Nestoras Mathioudakis

Adult-onset growth hormone deficiency: causes, complications and treatment options.

Purpose of reviewDescription of the progresses related to the complications and treatment of adult-onset growth hormone deficiency. Recent findingsGrowth hormone deficiency in adults has gained attention as a clinical syndrome associated with increased morbidity and possibly mortality. Many studies have been conducted on the consequences of growth hormone deficiency and of its replacement, supporting its use in appropriate patients. Early studies were characterized by a high incidence of side effects due to a lack of pilot data to guide appropriate dosing. Given the wide variability in individual responsiveness to growth hormone therapy based on age, sex, and body composition, recent work has been dedicated to understanding which patients derive benefit from therapy, minimizing side effects, and ensuring cost–effectiveness. SummaryLong-term prospective trials have shown that growth hormone replacement therapy results in improvements in body composition, dyslipidemia, bone mineral density, and quality of life. The effects on endpoints such as cardiovascular morbidity and mortality and fractures are, however, not fully proven. Randomized trials that compare homogenous groups of growth hormone deficiency patients are still needed. Given the high cost of treatment, dynamic testing for growth hormone deficiency should only be performed in patients in whom there is high clinical suspicion, and therapy should be limited to those with biochemically proven growth hormone deficiency.

The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system predicts wound healing but not major amputation in patients with diabetic foot ulcers treated in a multidisciplinary setting

Objective: The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) threatened limb classification has been shown to correlate well with risk of major amputation and time to wound healing in heterogeneous diabetic and nondiabetic populations. Major amputation continues to plague the most severe stage 4 WIfI patients, with 1‐year amputation rates of 20% to 64%. Our aim was to determine the association between WIfI stage and wound healing and major amputation among patients with diabetic foot ulcers (DFUs) treated in a multidisciplinary setting. Methods: All patients presenting to our multidisciplinary DFU clinic from July 2012 to December 2015 were enrolled in a prospective database. Wound healing and major amputation were compared for patients stratified by WIfI classification. Results: There were 217 DFU patients with 439 wounds (mean age, 58.3 ± 0.8 years; 58% male, 63% black) enrolled, including 28% WIfI stage 1, 11% stage 2, 33% stage 3, and 28% stage 4. Peripheral arterial disease and dialysis were more common in patients with advanced (stage 3 or 4) wounds (P ≤ .05). Demographics of the patients, socioeconomic status, and comorbidities were otherwise similar between groups. There was a significant increase in the number of active wounds per limb at presentation with increasing WIfI stage (stage 1, 1.1 ± 0.1; stage 4, 1.4 ± 0.1; P = .03). Mean wound area (stage 1, 2.6 ± 0.6 cm2; stage 4, 15.3 ± 2.8 cm2) and depth (stage 1, 0.2 ± 0.0 cm; stage 4, 0.8 ± 0.1 cm) also increased progressively with increasing wound stage (P < .001). Minor amputations (stage 1, 18%; stage 4, 56%) and revascularizations (stage 1, 6%; stage 4, 55%) were more common with increasing WIfI stage (P < .001). On Kaplan‐Meier analysis, WIfI classification was predictive of wound healing (P < .001) but not of major amputation (P = .99). For stage 4 wounds, the mean wound healing time was 190 ± 17 days, and risk of major amputation at 1 year was 5.7% ± 3.2%. Conclusions: Among patients with DFU, the WIfI classification system correlated well with wound healing but was not associated with risk of major amputation at 1 year. Although further prospective research is warranted, our results suggest that use of a multidisciplinary approach for DFUs may augment healing time and reduce amputation risk compared with previously published historical controls of standard wound care among patients with advanced stage 4 disease.

PREVENTION AND MANAGEMENT OF INSULIN-ASSOCIATED HYPOGLYCEMIA IN HOSPITALIZED PATIENTS.

