohydrate diet and are commonly used in Asia, where rice is a staple.
Dipeptidyl peptidase-4 (DPP-4) inhibitors increase circulating levels of GLP-1 (glucagon-like peptide-1), which is an incretin hormone secreted from the gut that helps improve insulin secretion and lower blood sugar levels. There are four available DPP-4 inhibitors: Sitagliptin, saxagliptin, linagliptin, and alogliptin. All except for linagliptin must be dose reduced for renal dysfunction.
Glucagon-like peptide receptor agonists (GLP-1 RAs) are injectable agents that directly act upon GLP-1 receptors. These agents tend to cause a greater HbA1c lowering than DPP-4 inhibitors and often cause weight loss, owing to an increase in satiety. Currently marketed agents include short-acting exenatide (given twice daily), long-acting exenatide (given once weekly) and liraglutide (once daily). GLP-1 RAs commonly cause nausea, vomiting, and diarrhea. Both GLP-1 RAs and DPP-4 inhibitors are associated with pancreatitis.
Sodium-glucose cotransporter 2 (SGLT2) blocks glucose reabsorption in renal tubules, increasing glycosuria and leading to a reduction in plasma glucose levels and possibly weight loss. Canagliflozin is the first such agent available in the United States. Side effects include an increased risk for urinary tract infection and vaginal and penile fungal infections. SGLT-2 inhibitors can also cause dehydration, electrolyte disturbances, and an increase in serum creatinine levels.
Bromocriptine (a dopamine-2 agonist) and colesevelam (a bile acid sequestrant) are both approved for the treatment of T2DM, but cause only mild reductions in A1c and are not widely used.
Insulin remains the therapy for patients with T1DM and patients with T2DM for whom oral agents do not achieve adequate glycemic control. The amylin analog pramlintide is an adjunctive therapy for patients with T1DM and insulin-treated T2DM.
ABNORMALITIES CAUSED BY HYPERGLYCEMIA
Acute hyperglycemia, even when not associated with DKA or the hyperglycemic hyperosmolar syndrome (HHS) is harmful for a number of reasons. If the blood glucose level exceeds the renal threshold for glucose (>240 mg/dL in a healthy person, but diminished with advancing age, renal insufficiency, and pregnancy), 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.
Chronic hyperglycemia is associated with an increased risk for the development of the microvascular and neuropathic complications of diabetes, as elegantly demonstrated in the Diabetes Control and Complications Trial (DCCT) for T1DM (10) and the United Kingdom Prospective Diabetes Study (UKPDS) for T2DM (11). 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 addition, when patients enrolled in the DCCT were followed over the next 12 years in the Epidemiology of Diabetes Interventions and Complications study, there was a significant reduction in rates of cardiovascular disease in those who had been intensely treated (12). In the UKPDS, aggressive treatment of blood glucose levels and hypertension was shown to decrease the risk of microvascular complications in patients with T2DM.
More recent studies, however, such as ACCORD, ADVANCE, and VADT have shown that in older patients with more advanced type 2 diabetes further intensifying control might cause harm (6). In the ACCORD trial those in the intensively treated group (target A1c of less than 6%) had an increased rate of mortality compared to those in the control group. The reasons for this increase in mortality is not well understood, but in all trials, in both intensive and control arms, episodes of severe hypoglycemia were associated with an increased risk for poorer outcomes, including death. Therefore, current guidelines suggest individualizing targets with a particular focus on decreasing the risk of severe hypoglycemia (6,7).
Among patients with known diabetes that is poorly controlled, there is no absolute level of blood glucose elevation that necessitates admission to the hospital or the administration of insulin. Admission is appropriate for the following:
1. DKA (see Chapter 205). Plasma glucose >250 mg/dL (>13.9 mmol/L) with (a) arterial pH <7.30 and serum bicarbonate level <15 mEq/L and (b) moderate ketonuria or ketonemia. DKA can occur in patients with normal blood glucose levels, particularly if they are vomiting frequently. Therefore, any blood sugar level in the setting of ketoacidosis can be indicative of DKA, even though an elevated blood sugar level is most common.
2. HHS (see Chapter 205). Impaired mental status and elevated plasma osmolality in a patient with hyperglycemia. This usually includes severe hyperglycemia (e.g., plasma glucose >600 mg/dL [>33.3 mmol/L]) and elevated serum osmolality (e.g., >320 mOsm/kg [>320 mmol/kg]).
