Sildenafil increases muscle protein synthesis and reduces muscle fatigue.

Reductions in skeletal muscle function occur during the course of healthy aging as well as with bed rest or diverse diseases such as cancer, muscular dystrophy, and heart failure. However, there are no accepted pharmacologic therapies to improve impaired skeletal muscle function. Nitric oxide may influence skeletal muscle function through effects on excitation-contraction coupling, myofibrillar function, perfusion, and metabolism. Here we show that augmentation of nitric oxide-cyclic guanosine monophosphate signaling by short-term daily administration of the phosphodiesterase 5 inhibitor sildenafil increases protein synthesis, alters protein expression and nitrosylation, and reduces fatigue in human skeletal muscle. These findings suggest that phosphodiesterase 5 inhibitors represent viable pharmacologic interventions to improve muscle function.

Crew resource management improved perception of patient safety in the operating room.

To improve safety in the operating theater, a company of aviation pilots was employed to guide implementation of preprocedural briefings. A 5-point Likert scale survey that assessed the attitudes of operating room personnel toward patient safety was distributed before and 6 months following implementation of the briefings. Using Mann-Whitney analysis, the survey showed a significant (P < .05) improvement in 2 questions (of 13) involving reporting error and 2 questions (of 11) involving patient safety climate. When analyzed by occupation, there were no significant changes for faculty physicians; for resident physicians, there was a significant improvement in 1 question (of 13) regarding error reporting. For nurses, there were significant improvements in 3 questions (of 4) involving teamwork, 1 question (of 13) involving reporting error, and 3 questions (of 11) regarding patient safety climate. These results suggest that aviation-based crew resource management initiatives lead to an improved perception of patient safety, which was largely demonstrated by nursing personnel.

Preoperative maneuvers to avert postoperative respiratory failure in elderly patients.

BACKGROUND: The elderly appear particularly vulnerable to pulmonary complications following surgical procedures. OBJECTIVE: The purpose of this study was to identify and assess the merit of various maneuvers employed to mitigate respiratory difficulties in elderly patients undergoing surgery. RESULTS: The literature revealed evidence that diminishing sputum production with selective antibiotics and augmentation of sputum clearance with assisted coughing, postural drainage, and bronchodilators were deemed important. Futhermore, efforts to optimize nutritional status and eliminate tobacco and alcohol consumption are also felt to be of value in improving postsurgical outcome. CONCLUSION: One significant aspect of this review was the apparent posity of recent work on this subject despite the profound magnitude of the demise related to postsurgical respiratory complications in elderly patients.

Assessment of adverse events in the demise of pediatric burn patients.

BACKGROUND: Given the contention that survival is to be expected from even the most severely burned child, then, intuitively, at least some pediatric burn victims die because of suboptimal care. The purpose of this study is to assess the impact of any adverse events that may have contributed to the death of burned children. METHODS: Four surgeons with specialty training in pediatric burn care reviewed the clinical course and autopsy findings of 71 burned children who died after admission to a burn center during a 10-year interval. Reviewers were asked to determine the predominant factor or factors contributing to each child's demise and to assess the significance of any deviations from optimal care. RESULTS: For the 10 years under review, overall mortality for all pediatric burns was 2.4%. Of these deaths, 25% had burns encompassing less than 50% body surface area. The reviewers identified lung damage as the most frequent cause of death, which was deemed largely unpreventable. Conversely, hypovolemia related to inadequate prehospital fluid resuscitation and failure to obtain and maintain a patent airway were considered the second and third most common factors in a child's death and deemed preventable under ideal circumstances. CONCLUSIONS: This review implies that deficiencies in health care contribute to the demise of many burned children. The most notable areas for improvement are in fluid resuscitation and airway control. This suggests that quality assurance and educational initiatives to improve these aspects of care may have the greatest impact on further improving survival of burned children.

Quantification of amino acid transport through interstitial fluid: assessment of four-compartment modeling for muscle protein kinetics.

