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      Transient and Persistent AKI and Outcomes in Patients Undergoing Major Abdominal Surgery

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          Abstract

          Introduction: Acute kidney injury (AKI) is a frequent diagnosis in surgical patients which has a detrimental effect on short-term and long-term outcomes. The purpose of this study was to evaluate the incidence and predictive factors of transient and persistent postoperative AKI in patients submitted to major abdominal surgery and to characterize the impact of AKI on in-hospital mortality. Methods: This study was a cross-examination of a retrospective analysis of clinical data of 450 patients who underwent major abdominal surgery from January 2010 to February 2011. Only AKI developing in the first 48 h after surgery was considered. AKI was diagnosed using the Kidney Disease: Improving Global Outcome (KDIGO) classification based on both serum creatinine (SCr) and urine output criteria. Persistent and transient AKI were defined according to the Acute Disease Quality Initiative (ADQI) workgroup definitions. Results: In our study, 22.4% of patients developed AKI in the first 48 h post-surgery ( n = 101), and 48% of patients had persistent AKI ( n = 49), defined as postoperative AKI, with a duration of more than 48 h. Older age (adjusted odds ratio [OR] 1.06 [1.00–1.11], p = 0.039), hypertension (adjusted OR 4.60 [1.17–18.11], p = 0.029), and higher preoperative SCr (adjusted OR 22.67 [4.00–128.46], p < 0.001) were independent predictors of persistent AKI. The overall in-hospital mortality was 6.4% ( n = 29). Persistent AKI was associated with higher mortality than transient AKI (51.9 vs. 20.7%; unadjusted OR 13.03 [5.78–29.36], p < 0.001; adjusted OR 4.20 [1.02–17.27], p = 0.047). Conclusion: In this cohort of patients submitted to major abdominal surgery, persistent AKI was an independent predictor of in-hospital mortality in contrast to transient AKI.

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          Standards of Medical Care in Diabetes—2009

          Diabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to references 1–3. The recommendations included are screening, diagnostic, and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E. I. CLASSIFICATION AND DIAGNOSIS A. Classification In 1997, ADA issued new diagnostic and classification criteria (4); in 2003, modifications were made regarding the diagnosis of impaired fasting glucose (5). The classification of diabetes includes four clinical classes: type 1 diabetes (results from β-cell destruction, usually leading to absolute insulin deficiency) type 2 diabetes (results from a progressive insulin secretory defect on the background of insulin resistance) other specific types of diabetes due to other causes, e.g., genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced (such as in the treatment of AIDS or after organ transplantation) gestational diabetes mellitus (GDM) (diabetes diagnosed during pregnancy) Some patients cannot be clearly classified as type 1 or type 2 diabetes. Clinical presentation and disease progression vary considerably in both types of diabetes. Occasionally, patients who otherwise have type 2 diabetes may present with ketoacidosis. Similarly, patients with type 1 may have a late onset and slow (but relentless) progression of disease despite having features of autoimmune disease. Such difficulties in diagnosis may occur in children, adolescents, and adults. The true diagnosis may become more obvious over time. B. Diagnosis of diabetes Current criteria for the diagnosis of diabetes in nonpregnant adults are shown in Table 2. Three ways to diagnose diabetes are recommended at the time of this statement, and each must be confirmed on a subsequent day unless unequivocal symptoms of hyperglycemia are present. Although the 75-g oral glucose tolerance test (OGTT) is more sensitive and modestly more specific than the fasting plasma glucose (FPG) to diagnose diabetes, it is poorly reproducible and difficult to perform in practice. Because of ease of use, acceptability to patients, and lower cost, the FPG has been the preferred diagnostic test. Though FPG is less sensitive than the OGTT, the vast majority of people who do not meet diagnostic criteria for diabetes by FPG but would by OGTT will have an A1C value well under 7.0% (6). Though the OGTT is not recommended for routine clinical use, it may be useful for further evaluation of patients in whom diabetes is still strongly suspected but who have normal FPG or IFG (see Section I.C). The use of the A1C for the diagnosis of diabetes has previously not been recommended due to lack of global standardization and uncertainty about diagnostic thresholds. However, with a world-wide move toward a standardized assay and with increasing observational evidence about the prognostic significance of A1C, an Expert Committee on the Diagnosis of Diabetes was convened in 2008. This joint committee of ADA, the European Association for the Study of Diabetes, and the International Diabetes Federation will likely recommend that the A1C become the preferred diagnostic test for diabetes. Diagnostic cut-points are being discussed at the time of publication of this statement. Updated recommendations will be published in Diabetes Care and will be available at diabetes.org. C. Diagnosis of pre-diabetes Hyperglycemia not sufficient to meet the diagnostic criteria for diabetes is categorized as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), depending on whether it is identified through the FPG or the OGTT: IFG = FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) IGT = 2-h plasma glucose 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) IFG and IGT have been officially termed “pre-diabetes.” Both categories of pre-diabetes are risk factors for future diabetes and for cardiovascular disease (CVD) (7). II. TESTING FOR PRE-DIABETES AND DIABETES IN ASYMPTOMATIC PATIENTS Recommendations Testing to detect pre-diabetes and type 2 diabetes in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI ≥25 kg/m2) and who have one or more additional risk factors for diabetes (Table 3). In those without these risk factors, testing should begin at age 45 years. (B) If tests are normal, repeat testing should be carried out at least at 3-year intervals. (E) To test for pre-diabetes or diabetes, an FPG test or 2-h OGTT (75-g glucose load) or both are appropriate. (B) An OGTT may be considered in patients with IFG to better define the risk of diabetes. (E) In those identified with pre-diabetes, identify and, if appropriate, treat other CVD risk factors. (B) For many illnesses, there is a major distinction between screening and diagnostic testing. However, for diabetes, the same tests would be used for “screening” as for diagnosis. Type 2 diabetes has a long asymptomatic phase and significant clinical risk markers. Diabetes may be identified anywhere along a spectrum of clinical scenarios ranging from a seemingly low-risk individual who happens to have glucose testing, to a higher-risk individual whom the provider tests because of high suspicion of diabetes, to the symptomatic patient. The discussion herein is primarily framed as testing for diabetes in those without symptoms. Testing for diabetes will also detect individuals with pre-diabetes. A. Testing for pre-diabetes and type 2 diabetes in adults Type 2 diabetes is frequently not diagnosed until complications appear, and approximately one-third of all people with diabetes may be undiagnosed. Although the effectiveness of early identification of pre-diabetes and diabetes through mass testing of asymptomatic individuals has not been definitively proven (and rigorous trials to provide such proof are unlikely to occur), pre-diabetes and diabetes meet established criteria for conditions in which early detection is appropriate. Both conditions are common, increasing in prevalence, and impose significant public health burdens. There is a long presymptomatic phase before the diagnosis of type 2 diabetes is usually made. Relatively simple tests are available to detect preclinical disease (8). Additionally, the duration of glycemic burden is a strong predictor of adverse outcomes, and effective interventions exist to prevent progression of pre-diabetes to diabetes (see Section IV) and to reduce risk of complications of diabetes (see Section VI). Recommendations for testing for pre-diabetes and diabetes in asymptomatic, undiagnosed adults are listed in Table 3. Testing should be considered in adults of any age with BMI ≥25 kg/m2 and one or more risk factors for diabetes. Because age is a major risk factor for diabetes, testing of those without other risk factors should begin no later than age 45 years. Either FPG testing or the 2-h OGTT is appropriate for testing. The 2-h OGTT identifies people with either IFG or IGT, and thus, more pre-diabetic people at increased risk for the development of diabetes and CVD. It should be noted that the two tests do not necessarily detect the same pre-diabetic individuals (9). The efficacy of interventions for primary prevention of type 2 diabetes (10–16) has primarily been demonstrated among individuals with IGT, not individuals with IFG (who do not also have IGT). As noted in the diagnosis section (Section I.B), the FPG test is more convenient, more reproducible, less costly, and easier to administer than the 2-h OGTT (4,5). An OGTT may be useful in patients with IFG to better define the risk of diabetes. The appropriate interval between tests is not known (17). The rationale for the 3-year interval is that false-negatives will be repeated before substantial time elapses, and there is little likelihood that an individual will develop significant complications of diabetes within 3 years of a negative test result. Because of the need for follow-up and discussion of abnormal results, testing should be carried out within the health care setting. Community screening outside a health care setting is not recommended because people with positive tests may not seek, or have access to, appropriate follow-up testing and care. Conversely, there may be failure to ensure appropriate repeat testing for individuals who test negative. Community screening may also be poorly targeted, i.e., it may fail to reach the groups most at risk and inappropriately test those at low risk (the worried well) or even those already diagnosed (18,19). B. Testing for type 2 diabetes in children The incidence of type 2 diabetes in adolescents has increased dramatically in the last decade, especially in minority populations (20), although the disease remains rare in the general adolescent population (21). Consistent with recommendations for adults, children and youth at increased risk for the presence or the development of type 2 diabetes should be tested within the health care setting (22). The recommendations of the ADA consensus statement on type 2 diabetes in children and youth, with some modifications, are summarized in Table 4. C. Screening for type 1 diabetes Generally, people with type 1 diabetes present with acute symptoms of diabetes and markedly elevated blood glucose levels, and most cases are diagnosed soon after the onset of hyperglycemia. However, evidence from type 1 prevention studies suggests that measurement of islet autoantibodies identifies individuals who are at risk for developing type 1 diabetes. Such testing may be appropriate in high-risk individuals, such as those with prior transient hyperglycemia or those who have relatives with type 1 diabetes, in the context of clinical research studies (see, for example, http://www2.diabetestrialnet.org). Widespread clinical testing of asymptomatic low-risk individuals cannot currently be recommended, as it would identify very few individuals in the general population who are at risk. Individuals who screen positive should be counseled about their risk of developing diabetes. Clinical studies are being conducted to test various methods of preventing type 1 diabetes, or reversing early type 1 diabetes, in those with evidence of autoimmunity. III. DETECTION AND DIAGNOSIS OF GDM Recommendations Screen for GDM using risk factor analysis and, if appropriate, use of an OGTT. (C) Women with GDM should be screened for diabetes 6–12 weeks postpartum and should be followed up with subsequent screening for the development of diabetes or pre-diabetes. (E) GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy (4). Although most cases resolve with delivery, the definition applies whether or not the condition persists after pregnancy and does not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy. Approximately 7% of all pregnancies (ranging from 1 to 14% depending on the population studied and the diagnostic tests employed) are complicated by GDM, resulting in more than 200,000 cases annually. Because of the risks of GDM to the mother and neonate, screening and diagnosis are warranted. The screening and diagnostic strategies, based on the 2004 ADA position statement on gestational diabetes mellitus (23), are outlined in Table 5. Results of the Hyperglycemia and Adverse Pregnancy Outcomes study (24), a large-scale (including ∼25,000 pregnant women) multinational epidemiologic study, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24–28 weeks, even within ranges previously considered normal for pregnancy. For most complications, there was no threshold for risk. These results have led to careful reconsideration of the diagnostic criteria for GDM. An international group representing multiple obstetrical and diabetes organizations, including ADA, is currently working on consensus toward 1) a world-wide standard for which diagnostic test to use for GDM and 2) rational diagnostic cut points. Because women with a history of GDM have a greatly increased subsequent risk for diabetes (25), they should be screened for diabetes 6–12 weeks postpartum, using nonpregnant OGTT criteria, and should be followed up with subsequent screening for the development of diabetes or pre-diabetes, as outlined in Section II. For information on the National Diabetes Education Program (NDEP) campaign to prevent type 2 diabetes in women with GDM, go to www.ndep.nih.gov/diabetes/pubs/NeverTooEarly_Tipsheet.pdf. IV. PREVENTION/DELAY OF TYPE 2 DIABETES Recommendations Patients with IGT (A) or IFG (E) should be referred to an effective ongoing support program for weight loss of 5–10% of body weight and for increasing physical activity to at least 150 min per week of moderate activity such as walking. Follow-up counseling appears to be important for