3. Hypoglycemia (see Chapter 206). Only those patients with prolonged, severe or recurrent hypoglycemia require hospitalization.
4. Severely symptomatic patient. Patients with T1DM who cannot tolerate oral fluids require hospitalization. Likewise, if the patient is severely symptomatic or the precipitating cause of hyperglycemia cannot be adequately treated in the ED, the patient needs to be admitted.
Generally, lowering the blood glucose level acutely in the ED in individuals without DKA or HHS has little benefit. It 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 over time and how glycemic control will be maintained. 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.
ED MANAGEMENT
New-Onset Diabetes
Most patients with diabetes have T2DM, and most of those are asymptomatic at diagnosis. The initial treatment for patients with newly discovered, asymptomatic diabetes is a trial of medical nutrition therapy (MNT; diet therapy) along with initiation of metformin 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-to-moderate 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 oral antidiabetic agent therapy.
Controversy exists over the management of markedly symptomatic patients with newly discovered T2DM 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 to 2 days, and, within a week, the blood glucose levels are markedly lower (13). Their sulfonylurea dose can be tapered as they comply with MNT and metformin is added. In some, diabetes can be controlled with diet alone. However, patients who cannot drink adequate amounts of fluid, who have serious coexisting medical conditions (e.g., MI or systemic infection), or who do not have reliable follow-up should generally be hospitalized for initiation of therapy.
Patients with new-onset T1DM need to be started on lifelong insulin therapy. Many present with DKA. An occasional patient with new-onset T1DM who presents with mild manifestations and is judged to be very compliant can be started on insulin as an outpatient. T1DM patients begun on insulin as outpatients require basic education on insulin administration, self-monitoring of blood glucose, and close follow-up. Patients should be seen as soon as possible to receive thorough diabetes and nutrition self-management education.
MANAGEMENT OF HYPERGLYCEMIA DURING MEDICAL ILLNESS AND SURGERY
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 intravenous fluids. Increases of glucagon, catecholamines, cortisol, and growth hormone antagonize the effects of insulin, and insulin secretion is itself inhibited by the α-adrenergic effect of increased catecholamine levels. The counter-regulatory hormones also directly increase hepatic gluconeogenesis.
Although it was previously thought that inpatients did better with tighter glycemic control more recent data refutes this concept. Thus, inpatient target blood sugar levels are 140 to 180 mg/dL (14). When managing patients in the hospital with pre-existing diabetes, it is necessary to modify treatment regimens to compensate for both decreased caloric intake and increased physiologic stress.
It is strongly recommended that continuous intravenous infusions of dextrose and insulin be used in patients who are undergoing general anesthesia or are critically ill. Crucial to prevent ketosis in patients with T1DM, this technique probably benefits patients with T2DM as well. Blood glucose levels must be measured with a glucose meter every hour, and the rates of insulin and dextrose infusion must be adjusted accordingly to prevent hypoglycemia or persistent hyperglycemia. Algorithms are available for insulin infusions, and the use of preprinted orders facilitates drug administration and reduces dosing errors.
• Frequent blood glucose monitoring is not always possible nor necessary for every patient, and patients with less serious illness or those undergoing minor surgery may do just as well with subcutaneously injected insulin. A basal bolus insulin regimen rather than sliding-scale regular insulin should be used in these patients (14). In patients going to surgery who have not received their dose of long/intermediate acting insulin for the day, giving 50% to 80% of the daily dose prior to surgery is often effective. At the same time, an intravenous infusion containing 5% dextrose should be started at a rate of 125 mL/hr. Blood glucose levels should be checked every 2 hours during surgery, and small doses of regular or rapid-acting insulin (lispro [Humalog], aspart [NovoLog], or glulisine [Apidra]) insulin should be given if values are >150 mg/dL.
The same principles of providing a constant source of insulin and carbohydrate apply to patients with T1DM who are not going to surgery but who must remain NPO owing to medical reasons. Patients should receive an injection of basal insulin (either glargine [Lantus] or detemir [Levemir]), with additional correction doses using regular insulin or a rapid-acting insulin (e.g., lispro), based on blood glucose levels. To avoid hypoglycemia, regular insulin should not be given more often than every 3 to 4 hours because a dose is effective for up to 6 hours. Rapid-acting insulins may be given every 3 hours. Once the patient is eating, a preprandial insulin dose can be added.
