Comparison of Six-Minute Walk Test and Modified Bruce Treadmill Test in Paediatric Patients With Severe Burns: A Cross-Over Study.

OBJECTIVE: To compare the six-minute walk test and the Modified Bruce treadmill test in paediatric patients with severe burns. SUBJECTS: A total of 67 children, aged 7-17 years, with severe burns. METHODS: Participants were assigned to perform the six-minute walk test and the Modified Bruce treadmill test in randomized order on discharge from acute burn care. Primary outcome measure was heart rate. Secondary outcome measures were distance walked, Borg's CR-10 rate of perceived exertion, and maximal oxygen uptake (VO2). RESULTS: A total of 67 participants were enrolled. Thirty-eight patients completed both tests. The mean six-minute walk test maximum heart rate was 135 ± 19 bpm (range 97-180 bpm) and the mean Modified Bruce treadmill test maximum heart rate was 148 ± 24 bpm (range 100-197 bpm; p ≤ 0.05), with a weak positive correlation of R² = 0.14. The mean six-minute walk test maximum distance was 294 ± 124 m (range 55 to 522 m) while the mean Modified Bruce treadmill test maximum distance was 439 ± 181 m (range 53 to 976 m; p ≤ 0.05), with no correlation of R² = 0.006. The mean RPE CR-10 score for the six-minute walk test was 3 ± 2.5 (range 0-10) vs a mean RPE CR-10 score of 10 ± 0 for the Modified Bruce treadmill test. CONCLUSION: The Modified Bruce treadmill test challenges the cardiorespiratory system significantly more than the six-minute walk test, as reflected by maximum heart rate measurements, and the perception of effort (i.e. rate of perceived exertion) by the patient. When possible, the Modified Bruce treadmill test should be used to assess cardiovascular functional capacity. However, the six-minute walk test may be more clinically feasible for use with paediatric patients with burns, and provides information about submaximal functional exercise capacity.

The effects of short bouts of ergometric exercise for severely burned children in intensive care: A randomized controlled trial.

OBJECTIVE: To determine the effects of short bouts of ergometric exercises on the number of days in the burn intensive care unit (ICU), body mass, and functional ambulation. DESIGN: Multi-center, randomized controlled trial. SETTING: Burn intensive care unit. PARTICIPANTS: Children ages 7-17 with severe burns covering over 30% total body surface area (TBSA). INTERVENTION: All patients received standard of care (Control) with the experimental group receiving additional exercise with a cycle ergometer (Exercise). MAIN MEASURES: The number of days in the ICU, total weight, lean body mass (LBM), and functional ambulation were taken shortly after randomization and again within one week of the scheduled hospital discharge. Results of outcomes are expressed as median ± interquartile range (IQR), unless otherwise noted (e.g. demographics). RESULTS: Fifty-four severely burned children (n = 18 Control, n = 36 Exercise) were included. The average ± standard deviation for age was 12 ± 3 years and TBSA was 48 ± 16%. The median ± IQR ICU days for Control was 46 ± 51 days vs 31 ± 29 days for Exercise. The median total weight loss for Control was 2.2 ± 1.2 kg vs 1.8 ± 1.4 kg in Exercise. Control lost 0.75 ± 0.8 kg of LBM vs 0.46 ± 0.43 kg in Exercise. Both groups showed significant improvement in functional ambulation (p < 0.01). However, exercise did not add additional benefits. CONCLUSION: Short bouts of ergometric exercises are feasible for severely burned patients while receiving care in the ICU but did not add additional benefits.

Clearance of Indocyanine Green in Severe Pediatric Burns.

