Objective To improve clinical outcome and to determine new treatment options, we studied the pathophysiologic response postburn in a large prospective, single center, clinical trial. Summary Background Data A severe burn injury leads to marked hypermetabolism and catabolism, which are associated with morbidity and mortality. The underlying pathophysiology and the correlations between humoral changes and organ function have not been well delineated. Methods Two hundred forty-two severely burned pediatric patients [>30% total body surface area (TBSA)], who received no anabolic drugs, were enrolled in this study. Demographics, clinical data, serum hormones, serum cytokine expression profile, organ function, hypermetabolism, muscle protein synthesis, incidence of wound infection sepsis, and body composition were obtained throughout acute hospital course. Results Average age was 8 ± 0.2 years, and average burn size was 56 ± 1% TBSA with 43 ± 1% third-degree TBSA. All patients were markedly hypermetabolic throughout acute hospital stay and had significant muscle protein loss as demonstrated by a negative muscle protein net balance (−0.05% ± 0.007 nmol/100 mL leg/min) and loss of lean body mass (LBM) (−4.1% ± 1.9%); P < 0.05. Patients lost 3% ± 1% of their bone mineral content (BMC) and 2 ± 1% of their bone mineral density (BMD). Serum proteome analysis demonstrated profound alterations immediately postburn, which remained abnormal throughout acute hospital stay; P < 0.05. Cardiac function was compromised immediately after burn and remained abnormal up to discharge; P < 0.05. Insulin resistance appeared during the first week postburn and persisted until discharge. Patients were hyperinflammatory with marked changes in IL-8, MCP-1, and IL-6, which were associated with 2.5 ± 0.2 infections and 17% sepsis. Conclusions In this large prospective clinical trial, we delineated the complexity of the postburn pathophysiologic response and conclude that the postburn response is profound, occurring in a timely manner, with derangements that are greater and more protracted than previously thought.

BackgroundMain contributors to adverse outcomes in severely burned pediatric patients are profound and complex metabolic changes in response to the initial injury. It is currently unknown how long these conditions persist beyond the acute phase post-injury. The aim of the present study was to examine the persistence of abnormalities of various clinical parameters commonly utilized to assess the degree hypermetabolic and inflammatory alterations in severely burned children for up to three years post-burn to identify patient specific therapeutic needs and interventions.Methodology/Principal FindingsPatients: Nine-hundred seventy-seven severely burned pediatric patients with burns over 30% of the total body surface admitted to our institution between 1998 and 2008 were enrolled in this study and compared to a cohort non-burned, non-injured children. Demographics and clinical outcomes, hypermetabolism, body composition, organ function, inflammatory and acute phase responses were determined at admission and subsequent regular intervals for up to 36 months post-burn. Statistical analysis was performed using One-way ANOVA, Student's t-test with Bonferroni correction where appropriate with significance accepted at p<0.05. Resting energy expenditure, body composition, metabolic markers, cardiac and organ function clearly demonstrated that burn caused profound alterations for up to three years post-burn demonstrating marked and prolonged hypermetabolism, p<0.05. Along with increased hypermetabolism, significant elevation of cortisol, catecholamines, cytokines, and acute phase proteins indicate that burn patients are in a hyperinflammatory state for up to three years post-burn p<0.05.ConclusionsSevere burn injury leads to a much more profound and prolonged hypermetabolic and hyperinflammatory response than previously shown. Given the tremendous adverse events associated with the hypermetabolic and hyperinflamamtory responses, we now identified treatment needs for severely burned patients for a much more prolonged time.

SUMMARY1. Twelve healthy subjects (33 + 3 years) with a variety of fitness levels (maximal oxygen uptake (VO2 max) = 61+4 ml kg-1 min-', range , exercised at 95 and 85 % V02, max to exhaustion (mean time = 14 + 3 and 31+8 min, expired ventilation (VE) over final minute of exercise = 149+9 and 126 + 10 1 min-').2. Bilateral transcutaneous supramaximal phrenic nerve stimulation (BPNS) was performed before and immediately after exercise at four lung volumes, and 400 ms tetanic stimulations were performed at 10 and 20 Hz. The coefficients of variation of repeated measurements for the twitch transdiaphragm pressures (Pdi) were +7-10 % and for compound muscle action potentials (M wave) ± 10-15 %. 5. The fPdi min-' and the fP. min-' (PO, oesophageal pressure) rose together from rest through the fifth to tenth minute of exercise, after which fPdi min-' plateaued even though fPO min-', VE and inspiratory flow rate all continued to rise substantially until exercise terminated. Thus, the relative contribution of the diaphragm to total respiratory motor output was progressively reduced with exercise duration.6. We conclude that significant diaphragmatic fatigue is caused by the ventilatory requirements imposed by heavy endurance exercise in healthy persons with a variety of fitness levels. The magnitude of the fatigue and the likelihood of its occurrence increases as the relative intensity of the exercise exceeds 85 % of V02 max,

