Role of Arginine and Omega-3 Fatty Acids in Wound Healing and Infection.

Significance: Only a few decades ago, the primary focus of nutritional supplementation was to prevent deficiencies of essential nutrients. It is now recognized that, at higher than essential levels, selected nutrients can have a pharmacologic effect to prevent or treat disease. Recent Advances: Two of the most important pharmaconutrients, arginine, and the omega-3 polyunsaturated fatty acids in fish oil, have been shown to have profound effects on wound healing and infections. Critical Issues: Both arginine and fish oils have independent benefits, but the combination appears to be much more effective. This combination has been shown to affect outcomes involving wound healing and infections, as reviewed here, and can also affect incidence and outcomes in cardiovascular disease, diabetes, organ transplant rejection, and other inflammatory conditions. These possibilities have not yet progressed to widespread clinical application. Future Directions: The optimal combinations of immunonutrients, timing of administration, and the doses needed for best results need to be determined in preclinical and clinical studies. Also, the mechanisms involved in the administration of pharmaconutrients need to be established.

Des-acyl-ghrelin (DAG) normalizes hyperlactacidemia and improves survival in a lethal rat model of burn trauma.

Critical illness, including burn injury, results in elevated plasma lactate levels. Dysregulation of PI3K/Akt signaling has been shown to play a predominant role in the inactivation of skeletal muscle PDC and, hence, in hyperlactacidemia in rat models of sepsis and endotoxemia. This observation, and our previous finding that DAG can reverse burn-induced skeletal muscle proteolysis through the activation of PI3K/Akt pathway, led us to hypothesize that DAG may also attenuate hyperlactacidemia in burn injury. Our investigations revealed that burn injury significantly elevated both skeletal muscle lactate production and plasma lactate levels. Moreover, this was accompanied in skeletal muscle by a 5-7 fold increase in mRNA expression of pyruvate dehydrogenase kinases (PDK) 2 and 4, and a ∼30% reduction in PDC activity. DAG treatment of burn rats completely normalized not only the mRNA expression of the PDKs and PDC activity, but also hyperlactacidemia within 24h of burn injury. DAG also normalized epinephrine-induced lactate production by isolated skeletal muscles from normal rats. Moreover, DAG also improved survival in a lethal rat model of burn trauma. These findings with DAG may have clinical implications because chances of survival for critically ill patients are greatly improved if plasma lactate levels are normalized within 24h of injury.

Immunonutrition in kidney and liver transplant recipients.

The immunonutrients arginine and omega-3 fatty acids decrease adverse outcomes after solid organ transplant in humans and experimental animals. Kidney transplant recipients who received daily supplements with arginine (9 g) and canola oil (30 mL) had significantly lower frequencies of complications between 30 days to 3 years than transplant recipients who did not receive supplements. In another study in kidney transplant recipients, arginine combined with either canola oil or fish oil was safe, effective, and provided good protection against rejection in patients who had steroid-free immunosuppression. In the 27 patients (50%) who had omega-3 index (percent omega-3 component of all fatty acids in red blood cell membranes) > 6 there was no acute rejection by 1 year after transplant; in 27 patients who had omega-3 index < 6, there were 5 patients (19%) who had acute rejection (P ≤ .01). No studies are available in liver transplant patients that have provided adequate doses or duration of immunonutrients. A prospective, randomized, double-blind clinical trial using immunonutrients is proposed for patients having primary liver transplant. In summary, immunonutrition in kidney transplant recipients with high doses of oral arginine and omega-3 fatty acids is effective, safe, and inexpensive, and may decrease the frequency of complications such as rejection, infection, new onset diabetes and cardiovascular disease. Further study with similar protocols in liver transplant recipients is justified.

Surveillance of bacterial colonization in operating rooms.