BACKGROUND: Clearance of indocyanine green dye (ICGc) reflects sinusoidal perfusion and hepatocyte cell membrane function. Thus, ICGc is a reflection of the functional reserve of intact hepatocytes. The purpose of this study was to identify predictors of ICGc in severely burned children during the acute hospitalization and at the time of discharge from the intensive care unit (ICU). A secondary aim was to determine the relationship between liver size and patient ICGc. METHODS: Twenty-six children (0.8-17 years old) with 35% or greater total body surface area burned (%TBSA-B) were included. Assessment of ICGc (in milliliters per minute per meter squared) was done during the acute hospitalization (median: 6 days after admission, median: 14 days postburn) and at the time of discharge from the ICU (median: 19 days after admission, median: 27 days postburn). Age, TBSA-B, % third-degree burns, inhalation injury, preexisting chronic malnutrition, hematocrit, liver dysfunction, and time from burn injury were incorporated in multiple linear regressions as predictive variables of ICGc. Only variables with p < 0.05 were retained in the final models. RESULTS: Time from injury and age were the strongest predictors of ICGc during the acute admission but not at the time of discharge from the ICU. Time from injury was negatively associated with ICGc, whereas age was positively associated. At the time of discharge from the ICU, ICGc was increased in proportion to the %TBSA-B, whereas inhalation injury and preexisting chronic malnutrition were associated with lower ICGc. There was no correlation between change-to-predicted liver length and ICGc. CONCLUSIONS: The intrinsic ability of the liver to extract ICG from plasma was lower in younger burned patients during the acute admission and in those with preexisting chronic malnutrition and inhalation injury at the time of discharge from the ICU. LEVEL OF EVIDENCE: Prognostic/Epidemiologic, level III.

Estimated versus achieved maximal oxygen consumption in severely burned children maximal oxygen consumption in burned children.

PURPOSE: In burned children, exercise training increases maximal oxygen consumption (VO2 max) and can be combined with the nonspecific beta-blocker propranolol to decrease cardiac work. VO2 max is estimated if indirect calorimetry is not available. We compared measured and estimated VO2 max in severely burned children treated with or without propranolol to determine the suitability of commonly used formulas in these populations. METHODS: Patients received propranolol or placebo (control) during acute hospitalization. VO2 max was measured during a modified Bruce treadmill test at discharge and compared to values obtained using the Cooper, Bruce, American College of Sports Medicine, and Porro formulas. Pearson correlations and Bland-Altman analyses were used to compare measured and estimated values. RESULTS: Ninety-nine children (propranolol n=46,control n=53) admitted at our facility between 2003 and 2016 were analyzed. Age at burn (propranolol 12±4years, control 12±3years,p=0.893) and total body surface area burned (propranolol 44±15%,control 49±14%,p=0.090) were comparable between groups. Measured VO2 max was higher in the propranolol group (25.5±6.0mL/min/kg vs. 22.0±4.7mL/min/kg,p=0.002) and was generally lower than estimated values. Age, sex, inhalation injury, body mass index, exercise time, and maximal speed were predictive of measured VO2 max in the control group. Age, sex, and maximal speed were predictive in the propranolol group. Backward selection yielded the formula [7.63+ 2.16×sex(females=0,males=1)+0.41×age(years)+0.15×maximal speed(m/min)] (R2=0.6525). CONCLUSIONS: Propranolol seems to have beneficial effects on cardiorespiratory capacity in burned children. However, estimated VO2 max with common formulas were too high. The VO2 max formula reported here is suitable for propranolol-treated children and the Porro formula for non-propranolol-treated children.

Propranolol and Oxandrolone Therapy Accelerated Muscle Recovery in Burned Children.