Patients with T2DM who are on insulin can follow similar guidelines. However, because patients with T2DM secrete some endogenous insulin and do not tend to develop ketosis, they can often be managed for brief periods without either insulin or dextrose. However, if the blood glucose is <100 mg/dL, or >180 mg/dL, appropriate treatment is required.
Patients who have been taking an oral insulin secretagogue (such as a sulfonylurea agent or meglitinide) should have their blood glucose levels monitored when oral intake is not allowed, and intravenous dextrose with or without insulin should be given to keep blood glucose levels between 140 and 180 mg/dL. Metformin should not be given to hospitalized patients until it is clear that their renal function is stable. In general, for the initially hospitalized patients, oral antidiabetic medication should be held and then restarted once the patient is less acutely ill. The exceptions are DPP-4 inhibitors, which can be used in the hospital setting, with dose adjustments as needed based on renal function.
The emergency physician caring for the patient with diabetes 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
Infections cause considerable morbidity and mortality among 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% to 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 among patients with diabetes, whereas 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, all diabetic patients are nevertheless not 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 200 mg/dL impair leukocyte function (15).
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 older patients with diabetes 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 and, although they often have a pre-existing 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 makes 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) is useful to define the extent of disease.
Prompt surgical consultation is mandatory for malignant otitis externa, because surgical debridement is often an essential part of therapy. Intravenous 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 they require close follow-up.
Mucormycosis is the name given collectively to the infections caused by various ubiquitous molds (16). Invasive disease occurs in poorly controlled diabetic patients, especially in conjunction with DKA although it can occur in individuals with type 2 diabetes, as well. 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 eyelid 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 helps to delineate the extent of disease. Treatment consists of control of the predisposing hyperglycemia and acidemia, intravenous amphotericin B, and immediate surgical debridement. Until the diagnosis is confirmed, treatment with antistaphylococcal antibiotics is appropriate.
Urinary Tract Infection
Patients with diabetes have a 60% increased risk of urinary tract infection compared to individuals without diabetes (17). More importantly, people with diabetes are increased risk 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 among 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.
Emphysematous pyelonephritis can occur in patients with diabetes (18). This 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, ultrasonography, or noncontrast helical CT urography. Management consists of intravenous antibiotics and supportive care plus percutaneous drainage or emergency nephrectomy in more severe cases.
Skin and Soft Tissue Infections
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 aureusor hemolytic streptococci and generally can be treated with a penicillinase-resistant synthetic penicillin or a first-generation cephalosporin. Diabetes, however, is a risk factor for the development of MRSA infections. Severe skin and soft tissue infections, and even minor purulent infections, should be treated with an antibiotic effective against MRSA, such as vancomycin for serious infections, and clindamycin or cephalexin plus trimethoprim-sulfamethoxazole for less severe infections.
Outpatient treatment of minor infections is appropriate if the patient is reliable, performs self-monitoring of blood glucose levels (and urine ketones for T1DM 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, S. 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 a 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. The consensus guidelines for diagnosing osteomyelitis recommend an aseptically obtained bone sample with histopathologic findings of inflammation and microorganisms found on culture (17). Other diagnostic tests for osteomyelitis are probing to bone, the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), sequential x-rays, and MRI. CT and nuclear medicine scans and are less helpful.
In the ED, where physical examination, ESR, and plain radiographs are the commonly employed diagnostic modalities, the diagnosis is more frequently suspected than definitively established. If osteomyelitis is apparent by radiograph or physical examination (e.g., if wounds are deep enough to expose tendons or bone, or probes to the bone), the patient should be admitted for intravenous 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 workup.
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 more than 50% of cases.
Diabetic patients have a greater incidence of staphylococcal and Klebsiella pneumonia than do persons without diabetes. Diabetes is also a risk factor for reactivation of tuberculosis. Cryptococcal infections and coccidioidomycoses are more virulent in diabetic patients.
Ophthalmologic Abnormalities
Visual complaints by diabetic patients should be taken very seriously. 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 it 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-up work during this period.
Rarely, patients with T1DM who are in extremely poor control (e.g., those with frequent episodes of DKA) can acutely develop a “snowflake” (or “metabolic”) cataract. Named for their snowflake or flocculent appearance, these cataracts can progress rapidly and create total opacification of the lens within a few days. Surgery is often required to restore vision. Patients with diabetes also tend to develop senile cataracts at a younger age than do persons without diabetes, although not in relation to the degree of glycemic control.