BACKGROUND: Surgical site infections (SSIs) continue to occur at an unacceptably high rate, incurring direct costs of up to $10 billion per year in the United States and far more than that in total economic costs. There is a continued need to identify potential sources of microbial contamination that lead to surgical infections. METHODS: Using contact culture plates, we randomly took a total of 517 samples of various surfaces in 33 operating rooms (ORs) over a 6-mo period. RESULTS: Flat surfaces treated with decontamination techniques (floors, anesthesia carts, operating tables, and other flat surfaces) grew small numbers of bacterial colonies, as did other surfaces that were decontaminated less often. Personal items, especially the tops of shoes and personal hats, had much higher contamination than the surfaces just described, which in the case of these two items averaged 50-60 CFU/20 cm(2). The outsides of face masks contained slightly more organisms than did floors, but the insides had almost 100 times more organisms, which was of concern because of high leakage rates at the mask-face interface. CONCLUSIONS: The culture system used in our study can be used as a simplified and cost-effective method of identifying the comparative densities of organisms on different surfaces for surveillance of microbial contamination in the OR. To reduce bacterial contamination, shoe covers and disposable hair coverings should be worn at every operation in which there are substantial risks of SSI. Masks that reduce leakage at the mask-face interface should be worn and discarded after each operation.

Updated recommendations for control of surgical site infections.

OBJECTIVE: The objective of this study is to provide updated guidelines for the prevention of surgical wound infections based upon review and interpretation of the current and past literature. BACKGROUND: The development and treatment of surgical wound infections has always been a limiting factor to the success of surgical treatment. Although continuous improvements have been made, surgical site infections continue to occur at an unacceptable rate, annually costing billions of dollars in economic loss caused by associated morbidity and mortality. METHODS: The Centers for Disease Control (CDC) provided extensive recommendations for the control of surgical infections in 1999. Review of the current literature with interpretation of the findings has been done to update the recommendations. RESULTS: New and sometimes conflicting studies indicate that coordination and application of techniques and procedures to decrease wound infections will be highly successful, even in patients with very high risks. CONCLUSIONS: This review suggests that uniform adherence to the proposed guidelines for the prevention of surgical infections could reduce wound infections significantly; namely to a target of less than 0.5% in clean wounds, less than 1% in clean contaminated wounds and less than 2% in highly contaminated wounds and decrease related costs to less than one-half of the current amount.

Banded sleeve gastrectomy--initial experience.

BACKGROUND: Isolated sleeve gastrectomy is being used with increasing frequency for the treatment of morbid obesity. This study was done to determine the potential benefit of placing a band of processed human dermis around the upper portion of a sleeve gastrectomy to prevent late dilatation and weight gain. METHODS: Twenty-seven patients underwent a sleeve gastrectomy followed by placement of a band of biological tissue (AlloDerm) placed 6 cm from the gastroesophageal junction. The results were compared to 54 patients with a Roux-en-Y gastric bypass (GBP), matched for sex, age, and initial body mass index. RESULTS: All 27 patients had improvement or resolution of their diabetes, hypertension, hyperlipidemia, and sleep apnea after banded sleeve gastrectomy (BSG) similar to the control GBP group. There were no deaths, but one patient had a pulmonary embolus and another had a presumed leak. Symptoms of gastroesophageal reflux disease generally improved. Overall, results were almost identical to patients with GBP. CONCLUSIONS: BSG provides results comparable to GBP in the short-term follow-up, but avoids potential long-term complications including internal hernias, postoperative bowel obstructions, anastomotic complications of the jejunojejunostomy, hypoglycemia, bacterial overgrowth, and a spectrum of malabsorptive problems. While this study documents the feasibility and possible benefits of this modification, prospective controlled studies with long-term follow-up are needed to establish its place in procedures for surgical weight loss.

History of the medical use of silver.

BACKGROUND: Silver has been used extensively throughout recorded history for a variety of medical purposes. METHODS: A review of the literature in English was undertaken, primarily using PUBMED, to identify the medical uses of silver before the clinical introduction of antibiotics in the 1940s. RESULTS: Silver has been used for at least six millennia to prevent microbial infections. It has been effective against almost all organisms tested and has been used to treat numerous infections and noninfectious conditions, sometimes with striking success. Silver also has played an important role in the development of radiology and in improving wound healing. CONCLUSION: Silver was the most important antimicrobial agent available before the introduction of antibiotics.

Prevention of surgical site infections by an infusion of topical antibiotics in morbidly obese patients.