INTRODUCTION: Severe burns result in prolonged hypermetabolism and skeletal muscle catabolism. Rehabilitative exercise training (RET) programs improved muscle mass and strength in severely burned children. The combination of RET with ß-blockade or testosterone analogs showed improved exercise-induced benefits on body composition and muscle function. However, the effect of RET combined with multiple drug therapy on muscle mass, strength, cardiorespiratory fitness, and protein turnover are unknown. In this placebo-controlled randomized trial, we hypothesize that RET combined with oxandrolone and propranolol (Oxprop) will improve muscle mass and function and protein turnover in severely burned children compared with burned children undergoing the same RET with a placebo. METHODS: We studied 42 severely burned children (7-17 yr) with severe burns over 30% of the total body surface area. Patients were randomized to placebo (22 control) or to Oxprop (20) and began drug administration within 96 h of admission. All patients began RET at hospital discharge as part of their standardized care. Muscle strength (N·m), power (W), V˙O2peak, body composition, and protein fractional synthetic rate and fractional breakdown rate were measured pre-RET (PRE) and post-RET (POST). RESULTS: Muscle strength and power, lean body mass, and V˙O2peak increased with RET in both groups (P < 0.01). The increase in strength and power was significantly greater in Oxprop versus control (P < 0.01), and strength and power was greater in Oxprop over control POST (P < 0.05). Fractional synthetic rate was significantly higher in Oxprop than control POST (P < 0.01), resulting in improved protein net balance POST (P < 0.05). CONCLUSIONS: Rehabilitative exercise training improves body composition, muscle function, and cardiorespiratory fitness in children recovering from severe burns. Oxprop therapy augments RET-mediated improvements in muscle strength, power, and protein turnover.

Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in adult and pediatric burn patients.

BACKGROUND: Burn patients are prone to infections which often necessitate broad antibiotic coverage. Vancomycin is a common antibiotic after burn injury and is administered alone (V), or in combination with imipenem-cilastin (V/IC) or piperacillin-tazobactam (V/PT). Sparse reports indicate that the combination V/PT is associated with increased renal dysfunction. The purpose of this study was to evaluate the short-term impact of the three antibiotic administration types on renal dysfunction. METHODS: All pediatric and adult patients admitted to our centers between 2004 and 2016 with a burn injury were included in this retrospective review if they met the criteria of exposition to either V, V/IC, or V/PT for at least 48 h, had normal baseline creatinine, and no pre-existing renal dysfunction. Creatinine was monitored for 7 days after initial exposure; the absolute and relative increase was calculated, and patient renal outcomes were classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria depending on creatinine increases and estimated creatinine clearance. Secondary endpoints (demographic and clinical data, incidences of septicemia, and renal replacement therapy) were analyzed. Antibiotic doses were modeled in logistic and linear multivariable regression models to predict categorical KDIGO events and relative creatinine increase. RESULTS: Out of 1449 patients who were screened, 718 met the inclusion criteria, 246 were adults, and 472 were children. Between the study cohorts V, V/IC, and V/PT, patient characteristics at admission were comparable. V/PT administration was associated with a statistically higher serum creatinine, and lower creatinine clearance compared to patients receiving V alone or V/IC in adults and children after burn injury. The incidence of KDIGO stages 1, 2, and 3 was higher after V/PT treatment. In children, the incidence of KDIGO stage 3 following administration of V/PT was greater than after V/IC. In adults, the incidence of renal replacement therapy was higher after V/PT compared with V or V/IC. Multivariate modeling demonstrated that V/PT is an independent predictor of renal dysfunction. CONCLUSION: Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in pediatric and adult burn patients when compared to vancomycin alone or vancomycin plus imipenem-cilastin. The mechanism of this increased nephrotoxicity remains elusive and warrants further scientific evaluation.

Correlation Between PaO2/FIO2 and Peripheral Capillary Oxygenation/FIO2 in Burned Children With Smoke Inhalation Injury.