The purpose of this study was to assess a novel technique for quantifying in vivo muscle protein metabolism and phenylalanine transport in septic patients and normal volunteers and thereby assess the influence of sepsis on muscle protein kinetics. In patients resuscitated from sepsis, blood flow and edema may influence the extent of muscle loss. Six adult patients septic from pneumonia underwent a study protocol consisting of infusion of isotopic phenylalanine, indocyanine green dye, and sodium bromide; biopsies of skeletal muscle; and sampling from the femoral artery, vein, and interstitial fluid. Study results demonstrate a substantial net catabolism of muscle, an accelerated flux of phenylalanine, and an increased leg blood flow for septic patients compared with normal volunteers. For septic patients and normal volunteers, the rate of phenylalanine transport through the interstitium was rate limiting for the movement of phenylalanine between vasculature and muscle. Measurements demonstrate a concentration gradient of phenylalanine favoring the net efflux of amino acids from the leg in the septic patients. Despite whole body edema, the extracellular fluid volume within muscle of septic patients was similar to normal. These findings demonstrate that the extent of muscle loss in critically ill patients results from the net increase in the rate of muscle protein breakdown, which subsequently drives amino acids through the interstitial compartment down their concentration gradient. Therefore, any effective therapy to correct illness-induced muscle catabolism should be directed at altering the rates of breakdown and synthesis of muscle protein and are not likely related to tissue edema.

Splanchnic oxygen consumption is impaired during severe acute normovolemic anemia in anesthetized humans.

BACKGROUND: In conscious humans, reduction in hemoglobin concentration to 5 g/dl did not produce inadequate systemic oxygenation. However, systemic measures of inadequate oxygenation may not be sufficiently sensitive to detect inadequate oxygenation in individual organs such as splanchnic organs. The authors tested the hypothesis that acute normovolemic anemia to hemoglobin less than 6.0 g/dl in anesthetized humans reduces splanchnic oxygen consumption because of diminished whole body oxygen delivery. METHODS: Elective spine (n = 12) and abdominal (n = 7) surgery patients underwent acute normovolemic anemia to decrease the hemoglobin concentration close to 6.0 g/dl. The authors assessed the development of supply-dependent conditions in systemic and regional vascular beds by two primary measures before and after acute normovolemic anemia: oxygen consumption and surrogate biochemical markers of anaerobic metabolism, including plasma lactate, regional lactate kinetics, and ketone body ratio. RESULTS: When hemoglobin was reduced from 13.6 +/- 1.2 to 5.9 +/- 0.3 g/dl, oxygen supply dependency occurred in the splanchnic and preportal tissues but not at the systemic level. Regional supply dependency was accompanied by biochemical markers of anaerobic metabolism. CONCLUSIONS: In anesthetized humans, a reduction in hemoglobin to 5.9 g/dl by acute normovolemic anemia diminished splanchnic and preportal whole body oxygen delivery and impaired splanchnic and preportal oxygen consumption. This was accompanied by increased plasma levels of regional lactate and an increased beta-hydroxybutyrate-to-acetoacetate ratio. These findings suggest that the risk to the gastrointestinal tract during acute normovolemic anemia may be underestimated.

Quantification of protein metabolism in vivo for skin, wound, and muscle in severe burn patients.

BACKGROUND: In response to injury, muscle catabolism can be extensive, and in theory, the wound consumes amino acids to support healing. The purpose of this study is to assess a technique by which in vivo protein kinetics of muscle, wound, and normal skin can be quantified in burn-injured patients. METHODS: Study protocol consisting of infusion of d5 phenylalanine; biopsies of skeletal muscle, skin, and donor-site wound on the leg; quantification of blood flow to total leg, wound, and skin; and sequential blood sampling from the femoral artery and vein. Five-compartment modeling was used to quantify the rates of protein synthesis, breakdown, and phenylalanine transport between muscle, wound, and skin. RESULTS: The study results demonstrated a net release of phenylalanine from muscle yet a net consumption of phenylalanine by the wound. Compared with skin, the wound had a substantially increased rate of protein synthesis and a reduced rate of protein breakdown (p < .01). Transport rates into and out of muscle were significantly higher than those for wound (p < .01). CONCLUSIONS: This novel methodology enables in vivo quantification of the integrated response of muscle, wound, and skin protein/amino acid metabolism and confirms the long-held theory of a net catabolism of muscle and a net anabolism of wound protein in patients after injury. This methodology can be used to assess the metabolic impact of such measures as nutrition, pharmacologic agents, and surgical procedures.

Supportive care in acute respiratory distress syndrome.

Although the central focus of acute respiratory distress syndrome (ARDS) is the pathology within the lung, ARDS is very much a systemic disease. As such, the whole body needs care and support while the disease process within the lung runs its course. The issues of pain management, sedation, fluid balance, nutrition, metabolic and hormonal processes, infection control, and patient positioning are important for any patient in a critical care setting. For patients with ARDS, the required ventilatory support and ARDS-associated systemic inflammation mandate the above supportive measures.