success. (B) Based on potential cost savings of diabetes prevention, such counseling should be covered by third-party payors. (E) In addition to lifestyle counseling, metformin may be considered in those who are at very high risk for developing diabetes (combined IFG and IGT plus other risk factors such as A1C >6%, hypertension, low HDL cholesterol, elevated triglycerides, or family history of diabetes in a first-degree relative) and who are obese and under 60 years of age. (E) Monitoring for the development of diabetes in those with pre-diabetes should be performed every year. (E) Randomized controlled trials have shown that individuals at high risk for developing diabetes (those with IFG, IGT, or both) can be given interventions that significantly decrease the rate of onset of diabetes (10–16). These interventions include intensive lifestyle modification programs that have been shown to be very effective (≥58% reduction after 3 years) and use of the pharmacologic agents metformin, acarbose, orlistat, and thiazolidinediones (TZDs), each of which has been shown to decrease incident diabetes to various degrees. A summary of major diabetes prevention trials is shown in Table 6. Two studies of lifestyle intervention have shown persistent reduction in the rate of conversion to type 2 diabetes with 3 (26) to 14 years (27) of postintervention follow-up. Based on the results of clinical trials and the known risks of progression of pre-diabetes to diabetes, an ADA Consensus Development Panel (7) concluded that persons with pre-diabetes (IGT and/or IFG) should be counseled on lifestyle changes with goals similar to those of the Diabetes Prevention Program (DPP) (5–10% weight loss and moderate physical activity of ∼30 min per day). Regarding the more difficult issue of drug therapy for diabetes prevention, the consensus panel felt that metformin should be the only drug considered for use in diabetes prevention. For other drugs, the issues of cost, side effects, and lack of persistence of effect in some studies led the panel to not recommend their use for diabetes prevention. Metformin use was recommended only for very-high-risk individuals (those with combined IGT and IFG who are obese and under 60 years of age with at least one other risk factor for diabetes). In addition, the panel highlighted the evidence that in the DPP, metformin was most effective compared to lifestyle in those with BMI of at least 35 kg/m2 and those under age 60 years. V. DIABETES CARE A. Initial evaluation A complete medical evaluation should be performed to classify the diabetes, detect the presence of diabetes complications, review previous treatment and glycemic control in patients with established diabetes, assist in formulating a management plan, and provide a basis for continuing care. Laboratory tests appropriate to the evaluation of each patient's medical condition should be performed. A focus on the components of comprehensive care (Table 7) will assist the health care team to ensure optimal management of the patient with diabetes. B. Management People with diabetes should receive medical care from a physician-coordinated team. Such teams may include, but are not limited to, physicians, nurse practitioners, physician's assistants, nurses, dietitians, pharmacists, and mental health professionals with expertise and a special interest in diabetes. It is essential in this collaborative and integrated team approach that individuals with diabetes assume an active role in their care. The management plan should be formulated as an individualized therapeutic alliance among the patient and family, the physician, and other members of the health care team. A variety of strategies and techniques should be used to provide adequate education and development of problem-solving skills in the various aspects of diabetes management. Implementation of the management plan requires that each aspect is understood and agreed on by the patient and the care providers and that the goals and treatment plan are reasonable. Any plan should recognize diabetes self-management education (DSME) as an integral component of care. In developing the plan, consideration should be given to the patient's age, school or work schedule and conditions, physical activity, eating patterns, social situation and personality, cultural factors, and presence of complications of diabetes or other medical conditions. C. Glycemic control 1. Assessment of glycemic control Two primary techniques are available for health providers and patients to assess the effectiveness of the management plan on glycemic control: patient self-monitoring of blood glucose (SMBG) or of interstitial glucose and measurement of A1C. a. Glucose monitoring Recommendations SMBG should be carried out three or more times daily for patients using multiple insulin injections or insulin pump therapy. (A) For patients using less frequent insulin injections, noninsulin therapies, or medical nutrition therapy (MNT) and physical activity alone, SMBG may be useful as a guide to the success of therapy. (E) To achieve postprandial glucose targets, postprandial SMBG may be appropriate. (E) When prescribing SMBG, ensure that patients receive initial instruction in, and routine follow-up evaluation of, SMBG technique and their ability to use data to adjust therapy. (E) Continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens can be a useful tool to lower A1C in selected adults (age ≥25 years) with type 1 diabetes (A). Although the evidence for A1C lowering is less strong in children, teens, and younger adults, CGM may be helpful in these groups. Success correlates with adherence to ongoing use of the device. (C) CGM may be a supplemental tool to SMBG in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes. (E) The ADA's consensus and position statements on SMBG provide a comprehensive review of the subject (31,32). Major clinical trials of insulin-treated patients that demonstrated the benefits of intensive glycemic control on diabetes complications have included SMBG as part of multifactorial interventions, suggesting that SMBG is a component of effective therapy. SMBG allows patients to evaluate their individual response to therapy and assess whether glycemic targets are being achieved. Results of SMBG can be useful in preventing hypoglycemia and adjusting medications (particularly prandial insulin doses), MNT, and physical activity. The frequency and timing of SMBG should be dictated by the particular needs and goals of the patients. SMBG is especially important for patients treated with insulin to monitor for and prevent asymptomatic hypoglycemia and hyperglycemia. For most patients with type 1 diabetes and pregnant women taking insulin, SMBG is recommended three or more times daily. For this population, significantly more frequent testing may be required to reach A1C targets safely without hypoglycemia. The optimal frequency and timing of SMBG for patients with type 2 diabetes on noninsulin therapy is unclear. A meta-analysis of SMBG in non–insulin-treated patients with type 2 diabetes concluded that some regimen of SMBG was associated with a reduction in A1C of ≥0.4%. However, many of the studies in this analysis also included patient education with diet and exercise counseling and, in some cases, pharmacologic intervention, making it difficult to assess the contribution of SMBG alone to improved control (33). Several recent trials have called into question the clinical utility and cost-effectiveness of routine SMBG in non–insulin-treated patients (34–36). Because the accuracy of SMBG is instrument and user dependent (37), it is important to evaluate each patient's monitoring technique, both initially and at regular intervals thereafter. In addition, optimal use of SMBG requires proper interpretation of the data. Patients should be taught how to use the data to adjust food intake, exercise, or pharmacological therapy to achieve specific glycemic goals, and these skills should be reevaluated periodically. CGM through the measurement of interstitial glucose (which correlates well with plasma glucose) is available. These sensors require calibration with SMBG, and the latter are still recommended for making acute treatment decisions. CGM devices also have alarms for hypo- and hyperglycemic excursions. Small studies in selected patients with type 1 diabetes have suggested that CGM use reduces the time spent in hypo- and hyperglycemic ranges and may modestly improve glycemic control. A larger 26-week randomized trial of 322 type 1 patients showed that adults age 25 years and older using intensive insulin therapy and CGM experienced a 0.5% reduction in A1C (from ∼7.6 to 7.1%) compared with usual intensive insulin therapy with SMBG (38). Sensor use in children, teens, and adults to age 24 years did not result in significant A1C lowering, and there was no significant difference in hypoglycemia in any group. Importantly, the greatest predictor of A1C lowering in this study for all age-groups was frequency of sensor use, which was lower in younger age-groups. Although CGM is an evolving technology, emerging data suggest that, in appropriately selected patients who are motivated to wear it most of the time, it may offer benefit. CGM may be particularly useful in those with hypoglycemia unawareness and/or frequent episodes of hypoglycemia, and studies in this area are ongoing. b. A1C Recommendations Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control). (E) Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. (E) Use of point-of-care testing for A1C allows for timely decisions on therapy changes, when needed. (E) Because A1C is thought to reflect average glycemia over several months (37), and has strong predictive value for diabetes complications (10,39), A1C testing should be performed routinely in all patients with diabetes at initial assessment and then as part of continuing care. Measurement approximately every 3 months determines whether a patient's glycemic targets have been reached and maintained. For any individual patient, the frequency of A1C testing should be dependent on the clinical situation, the treatment regimen used, and the judgment of the clinician. Some patients with stable glycemia well within target may do well with testing only twice per year, while unstable or highly intensively managed patients (e.g., pregnant type 1 women) may be tested more frequently than every 3 months. The availability of the A1C result at the time that the patient is seen (point-of-care testing) has been reported to result in increased intensification of therapy and improvement in glycemic control (40,41). The A1C test is subject to certain limitations. Conditions that affect erythrocyte turnover (hemolysis, blood loss) and hemoglobin variants must be considered, particularly when the A1C result does not correlate with the patient's clinical situation (37). In addition, A1C does not provide a measure of glycemic variability or hypoglycemia. For patients prone to glycemic variability (especially type 1 patients, or type 2 patients with severe insulin deficiency), glycemic control is best judged by the combination of results of SMBG testing and the A1C. The A1C may also serve as a check on the accuracy of the patient's meter (or the patient's reported SMBG results) and the adequacy of the SMBG testing schedule. Table 8 contains the correlation between A1C levels and mean plasma glucose levels based on data from the international A1C-Derived Average Glucose (ADAG) trial utilizing frequent SMBG and continuous glucose monitoring in 507 adults (83% Caucasian) with type 1, type 2, and no diabetes (49) The ADA and American Association of Clinical Chemists have determined that the correlation (r = 0.92) is strong enough to justify reporting both an A1C result and an estimated average glucose (eAG) result when a clinician orders the A1C test. The table in previous versions of the Standards of Medical Care in Diabetes describing the correlation between A1C and mean glucose was derived from relatively sparse data (one seven-point profile over 1 day per A1C reading) in the primarily Caucasian type 1 participants in the Diabetes Control and Complications Trial (DCCT) trial (43). Clinicians should note that the numbers in the table are now different, as they are based on ∼2,800 readings per A1C in the ADAG trial. In the ADAG study, there were no significant differences among racial and ethnic groups in the regression lines between A1C and mean glucose, although there was a trend toward a difference between African/African-American and Caucasian participants’ regression lines that might have been significant had more African/African-American participants been studied. A recent study comparing A1C to CGM data in 48 type 1 children found a highly statistically significant correlation between A1C and mean blood glucose, although the correlation (r = 0.7) was significantly lower than in the ADAG trial (44). Whether there are significant differences in how A1C relates to average glucose in children or in African-American patients is an area for further study. For the time being, the question has not led to different recommendations about testing A1C or to different interpretations of the clinical meaning of given levels of A1C in those populations. For patients in whom A1C/eAG and measured blood glucose appear discrepant, clinicians should consider the possibilities of hemoglobinopathy or altered red cell turnover and the options of more frequent and/or different timing of SMBG or use of CGM. Other measures of chronic glycemia such as fructosamine are available, but their linkage to average glucose and their prognostic significance are not as clear as is the case for A1C. 2. Glycemic goals in adults Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore, for microvascular disease prevention, the A1C goal for nonpregnant adults in general is 9%) to good control (e.g., A1C 64 years of age previously immunized when they were 5 years ago. Other indications for repeat vaccination include nephrotic syndrome, chronic renal disease, and other immunocompromised states, such as after transplantation. (C) Influenza and pneumonia are common, preventable infectious diseases associated with high mortality and morbidity in the elderly and in people with chronic diseases. Though there are limited studies reporting the morbidity and mortality of influenza and pneumococcal pneumonia specifically in people with diabetes, observational studies of patients with a variety of chronic illnesses, including diabetes, show that these conditions are associated with an increase in hospitalizations for influenza and its complications. People with diabetes may be at increased risk of the bacteremic form of pneumococcal infection and have been reported to have a high risk of nosocomial bacteremia, which has a mortality rate as high as 50% (150). Safe and effective vaccines are available that can greatly reduce the risk of serious complications from these diseases (151,152). In a case-control series, influenza vaccine was shown to reduce diabetes-related hospital admission by as much as 79% during flu epidemics (151). There is sufficient evidence to support that people with diabetes have appropriate serologic and clinical responses to these vaccinations. The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommends influenza and pneumococcal vaccines for all individuals with diabetes (http://www.cdc.gov/vaccines/recs/). For a complete discussion on the prevention of influenza and pneumococcal disease in people with diabetes, consult the technical review and position statement on this subject (150,153). VI. PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS A. CVD CVD is the major cause of morbidity and mortality for individuals with diabetes and the largest contributor to the direct and indirect costs of diabetes. The common conditions coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are clear risk factors for CVD, and diabetes itself confers independent risk. Numerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing or slowing CVD in people with diabetes. Large benefits are seen when multiple risk factors are addressed globally (154). Evidence is summarized in the following sections and reviewed in detail in the ADA technical reviews on hypertension (155), dyslipidemia (156), aspirin therapy (157), and smoking cessation (158) and in the American Heart Association (AHA)/ADA scientific statement on prevention of CVD in people with diabetes (159). 