OBJECTIVES: Determine whether the peripheral capillary oxygenation/FIO2 ratio correlates with the PaO2/FIO2 ratio in burned children with smoke inhalation injury, with the goal of understanding if the peripheral capillary oxygenation/FIO2 ratio can serve as a surrogate for the PaO2/FIO2 ratio for the diagnosis of acute respiratory distress syndrome. DESIGN: Retrospective chart review. SETTING: Shriners Hospitals for Children-Galveston. PATIENTS: All burned children with smoke inhalation injury who were admitted from 1996 to 2014 and had simultaneously obtained peripheral capillary oxygenation, FIO2 and PaO2 measurements. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred seventy-three patients (63% male, 8 ± 5 yr, 53% ± 24% total body surface area burns) were analyzed. Peripheral capillary oxygenation/FIO2 ratios were divided into four subgroups based on peripheral capillary oxygenation values (≤ 100%, ≤ 98%, ≤ 95%, and ≤ 92%). Significance was accepted at r greater than 0.81. The r (number of matches) was 0.66 (23,072) for less than or equal to 100%, 0.87 (18,932) for less than or equal to 98%, 0.89 (7,056) for less than or equal to 95%, and 0.93 (4,229) for less than or equal to 92%. In the subgroup of patients who developed acute respiratory distress syndrome, r was 0.65 (8,357) for less than or equal to 100%, 0.89 (7,578) for less than or equal to 98%, 0.89 (4,115) for less than or equal to 95%, and 0.91 (2,288) less than or equal to 92%. CONCLUSIONS: PaO2/FIO2 and peripheral capillary oxygenation/FIO2 strongly correlate in burned children with smoke inhalation injury, with a peripheral capillary oxygenation of less than 92% providing the strongest correlation. Thus, peripheral capillary oxygenation/FIO2 ratio may be able to serve as surrogate for PaO2/FIO2, especially when titrating FIO2 to achieve a peripheral capillary oxygenation of 90-95% (i.e., in the acute respiratory distress syndrome range).

Safety of Nebulized Epinephrine in Smoke Inhalation Injury.

This pilot study was conducted to profile safety of nebulized racemic epinephrine when used as a therapy for smoke inhalation injury in severely burned children. We enrolled 16 patients who were 7 to 19 years of age ([mean ± SD], 12 ± 4 years) with burns covering more than 30% of the TBSA (55 ± 17%) and smoke inhalation injury, as diagnosed by bronchoscopy at burn center admission. Patients were randomized to receive either standard of care (n = 8), which consisted of nebulized acetylcysteine, nebulized heparin, and nebulized albuterol, or to receive standard of care plus nebulized epinephrine (n = 8). Primary endpoints were death, chest pain, and adverse changes in cardiopulmonary hemodynamics (arrhythmia, arterial blood pressure, electrocardiographic [ST segment] changes, and peak inspiratory pressure). Additional endpoints included total days on ventilator, pulmonary function, and physiological cardiopulmonary measurements at intensive care unit discharge. No adverse events were observed during or after the nebulization of epinephrine, and no deaths were reported that were attributable to the administration of nebulized epinephrine. The groups did not significantly differ with regard to age, sex, burn size, days on ventilator, pulmonary function, or cardiopulmonary fitness. Results of this pilot trial indicate epinephrine to be safe when administered to pediatric burn patients with smoke inhalation injury. Current data warrant future efficacy studies with a greater number of patients.

ß-Adrenergic blockade does not impair the skin blood flow sensitivity to local heating in burned and nonburned skin under neutral and hot environments in children.

OBJECTIVE: We tested the hypothesis that propranolol, a drug given to burn patients to reduce hypermetabolism/cardiac stress, may inhibit heat dissipation by changing the sensitivity of skin blood flow (SkBF) to local heating under neutral and hot conditions. METHODS: In a randomized double-blind study, a placebo was given to eight burned children, while propranolol was given to 13 burned children with similar characteristics (mean±SD: 11.9±3 years, 147±20 cm, 45±23 kg, 56±12% Total body surface area burned). Nonburned children (n=13, 11.4±3 years, 152±15 cm, 52±13 kg) served as healthy controls. A progressive local heating protocol characterized SkBF responses in burned and unburned skin and nonburned control skin under the two environmental conditions (23 and 34°C) via laser Doppler flowmetry. RESULTS: Resting SkBF was greater in burned and unburned skin compared to the nonburned control (main effect: skin, P<.0001; 57±32 burned; 38±36 unburned vs 9±8 control %SkBFmax ). No difference was found for maximal SkBF capacity to local heating between groups. Additionally, dose-response curves for the sensitivity of SkBF to local heating were not different among burned or unburned skin, and nonburned control skin (EC50 , P>.05) under either condition. CONCLUSION: Therapeutic propranolol does not negatively affect SkBF under neutral or hot environmental conditions and further compromise temperature regulation in burned children.

Effects of different duration exercise programs in children with severe burns.