Summary Severe burns incur a profound stress response, which is unrivaled in terms of its magnitude and duration. Recent evidence suggests that the pathophysiological stress response to severe burns persists for several years post injury. Thus, there is a pressing need for novel strategies that mitigate this response and restore normal metabolic function in burn survivors. This is the first installment of a three-part series exploring the stress response to severe burn trauma. In this article we aim to distill the current knowledge pertaining to the stress response to burn trauma, highlighting recent developments and important knowledge gaps that need to be pursued in order to develop novel therapeutic strategies which improve outcomes in burn survivors.

The posttraumatic response to burn injury leads to marked and prolonged skeletal muscle catabolism and weakness, which persist despite standard rehabilitation programs of occupational and physical therapy. We investigated whether a resistance exercise program would attenuate muscle loss and weakness that is typically found in children with thermal injury. We assessed the changes in leg muscle strength and lean body mass in severely burned children with >40% total body surface area burned. Patients were randomized to a 12-wk standard hospital rehabilitation program supplemented with an exercise training program (n = 19) or to a home-based rehabilitation program without exercise (n = 16). Leg muscle strength was assessed before and after the 12-wk rehabilitation or training program at an isokinetic speed of 150 degrees /s. Lean body mass was assessed using dual-energy X-ray absorptiometry. We found that the participation in a resistance exercise program results in a significant improvement in muscle strength, power, and lean body mass relative to a standard rehabilitation program without exercise.

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Objective To determine the safety and efficacy of propranolol given for 1 year on cardiac function, resting energy expenditure, and body composition in a prospective randomized single-center controlled study in pediatric patients with large burns. Summary Background Data Severe burns trigger a hypermetabolic response that persists for up to 2 years after burn. Propranolol given for 1 month post burn blunts this response. Whether propranolol administration for 1 year after injury provides a continued benefit is currently unclear. Methods One-hundred seventy nine pediatric patients with >30% total body surface area burns were randomized to receive control (n = 89) or 4 mg/kg/d propranolol (n = 90) for 12 months after burn. Changes in resting energy expenditure, cardiac function, and body composition were measured acutely at 3, 6, 9, and 12 months postburn. Statistical analyses included techniques that adjust for non-normality, repeated measures, and regression analyses. P <0.05 was considered significant. Results Long-term propranolol treatment significantly reduced the percent of the predicted heart rate and percent of the predicted resting energy expenditure, decreased accumulation of central mass and central fat, prevented bone loss, and improved lean body mass accretion. There were very few adverse effects from the dose of propranolol used. Conclusions Propranolol treatment for 12 months, following thermal injury, ameliorates the hyperdynamic, hypermetabolic, hypercatabolic, and osteopenic responses in pediatric patients. This study is registered at clinicaltrials.gov, NCT00675714.

In nine normal humans we compared the effects on diaphragm fatigue of whole body exercise to exhaustion (86-93% of maximal O2 uptake for 13.2 +/- 2.0 min) to voluntary increases in the tidal integral of transdiaphragmatic pressure (integral of Pdi) while at rest at the same magnitude and frequency and for the same duration as those during exercise. After the endurance exercise, we found a consistent and significant fall (-26 +/- 2.9%, range -19.2 to -41.0%) in the Pdi response to supramaximal bilateral phrenic nerve stimulation at all stimulation frequencies (1, 10, and 20 Hz). Integral of Pdi.fB (where fB is breathing frequency) achieved during exercise averaged 509 +/- 81.0 cmH2O/min (range 304.0-957.0 cmH2O/min). At rest, voluntary production of integral of Pdi.fB, which was < 550-600 cmH2O/min (approximately 4 times the resting eupenic integral of Pdi.fB or 60-70% of Pdi capacity), did not result in significant diaphragmatic fatigue, whereas sustained voluntary production of integral of Pdi.fB in excess of these threshold values usually did result in significant fatigue. Thus, with few exceptions (5 of 23 tests) the ventilatory requirements of whole body endurance exercise demanded a level of integral of Pdi.fB that, by itself, was not fatiguing. The rested first dorsal interosseous muscle showed no fatigue in response to supramaximal ulnar nerve stimulation after whole body exercise. We postulate that the effects of locomotor muscle activity, such as competition for blood flow distribution and/or extracellular fluid acidosis, in conjunction with a contracting diaphragm account for most of the exercise-induced diaphragm fatigue.