1. Hypertension/blood pressure control Recommendations Screening and diagnosis Blood pressure should be measured at every routine diabetes visit. Patients found to have a systolic blood pressure of ≥130 mmHg or a diastolic blood pressure of ≥80 mmHg should have blood pressure confirmed on a separate day. Repeat systolic blood pressure of ≥130 mmHg or diastolic blood pressure of ≥80 mmHg confirms a diagnosis of hypertension. (C) Goals Patients with diabetes should be treated to a systolic blood pressure 115/75 mmHg is associated with increased cardiovascular event rates and mortality in individuals with diabetes (160,166,167). Therefore, a target blood pressure goal of 50 mg/dl, and triglycerides 40 mg/dl (1.0 mmol/l) in men and >50 mg/dl (1.3 mmol/l) in women are desirable. However, LDL cholesterol–targeted statin therapy remains the preferred strategy. (C) If targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CVD outcomes or safety. (E) Statin therapy is contraindicated in pregnancy. (E) Evidence for benefits of lipid-lowering therapy Patients with type 2 diabetes have an increased prevalence of lipid abnormalities, contributing to their high risk of CVD. For the past decade or more, multiple clinical trials demonstrated significant effects of pharmacologic (primarily statin) therapy on CVD outcomes in subjects with CHD and for primary CVD prevention (185). Subanalyses of diabetic subgroups of larger trials (186–190) and trials specifically in subjects with diabetes (191,192) showed significant primary and secondary prevention of CVD events ± CHD deaths in diabetic populations. As shown in Table 10, and similar to findings in nondiabetic subjects, reduction in “hard” CVD outcomes (CHD death and nonfatal MI) can be more clearly seen in diabetic subjects with high baseline CVD risk (known CVD and/or very high LDL cholesterol levels), but overall the benefits of statin therapy in people with diabetes at moderate or high risk for CVD are convincing. Low levels of HDL cholesterol, often associated with elevated triglyceride levels, are the most prevalent pattern of dyslipidemia in persons with type 2 diabetes. However, the evidence base for drugs that target these lipid fractions is significantly less robust than that for statin therapy (193). Nicotinic acid has been shown to reduce CVD outcomes (194), although the study was done in a nondiabetic cohort. Gemfibrozil has been shown to decrease rates of CVD events in subjects without diabetes (195,196) and in the diabetic subgroup in one of the larger trials (195). However, in a large trial specific to diabetic patients, fenofibrate failed to reduce overall cardiovascular outcomes (197). Dyslipidemia treatment and target lipid levels For most patients with diabetes, the first priority of dyslipidemia therapy (unless severe hypertriglyceridemia is the immediate issue) is to lower LDL cholesterol to a target goal of 40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). (C) Use aspirin therapy (75–162 mg/day) as a secondary prevention strategy in those with diabetes with a history of CVD. (A) For patients with CVD and documented aspirin allergy, clopidogrel (75 mg/day) should be used. (B) Combination therapy with ASA (75–162 mg/day) and clopidogrel (75 mg/day) is reasonable for up to a year after an acute coronary syndrome. (B) Aspirin therapy is not recommended in people under 30 years of age due to lack of evidence of benefit and is contraindicated in patients under the age of 21 years because of the associated risk of Reye's syndrome. (E) The use of aspirin in diabetes is reviewed in detail in the ADA technical review (157) and position statement (210) on this topic. Aspirin has been recommended for primary (211,212) and secondary (213,214) prevention of cardiovascular events in high-risk diabetic and nondiabetic individuals. One large meta-analysis and several clinical trials demonstrate the efficacy of using aspirin as a preventive measure for cardiovascular events, including stroke and myocardial infarction. Many trials have shown an ∼30% decrease in myocardial infarction and a 20% decrease in stroke in a wide range of patients, including young and middle-aged patients, patients with and without a history of CVD, men and women, and patients with hypertension. Dosages used in most clinical trials ranged from 75 to 325 mg/day. There is little evidence to support any specific dose, but using the lowest possible dosage may help reduce side effects (215). Conversely, a randomized trial of 100 mg of aspirin daily showed less of a primary prevention effect, without statistical significance, in the large diabetic subgroup in contrast to significant benefit in those without diabetes (216), raising the issue of aspirin resistance in those with diabetes. The systematic review of evidence for the U.S. Preventive Services Task Force (USPSTF) estimated that aspirin reduced the risk for nonfatal and fatal MI (odds ratio 0.72 [95% CI 0.60–0.87]). The review acknowledged the low numbers of diabetic subjects in most trials but concluded that subset analyses and a single trial in diabetic patients suggested that the estimates extended to those with diabetes (211). The USPSTF stated that the risk-to-benefit ratio favors aspirin use when 5-year CHD risk equals or exceeds 3% and suggested aspirin therapy be considered for men >40 years of age, postmenopausal women, and younger persons with CHD risk factors (including diabetes) (212). There is no evidence for a specific age at which to start aspirin, but aspirin has not been studied at ages 40 years of age with another cardiovascular risk factor (hypertension, family history, dyslipidemia, microalbuminuria, cardiac autonomic neuropathy, or smoking), aspirin and statin therapy (if not contraindicated) should be used to reduce the risk of cardiovascular events. (B) In patients with CHF, TZD use is contraindicated. (C) Metformin may be used in patients with stable CHF if renal function is normal. It should be avoided in unstable or hospitalized patients with CHF. (C) Screening for CAD is reviewed in a recently updated consensus statement (123). To identify the presence of CAD in diabetic patients without clear or suggestive symptoms, a risk factor–based approach to the initial diagnostic evaluation and subsequent follow-up has intuitive appeal. However, recent studies concluded that using this approach fails to identify which patients will have silent ischemia on screening tests (130,221). Candidates for cardiac testing include those with 1) typical or atypical cardiac symptoms and 2) an abnormal resting electrocardiogram (ECG). The screening of asymptomatic patients remains controversial, especially as intensive medical therapy indicated in diabetic patients at high risk for CVD has an increasing evidence base for providing equal outcomes to invasive revascularization, including in diabetic patients (222). There is also recent preliminary evidence that silent myocardial ischemia may reverse over time, adding to the controversy concerning aggressive screening strategies (223). Finally, a recent randomized observational trial presented at the ADA's Scientific Sessions in June 2008 demonstrated no clinical benefit to routine screening of asymptomatic patients with type 2 diabetes and normal ECGs. Despite abnormal myocardial perfusion imaging in more than one in five patients, cardiac outcomes were essentially equal (and very low) in screened versus unscreened patients. In all patients with diabetes, cardiovascular risk factors should be assessed at least annually. These risk factors include dyslipidemia, hypertension, smoking, a positive family history of premature coronary disease, and the presence of micro- or macroalbuminuria. Abnormal risk factors should be treated as described elsewhere in these guidelines. Patients at increased CHD risk should receive aspirin and a statin and ACE inhibitor or ARB therapy if hypertensive, unless there are contraindications to a particular drug class. While clear benefit exists for ACE inhibitor and ARB therapy in patients with nephropathy or hypertension, the benefits in patients with CVD in the absence of these conditions is less clear, especially when LDL cholesterol is concomitantly controlled (224,225) B. Nephropathy screening and treatment Recommendations General recommendations To reduce the risk or slow the progression of nephropathy, optimize glucose control. (A) To reduce the risk or slow the progression of nephropathy, optimize blood pressure control. (A) Screening Perform an annual test to assess urine albumin excretion in type 1 diabetic patients with diabetes duration of ≥5 years and in all type 2 diabetic patients, starting at diagnosis. (E) Measure serum creatinine at least annually in all adults with diabetes regardless of the degree of urine albumin excretion. The serum creatinine should be used to estimate GFR and stage the level of chronic kidney disease (CKD), if present. (E) Treatment In the treatment of the nonpregnant patient with micro- or macroalbuminuria, either ACE inhibitors or ARBs should be used. (A) While there are no adequate head-to-head comparisons of ACE inhibitors and ARBs, there is clinical trial support for each of the following statements: In patients with type 1 diabetes, hypertension, and any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. (A) In patients with type 2 diabetes, hypertension, and microalbuminuria, both ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria. (A) In patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dl), ARBs have been shown to delay the progression of nephropathy. (A) If one class is not tolerated, the other should be substituted. (E) Reduction of protein intake to 0.8–1.0 g · kg body wt−1 · day−1 in individuals with diabetes and the earlier stages of CKD and to 0.8 g · kg body wt−1 · day−1 in the later stages of CKD may improve measures of renal function (urine albumin excretion rate, GFR) and is recommended. (B) When ACE inhibitors, ARBs, or diuretics are used, monitor serum creatinine and potassium levels for the development of acute kidney disease and hyperkalemia. (E) Continued monitoring of urine albumin excretion to assess both response to therapy and progression of disease is recommended. (E) Consider referral to a physician experienced in the care of kidney disease when there is uncertainty about the etiology of kidney disease (active urine sediment, absence of retinopathy, rapid decline in GFR), difficult management issues, or advanced kidney disease. (B) Diabetic nephropathy occurs in 20–40% of patients with diabetes and is the single leading cause of end-stage renal disease (ESRD). Persistent albuminuria in the range of 30–299 mg/24 h (microalbuminuria) has been shown to be the earliest stage of diabetic nephropathy in type 1 diabetes and a marker for development of nephropathy in type 2 diabetes. Microalbuminuria is also a well-established marker of increased CVD risk (226,227). Patients with microalbuminuria who progress to macroalbuminuria (300 mg/24 h) are likely to progress to ESRD (228,229). However, a number of interventions have been demonstrated to reduce the risk and slow the progression of renal disease. Intensive diabetes management with the goal of achieving near normoglycemia has been shown in large prospective randomized studies to delay the onset of microalbuminuria and the progression of micro- to macroalbuminuria in patients with type 1 (230,231) and type 2 (49,50) diabetes. The UKPDS provided strong evidence that control of blood pressure can reduce the development of nephropathy (163). In addition, large prospective randomized studies in patients with type 1 diabetes have demonstrated that achievement of lower levels of systolic blood pressure ( 30 mg/g) to the normal or near-normal range may improve renal and cardiovascular prognosis, but this approach has not been formally evaluated in prospective trials. Complications of kidney disease correlate with level of kidney function. When the estimated GFR is 87% sensitivity in detecting DPN. Loss of 10-g monofilament perception and reduced vibration perception predict foot ulcers (270). Diabetic autonomic neuropathy (271) The symptoms and signs of autonomic dysfunction should be elicited carefully during the history and physical examination. Major clinical manifestations of diabetic autonomic neuropathy include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, “brittle diabetes,” and hypoglycemic autonomic failure. Cardiovascular autonomic neuropathy, a CVD risk factor (93), is the most studied and clinically important form of diabetic autonomic neuropathy. Cardiovascular autonomic neuropathy may be indicated by resting tachycardia (>100 bpm), orthostasis (a fall in systolic blood pressure >20 mmHg upon standing without an appropriate heart rate response), or other disturbances in autonomic nervous system function involving the skin, pupils, or gastrointestinal and genitourinary systems. Gastrointestinal neuropathies (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, fecal incontinence) are common, and any section of the gastrointestinal tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control or with upper gastrointestinal symptoms without other identified cause. Evaluation of solid-phase gastric emptying using double-isotope scintigraphy may be done if symptoms are suggestive, but test results often correlate poorly with symptoms. Constipation is the most common lower-gastrointestinal symptom but can alternate with episodes of diarrhea. Diabetic autonomic neuropathy is also associated with genitourinary tract disturbances. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. Symptomatic treatments DPN The first step in management of patients with DPN should be to aim for stable and optimal glycemic control. Although controlled trial evidence is lacking, several observational studies suggest that neuropathic symptoms improve not only with optimization of control, but also with the avoidance of extreme blood glucose fluctuations. Patients with painful DPN may benefit from pharmacological treatment of their symptoms: many agents have efficacy confirmed in published randomized controlled trials, with several FDA-approved for the management of painful DPN. See Table 14 for examples of agents to treat DPN pain. Treatment of autonomic neuropathy Gastroparesis symptoms may improve with dietary changes and prokinetic agents such as metoclopramide or erythromycin. Treatments for erectile dysfunction may include phosphodiesterase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses. Interventions for other manifestations of autonomic neuropathy are described in the ADA statement on neuropathy (270). As with DPN treatments, these interventions do not change the underlying pathology and natural history of the disease process but may have a positive impact on the quality of life of the patient. E. Foot care Recommendations For all patients with diabetes, perform an annual comprehensive foot examination to identify risk factors predictive of ulcers and amputations. The foot examination should include inspection, assessment of foot pulses, and testing for loss of protective sensation (10-g monofilament plus testing any one of the following: vibration using 128-Hz tuning fork, pinprick sensation, ankle reflexes, or vibration perception threshold). (B) Provide general foot self-care education to all patients with diabetes. (B) A multidisciplinary approach is recommended for individuals with foot ulcers and high-risk feet, especially those with a history of prior ulcer or amputation. (B) Refer patients who smoke, have loss of protective sensation and structural abnormalities, or have history of prior lower-extremity complications to foot care specialists for ongoing preventive care and life-long surveillance. (C) Initial screening for peripheral arterial disease (PAD) should include a history for claudication and an assessment of the pedal pulses. Consider obtaining an ankle-brachial index (ABI), as many patients with PAD are asymptomatic. (C) Refer patients with significant claudication or a positive ABI for further vascular assessment and consider exercise, medications, and surgical options. (C) Amputation and foot ulceration, consequences of diabetic neuropathy and/or PAD, are common and major causes of morbidity and disability in people with diabetes. Early recognition and management of risk factors can prevent or delay adverse outcomes. The risk of ulcers or amputations is increased in people who have the following risk factors: previous amputation past foot ulcer history peripheral neuropathy foot deformity peripheral vascular disease vision impairment diabetic nephropathy (especially patients on dialysis) poor glycemic control cigarette smoking Many studies have been published proposing a range of tests that might usefully identify patients at risk of foot ulceration, creating confusion among practitioners as to which screening tests should be adopted in clinical practice. An ADA task force was therefore assembled in 2008 to concisely summarize recent literature in this area and then recommend what should be included in the comprehensive foot exam for adult patients with diabetes. Their recommendations are summarized below, but clinicians should refer to the task force report (272) for further details and practical descriptions of how to perform components of the comprehensive foot examination. At least annually, all adults with diabetes should undergo a comprehensive foot examination to identify high-risk conditions. Clinicians should ask about history of previous foot ulceration or amputation, neuropathic or peripheral vascular symptoms, impaired vision, tobacco use, and foot care practices. A general inspection of skin integrity and musculoskeletal deformities should be done in a well-lit room. Vascular assessment should include inspection and assessment of pedal pulses. The neurologic exam recommended is designed to identify loss of protective sensation (LOPS) rather than early neuropathy. The clinical examination to identify LOPS is simple and requires no expensive equipment. Five simple clinical tests (use of a 10-g monofilament, vibration testing using a 128-Hz tuning fork, tests of pinprick sensation, ankle reflex assessment, and testing vibration perception threshold with a biothesiometer), each with evidence from well-conducted prospective clinical cohort studies, are considered useful in the diagnosis of LOPS in the diabetic foot. The task force agrees that any of the five tests listed could be used by clinicians to identify LOPS, although ideally two of these should be regularly performed during the screening exam—normally the 10-g monofilament and one other test. One or more abnormal tests would suggest LOPS, while at least two normal tests (and no abnormal test) would rule out LOPS. The last test listed, vibration assessment using a biothesiometer or similar instrument, is widely used in the U.S.; however, identification of the patient with LOPS can easily be carried out without this or other expensive equipment. Initial screening for PAD should include a history for claudication and an assessment of the pedal pulses. A diagnostic ABI should be performed in any patient with symptoms of PAD. Due to the high estimated prevalence of PAD in patients with diabetes and the fact that many patients with PAD are asymptomatic, an ADA consensus statement on PAD (273) suggested that a screening ABI be performed in patients over 50 years of age and be considered in patients under 50 years of age who have other PAD risk factors (e.g., smoking, hypertension, hyperlipidemia, or duration of diabetes >10 years). Refer patients with significant symptoms or a positive ABI for further vascular assessment and consider exercise, medications, and surgical options (273). Patients with diabetes and high-risk foot conditions should be educated regarding their risk factors and appropriate management. Patients at risk should understand the implications of the loss of protective sensation, the importance of foot monitoring on a daily basis, the proper care of the foot, including nail and skin care, and the selection of appropriate footwear. Patients with loss of protective sensation should be educated on ways to substitute other sensory modalities (hand palpation, visual inspection) for surveillance of early foot problems. The patient's understanding of these issues and their physical ability to conduct proper foot surveillance and care should be assessed. Patients with visual difficulties, physical constraints preventing movement, or cognitive problems that impair their ability to assess the condition of the foot and to institute appropriate responses will need other people, such as family members, to assist in their care. People with neuropathy or evidence of increased plantar pressure (e.g., erythema, warmth, callus, or measured pressure) may be adequately managed with well-fitted walking shoes or athletic shoes that cushion the feet and redistribute pressure. Callus can be debrided with a scalpel by a foot care specialist or other health professional with experience and training in foot care. People with bony deformities (e.g., hammertoes, prominent metatarsal heads, bunions) may need extra-wide or -depth shoes. People with extreme bony deformities (e.g., Charcot foot) who cannot be accommodated with commercial therapeutic footwear may need custom-molded shoes. Foot ulcers and wound care may require care by a podiatrist, orthopedic or vascular surgeon, or rehabilitation specialist experienced in the management of individuals with diabetes. For a complete discussion, see the ADA's consensus statement on diabetic foot wound care (274). VII. DIABETES CARE IN SPECIFIC POPULATIONS A. Children and adolescents 1. Type 1 diabetes Three-quarters of all cases of type 1 diabetes are diagnosed in individuals 1% higher than that achieved by adult DCCT subjects and above current ADA recommendations for patients in general. However, the increased frequency of use of basal bolus regimens (including insulin pumps) in youth from infancy through adolescence has been associated with more children reaching ADA blood glucose targets (279,280) in those families in which both parents and the child with diabetes are motivated to perform the required diabetes-related tasks. In selecting glycemic goals, the benefits on long-term health outcomes of achieving a lower A1C must be weighed against the unique risks of hypoglycemia and the difficulties achieving near normoglycemia in children and youth. Age-specific glycemic and A1C goals are presented in Table 15. b. Screening and management of chronic complications in children and adolescents with type 1 diabetes i. Nephropathy Recommendations Annual screening for microalbuminuria, with a random spot urine sample for microalbumin-to-creatinine ratio, should be initiated once the child is 10 years of age and has had diabetes for 5 years. (E) Confirmed, persistently elevated microalbumin levels on two additional urine specimens should be treated with an ACE inhibitor, titrated to normalization of microalbumin excretion if possible. (E) ii. Hypertension Recommendations Treatment of high-normal blood pressure (systolic or diastolic blood pressure consistently between the 90–95th percentile for age, sex, and height) should include dietary intervention and exercise aimed at weight control and increased physical activity, if appropriate. If target blood pressure is not reached with 6–12 months of lifestyle intervention, pharmacologic treatment should be initiated. (E) Pharmacologic treatment of high blood pressure (systolic or diastolic blood pressure consistently above the 95th percentile for age, sex, and height or consistently >130/80 mmHg for adolescents) should be initiated along with lifestyle intervention as soon as the diagnosis is confirmed. (E) ACE inhibitors should be considered for the initial treatment of hypertension. (E) The goal of treatment is a blood pressure consistently 240 mg/dl) or a cardiovascular event before age 55 years, or if family history is unknown, then a fasting lipid profile should be performed on children >2 years of age soon after diagnosis (after glucose control has been established). If family history is not of concern, then the first lipid screening should be performed at puberty (≥10 years). All children diagnosed with diabetes at or after puberty should have a fasting lipid profile performed soon after diagnosis (after glucose control has been established). (E) For both age-groups, if lipids are abnormal, annual monitoring is recommended. If LDL cholesterol values are within the accepted risk levels ( 160 mg/dl (4.1 mmol/l) or LDL cholesterol >130 mg/dl (3.4 mmol/l) and one or more CVD risk factors. (E) The goal of therapy is an LDL cholesterol value 1% above the normal range for a nondiabetic pregnant woman. Preconception care of diabetes appears to reduce the risk of congenital malformations. Five nonrandomized studies compared rates of major malformations in infants between women who participated in preconception diabetes care programs and women who initiated intensive diabetes management after they were already pregnant. The preconception care programs were multidisciplinary and designed to train patients in diabetes self-management with diet, intensified insulin therapy, and SMBG. Goals were set to achieve normal blood glucose concentrations, and >80% of subjects achieved normal A1C concentrations before they became pregnant (299–303). In all five studies, the incidence of major congenital malformations in women who participated in preconception care (range 1.0–1.7% of infants) was much lower than the incidence in women who did not participate (range 1.4–10.9% of infants). One limitation of these studies is that participation in preconception care was self-selected rather than randomized. Thus, it is impossible to be certain that the lower malformation rates resulted fully from improved diabetes care. Nonetheless, the evidence supports the concept that malformations can be reduced or prevented by careful management of diabetes before pregnancy. Planned pregnancies greatly facilitate preconception diabetes care. Unfortunately, nearly two-thirds of pregnancies in women with diabetes are unplanned, leading to a persistent excess of malformations in infants of diabetic mothers. To minimize the occurrence of these devastating malformations, standard care for all women with diabetes who have child-bearing potential, beginning at the onset of puberty or at diagnosis, should include 1) education about the risk of malformations associated with unplanned pregnancies and poor metabolic control and 2) use of effective contraception at all times, unless the patient has good metabolic control and is actively trying to conceive. Women contemplating pregnancy need to be seen frequently by a multidisciplinary team experienced in the management of diabetes before and during pregnancy. The goals of preconception care are to 1) involve and empower the patient in the management of her diabetes, 2) achieve the lowest A1C test results possible without excessive hypoglycemia, 3) assure effective contraception until stable and acceptable glycemia is achieved, and 4) identify, evaluate, and treat long-term diabetic complications such as retinopathy, nephropathy, neuropathy, hypertension, and CHD. Among the drugs commonly used in the