INTRODUCTION: Burns lead to persistent and detrimental muscle breakdown and weakness. Standard treatment at our institution includes a voluntary 12-week rehabilitative exercise program to limit and reverse the effects of increased muscle catabolism. In the present work, we investigated if different durations of exercise, 6 or 12 weeks, produce comparable improvements in muscle strength, body composition, and cardiopulmonary fitness. METHODS: We prospectively enrolled and randomized patients with ≥30% total body surface area (TBSA) burned to receive 6 or 12 weeks of exercise rehabilitation. Patients were evaluated for muscle strength, oxygen consumption capacity, and lean body mass at discharge (n=42) and after exercise. After 6 weeks (n=18) or 12 weeks (n=24) of exercise training, leg muscle strength was assessed as peak torque per body weight using a Biodex isokinetic dynamometer. Oxygen consumption capacity, measured as peak VO2, was studied using a standard treadmill-based test, and lean body mass was determined using dual-energy X-ray absorptiometry. RESULTS: Significant improvements in muscle strength, peak VO2, and lean body mass were seen after 6 weeks of exercise training (p<0.001), with only significant improvements in peak VO2 being seen after 6 weeks more of training. CONCLUSION: These data suggest that a 6-week rehabilitative exercise program is sufficient for improving muscle strength, body composition, and cardiopulmonary fitness in pediatric burn patients. However, continuation of at- or near-home cardiopulmonary training following the 6 weeks of at-hospital rehabilitation may be useful.

Functional Exercise Capacity in Children With Electrical Burns.

Electrical burns are a severe form of thermal injury extending deep into tissue. Here, we investigated the effect of electrical burns on metabolic rate, body composition, and aerobic capacity. We prospectively studied a cohort of 24 severely burned children. Twelve patients had a combination of electrical and flame burns and 12 matched controls had only flame burns. Endpoints were cardiopulmonary fitness (maximal oxygen consumption [VO2]), muscle strength (peak torque per body weight), body mass index, lean body mass index, and days of myoglobinemia (≥500 mg/dl). Demographics of both the groups were comparable. The electrical burn group had more days of myoglobinemia during acute hospitalization than the flame burn group (3.6 ± 1.8 days vs 0.3 ± 0.5 days, P < .0001). Maximal VO2 was significantly lower in the electrical burn group than in the flame burn group at intensive care unit discharge (27 ± 6 ml/kg/min vs 34 ± 5 ml/kg/min, P < .0014). Electrical burns are associated with myoglobinemia and decreased cardiopulmonary fitness.

Long-term effects of physical exercise during rehabilitation in patients with severe burns.

BACKGROUND: We have reported that a 12-week exercise program is beneficial for the exercise performance of severely burned children. It is not known, however, whether the beneficial effects remain at 2 years postburn. METHODS: Severely burned children who received no long-term anabolic drugs were consented to this Institutional Review Board-approved study. Patients chose between a voluntary exercise program (EX-group) and no exercise (NoEX-group) after discharge from the acute burn unit. Peak torque per lean leg mass, maximal oxygen consumption, and percent predicted peak heart rate were assessed. In addition, body mass index percentile and lean body mass index were recorded. Both groups were compared for up to 2 years postburn using mixed multiple analysis of variance. RESULTS: A total of 125 patients with a mean age of 12 ± 4 years were analyzed. Demographics between the EX-group (N = 82) and NoEX-group (N = 43) were comparable. In the EX-group, peak torque per lean leg mass, percent predicted peak heart rate, and maximal oxygen consumption increased significantly with exercise (P < .01). Between discharge and 12-24 months, body mass index percentile increased significantly in the EX-Group (P < .05) but did not change in the NoEX-group. There were no significant differences between groups in body mass index percentile, lean body mass index, peak torque per lean leg mass, and maximal oxygen consumption at 24 months postburn. CONCLUSION: Exercise significantly improves the physical performance of burned children. The benefits are limited to early time points, however, and greatly narrow with further recovery time. Continued participation in exercise activities or a maintenance exercise program is recommended for exercise-induced adaptations to continue.