BACKGROUND: The reported incidence of surgical site infection after abdominal surgery in morbidly obese patients is high (about 15% in most studies), and this is associated with considerable disability and an increased economic burden. Topical antibiotics may reduce the incidence of serious infections. METHODS: Standard techniques for the prevention of surgical site infections were used along with the introduction of kanamycin into the subcutaneous space of morbidly obese patients at the time of closure and allowing it to dwell for 2 h. Eight hundred thirty-seven evaluable patients were followed for the development of site complications for at least six weeks postoperatively. RESULTS: One of the 65 patients with a revisional procedure had a primary deep incisional surgical site infection, as did one of the 772 patients with a primary operation. Secondary deep incisional surgical site infections occurred in four patients, two after spontaneous evacuation of a seroma, one from excessive superficial contamination, and one following separation of a nonhealing surgical site. Additionally, 21 patients had minor surgical site complications including incisional separation and stitch-related infections, which required no significant expenditure of resources. CONCLUSIONS: Prolonged contact (2 h) of topical kanamycin solution with the surgical site greatly reduces the incidence of primary infections in the deep subcutaneous space of laparotomy sites in morbidly obese patients.

Improvement and stabilization of chronic kidney disease after gastric bypass.

BACKGROUND: To more clearly establish the extent to which surgical weight loss can alter the course of established renal disease at a bariatric surgical service at a university-affiliated hospital. METHODS: Of a series of 45 nontransplant patients with established renal disease who had undergone gastric bypass, 9 had resolution, improvement, or stabilization of their kidney function. Two of these patients were already receiving, or were ready for, dialysis. Their average age at gastric bypass was 43.0+/-4.3 years, and their mean body mass index was 48.9+/-1.9 kg/m2. Of these 9 patients, 5 had a primary diagnosis of focal segmental glomerulosclerosis, 2 had membranous glomerulonephritis, and 2 had diabetic nephropathy. RESULTS: No leaks, splenic injury, transfusions, infections starting in the deep parts of the wound, death, or serious complications occurred. One patient had biopsy-proven membranous glomerulonephritis that completely resolved and has had 9 years of postoperative follow-up. The 2 dialysis patients were able to discontinue dialysis for 27 and 7 months, respectively. The remaining patients had stable renal function for 2-5 years postoperatively. CONCLUSION: In some patients with chronic kidney disease, gastric bypass results in stabilization or improvement of their kidney disease. Excess body weight loss seems to have the most positive effect in patients with obesity-related focal segmental glomerulosclerosis.

Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes.

BACKGROUND: The incidence of obesity has risen dramatically over the last few decades. This epidemic may be affected by exposure to xenobiotic chemicals. Bisphenol A (BPA), an endocrine disruptor, is detectable at nanomolar levels in human serum worldwide. Adiponectin is an adipocyte-specific hormone that increases insulin sensitivity and reduces tissue inflammation. Thus, any factor that suppresses adiponectin release could lead to insulin resistance and increased susceptibility to obesity-associated diseases. OBJECTIVES: In this study we aimed to compare a) the effects of low doses of BPA and estradiol (E(2)) on adiponectin secretion from human breast, subcutaneous, and visceral adipose explants and mature adipocytes, and b) expression of putative estrogen and estrogen-related receptors (ERRs) in these tissues. METHODS: We determined adiponectin levels in conditioned media from adipose explants or adipocytes by enzyme-linked immunosorbant assay. We determined expression of estrogen receptors (ERs) alpha and beta, G-protein-coupled receptor 30 (GPR30), and ERRs alpha, beta, and gamma by quantitative real-time polymerase chain reaction. RESULTS: BPA at 0.1 and 1 nM doses suppressed adiponectin release from all adipose depots examined. Despite substantial variability among patients, BPA was as effective, and often more effective, than equimolar concentrations of E(2). Adipose tissue expresses similar mRNA levels of ERalpha, ERbeta, and ERRgamma, and 20- to 30-fold lower levels of GPR30, ERRalpha, and ERRbeta. CONCLUSIONS: BPA at environmentally relevant doses inhibits the release of a key adipokine that protects humans from metabolic syndrome. The mechanism by which BPA suppresses adiponectin and the receptors involved remains to be determined.

Influence of long chain polyunsaturated fatty acids and ornithine concentrations on complications after renal transplant.