treatment of patients with diabetes, a number may be relatively or absolutely contraindicated during pregnancy. Statins are category X (contraindicated for use in pregnancy) and should be discontinued before conception, as should ACE inhibitors (304). ARBs are category C (risk cannot be ruled out) in the first trimester but category D (positive evidence of risk) in later pregnancy and should generally be discontinued before pregnancy. Among the oral antidiabetic agents, metformin and acarbose are classified as category B (no evidence of risk in humans) and all others as category C. Potential risks and benefits of oral antidiabetic agents in the preconception period must be carefully weighed, recognizing that data are insufficient to establish the safety of these agents in pregnancy. For further discussion of preconception care, see the ADA's technical review (305) and position statement (306) on this subject. C. Older adults Recommendations Older adults who are functional, cognitively intact, and have significant life expectancy should receive diabetes treatment using goals developed for younger adults. (E) Glycemic goals for older adults not meeting the above criteria may be relaxed using individual criteria, but hyperglycemia leading to symptoms or risk of acute hyperglycemic complications should be avoided in all patients. (E) Other cardiovascular risk factors should be treated in older adults with consideration of the time frame of benefit and the individual patient. Treatment of hypertension is indicated in virtually all older adults, and lipid and aspirin therapy may benefit those with life expectancy at least equal to the time frame of primary or secondary prevention trials. (E) Screening for diabetes complications should be individualized in older adults, but particular attention should be paid to complications that would lead to functional impairment. (E) Diabetes is an important health condition for the aging population; at least 20% of patients over the age of 65 years have diabetes, and this number can be expected to grow rapidly in the coming decades. Older individuals with diabetes have higher rates of premature death, functional disability, and coexisting illnesses such as hypertension, CHD, and stroke than those without diabetes. Older adults with diabetes are also at greater risk than other older adults for several common geriatric syndromes, such as polypharmacy, depression, cognitive impairment, urinary incontinence, injurious falls, and persistent pain. The American Geriatric Society's guidelines for improving the care of the older person with diabetes (307) have influenced the following discussion and recommendations. The care of older adults with diabetes is complicated by their clinical and functional heterogeneity. Some older individuals developed diabetes years earlier and may have significant complications; others who are newly diagnosed may have had years of undiagnosed diabetes with resultant complications or may have few complications from the disease. Some older adults with diabetes are frail and have other underlying chronic conditions, substantial diabetes-related comorbidity, or limited physical or cognitive functioning. Other older individuals with diabetes have little comorbidity and are active. Life expectancies are highly variable for this population, but often longer than clinicians realize. Providers caring for older adults with diabetes must take this heterogeneity into consideration when setting and prioritizing treatment goals. There are few long-term studies in older adults demonstrating the benefits of intensive glycemic, blood pressure, and lipid control. Patients who can be expected to live long enough to reap the benefits of long-term intensive diabetes management and who are active, have good cognitive function, and are willing to undertake the responsibility of self-management should be encouraged to do so and be treated using the goals for younger adults with diabetes. For patients with advanced diabetes complications, life-limiting comorbid illness, or substantial cognitive or functional impairment, it is reasonable to set less intensive glycemic target goals. These patients are less likely to benefit from reducing the risk of microvascular complications and more likely to suffer serious adverse effects from hypoglycemia. However, patients with poorly controlled diabetes may be subject to acute complications of diabetes, including dehydration, poor wound healing, and hyperglycemic hyperosmolar coma. Glycemic goals at a minimum should avoid these consequences. Although control of hyperglycemia may be important in older individuals with diabetes, greater reductions in morbidity and mortality may result from control of other cardiovascular risk factors rather than from tight glycemic control alone. There is strong evidence from clinical trials of the value of treating hypertension in the elderly (308,309). There is less evidence for lipid-lowering and aspirin therapy, although the benefits of these interventions for primary and secondary prevention are likely to apply to older adults whose life expectancies equal or exceed the time frames seen in clinical trials. Special care is required in prescribing and monitoring pharmacologic therapy in older adults. Metformin is often contraindicated because of renal insufficiency or significant heart failure. TZDs can cause fluid retention, which may exacerbate or lead to heart failure. They are contraindicated in patients with CHF (New York Heart Association class III and IV) and if used at all should be used very cautiously in those with, or at risk for, milder degrees of CHF. Sulfonylureas, other insulin secretagogues, and insulin can cause hypoglycemia. Insulin use requires that patients or caregivers have good visual and motor skills and cognitive ability. Drugs should be started at the lowest dose and titrated up gradually until targets are reached or side effects develop. Screening for diabetes complications in older adults also should be individualized. Particular attention should be paid to complications that can develop over short periods of time and/or that would significantly impair functional status, such as visual and lower-extremity complications. VIII. DIABETES CARE IN SPECIFIC SETTINGS A. Diabetes care in the hospital Recommendations All patients with diabetes admitted to the hospital should have their diabetes clearly identified in the medical record. (E) All patients with diabetes should have an order for blood glucose monitoring, with results available to all members of the health care team. (E) Goals for blood glucose levels: Critically ill surgical patients’ blood glucose levels should be kept as close to 110 mg/dl (6.1 mmol/l) as possible and generally 220 mg/dl (12.2 mmol/l) on the first postoperative day have significantly higher infection rates (315). When admissions on general medicine and surgery units were studied, patients with new hyperglycemia had significantly increased in-hospital mortality, as did patients with known diabetes. In addition, length of stay was higher for the new hyperglycemic group, and patients in either hyperglycemic group were more likely to require intensive care unit (ICU) care and transitional or nursing home care. Better outcomes were demonstrated in patients with fasting and admission blood glucose <126 mg/dl (7 mmol/l) and all random blood glucose levels <200 mg/dl (11.1 mmol/l) (316). b. CVD and critical care. A significant relationship exists between blood glucose levels and mortality in the setting of acute myocardial infarction. A meta-analysis of 15 studies compared in-hospital mortality in both hyper- and normoglycemic patients with and without diabetes. In subjects without known diabetes whose admission blood glucose averaged 109.8 mg/dl (6.1 mmol/l), the relative risk for in-hospital mortality was increased significantly. When diabetes was present and admission glucose averaged 180 mg/dl (10 mmol/l), risk of death was moderately increased compared with patients who had diabetes but less hyperglycemia on admission (317). Another study (318) demonstrated a strong independent relationship between admission blood glucose values and both in-hospital and 1-year mortality; rates were significantly lower in subjects with admission plasma glucose <100.8 mg/dl (5.6 mmol/l) than in those with plasma glucose 199.8 mg/dl (11 mmol/l). These studies focused on admission blood glucose as a predictor of outcomes, rather than inpatient glycemic management per se. Higher admission plasma glucose levels in patients with a prior history of diabetes could reflect the degree of glycemic control in the outpatient setting, thus linking outpatient glycemic control to outcomes in the inpatient population. In patients without a prior history of diabetes, admission hyperglycemia could represent case finding of patients with previously undiagnosed diabetes, an unmasking of risk in a population at high risk for diabetes or more severe illness at admission. In the initial Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study (319,320), insulin-glucose infusion followed by at least 3 months of subcutaneous insulin treatment in diabetic patients with acute myocardial infarction improved long-term survival. Mean blood glucose in the intensive insulin intervention arm was 172.8 mg/dl (9.6 mmol/l), compared with 210.6 mg/dl (11.7 mmol/l) in the “conventional” group. The broad range of blood glucose levels within each arm limits the ability to define specific blood glucose target thresholds. Three more recent studies (321–323) using an insulin-glucose infusion did not show a reduction in mortality in the intervention groups. However, in each of these studies, blood glucose levels were positively correlated with mortality. In the Hyperglycemia: Intensive Insulin Infusion In Infarction (HI-5) study, a decrease in both CHF and reinfarction was observed in the group receiving intensive insulin therapy for at least 24 h. c. Cardiac surgery. Attainment of targeted glucose control in patients with diabetes undergoing cardiac surgery is associated with reduced mortality and risk of deep sternal wound infections (324,325). Although these studies used historical controls and were not randomized, they support the concept that perioperative hyperglycemia is an independent predictor of infection in patients with diabetes (326), with the lowest mortality in patients with blood glucose <150 mg/dl (8.3 mmol/l) (327). d. Critical care. A mixed group of patients with and without diabetes admitted to a surgical ICU were randomized to receive intensive insulin therapy (target blood glucose 80–110 mg/dl [4.4–6.1 mmol/l]) or conventional therapy. Intensive insulin therapy achieved a mean blood glucose of 103 mg/dl (5.7 mmol/l) and was associated with reduced mortality during the ICU stay and decreased overall in-hospital mortality (328). Hospital and ICU survival were linearly associated with ICU glucose levels, with the highest survival rates occurring in patients achieving an average blood glucose <110 mg/dl (6.1 mmol/l) (329). A subsequent study of a similar intervention in patients in a medical ICU (330) showed that the group receiving intensive insulin therapy had reduced morbidity but no difference in mortality overall. Death rates were significantly lower in those patients who were treated for longer than 3 days; but these patients could not be identified before therapy. In another study using a similar intervention targeting a blood glucose range of 4.4–6.1 mmol in patients admitted with sepsis, no difference in mortality from the conventionally treated group was observed. There were more episodes of hypoglycemia, defined as a blood glucose <40 mg/dl (2.2 mmol/l), and more serious adverse events in the group receiving intensive insulin therapy (331). While an earlier meta-analysis concluded that insulin therapy in critically ill patients had a beneficial effect on short-term mortality in different clinical settings (332), a more recent meta-analysis, involving 29 studies and over 8,000 patients, failed to show any mortality benefit from intensive glucose control. Tight glucose control did reduce the relative risk of septicemia by 26% (333). While this latter meta-analysis investigated strategies with target blood glucose levels of 80–110 mg/dl (4.4–6.1 mmol/l), studies with less stringent glucose targets were also included. Stratification by glucose target did not demonstrate any heterogeneity. The authors of this analysis as well as an accompanying editorial both recommend that glycemic targets in critically ill patients be revisited (328–331). While results from ongoing clinical trials are still pending, it is clear that uncontrolled hyperglycemia is associated with adverse outcomes in critically ill patients and that achieving levels of glucose control below 140 mg/dl are reasonable, provided that protocols that minimize risk for hypoglycemia are utilized and that personnel are well educated in the direct application of these protocols. 