Long-Term Administration of Oxandrolone Improves Lung Function in Pediatric Burned Patients.

Pulmonary dysfunction is a significant contributor to morbidity and mortality in the pediatric burned population. We have previously reported that the administration of a synthetic testosterone derivative, oxandrolone, significantly reduced hypermetabolism, and significantly increased height percentile, bone mineral content, lean body mass, and strength in pediatric burned patients. We hypothesize that the administration of oxandrolone will improve pulmonary function in burned pediatric subjects. A subset of severely burned pediatric subjects from a prospective clinical trial (n = 222) were included in our study (n = 54, 7-18 years, ≥30% TBSA burn). The subjects were previously randomized to either the control arm (n = 35) or the oxandrolone arm (0.1 mg/kg twice/day for 12 months, n = 19). Maximum voluntary ventilation, the ratio between forced expiratory volume and forced vital capacity, and diffusion capacity were measured 6 months following burn injury, and results were compared between burned subjects with and without oxandrolone administration. Maximum expired ventilation (VEmax) was also measured in a subset of burned subjects. Subjects treated with oxandrolone had a significantly higher maximum voluntary ventilation (98 ± 53 L/min vs 115 ± 56 with treatment, P = .03). During maximal exercise, subjects treated with oxandrolone had a significantly higher VEmax compared with untreated subjects (32.0 ± 8.7 L/min vs 43.7 ± 13.6 with treatment, P = .02). The administration of oxandrolone was associated with improved lung function in pediatric burned patients.

Nebulized Epinephrine Limits Pulmonary Vascular Hyperpermeability to Water and Protein in Ovine With Burn and Smoke Inhalation Injury.

OBJECTIVES: To test the hypothesis that nebulized epinephrine ameliorates pulmonary dysfunction by dual action-bronchodilation (ß2-adrenergic receptor agonism) and attenuation of airway hyperemia (α1-adrenergic receptor agonism) with minimal systemic effects. DESIGN: Randomized, controlled, prospective, and large animal translational studies. SETTING: University large animal ICU. SUBJECTS: Twelve chronically instrumented sheep. INTERVENTIONS: The animals were exposed to 40% total body surface area third degree skin flame burn and 48 breaths of cooled cotton smoke inhalation under deep anesthesia and analgesia. The animals were then placed on a mechanical ventilator, fluid resuscitated, and monitored for 48 hours in a conscious state. After the injury, sheep were randomized into two groups: 1) epinephrine, nebulized with 4 mg of epinephrine every 4 hours starting 1 hour post injury, n = 6; or 2) saline, nebulized with saline in the same manner, n = 6. MEASUREMENTS AND MAIN RESULTS: Treatment with epinephrine had a significant reduction of the pulmonary transvascular fluid flux to water (p < 0.001) and protein (p < 0.05) when compared with saline treatment from 12 to 48 hours and 36 to 48 hours, respectively. Treatment with epinephrine also reduced the systemic accumulation of body fluids (p < 0.001) with a mean of 1,410 ± 560 mL at 48 hours compared with 3,284 ± 422 mL of the saline group. Hemoglobin levels were comparable between the groups. Changes in respiratory system dynamic compliance, mean airway pressure, PaO2/FiO2 ratio, and oxygenation index were also attenuated with epinephrine treatment. No considerable systemic effects were observed with epinephrine treatment. CONCLUSIONS: Nebulized epinephrine should be considered for use in future clinical studies of patients with burns and smoke inhalation injury.

A Survey of Mechanical Ventilator Practices Across Burn Centers in North America.