National survey of surgical morbidity and mortality conferences.

BACKGROUND: Morbidity and mortality conferences historically have been a paramount meeting for education and quality assurance within surgical departments of teaching institutions. The purpose of this survey was to assess the present educational value and the quality assurance aspect of surgical mortality conferences. METHODS: Surveys were sent to every academic surgical training program director within the United States and Canada (n = 127) and queried the general format and an individual's experience and attitude toward their institutions conference. RESULTS: A total of 546 individuals from 34 institutions returned completed surveys. The survey findings showed that 74% of these surgical departments discussed all deaths and 50% discussed all complications. There was general agreement that surgical morbidity and mortality conferences are of good educational value and effective in reducing future error. The majority of respondents expressed that evidence-based literature should be the primary basis of discussion, with comprehensive presentations that focus on analysis of error. CONCLUSIONS: This survey showed that morbidity and mortality conferences are both educational and perceived by the respondents as effective in reducing future error.

Hemodynamic and metabolic effects of selective beta1 adrenergic blockade during sepsis.

BACKGROUND: Selective beta adrenergic antagonists are commonly used to reduce myocardial demise in patients at risk for cardiac-related death. The purpose of this study was to examine the hemodynamic and metabolic effects of cardiac selective beta adrenergic blockade in patients. METHODS: Muscle protein kinetics were quantified using isotopic tracer methodology in 6 moderately septic, mechanically ventilated patients with pneumonia before and then at the conclusion of a 3-hour infusion of esmolol of sufficient dose to reduce heart rate by 20% from baseline. A battery of hemodynamic measurements as facilitated by a thermodilution pulmonary artery catheter and indirect calorimetry were also measured before and after the 3-hour selective beta adrenergic blockade. RESULTS: Selective beta adrenergic blockade was associated with the 20% reduction in heart rate and a comparable decrease in cardiac output. Esmolol administration failed to affect systemic or pulmonary vascular resistance, oxygen consumption, hepatic or leg blood flow, energy expenditure, or ATP availability/energy charge within muscle. Esmolol infuse did incite a shift in fuel oxidation toward an increase in palmitate oxidation and with a decrease in the oxidation of glucose. There was no demonstrable influence beta1 adrenergic blockade on muscle protein kinetics. CONCLUSIONS: Cardiac selective beta adrenergic blockade with esmolol reduces cardiac output in proportion to the percentage decreases in heart rate in moderately severe septic patients without adversely affecting oxygen utilization or hepatic, peripheral blood flow.

Comparison of peripheral metabolic effects of insulin and metformin following severe burn injury.

OBJECTIVE: Both insulin and metformin have been shown to attenuate hyperglycemia and reduce net muscle protein catabolism following burn injury. The purpose of this study was to compare the peripheral metabolic effects of insulin and metformin in severe burn patients. METHODS: Six adult patients with burns greater than 40% of their body surface underwent metabolic evaluation utilizing isotopic dilution of phenylalanine, femoral arterial and venous blood sampling, and sequential biopsies of leg muscle. Following baseline measurements, insulin was infused into the femoral artery at 0.45 mIU/min 100 mL leg volume. Patients were then given metformin (850 mg every 8 hours) for seven days with repeat metabolic evaluation before and during intra-arterial infusion of insulin. RESULTS: Intra-arterial administration of insulin significantly increased insulin concentrations within the femoral vein, creating hyperinsulinemia localized to the extremity. Metformin had no significant effect on either peripheral glucose clearance or the rate of glucose oxidation. Furthermore, the availability of ATP and energy charge within muscle was not overtly affected by either insulin or metformin. Metformin did significantly increase the fractional synthetic rate of muscle protein which increased even further with insulin administration. Both metformin and insulin separately increased the rate of muscle protein synthesis as calculated using three compartment modeling. CONCLUSION: This study demonstrates a significant anabolic effect on muscle protein with metformin and a modest response with insulin. Findings also suggest that metformin and insulin may work synergistically to further improve muscle protein kinetics.

Temporal changes in cellular energy following burn injury.