OBJECTIVE To determine whether appropriate therapeutic changes in insulin doses are made to prevent and manage insulin-associated hypoglycemic events in non-critically ill hospitalized patients. METHODS This retrospective study was conducted in hospitalized adults on medical or surgical floors with insulin-associated hypoglycemia, excluding treatment with insulin infusions, insulin pumps, and parenteral nutrition. The first hypoglycemic event after 48 hours of admission was the index event. Over the 1-year study period, a total of 457 insulin-associated hypoglycemic events were included as index events. RESULTS An indication for an insulin dose adjustment was identified in 32 and 42% of patients on day -2 and day -1, respectively, before the index hypoglycemic event, of which 35 and 55%, respectively, had an insulin dose reduction ≥10%. Following the hypoglycemic event, 44% of patients had an insulin dose reduction of ≥20%. Therapeutic reduction of the total daily insulin dose by ≥20% was associated with increased odds of normoglycemia and lower odds of hyperglycemia but was not associated with lower odds of recurrent hypoglycemia on the day following the index hypoglycemic event. There was a high prevalence of hypoglycemic risk factors in this population, with kidney disease and nil per os status being the most prevalent contributing factors. CONCLUSION Adherence to the current practice recommendation to reduce insulin doses in patients with borderline hypoglycemia and following overt hypoglycemia was modest. Further studies are needed to understand the associated risks and to define appropriate therapeutic changes for insulin treated patients with borderline and overt hypoglycemia. ABBREVIATIONS AKI = acute kidney injury BG = blood glucose CKD = chronic kidney disease ESRD = end-stage renal disease ICU = intensive care unit NPH = Neutral Protamine Hagedorn NPO = nil per os OR = odds ratio TDD = total daily dose.

Metabolic syndrome reduces the survival benefit of the obesity paradox after infrainguinal bypass

BACKGROUND Metabolic syndrome, having risen to epidemic proportions in the United States, is associated with future cardiovascular disease and mortality and increased postoperative complication rates. However, the impact of metabolic syndrome on outcomes after infrainguinal bypass surgery remains poorly defined. METHODS Using the American College of Surgeons-National Surgical Quality Improvement Program database from 2005-2011, patients undergoing infrainguinal bypass were identified. Data on preoperative risk factors, operative details, and 30-day outcomes were collected. Metabolic syndrome was defined as the concomitant presence of obesity (body mass index: >30 kg/m(2)), hypertension, and diabetes mellitus. RESULTS A total of 19,604 patients underwent an infrainguinal bypass, 16% of whom suffered from metabolic syndrome. Patients with metabolic syndrome were younger (P < 0.001), more obese (P < 0.001), and suffered from more comorbidities overall. On univariate analysis, metabolic syndrome was associated with an increased risk of developing any complication (odds ratio [OR]: 1.67; P < 0.001), including superficial surgical site infection (SSI), deep SSI, wound dehiscence, bleeding, cardiac arrest, myocardial infarction, renal insufficiency, sepsis, and returning to the operating room. However, metabolic syndrome was protective of 30-day mortality (OR: 0.71; P = 0.02). On multivariate regression, metabolic syndrome remained associated with the development of any complication (OR: 1.55; P < 0.001), any wound complication (OR: 1.84; P < 0.001), and renal insufficiency (OR: 1.75; P < 0.03). There was a trend for metabolic syndrome to be protective of 30-day mortality (OR: 0.74; P = 0.09). When compared to obese patients without metabolic syndrome, those with metabolic syndrome had a higher rate of any postoperative complication (22.5% vs. 16.6%) and death (1.82% vs. 1.42%). CONCLUSIONS Patients with metabolic syndrome are at an increased risk of postoperative complications after infrainguinal bypass. Despite increased morbidity, metabolic syndrome was not associated with inferior 30-day mortality, but did diminish the survival benefit of the obesity paradox.

The effect of vitamin D supplementation on glucose metabolism in type 2 diabetes mellitus: A systematic review and meta-analysis of intervention studies

AIMS We aimed to assess whether vitamin D supplementation improves glucose metabolism in adults with type 2 diabetes. METHODS PubMed and Cochrane database were searched up to July 1st 2016 for randomized controlled trials that assessed the relationship between vitamin D supplementation and glucose metabolism (change in hemoglobin A1C (HbA1C) and fasting blood glucose (FBG)) among adults with type 2 diabetes. RESULTS Twenty nine trials (3324 participants) were included in the systematic review. Among 22 studies included in the meta-analysis, 19 reported HbA1C, 16 reported FBG outcomes and 15 were deemed poor quality. There was a modest reduction in HbA1C (-0.32% [-0.53 to -0.10], I2=91.9%) compared to placebo after vitamin D supplementation but no effect on FBG (-2.33mg/dl [-6.62 to 1.95], I2=59.2%). In studies achieving repletion of vitamin D deficiency (n=7), there were greater mean reductions in HbA1C (-0.45%, [-1.09 to 0.20]) and FBG (-7.64mg/dl [-16.25 to 0.97]) although not significant. CONCLUSIONS We found a modest reduction of HbA1C after vitamin D treatment in adults with type 2 diabetes albeit with substantial heterogeneity between studies and no difference in FBG. Larger studies are needed to further evaluate the glycemic effects of vitamin D treatment especially in patients with vitamin D deficiency.