2. Glycemic targets in hospitalized patients There is relatively strong evidence from randomized controlled trials for a glycemic target of blood glucose <110 mg/dl (6.1 mmol/l) in surgical patients in critical care units (328–330). However, in several studies of critically ill medical patients (330,331,333), the incidence of severe hypoglycemia (blood glucose <40 mg/dl) was approximately threefold greater in intensively treated patients. The identification of hypoglycemia as an independent risk factor for death in the medical ICU population (334) may merit caution in widely promoting the 80–110 mg/dl target range for all critically ill populations. For patients in general medical-surgical units, the evidence for specific glycemic goals is less definitive. Epidemiologic and physiologic data suggest that higher blood glucose levels are associated with worse outcomes, but whether glucose is simply a marker of the severity of underlying illness or a mediator of adverse outcomes is unclear. Glycemic targets similar to those of outpatients may be difficult to achieve in the hospital due to the effects of stress hyperglycemia, altered nutritional intake, and multiple interruptions to medical care. Blood glucose levels shown to be associated with improved outcomes in these patients (fasting glucose <126 mg/dl and all blood glucose readings <180–200 mg/dl) would appear reasonable, if they can be safely achieved. In both the critical care and noncritical care venue, glycemic goals must take into account the individual patient's situation as well as hospital system support for achieving these goals. A continuous quality improvement strategy may facilitate gradual improvement in mean glycemia hospital wide. 3. Treatment options in hospitalized patients a. Noninsulin glucose-lowering agents. No large studies have investigated the potential roles of various noninsulin glucose-lowering agents on outcomes of hospitalized patients with diabetes. Use of the various noninsulin classes in the inpatient setting presents some specific issues. The long action of sulfonylureas and their predisposition to hypoglycemia in patients not consuming their normal nutrition serve as relative contraindications to routine use of these agents in the hospital (335). While the meglitinides, repaglinide and neteglinide, theoretically would produce less hypoglycemia than sulfonylureas, lack of clinical trial data for these agents, and the fact that they are primarily prandial in effect, would preclude their use. The major limitation to metformin use in the hospital is a number of specific contraindications to its use, related to risk of lactic acidosis, many of which occur in the hospital. The most common risk factors for lactic acidosis in metformin-treated patients are cardiac disease, including decompensated CHF, hypoperfusion, renal insufficiency, old age, and chronic pulmonary disease (336). Lactic acidosis is a rare complication in the outpatient setting (337), despite the relative frequency of risk factors (338). However, in the hospital the risks of hypoxia, hypoperfusion, and renal insufficiency are much higher, and it is prudent to avoid the use of metformin in most patients. TZDs are not suitable for initiation in the hospital because of their delayed onset of effect. In addition, they increase intravascular volume, a particular problem in those predisposed to CHF and potentially a problem for patients with hemodynamic changes related to admission diagnoses (e.g., acute coronary ischemia) or interventions common in hospitalized patients. Pramlintide and exenatide work mainly by reducing postprandial hyperglycemia and would therefore not be appropriate for patients not eating (nil per os, NPO) or with reduced caloric consumption. Furthermore, initiation of these drugs in the inpatient setting would be problematic due to alterations in normal food intake and their propensity to induce nausea initially. There is limited experience, and no published data, on the DPP-IV inhibitors in the hospital setting, although there are no specific safety concerns. They are mainly effective on postprandial glucose and therefore would have limited effect in patients who are not eating. In summary, each of the major classes of noninsulin glucose-lowering drugs has significant limitations for inpatient use. Additionally, they provide little flexibility or opportunity for titration in a setting where acute changes often demand these characteristics. Therefore, insulin, when used properly, is preferred for the majority of hyperglycemic patients in the hospital setting. b. Insulin i. Subcutaneous insulin therapy. Subcutaneous insulin therapy may be used to attain glucose control in most hospitalized patients with diabetes outside of the critical care arena. The components of the daily insulin dose requirement can be met by a variety of insulins, depending on the particular hospital situation. Subcutaneous insulin therapy should cover both basal and nutritional needs and is subdivided into scheduled insulin and supplemental, or correction-dose, insulin. Correction-dose insulin therapy is an important adjunct to scheduled insulin, both as a dose-finding strategy and as a supplement when rapid changes in insulin requirements lead to hyperglycemia. If correction doses are frequently required, the appropriate scheduled insulin doses should be increased to accommodate the increased insulin needs. There are currently no published studies comparing human regular insulin with rapid-acting analogs for use as correction-dose insulin. The traditional “sliding-scale” insulin regimens, usually consisting of regular insulin without any intermediate or long-acting insulins, have been shown to be ineffective when used as monotherapy in patients with an established insulin requirement (339–341). Problems with sliding-scale insulin regimens include the fact that the sliding-scale regimen prescribed on admission is likely to be used throughout the hospital stay without modification, even when control remains poor. Additionally, sliding-scale insulin therapy treats hyperglycemia after it has already occurred, instead of preventing the occurrence of hyperglycemia. This “reactive” approach can lead to rapid changes in blood glucose levels, which may exacerbate both hyper- and hypoglycemia. A recent study demonstrated the safety and efficacy of using basal-bolus insulin therapy utilizing weight-based dosing in insulin-naïve hospitalized patients with type 2 diabetes (342). Glycemic control, defined as a mean blood glucose <140 mg/dl, was achieved in 68% of patients receiving basal-bolus insulin versus only 38% of those receiving sliding-scale insulin alone. There were no differences in hypoglycemia between the two groups. It is important to note that the patients in this study were obese, and the doses used in this study (0.4 to 0.5 units · kg · day−1 ) are higher than what may be required in patients who are more sensitive to insulin, such as those who are lean or who have type 1 diabetes. ii. Intravenous insulin infusion. The only method of insulin delivery specifically developed for use in the hospital is continuous intravenous infusion, using regular crystalline insulin. There is no advantage to using rapid acting analogs, whose structural modifications increase the rate of absorption from subcutaneous depots, in an intravenous insulin infusion. The medical literature supports the use of intravenous insulin infusion in preference to the subcutaneous route of insulin administration for several clinical indications among nonpregnant adults. These include DKA and nonketotic hyperosmolar state; general preoperative, intraoperative, and postoperative care; the postoperative period following heart surgery; following organ transplantation; with cardiogenic shock; exacerbated hyperglycemia during high-dose glucocorticoid therapy; type 1 patients who are NPO; or in critical care illness in general. It may be used as a dose-finding strategy in anticipation of initiation or reinitiation of subcutaneous insulin therapy in type 1 or type 2 diabetes. Many institutions use insulin infusion algorithms that can be implemented by nursing staff. Although numerous algorithms have been published, there have been no head-to-head comparisons between insulin infusion strategies. Algorithms should incorporate the concepts that maintenance requirements differ between patients and change over the course of treatment. Ideally, intravenous insulin algorithms should consider both current and previous glucose levels, the rate of change of plasma glucose, and the current intravenous insulin infusion rate. For all algorithms, frequent (Q 1–2 h) bedside glucose testing is required. iii. Transition from intravenous to subcutaneous insulin therapy. For those who will require subcutaneous insulin, the very short half-life of intravenous insulin necessitates administering the first dose of subcutaneous insulin before discontinuation of the intravenous insulin infusion. If short or rapid-acting insulin is used, it should be injected 1–2 h before stopping the infusion. If intermediate- or long-acting insulin is used alone, it should be injected 2–3 h before. A combination of short/rapid- and intermediate/long-acting insulin is usually preferred. Basal insulin therapy can be initiated at any time of the day and should not be withheld to await a specific dosing time, such as bedtime. A recent clinical trial demonstrated that a regimen using 80% of the intravenous insulin requirement over the preceding 24 h, divided into basal and bolus insulin components, was effective at achieving blood glucose levels between 80 and 150 mg/dl following discontinuation of the intravenous insulin (343). 4. Self-management in the hospital Self-management of diabetes in the hospital may be appropriate for competent adult patients who have a stable level of consciousness, have reasonably stable daily insulin requirements, successfully conduct self-management of diabetes at home, have physical skills needed to successfully self-administer insulin and perform SMBG, have adequate oral intake, and are proficient in carbohydrate counting, use of multiple daily insulin injections or insulin pump therapy, and sick-day management. The patient and physician, in consultation with nursing staff, must agree that patient self-management is appropriate under the conditions of hospitalization. For patients conducting self-management in the hospital, it is imperative that basal, prandial, and correction doses of insulin and results of bedside glucose monitoring be recorded as part of the patient's hospital medical record. While many institutions allow patients on insulin pumps to continue these devices in the hospital, others express concern regarding use of a device unfamiliar to staff, particularly in patients who are not able to manage their own pump therapy. If a patient is too ill to self-manage either multiple daily injections or CSII, then appropriate subcutaneous doses can be calculated on the basis of their basal and bolus insulin needs during hospitalization, with adjustments for changes in nutritional or metabolic status. 5. Preventing hypoglycemia Hypoglycemia, especially in insulin-treated patients, is the leading limiting factor in the glycemic management of type 1 and type 2 diabetes (146). In the hospital, multiple additional risk factors for hypoglycemia are present, even among patients who are neither “brittle” nor tightly controlled. Patients with or without diabetes may experience hypoglycemia in the hospital in association with altered nutritional state, heart failure, renal or liver disease, malignancy, infection, or sepsis (344,345). Additional triggering events leading to iatrogenic hypoglycemia include sudden reduction of corticosteroid dose, altered ability of the patient to self-report symptoms, reduction of oral intake, emesis, new NPO status, inappropriate timing of short- or rapid-acting insulin in relation to meals, reduction of rate of administration of intravenous dextrose, and unexpected interruption of enteral feedings or parenteral nutrition. Despite the preventable nature of many inpatient episodes of hypoglycemia, institutions are more likely to have nursing protocols for the treatment of hypoglycemia than for its prevention. Tracking such episodes and analyzing their causes are important quality improvement activities. 6. Diabetes care providers in the hospital Inpatient diabetes management may be effectively provided by primary care physicians, endocrinologists, or hospitalists, but involvement of appropriately trained specialists or specialty teams may reduce length of stay, improve glycemic control, and improve outcomes (346–349). In the care of diabetes, implementation of standardized order sets for scheduled and correction-dose insulin may reduce reliance on sliding-scale management. A team approach is needed to establish hospital pathways. To achieve glycemic targets associated with improved hospital outcomes, hospitals will need multidisciplinary support for using insulin infusion therapy outside of critical care units or will need to develop protocols for subcutaneous insulin therapy that effectively and safely achieve glycemic targets (350). 7. DSME in the hospital Teaching diabetes self-management to patients in hospitals is a challenging task. Patients are ill, under increased stress related to their hospitalization and diagnosis, and in an environment not conducive to learning. Ideally, people with diabetes should be taught at a time and place conducive to learning, as outpatients in a recognized program of diabetes education. For the hospitalized patient, diabetes “survival skills” education is generally a feasible approach. Patients and/or family members receive sufficient information and training to enable safe care at home. Those newly diagnosed with diabetes or who are new to insulin and/or blood glucose monitoring need to be instructed before discharge. Those patients hospitalized because of a crisis related to diabetes management or poor care at home need education to prevent subsequent episodes of hospitalization. An assessment of the need for a home health referral or referral to an outpatient diabetes education program should be part of discharge planning for all patients. 8. MNT in the hospital Hospital diets continue to be ordered by calorie levels based on the “ADA diet.” However, since 1994 the ADA has not endorsed any single meal plan or specified percentages of macronutrients, and the term “ADA diet” should no longer be used. Current nutrition recommendations advise individualization based on treatment goals, physiologic parameters, and medication usage. Because of the complexity of nutrition issues in the hospital, a registered dietitian, knowledgeable and skilled in MNT, should serve as an inpatient team member. The dietitian is responsible for integrating information about the patient's clinical condition, eating, and lifestyle habits and for establishing treatment goals in order to determine a realistic plan for nutrition therapy (351,352). 