Availability of ADP is a predominant influence on respiratory control. Associated with severe burn injury is an increase in energy expenditure. The purpose of this study was to determine the temporal changes in ATP, ADP, NAD, and NADH following severe burn and thereby assess any related alterations in respiratory control and energy deficit. During isoflurane anesthesia and following intraperitoneal injection of saline, 32 mice were flame burned at 40% body surface area. Twelve mice served as controls. At 12, 24, 72, and 168 h post-burn, groups of mice underwent celiotomy with determination of hepatic surface blood flow using laser Doppler and oxygen saturation using pulse oximetry. Biopsies of liver were then frozen in liquid nitrogen for subsequent quantification of ATP, ADP, AMP, NAD, and NADH by HPLC. Mortality was 12.5% at 72 h post-burn and 25% at 1 week. Oxygen saturation and hepatic surface blood flow remained similar to control values throughout the week after burn. ATP, ADP, and energy charge decreased progressively following burn reaching a significant decrease from unburned controls at 72 h. Availability of NADH remained statistically similar to unburned controls throughout the week after burn. These results demonstrate that despite maintenance of baseline oxygen delivery, there was a nadir in ATP and ADP availability and energy charge in the liver at 72 h after burn. This finding supports the concept of a limitation in phosphorylation after injury. Availability of NADH remained at or above pre-burn concentrations suggesting that the rate of fuel oxidation was not a limiting factor for ongoing oxidative phosphorylation for energy.

Utility of acellular allograft dermis in the care of elderly burn patients.

BACKGROUND: Because skin thins with advancing age, traditional thickness skin grafts cannot always be obtained in very elderly burn patients without creating a new full-thickness wound at the skin graft donor site. MATERIALS AND METHODS: In an attempt to circumvent this problem, acellular allograft dermis (Alloderm, Life Cell Corp., The Woodlands, TX) and thin autograft (depth 0.005 inches) was used in skin grafting 10 elderly burn patients (age 78 year +/- 2, TBSA burn 17% +/- 2; mean +/- SEM) over a 1-year period. The outcome of patients receiving Alloderm was compared retrospectively to a similar group of 18 elderly patients admitted over the prior year, eight of whom underwent operative wound excision and autografting (depth 0.014 inches) without Alloderm. RESULTS: Length of hospital stay was significantly reduced in patients treated with Alloderm compared to the total group of elderly in whom selective use of operative debridement and skin grafting was used. Functional outcome was improved in those patients who underwent skin grafting regardless of operative technique. Donor site healing time was significantly reduced with Alloderm (12 days +/- 1 versus 18 days +/- 2), while graft take was similar to conventional autografting. Unfortunately, 3-month mortality remained poor regardless of operative skin grafting or technique used. CONCLUSIONS: This initial experience suggests that use of Alloderm may allow more elderly burn patients to undergo operative wound closure, thus improving functional outcome and reducing hospitalization. Unfortunately, long-term survival for very elderly burn patients remains poor.

Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury.

SUMMARY BACKGROUND DATA: Hyperglycemia and accelerated muscle catabolism have been shown to adversely affect immune response and survival. The purpose of this study was to determine the effect of metformin on glucose kinetics and muscle protein metabolism in severely burned patients and assess any potential benefit of metformin in this clinical setting. METHODS: In a double-blind, randomized manner, 8 adult burn patients received metformin (850 mg every 8 hours x 7 days), while 5 burn patients received placebo. Infusions of 6,6d2 glucose, d5 phenylalanine, sequential muscle biopsies, and femoral arterial, venous blood sampling allowed determination of glucose and muscle protein kinetics. Measurements were obtained immediately prior and at the conclusion of 7 days of treatment (metformin versus placebo). All patients received enteral feeds of comparable amounts during study. RESULTS: Patients receiving metformin had a significant decrease in their plasma glucose concentration, the rate of glucose production, and an increase in glucose clearance. Metformin administration was also associated with a significant increase in the fractional synthetic rate of muscle protein and improvement in net muscle protein balance. Glucose kinetics and muscle protein metabolism were not significantly altered in the patients receiving placebo. CONCLUSIONS: Metformin attenuates hyperglycemia and increases muscle protein synthesis in severely burned patients, thereby indicating a metabolic link between hyperglycemia and muscle loss following severe injury. Therefore, therapies that improve glucose tolerance such as metformin may be of clinical value in ameliorating muscle catabolism in critically injured patients.

Angiosarcoma of the of scalp with calvarium involvement in a 50-year-old African-American man.