Diabetic retinopathy remains the leading cause of blindness among persons aged 20 to 64 in the United States (19). Some degree of diabetic retinopathy can be expected to develop in nearly all patients with TIDM and approximately 60% of patients with T2DM who have had the disease for 20 years or more. Patients with T2DM may already have diabetic retinopathy at the time their diabetes is diagnosed.
There are five 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 two stages of diabetic retinopathy are known as “background” or nonproliferative retinopathy. Initially, the retinal venules dilate, then microaneurysms, which appear as tiny red dots on the retina and cause no visual impairment, develop. As the microaneurysms or retinal capillaries become more permeable, hard exudates appear, reflecting the leakage of plasma. These are sharply defined yellow deposits composed mostly of lipid material. Rupture of intraretinal capillaries results in hemorrhage. If these ruptures occur deep in the retina, they appear as “dot blot” hemorrhages that can be difficult to distinguish from microaneurysms. 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 include 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 in decreasing macular edema and preserving vision, but it is less effective in restoring vision once it is lost. The advent of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy has added a new dimension to the treatment of diabetic retinopathy, particularly macular edema where it is considered by many to be first-line therapy (20).
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 owing 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 with T2DM do not develop proliferative retinopathy as often as those with T1DM.
Often, the first hemorrhage is small and is noted by the patient as a fleeting, dark area, or “floater,” in the field of vision. Because subsequent hemorrhages can be larger and more serious, the patient should be referred immediately to an ophthalmologist for laser therapy anti-VEGF treatment, or both. 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 condition is a relative contraindication to the use of thrombolytic agents.
Diabetic Nephropathy
Diabetes is the leading single cause of end-stage renal failure in the United States. Although the prevalence of diabetic nephropathy varies with the duration of diabetes and can be substantially reduced by improved glycemic and hypertension management, all patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. 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, creatinine clearance, or estimated glomerular filtration rate (eGFR).
The use of contrast media, including ionic and nonionic contrast can cause reductions in renal function, and precipitate acute renal failure in patients with underlying diabetic nephropathy. While most patients recover within 10 days, some develop irreversible renal failure. Caution should be used when contrast-enhanced studies are being considered in patients with diabetes with an eGFR) <60 mL/min or a serum creatinine level ≤1.5 mg/dL. In general an ultrasound or a noncontrast study should be performed.
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. Data are mixed both with regard to the use of isotonic saline versus a sodium bicarbonate containing fluid for hydration, and the utility of oral N-acetylcysteine to reduce nephrotoxicity (21). The appropriate selection of contrast agents may also reduce nephrotoxicity. Iso-osmolar iodixanol or a nonionic low osmolal agent (e.g., iopamidol or ioversol) are preferable to iohexol (22).
In contrast, the administration of gadolinium-containing contrast agents used in MRI scanning are of concern only in patients with chronic kidney disease (CKD), in whom there is a risk of a serious adverse reaction termed nephrogenic systemic fibrosis. Since many patients with long-standing diabetes have CKD, caution is warranted in those in whom gadolinium contrast is being considered. Because 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 or angiotensin receptor blocker (ARB) is a good choice because these agents have been found to reduce the rate of decline in renal function, independent of their effect on blood pressure. They also decrease proteinuria among patients with diabetic nephropathy. It should be kept in mind, however, that ACE inhibitors and ARBs tend to increase the serum potassium level and should thus be used with caution in patients with renal insufficiency or somewhat elevated serum potassium levels.
Diabetic Neuropathy
Diabetic neuropathy is common, and distal symmetric sensorimotor polyneuropathy (in a “glove-and-stocking” distribution) is the most frequent pattern. In addition to the pain often experienced in its early stages, this type of neuropathy eventually leads to loss of sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation.
A variety of acute-onset neuropathies occur in diabetic patients, including acute cranial mononeuropathies, mononeuropathy multiplex, focal lesions of the brachial or lumbosacral plexus, and radiculopathies. Of the cranial neuropathies, third oculomotor nerve palsy is the most common, followed by sixth (abducens) and fourth (trochlear) nerve palsies. Patients can present with diplopia and eye pain. In diabetic third-nerve palsy, the pupil is usually spared, whereas in third-nerve palsy owing to intracranial aneurysm or tumor, the pupil is affected in 80% to 90% of cases. It is important to consider nondiabetic causes for cranial nerve palsies, including intracranial tumors, aneurysms, and brainstem stroke (23). Evaluation should, therefore, include either nonenhanced and contrast medium–enhanced CT or, preferably magnetic resonance imaging. Neurologic consultation is recommended. Acute cranial nerve mononeuropathies usually resolve within 2 to 9 months. Acute thrombosis of the blood vessels supplying the nerve involved is thought to be the cause.
Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains and produce myriad manifestations (24). Patients likely to seek care in the ED include those with diabetic gastroparesis and vomiting, severe diarrhea, bladder dysfunction and urinary retention, and symptomatic orthostatic hypotension. Symptoms tend to wax and wane over time. Treatment is only symptomatic. Patients with gastroparesis may benefit from the use of metoclopramide or erythromycin. Before these therapies are started, the degree of dehydration and metabolic imbalance must be assessed, and other serious causes of vomiting must be excluded. In severe cases, gastric pacing has been used. Patients with disabling orthostatic hypotension may be treated with salt tablets, support stockings, or fludrocortisone. 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.
The Diabetic Foot
Fifty percent to 70% of all nontraumatic lower-extremity amputations occur in patients with diabetes (25). 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.
Wounds, infections, or ulcers of the feet demand particular attention in the diabetic patient. In addition to appropriate use of antibiotics, it is mandatory to avoid further trauma to the healing foot through use of crutches, a wheelchair, or bed rest. If bone or tendon is visible, osteomyelitis is present, and hospitalization for intravenous antibiotics is often necessary. Many patients need a vascular evaluation in conjunction with local treatment of the foot ulcer, because, in some cases, a revascularization procedure may be required to provide adequate blood flow for wound healing. For patients who may be discharged, every attempt should be made to ensure frequent follow-up, optimally with a podiatrist or an orthopedist with experience in the care of a diabetic foot. If such follow-up is not available, hospitalization may be necessary for initial treatment.
Because curing ulcers and foot infections is difficult, their prevention is extremely important. 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 contribute to prevention by briefly inspecting the feet of each patient with diabetes and by educating them about the need for proper foot care and maintenance of near-normal blood sugar levels. Patients who have a loss of sensation and/or structural abnormalities, who smoke, or have a history of prior lower-extremity complications should be referred to a foot care specialist for ongoing preventive care and lifelong surveillance.
Macrovascular Complications
Macrovascular disease is the leading cause of death in patients with diabetes. It is responsible for approximately 65% to 75% of deaths in patients with diabetes, compared with approximately 35% of deaths in the general population. Subtle differences in the pathophysiology of atherosclerosis in patients with diabetes result in both earlier development and a more malignant course. The presence of diabetes causes a twofold increase in MI in men and a fourfold increase in women. The risk of stroke is doubled, and the risk of developing peripheral vascular disease is increased fourfold. In fact, it has been shown that patients with T2DM who have never had an MI have the same risk of having an MI as patients without diabetes who have had a prior MI.
Patients with diabetes may have an increased incidence of silent ischemia. However, silent ischemia is common in many patients with CAD, and the apparently increased incidence may be because patients with diabetes are more likely than others to have CAD to begin with. Nevertheless, electrocardiography is prudent in patients with diabetes and a serious illness or who present with generalized weakness, malaise, or other nonspecific symptoms that are not expected to be due to myocardial ischemia.
Hypertension, which also increases the risk of atherosclerosis, is twice as common among patients with T2DM. Because of their high-risk profile, most patients with type 2 diabetes should be taking a daily aspirin (81 mg to start), an HMG-CoA-reductase inhibitor (statin), and an ACE inhibitor or an ARB agent. Aggressive global risk reduction, reinforced by all health care providers, is needed to lower the morbidity and mortality associated with diabetes.
CRITICAL INTERVENTIONS
• Maintain the blood glucose levels of patients with wounds or active infections <180 mg/dL.
• Provide adequate hydration to patients with mild diabetic nephropathy before contrast material is given to avoid precipitating acute renal failure.
Common Pitfalls
• Failure to provide patients who have T1DM with a continuous source of insulin and glucose when they are unable to tolerate oral intake.
• Underestimating the severity of diabetic retinopathy on funduscopic examination through undilated pupils. Any patient with lesions near the macula should be referred urgently to an ophthalmologist.
• Failure to examine the feet; overlooking small ulcers or underestimating their seriousness.
• Failure to consider myocardial ischemia in patients with nonspecific symptoms.
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