9. Bedside blood glucose monitoring Implementing intensive diabetes therapy in the hospital setting requires frequent and accurate blood glucose data. This measure is analogous to an additional “vital sign” for hospitalized patients with diabetes. Bedside glucose monitoring using capillary blood has advantages over laboratory venous glucose testing because the results can be obtained rapidly at the “point of care,” where therapeutic decisions are made. Bedside blood glucose testing is usually performed with portable meters that are similar or identical to devices for home SMBG. Staff training and ongoing quality control activities are important components of ensuring accuracy of the results. Ability to track the occurrence of hypo- and hyperglycemia is necessary. Results of bedside glucose tests should be readily available to all members of the care team. For patients who are eating, commonly recommended testing frequencies are premeal and at bedtime. For patients not eating, testing every 4–6 h is usually sufficient for determining correction insulin doses. Patients on continuous intravenous insulin typically require hourly blood glucose testing until the blood glucose levels are stable, then every 2 h. 10. Discharge planning It is important to anticipate the postdischarge antihyperglycemic regimen in all patients with diabetes or newly discovered hyperglycemia. The optimal program will need to consider the type and severity of diabetes, the effects of the patient's illness on blood glucose levels, and the capacities and desires of the patient. Smooth transition to outpatient care should be ensured, especially in those new to insulin therapy or in whom the diabetes regimen has been substantially altered during the hospitalization. All patients in whom the diagnosis of diabetes is new should have, at minimum, “survival skills” training before discharge. More expanded diabetes education can be arranged in the community. For those with hyperglycemia who do not require treatment upon discharge, follow-up testing through their primary care physician should be arranged, since many of these individuals are found to have diabetes when tested after discharge. B. Diabetes care in the school and day care setting (353) Recommendations An individualized Diabetes Medical Management Plan (DMMP) should be developed by the parent/guardian and the student's personal diabetes health care team with input from the parent/guardian. (E) All school staff members who have responsibility for a student with diabetes should receive training that provides a basic understanding of diabetes and a student's needs. (E) While the school nurse is the coordinator and primary provider of diabetes care, a small number of school personnel should be trained in routine and emergency diabetes procedures (including monitoring of blood glucose levels and administration of insulin and glucagon) and in the appropriate response to high and low blood glucose levels and should perform these diabetes care tasks when the school nurse is not available to do so. These school personnel need not be health care professionals. (E) As specified in the DMMP and as developmentally appropriate, the student with diabetes should have immediate access to diabetes supplies at all times and should be permitted to self-manage his or her diabetes in the classroom or anywhere the student may be in conjunction with a school activity. Such self-management should include blood glucose monitoring and responding to blood glucose levels with needed food and medication. (E) There are ∼186,300 individuals <20 years of age with diabetes in the U.S., most of whom attend school and/or some type of day care and need knowledgeable staff to provide a safe environment. Despite legal protections, including coverage of children with diabetes under Section 504 of the Rehabilitation Act of 1973, the Individuals with Disabilities Education Act, and the Americans with Disabilities Act, children in the school and day care setting still face discrimination. The ADA position statement on Diabetes Care in the School and Day Care Setting (353) provides the legal and medical justifications for the recommendations provided herein. Appropriate diabetes care in the school and day care setting is necessary for the child's immediate safety, long-term well-being, and optimal academic performance. Parents and the health care team should provide school systems and day care providers with the information necessary for children with diabetes to participate fully and safely in the school/day care experience by developing an individualized DMMP. The school nurse should be the key coordinator and provider of care and should coordinate the training of an adequate number of school personnel and ensure that if the school nurse is not present at least one adult is present who is trained to perform the necessary diabetes procedures (e.g., blood glucose monitoring and insulin and glucagon administration) and provide the appropriate response to high and low blood glucose levels in a timely manner while the student is at school, on field trips, participating in school-sponsored extracurricular activities, and on transportation provided by the school or day care facility. These school personnel need not be health care professionals. The student with diabetes should have immediate access to diabetes supplies at all times, with supervision as needed. The student should be able to obtain a blood glucose level and respond to the results as quickly and conveniently as possible in the classroom or wherever the child is in conjunction with a school-related activity, minimizing the need for missing instruction in the classroom and avoiding the risk of worsening hypoglycemia or hyperglycemia if the child must go somewhere else for treatment. The student's desire for privacy during blood glucose monitoring and insulin administration should also be accommodated. The ADA and partner organizations have developed tools for school personnel to provide a safe and nondiscriminatory educational environment for all students with diabetes (354,355). C. Diabetes care at diabetes camps (356) Recommendations Each camper should have a standardized medical form completed by his/her family and the physician managing the diabetes. (E) Camp medical staff should be led by with a physician with expertise in managing type 1 and type 2 diabetes and include nurses (including diabetes educators and diabetes clinical nurse specialists) and registered dietitians with expertise in diabetes. (E) All camp staff, including physicians, nurses, dietitians, and volunteers, should undergo background testing to ensure appropriateness in working with children. (E) The concept of specialized residential and day camps for children with diabetes has become widespread throughout the U.S. and many other parts of the world. The mission of diabetes camps is to provide a camping experience in a safe environment. An equally important goal is to enable children with diabetes to meet and share their experiences with one another while they learn to be more personally responsible for their disease. For this to occur, a skilled medical and camping staff must be available to ensure optimal safety and an integrated camping/educational experience. Each camper should have a standardized medical form completed by his/her family and the physician managing the diabetes that details the camper's past medical history, immunization record, and diabetes regimen. The home insulin dosage should be recorded for each camper, including type(s) of insulin used, number and timing of injections, and the correction factor and carbohydrate ratios used for determining bolus dosages for basal-bolus regimens. Campers using CSII should also have their basal rates specified. Because camp is often associated with more physical activity than experienced at home, the insulin dose may have to be decreased during camp. The diabetes camping experience is short term, with food and activity different than the home environment. Thus, goals of glycemic control at camp are to avoid extremes in blood glucose levels rather than attempting optimization of intensive glycemic control. During camp, a daily record of the camper's progress should be made, including all blood glucose levels and insulin dosages. To ensure safety and optimal diabetes management, multiple blood glucose determinations should be made throughout each 24-h period: before meals, at bedtime, after or during prolonged and strenuous activity, and in the middle of the night when indicated for prior hypoglycemia. If major alterations of a camper's regimen appear to be indicated, it is important to discuss this with the camper and the family in addition to the child's local physician. The record of what transpired during camp should be discussed with the family at the end of the camp session and a copy sent to the child's physician. Each camp should secure a formal relationship with a nearby medical facility so that camp medical staff can refer to this facility for prompt treatment of medical emergencies. ADA requires that the camp medical director be a physician with expertise in managing type 1 and type 2 diabetes. Nursing staff should include diabetes educators and diabetes clinical nurse specialists. Registered dietitians with expertise in diabetes should have input into the design of the menu and the education program. All camp staff, including medical, nursing, nutrition, and volunteer, should undergo background testing to ensure appropriateness in working with children. D. Diabetes management in correctional institutions (357) Recommendations Correctional staff should be trained in the recognition, treatment, and appropriate referral for hypo- and hyperglycemia, including serious metabolic decompensation. (E) Patients with a diagnosis of diabetes should have a complete medical history and physical examination by a licensed health care provider with prescriptive authority in a timely manner upon entry. Insulin-treated patients should have a capillary blood glucose (CBG) determination within 1–2 h of arrival. Staff should identify patients with type 1 diabetes who are at high risk for DKA with omission of insulin. (E) Medications and MNT should be continued without interruption upon entry into the correctional environment. (E) In the correctional setting, policies and procedures should enable CBG monitoring to occur at the frequency necessitated by the patient's glycemic control and diabetes regimen and should require staff to notify a physician of all CBG results outside of a specified range, as determined by the treating physician. (E) For all inter-institutional transfers, a medical transfer summary should be transferred with the patient, and diabetes supplies and medication should accompany the patient. (E) Correctional staff should begin discharge planning with adequate lead time to ensure continuity of care and facilitate entry into community diabetes care. (E) At any given time, over 2 million people are incarcerated in prisons and jails in the U.S., and it is estimated that nearly 80,000 of these inmates have diabetes. In addition, many more people with diabetes pass through the corrections system in a given year. People with diabetes in correctional facilities should receive care that meets national standards. Correctional institutions have unique circumstances that need to be considered so that all standards of care may be achieved. Correctional institutions should have written policies and procedures for the management of diabetes and for training of medical and correctional staff in diabetes care practices. Reception screening should emphasize patient safety. In particular, rapid identification of all insulin-treated individuals with diabetes is essential in order to identify those at highest risk for hypo- and hyperglycemia and DKA. All insulin-treated patients should have a CBG determination within 1–2 h of arrival. Patients with a diagnosis of diabetes should have a complete medical history and physical examination by a licensed health care provider with prescriptive authority in a timely manner. It is essential that medication and MNT be continued without interruption upon entry into the correctional system, as a hiatus in either medication or appropriate nutrition may lead to either severe hyper- or hypoglycemia. Patients must have access to prompt treatment of hypo- and hyperglycemia. Correctional staff should be trained in the recognition and treatment of these conditions, and appropriate staff should be trained to administer glucagon. Institutions should implement a policy requiring staff to notify a physician of all CBG results outside of a specified range, as determined by the treating physician. Correctional institutions should have systems in place to ensure that insulin administration and meals are coordinated to prevent hypo- and hyperglycemia, taking into consideration the transport of residents off site and the possibility of emergency schedule changes. The frequency of CBG monitoring will vary by patients’ glycemic control and diabetes regimens. Policies and procedures should ensure that the health care staff has adequate knowledge and skills to direct the management and education of individuals with diabetes. Patients in jails may be housed for a short period of time before being transferred or released, and patients in prison may be transferred within the system several times during their incarceration. Transferring a patient with diabetes from one correctional facility to another requires a coordinated effort, as does planning for discharge. The ADA position statement on Diabetes Management in Correctional Institutions (357) should be consulted for more information on this topic. E. Emergency and disaster preparedness (358) Recommendations People with diabetes should maintain a disaster kit that includes items important to their diabetes self-management and continuing medical care. (E) The kit should be reviewed and replenished at least twice yearly. (E) The difficulties encountered by people with diabetes and their health care providers in the wake of Hurricane Katrina (359) highlight the need for people with diabetes to be prepared for emergencies, whether natural or otherwise, affecting a region or just their household. Such preparedness will lessen the impact an emergency may have on their condition. It is recommended that people with diabetes keep a waterproof and insulated disaster kit ready with items critically important to their self-management. These may include glucose testing strips, lancets, and a glucose-testing meter; medications including insulin in a cool bag; syringes; glucose tabs or gels; antibiotic ointments/creams for external use; glucagon emergency kits; and photocopies of relevant medical information, particularly medication lists and recent lab tests/procedures if available. If possible, prescription numbers should be noted, since many chain pharmacies throughout the country will refill medications based on the prescription number alone. In addition, it may be important to carry a list of contacts for national organizations, such as the American Red Cross and ADA. This disaster kit should be reviewed and replenished at least twice yearly. IX. DIABETES AND EMPLOYMENT (360) Recommendations When questions arise about the medical fitness of a person with diabetes for a particular job, a health care professional with expertise in treating diabetes should perform an individualized assessment; input from the treating physician should always be included. (E) Proper safety assessments for employment should include review of blood glucose test results, history of severe hypoglycemia, presence of hypoglycemia unawareness, and presence of diabetes-related complications but should not include urine glucose or A1C/eAG tests or be