BACKGROUND: Angiosarcoma of the scalp is a rare, aggressive, and deadly cancer that affects mainly elderly Caucasian men. OBJECTIVES: The insidious and masquerading presentation of angiosarcoma poses enormous diagnostic challenges for primary care providers. PATIENTS/METHODS: We present a case of a 50-year-old black man referred for evaluation of a 3.7-cm-x-5.4-cm ulcerated, fluctuant scalp lesion that had failed to respond to different antibiotics and proper wound care. RESULTS: Surgical excision and subsequent histopathology revealed angiosarcoma. CONCLUSIONS: This case report highlights the importance of high index of suspicion for early diagnosis of cancerous lesions in wounds and stresses the need to include angiosarcoma in the differential diagnosis for all face and scalp lesions, as early detection may save lives. A comprehensive literature review is also presented.

In vivo muscle amino acid transport involves two distinct processes.

We have tested the hypothesis that transit through the interstitial fluid, rather than across cell membranes, is rate limiting for amino acid uptake from blood into muscle in human subjects. To quantify muscle transmembrane transport of naturally occurring amino acids, we developed a novel 4-pool model that distinguishes between the interstitial and intracellular fluid compartments. Transport kinetics of phenylalanine, leucine, lysine, and alanine were quantified using tracers labeled with stable isotopes. The results indicate that interstitial fluid is a functional compartment insofar as amino acid kinetics are concerned. In the case of leucine and alanine, transit between blood and interstitial fluid was potentially rate limiting for muscle amino acid uptake and release in the postabsorptive state. For example, in the case of leucine, the rate of transport between blood and interstitial fluid compared with the corresponding rate between interstitial fluid and muscle was 247 +/- 36 vs. 610 +/- 95 nmol.min(-1).100 ml leg(-1), respectively (P < 0.05). Our results are consistent with the process of diffusion governing transit from blood to interstitial fluid without selectivity, and of specific amino acid transport systems with varying degrees of efficiency governing transit from interstitial fluid to muscle. These results imply that changes in factors that affect the transit of amino acids from blood through interstitial fluid, such as muscle blood flow or edema, could play a major role in controlling the rate of muscle amino acid uptake.

Increased VLDL-TAG turnover during and after acute moderate-intensity exercise.

PURPOSE AND METHODS: Breakdown rates of very low density lipoprotein triacylglycerols (VLDL-TAG) were quantified before (3 h), during (45 min), and after (3 h) moderate physical exercise at 40% VO2 max in young sedentary subjects (four male and four female, age 29.8 +/-1.6 yr, BMI 24.1 +/- 0.9 kg x m, VO2max 37.0 +/- 1.7 mL x kg x min), using boluses of H5-glycerol (100 mu mol x kg) and H2-palmitate (6.6 mu mol x kg). The catabolic rates of VLDL-TAG were calculated from the decay in the isotopic enrichment using a single-pool model. The results were compared with those obtained during 6 h of rest in five of the same volunteers. RESULTS: VLDL-TAG concentration remained constant throughout the study with exercise (P = NS). The fractional catabolic rate was nearly doubled from rest to exercise (P < 0.05 vs rest) and increased to an even greater extent during the early phase of recovery (P < 0.001 vs rest). During the late recovery phase, the value returned to the preexercise value (P = NS vs rest). The values for the absolute catabolic rate (kabs) followed the same trend. CONCLUSION: VLDL-TAG turnover was increased during exercise and during the early phase of recovery.

Extremity hyperinsulinemia stimulates muscle protein synthesis in severely injured patients.

Insulin has a well-recognized anabolic effect on muscle protein, yet critically ill, severely injured patients are often considered "resistant" to the action of insulin. The purpose of this study was to assess the in vivo effects of hyperinsulinemia on human skeletal muscle in severely injured patients. To accomplish this goal, 14 patients with burns encompassing >40% of their body surface area underwent metabolic evaluation utilizing isotopic dilution of phenylalanine, femoral artery and vein blood sampling, and sequential muscle biopsies of the leg. After baseline metabolic measurements were taken, insulin was infused into the femoral artery at 0.45 mIU.min(-1).100 ml leg volume(-1) to create a local hyperinsulinemia but with minimal systemic perturbations. Insulin administration increased femoral venous concentration of insulin (P < 0.01) but with only a 4% (insignificant) decrease in the arterial glucose concentration and a 7% (insignificant) decrease in the arterial concentration of phenylalanine. Extremity hyperinsulinemia significantly increased leg blood flow (P < 0.05) and the rate of muscle protein synthesis (P < 0.05). Neither the rate of muscle protein breakdown nor the rate of transmembrane transport of phenylalanine was significantly altered with extremity hyperinsulinemia. In conclusion, this study demonstrates that insulin directly stimulates muscle protein synthesis in severely injured patients.