OBJECTIVES: The present study, registered at clinicaltrials.gov with the unique registration number NCT00560014, sought to evaluate the relations between fatty acid concentrations in red blood cells or plasma and amino acid concentrations in plasma on rejection, calcineurin inhibitor toxicity, and new-onset diabetes mellitus. MATERIALS AND METHODS: Lipid profiles on plasma or red blood cell samples were performed preoperatively and postoperatively in 54 patients. Plasma amino acid profiles were obtained in 49 of these patients. RESULTS: High concentrations of total omega-3 fatty acids, eicosapentaenoic and docosahexaenoic acids in red blood cells, and ornithine in plasma, all were associated with a significantly lower incidence of rejection, whereas high total omega-6 fatty acids were associated with a high rejection rate. Calcineurin inhibitor toxicity was associated with low levels of docosahexaenoic acid, ornithine, and the omega-3 index, and high total omega-6 and omega-3/omega-6 ratios. Inhibition of new-onset diabetes mellitus was seen only with high levels of ornithine. Peak concentrations of fatty acids in red blood cells were not obtained until after 30 days. High levels of arginine were not associated with reduced complications. CONCLUSIONS: The levels of selected nutrients in plasma and red blood cell membranes appear to have a profound effect on complications after renal transplant. These preliminary results need confirmation in prospective randomized clinical trials.

The impact of medicaid status on outcome after gastric bypass.

BACKGROUND: Socioeconomic status has been a predictor of poor outcome in many surgical diseases including morbid obesity. Potential differences in treatment and initial severity of disease have often not been well controlled in patients with bariatric surgery. This study was performed to compare the results of bariatric procedures in financially disadvantaged Medicaid patients compared to patients with Medicare and those with Commercial insurance under controlled conditions. METHODS: Prospectively collected data from 183 Medicaid, 77 Medicare and 570 Commercial/self-pay insurances were compared to determine the influence of poor economic status on outcome. All the patients received surgical care by the same surgeon at a large University-affiliated private hospital. RESULTS: Medicaid patients were larger (BMI 58.4 vs. 52.8 and 50.9, respectively) and had a greater incidence of serious comorbid conditions at outset. The death rate and complications were also significantly higher postoperatively in Medicaid patients. However, when the patients were matched for age and BMI, results became similar. CONCLUSION: Increases in postoperative mortality and morbidity appear to be associated with advanced disease because of poor access to care. When matched for age, BMI, and severity of disease, outcomes are similar. Changes in Medicaid policies could improve access and outcome.

Pharmacokinetics of mycophenolic acid, tacrolimus and sirolimus after gastric bypass surgery in end-stage renal disease and transplant patients: a pilot study.

BACKGROUND: Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population. METHODS: Data are presented on six subjects who participated in this trial--four were on dialysis and two were renal transplant recipients. Dialysis-dependent bypass subjects received a single dose of 6 mg of sirolimus, two 4-mg doses of tacrolimus and two 1000-mg doses of mycophenolate mofetil (MMF) over the 24-h study period. Transplant recipients continued their current regimen. Maximum plasma concentration (C(max)), time to reach the maximum plasma concentration (T(max)) and the area under the plasma concentration vs. time curve (AUC(0-12) and AUC(0-infinity) where appropriate) were calculated for tacrolimus, sirolimus, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG). RESULTS: Significant inter-patient variability in the C(max), T(max) and AUC of tacrolimus, sirolimus MPA and MPAG was observed. A notable difference in the AUC:dose ratio for tacrolimus was seen when comparing data with published data in the non-bypass population. Similar differences in PK were seen with sirolimus, MPA and MPAG. CONCLUSIONS: When comparing the PK of sirolimus, tacrolimus, MPA and MPAG to published PK data in the non-bypass population, significant differences are observed. It is likely that transplant recipients with GBS would need higher doses of tacrolimus, sirolimus and MMF to provide similar exposure to a non-bypass patient.

Gastric bypass in chronic renal failure and renal transplant.

BACKGROUND: Morbid obesity has reached epidemic proportions in developed nations worldwide, causing considerable mortality and increased healthcare expenditures. The use of gastric bypass surgery to achieve weight loss in morbidly obese patients with chronic renal failure (CRF) and postrenal transplant patients has not been studied adequately. METHODS: Forty-one patients with different stages of CRF (25 already receiving dialysis) underwent a gastric bypass (GBP), and an additional 10 patients underwent a GBP after becoming morbidly obese after transplantation. RESULTS: Of the 41 patients with CRF, 5 stabilized or resolved their kidney disease and 9 underwent successful transplantation. These patients had a loss of 68% excess body mass index (BMI) by 12 months after GBP. Of the 10 patients with GBP after transplant, the mean loss of excess BMI was 70.5%. There were no in-hospital or 30-day mortalities, but 8 of the 51 patients died from 112 to 2869 days postoperatively, 7 from cardiac or vascular events and 1 from an automobile accident. This compares with an approximate 10% mortality per year for patients receiving dialysis. Comorbid conditions associated with morbid obesity improved in all patients and permitted eligibility for transplantation. CONCLUSIONS: GBP for massive weight reduction in morbidly obese renal failure and transplant patients leads to a reduction in comorbid conditions that are associated with an increased risk for cardiovascular deaths. There was no operative mortality in this series, and all but 1 death were related to previously existing disease of the cardiovascular system.