A Gap Analysis Needs Assessment Tool to Drive a Care Delivery and Research Agenda for Integration of Care and Sharing of Best Practices Across a Health System

BACKGROUND In a complex health system, it is important to establish a systematic and data-driven approach to identifying needs. The Diabetes Clinical Community (DCC) of Johns Hopkins Medicines Armstrong Institute for Patient Safety and Quality developed a gap analysis tool and process to establish the systems current state of inpatient diabetes care. METHODS The collectively developed tool assessed the following areas: program infrastructure; protocols, policies, and order sets; patient and health care professional education; and automated data access. For the purposes of this analysis, gaps were defined as those instances in which local resources, infrastructure, or processes demonstrated a variance against the current national evidence base or institutionally defined best practices. RESULTS Following the gap analysis, members of the DCC, in collaboration with health system leadership, met to identify priority areas in order to integrate and synergize diabetes care resources and efforts to enhance quality and reduce disparities in care across the system. Key gaps in care identified included lack of standardized glucose management policies, lack of standardized training of health care professionals in inpatient diabetes management, and lack of access to automated data collection and analysis. These results were used to gain resources to support collaborative diabetes health system initiatives and to successfully obtain federal research funding to develop and pilot a pragmatic diabetes educational intervention. CONCLUSION At a health system level, the summary format of this gap analysis tool is an effective method to clearly identify disparities in care to focus efforts and resources to improve care delivery.

Modeling Inpatient Glucose Management Programs on Hospital Infection Control Programs: An Infrastructural Model of Excellence

Infection control programs (ICPs) emerged in the United States in the late 1950s in response to nosocomial epidemics of staphylococcal infections.1 By the early 1970s, the Centers for Disease Control and Prevention (CDC) recommended that hospitals establish ICPs to prevent hospital-acquired infections.2 The Joint Commission followed suit shortly thereafter, releasing standards for ICPs as a criterion for hospital accreditation in 1976.3*† It was not until completion of the large-scale SENIC (Study on the Efficacy of Nosocomial Infection Control) Project in 1983, however, that the efficacy of ICPs was established: nearly one third of health care–associated infections could be prevented by infection control teams integrated into the hospital infrastructure.4 In 1986 the Centers for Medicare & Medicaid Services (CMS) included the presence of an ICP in hospitals as a condition of participation in the Medicare program. During the subsequent three decades, several additional studies demonstrated the efficacy and cost-effectiveness of hospital ICPs and of the potential to substantially reduce hospital-acquired infections when infection prevention professionals partner with clinicians. 5 Among the causes of preventable patient harm, in the United States, health care–associated infections (notably, central line-associated bloodstream infections and catheter-associated urinary tract infections) have the most robust evidence demonstrating that harm has been recently reduced.6 Given the dramatic success of ICPs, it might be advantageous to apply the scientific and organizational methodology that formed the basis of these programs to more broadly reduce other types of preventable harm. Despite significant efforts to improve inpatient glucose management during the last decade, harm from hypo- and hyperglycemia (“dysglycemia”) continues unabated and remains far too common.7,8 Both infection control and glycemic control face unique challenges in the hospital compared to the ambulatory setting, and inpatient dysglycemia is a perfect example of a preventable harm that could be reduced by applying the ICP paradigm. In this article, we outline parallels in the structure, goals, and functions between ICPs and glucose management programs (GMPs). We then propose that the quality improvement (QI) methodology used by ICPs could serve as an excellent model for QI efforts in hospital-based GMPs.