based on a general assessment of level of control. (E) Any person with diabetes, whether insulin treated or noninsulin treated, should be eligible for any employment for which he/she is otherwise qualified. Questions are sometimes raised by employers about the safety and effectiveness of individuals with diabetes in a given job. When such questions are legitimately raised, a person with diabetes should be individually assessed by a health care professional with expertise in diabetes to determine whether or not that person can safely and effectively perform the particular duties of the job in question. Employment decisions should never be based on generalizations or stereotypes regarding the effects of diabetes. “Blanket bans” that restrict individuals with diabetes from certain jobs or classes of employment solely because of the diagnosis of diabetes or the use of insulin are medically and legally inappropriate and ignore the many advancements in diabetes management that range from the types of medications used to the tools used to administer them and to monitor blood glucose levels. For most types of employment, there is no reason to believe that the individual's diabetes will put employees or the public at risk. In certain safety-sensitive positions the safety concern is whether the employee will become suddenly disoriented or incapacitated. Episodes of severe hypoglycemia should be examined by a health care professional with expertise in diabetes to determine any impact on safe performance of the job. Hyperglycemia is not typically a barrier to employment unless long-term complications are present that interfere with the performance of the job. Most accommodations that help an individual with diabetes do his or her job may be provided easily and with little or no cost to the employer. Typical accommodations include breaks to test blood glucose, administer insulin, or access food and beverages. Some individuals may need leave or a flexible work schedule or accommodations for diabetes-related complications. The ADA position statement on Diabetes and Employment should be consulted for more information on this topic. X. THIRD-PARTY REIMBURSEMENT FOR DIABETES CARE, SELF-MANAGEMENT EDUCATION, AND SUPPLIES (361) Recommendations Patients and practitioners should have access to all classes of antidiabetic medications, equipment, and supplies without undue controls. (E) MNT and DSME should be covered by insurance and other payors. (E) To achieve optimal glucose control, the person with diabetes must be able to access health care providers who have expertise in the field of diabetes. Treatments and therapies that improve glycemic control and reduce the complications of diabetes will also significantly reduce health care costs. Access to the integral components of diabetes care, such as health care visits, diabetes supplies and medications, and self-management education, is essential. All medications and supplies, such as syringes, strips, and meters, related to the daily care of diabetes must also be reimbursed by third-party payors. It is recognized that the use of formularies, prior authorization, and provisions such as competitive bidding can manage provider practices as well as costs to the potential benefit of payors and patients. However, any controls should ensure that all classes of anti-diabetic agents with unique mechanisms of action and all classes of equipment and supplies designed for use with such equipment are available to facilitate achieving glycemic goals and to reduce the risk of complications. Without appropriate safeguards, undue controls could constitute an obstruction of effective care. Medicare and many other third-party payors cover DSME (Centers for Medicare and Medicaid Services [CMS] term is diabetes self-management training [DSMT]) that meets the national standards for DSME (107) and MNT. The qualified beneficiary, with referral from the provider managing his or her diabetes, can receive an initial benefit of 10 h of DSMT and 3 h of MNT, with a potential total of 13 h of initial. More information on Medicare policy, including follow-up benefits, is available at www.diabetes.org/for-health-professionals-and-scientists/recognition.jsp or on the CMS Web sites: DSME, www.cms.hhs.gov/DiabetesSelfManagement; and diabetes MNT, www.cms.hhs.gov/MedicalNutritionTherapy, reimbursement. XI. STRATEGIES FOR IMPROVING DIABETES CARE The implementation of the standards of care for diabetes has been suboptimal in most clinical settings. A recent report (362) indicated that only 37% of adults with diagnosed diabetes achieved an A1C of <7%, only 36% had a blood pressure <130/80 mmHg, and just 48% had a total cholesterol <200 mg/dl. Most distressing was that only 7.3% of people with diabetes achieved all three treatment goals. While numerous interventions to improve adherence to the recommended standards have been implemented, the challenge of providing uniformly effective diabetes care has thus far defied a simple solution. A major contributor to suboptimal care is a delivery system that too often is fragmented, lacks clinical information capabilities, often duplicates services, and is poorly designed for the delivery of chronic care. The Institute of Medicine has called for changes so that delivery systems provide care that is evidence based, patient centered, and systems oriented and takes advantage of information technologies that foster continuous quality improvement. Collaborative, multidisciplinary teams should be best suited to provide such care for people with chronic conditions like diabetes and to empower patients’ performance of appropriate self-management. Alterations in reimbursement that reward the provision of quality care, as defined by the attainment of quality measures developed by such programs as the ADA/National Committee for Quality Assurance Diabetes Provider Recognition Program will also be required to achieve desired outcome goals. The NDEP recently launched a new online resource to help health care professionals better organize their diabetes care. The www.betterdiabetescare.nih.gov Web site should help users design and implement more effective health care delivery systems for those with diabetes. In recent years, numerous health care organizations, ranging from large health care systems such as the U.S. Veterans Administration to small private practices, have implemented strategies to improve diabetes care. Successful programs have published results showing improvement in process measures such as measurement of A1C, lipids, and blood pressure. Effects on important intermediate outcomes, such as mean A1C for populations, have been more difficult to demonstrate (363–365), although examples do exist (366–370). Successful interventions have been focused at the level of health care professionals, delivery systems, and patients. Features of successful programs reported in the literature include: Improving health care professional education regarding the standards of care through formal and informal education programs. Delivery of DSME, which has been shown to increase adherence to standard of care. Adoption of practice guidelines, with participation of health care professionals in the process. Guidelines should be readily accessible at the point of service, such as on patient charts, in examining rooms, in “wallet or pocket cards,” on PDAs, or on office computer systems. Guidelines should begin with a summary of their major recommendations instructing health care professionals what to do and how to do it. Use of checklists that mirror guidelines have been successful at improving adherence to standards of care. Systems changes, such as provision of automated reminders to health care professionals and patients, reporting of process and outcome data to providers, and especially identification of patients at risk because of failure to achieve target values or a lack of reported values. Quality improvement programs combining continuous quality improvement or other cycles of analysis and intervention with provider performance data. Practice changes, such as clustering of dedicated diabetes visits into specific times within a primary care practice schedule and/or visits with multiple health care professionals on a single day and group visits. Tracking systems with either an electronic medical record or patient registry have been helpful at increasing adherence to standards of care by prospectively identifying those requiring assessments and/or treatment modifications. They likely could have greater efficacy if they suggested specific therapeutic interventions to be considered for a particular patient at a particular point in time (371). A variety of nonautomated systems, such as mailing reminders to patients, chart stickers, and flow sheets, have been useful to prompt both providers and patients. Availability of case or (preferably) care management services, usually by a nurse (372). Nurses, pharmacists, and other nonphysician health care professionals using detailed algorithms working under the supervision of physicians and/or nurse education calls have also been helpful. Similarly, dietitians using MNT guidelines have been demonstrated to improve glycemic control. Availability and involvement of expert consultants, such as endocrinologists and diabetes educators. Evidence suggests that these individual initiatives work best when provided as components of a multifactorial intervention. Therefore, it is difficult to assess the contribution of each component; however, it is clear that optimal diabetes management requires an organized, systematic approach and involvement of a coordinated team of health care professionals.
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            Long-term risk of mortality and acute kidney injury during hospitalization after major surgery.

            To determine the relationship between long-term mortality and acute kidney injury (AKI) during hospitalization after major surgery. AKI is associated with a risk of short-term mortality that is proportional to its severity; however the long-term survival of patients with AKI is poorly studied. This is a retrospective cohort study of 10,518 patients with no history of chronic kidney disease who were discharged after a major surgery between 1992 and 2002. AKI was defined by the RIFLE (Risk, Injury, Failure, Loss, and End-stage Kidney) classification, which requires at least a 50% increase in serum creatinine (sCr) and stratifies patients into 3 severity stages: risk, injury, and failure. Patient survival was determined through the National Social Security Death Index. Long-term survival was analyzed using a risk-adjusted Cox proportional hazards regression model. In the risk-adjusted model, survival was worse among patients with AKI and was proportional to its severity with an adjusted hazard ratio of 1.18 (95% confidence interval [CI], 1.08-1.29) for the RIFLE-Risk class and 1.57 (95% CI, 1.40-1.75) for the RIFLE-Failure class, compared with patients without AKI (P < 0.001). Patients with complete renal recovery after AKI still had an increased adjusted hazard ratio for death of 1.20 (95% CI, 1.10-1.31) compared with patients without AKI (P < 0.001). In a large single-center cohort of patients discharged after major surgery, AKI with even small changes in sCr level during hospitalization was associated with an independent long-term risk of death.
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              Recovery of kidney function after acute kidney injury in the elderly: a systematic review and meta-analysis.

              The prevalence of elderly individuals continues to increase over time, as does the incidence of acute kidney injury (AKI). However, it is not known whether age is an important prognostic predictor for renal recovery after an episode of AKI. Systematic review of MEDLINE and EMBASE databases and meta-analysis of pooled data using random-effect models. Adults with AKI, not including kidney transplant recipients. Studies published in English between 2000 and 2007 were eligible for this analysis if they met the following inclusion criteria: (1) clear definition of AKI and recovery of kidney function, (2) assessment of kidney function recovery as the primary or secondary outcome, and (3) participant age reported. We contacted the investigators of studies and requested data for recovery of kidney function by patient age. Patient age of 65 years and older and younger than 65 years. Recovery of kidney function defined as independence from dialysis therapy, decrease in serum creatinine level to less than a defined threshold, or return to baseline kidney function. We obtained data for recovery of kidney function by age from 17 studies of patients with AKI. Overall, 31.3% of surviving elderly patients did not recover kidney function compared with 26% of younger patients (pooled relative risk, 1.28, 95% confidence interval, 1.06 to 1.55; P < 0.05). The increased risk of nonrecovery in the elderly remained greater in several subgroups examined through sensitivity analyses, including those stratified by type of dialysis support, time of assessment of recovery (short versus long term), and definition of renal recovery. There was significant heterogeneity among studies with respect to comorbid factors, definition of AKI, and study design. There is impaired recovery of kidney function after AKI in aged individuals. Future studies should be cognizant of "age" as a potential effect modifier in the prognosis after AKI, and clinical trials should focus on improving outcomes in the elderly cohort.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2020
                May 2020
                21 April 2020
                : 144
                : 5
                : 236-244
                Affiliations
                aDivision of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal
                bDepartment of Surgery, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal
                Author notes
                *Dr. Joana Gameiro, Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE Av. Prof. Egas Moniz, PT–1649-035 Lisbon (Portugal), joana.estrelagameiro@gmail.com
                Article
                506397 Nephron 2020;144:236–244
                10.1159/000506397
                32316024
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 3, Pages: 9
                Categories
                Clinical Practice: Research Article

                Cardiovascular Medicine, Nephrology

                Mortality, Surgery, Duration, Persistent, Transient, Acute kidney injury

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