Corticosteroid elimination: the Cincinnati experience.

Elimination of corticosteroid-related morbidity has been a goal of transplant clinicians from the earliest days of renal transplantation more than 50 years ago. Over the past decade, this goal has begun to be realized. Herein, we describe our efforts to eliminate corticosteroid therapy from maintenance immunosuppression-efforts that have spanned 15 years and have included design and conduct of five multicenter trials and over ten single center trials with over 650 patients at the University of Cincinnati. These efforts have led to a near complete elimination of corticosteroid-related morbidity, and, importantly, a more precise definition of the risk/benefit assessments of corticosteroid withdrawal in individual patient populations, which has allowed individualization and tailoring of corticosteroid-free immunosuppression.

Gastric bypass for morbidly obese patients with established cardiac disease.

BACKGROUND: Bariatric surgery has often been avoided in patients with known cardiac disease because of the risks inherent in this patient population. This study was done to evaluate both the risks and benefits of Roux-en-Y gastric bypass (RYGBP) in morbidly obese patients with established cardiac disease. METHODS: Data were analyzed to compare preoperative with postoperative co-morbid cardiac risk factors, peri-operative and postoperative complications, and change in body mass index (BMI) in 77 consecutive patients who had a preoperative diagnosis of cardiac disease and underwent RYGBP between March 1998 and January 31, 2006. Findings were compared to a concomitant control group without cardiac disease. RESULTS: The preoperative presence of cardiac disease was manifested primarily as coronary artery disease (CAD) (45 patients) or as congestive heart failure (CHF) (32 patients). Of the patients with CAD, 60% had diabetes, 91% had hypertension and 39% had hyperlipidemia. 58% had one or more prior invasive cardiac procedures. In the CHF group, 50% had diabetes, 71% had hypertension and 44% had hyperlipidemia. The average length of stay was 3.7 days for CAD patients and 3.3 days for CHF compared to 3.0 days for controls. All co-morbid conditions were improved, and no patient died from cardiac disease. However, one patient died as a complication of GI bleeding, one patient subsequently underwent revascularization and another underwent stenting. Other complications up to 5 years postoperatively were frequent but seldom life-threatening. CONCLUSION: RYGBP surgery in patients with existing cardiac disease appears to have acceptable risk and is effective in reducing the co-morbid conditions of diabetes, hypertension, hyperlipidemia, sleep apnea and arthritis, but longer term data are needed.

Simultaneous corticosteroid avoidance and calcineurin inhibitor minimization in renal transplantation.

Steroids and calcineurin inhibitors (CNI) have been mainstays of immunosuppression but both have numerous side effects that are associated with substantial morbidity and mortality. This study was carried out to determine if steroids can be eliminated with early discontinuation of cyclosporine A (CsA) and later discontinuation of mycophenolate mofetil (MMF). Ninety-six patients with kidney transplants were entered into four subgroups of two pilot studies. All patients received Thymoglobulin induction, rapamycin (RAPA), and the immunonutrients arginine and an oil containing omega-3 fatty acids. Mycophenolate mofetil was started in standard doses and discontinued by 2 years. CsA was given in reduced doses for either 4, 6, or 12 months. Follow-up was 12-36 months. Thirteen first rejection episodes occurred during the first year (14%). Combining all patients, 86% were rejection-free at 1 year, 80% at 2 years and 79% at 3 years. No kidney has been lost to acute rejection. Ninety percent of the 84 patients at risk at the end of the study were steroid-free and 87% were off CNI. Fifty-seven percent of 54 patients with a functioning kidney at 3 years were receiving monotherapy with RAPA. We conclude that this therapeutic strategy is worthy of a prospective multi-center clinical trial.