Association of Hemoglobin A1c and Wound Healing in Diabetic Foot Ulcers

OBJECTIVE This study evaluated the association between hemoglobin A1c (A1C) and wound outcomes in patients with diabetic foot ulcers (DFUs). RESEARCH DESIGN AND METHODS We conducted a retrospective analysis of an ongoing prospective, clinic-based study of patients with DFUs treated at an academic institution during a 4.7-year period. Data from 270 participants and 584 wounds were included in the analysis. Cox proportional hazards regression was used to assess the incidence of wound healing at any follow-up time in relation to categories of baseline A1C and the incidence of long-term (≥90 days) wound healing in relation to tertiles of nadir A1C change and mean A1C change from baseline, adjusted for potential confounders. RESULTS Baseline A1C was not associated with wound healing in univariate or fully adjusted models. Compared with a nadir A1C change from baseline of −0.29 to 0.0 (tertile 2), a nadir A1C change of 0.09 to 2.4 (tertile 3) was positively associated with long-term wound healing in the subset of participants with baseline A1C <7.5% (hazard ratio [HR] 2.07; 95% CI 1.08–4.00), but no association with wound healing was seen with the mean A1C change from baseline in this group. Neither nadir A1C change nor mean A1C change were associated with long-term wound healing in participants with baseline A1C ≥7.5%. CONCLUSIONS There does not appear to be a clinically meaningful association between baseline or prospective A1C and wound healing in patients with DFUs. The paradoxical finding of accelerated wound healing and increase in A1C in participants with better baseline glycemic control requires confirmation in further studies.

Development and validation of a prediction model for insulin-associated hypoglycemia in non-critically ill hospitalized adults

Objective To develop and validate a multivariable prediction model for insulin-associated hypoglycemia in non-critically ill hospitalized adults. Research design and methods We collected pharmacologic, demographic, laboratory, and diagnostic data from 128 657 inpatient days in which at least 1 unit of subcutaneous insulin was administered in the absence of intravenous insulin, total parenteral nutrition, or insulin pump use (index days). These data were used to develop multivariable prediction models for biochemical and clinically significant hypoglycemia (blood glucose (BG) of ≤70 mg/dL and <54 mg/dL, respectively) occurring within 24 hours of the index day. Split-sample internal validation was performed, with 70% and 30% of index days used for model development and validation, respectively. Results Using predictors of age, weight, admitting service, insulin doses, mean BG, nadir BG, BG coefficient of variation (CVBG), diet status, type 1 diabetes, type 2 diabetes, acute kidney injury, chronic kidney disease (CKD), liver disease, and digestive disease, our model achieved a c-statistic of 0.77 (95% CI 0.75 to 0.78), positive likelihood ratio (+LR) of 3.5 (95% CI 3.4 to 3.6) and negative likelihood ratio (−LR) of 0.32 (95% CI 0.30 to 0.35) for prediction of biochemical hypoglycemia. Using predictors of sex, weight, insulin doses, mean BG, nadir BG, CVBG, diet status, type 1 diabetes, type 2 diabetes, CKD stage, and steroid use, our model achieved a c-statistic of 0.80 (95% CI 0.78 to 0.82), +LR of 3.8 (95% CI 3.7 to 4.0) and −LR of 0.2 (95% CI 0.2 to 0.3) for prediction of clinically significant hypoglycemia. Conclusions Hospitalized patients at risk of insulin-associated hypoglycemia can be identified using validated prediction models, which may support the development of real-time preventive interventions.

The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system correlates with cost of care for diabetic foot ulcers treated in a multidisciplinary setting

Objective: We have previously demonstrated that the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification correlates with wound healing time in patients with diabetic foot ulcers (DFUs) treated in a multidisciplinary setting. Our aim was to assess whether the charges and costs associated with DFU care increase with higher WIfI stages. Methods: All patients presenting to our multidisciplinary diabetic limb preservation service from June 2012 to June 2016 were enrolled in a prospective database. Inpatient and outpatient charges, costs, and total revenue from initial visit until complete wound healing were compared for wounds stratified by WIfI classification. Results: A total of 319 wound episodes in 248 patients were captured, including 31% WIfI stage 1, 16% stage 2, 30% stage 3, and 24% stage 4 wounds. Limb salvage at 1 year was 95% ± 2%, and wound healing was achieved in 85% ± 2%. The mean number of overall inpatient admissions (stage 1, 2.07 ± 0.48 vs stage 4, 3.40 ± 0.27; P < .001), procedure‐related admissions (stage 1, 1.86 ± 0.45 vs stage 4, 2.28 ± 0.24; P < .001), and inpatient vascular interventions (stage 1, 0.14 ± 0.10 vs stage 4, 0.80 ± 0.12; P < .001) increased significantly with increasing WIfI stage. There were no significant differences in mean number of inpatient podiatric interventions or outpatient procedures between groups (P ≥ .10). The total cost of care per wound episode increased progressively from stage 1 (