Burn injury introduces unique clinical challenges that make it difficult to extrapolate mechanical ventilator (MV) practices designed for the management of general critical care patients to the burn population. We hypothesize that no consensus exists among North American burn centers with regard to optimal ventilator practices. The purpose of this study is to examine various MV practice patterns in the burn population and to identify potential opportunities for future research. A researcher designed, 24-item survey was sent electronically to 129 burn centers. The χ, Fisher's exact, and Cochran-Mantel-Haenszel tests were used to determine if there were significant differences in practice patterns. We analyzed 46 questionnaires for a 36% response rate. More than 95% of the burn centers reported greater than 100 annual admissions. Pressure support and volume assist control were the most common initial MV modes used with or without inhalation injury. In the setting of Berlin defined mild acute respiratory distress syndrome (ARDS), ARDSNet protocol and optimal positive end-expiratory pressure were the top ventilator choices, along with fluid restriction/diuresis as a nonventilator adjunct. For severe ARDS, airway pressure release ventilation and neuromuscular blockade were the most popular. The most frequently reported time frame for mechanical ventilation before tracheostomy was 2 weeks (25 of 45, 55%); however, all respondents reported in the affirmative that there are certain clinical situations where early tracheostomy is warranted. Wide variations in clinical practice exist among North American burn centers. No single ventilator mode or adjunct prevails in the management of burn patients regardless of pulmonary insult. Movement toward American Burn Association-supported, multicenter studies to determine best practices and guidelines for ventilator management in burn patients is prudent in light of these findings.

FIVE-YEAR OUTCOMES AFTER LONG-TERM OXANDROLONE ADMINISTRATION IN SEVERELY BURNED CHILDREN: A RANDOMIZED CLINICAL TRIAL.

Administration of oxandrolone, a nonaromatizable testosterone analog, to children for 12 months following severe burn injury has been shown to improve height, increase bone mineral content (BMC), reduce cardiac work, and augment muscle strength. Surprisingly, the increase in BMC persists well beyond the period of oxandrolone administration. This study was undertaken to determine if administration of oxandrolone for 2 years yields greater effects on long-term BMC and bone mineral density (BMD). Patients between 0 and 18 years of age with ≥30% of total body surface area burned were consented to an IRB-approved protocol and randomized to receive either placebo (n = 84) or 0.1 mg/kg oxandrolone orally twice daily for 24 months (n = 35). Patients were followed prospectively from the time of admission until 5 years postburn in a single-center, intent-to-treat setting. Height, weight, BMC, and BMD were recorded annually through 5 years postinjury. The long-term administration of oxandrolone for 16 ± 1 months postburn (range, 12.1-25.2 months) significantly increased whole-body (WB) BMC (p < 0.02) and lumbar spine (LS) BMC (p < 0.05); these effects were significantly pronounced for a longer time in patients who were in growth spurt years (7-18 years). When adjusted for height, sex, and age, LS BMD was found to significantly increase with long-term oxandrolone administration (p < 0.0009). Fewer patients receiving oxandrolone exhibited LS BMD z scores below -2.0 as compared with controls, indicating a significantly reduced risk for future fracture with oxandrolone administration. Long-term oxandrolone patients had significantly greater height velocity than controls throughout the first 2-year postburn (p < 0.05). No adverse side effects were attributed to the long-term administration of oxandrolone. A comparison of the current patients receiving long-term oxandrolone to previously described patients receiving 12 months of oxandrolone revealed that long-term oxandrolone administration imparted significantly greater increases in WB-BMC, WB-BMD, and LS-BMD (p < 0.05). In conclusion, the administration of oxandrolone for up to 24 months to severely burned pediatric patients significantly improves WB BMC, LS BMC, LS BMD, and height velocity. The administration of long-term oxandrolone was more efficacious than administration for 12 months. Additionally, fewer patients in the oxandrolone cohort met the diagnostic criteria for pediatric osteoporosis, pointing to a reduced risk for future bone fracture. This study demonstrates that administering oxandrolone for up to 2 years following severe burn injury results in greater improvements in BMC, BMD, and height velocity.

High tidal volume decreases adult respiratory distress syndrome, atelectasis, and ventilator days compared with low tidal volume in pediatric burned patients with inhalation injury.

BACKGROUND: Inhalation injury, which is among the causes of acute lung injury and acute respiratory distress syndrome (ARDS), continues to represent a significant source of mortality in burned patients. Inhalation injury often requires mechanical ventilation, but the ideal tidal volume strategy is not clearly defined in burned pediatric patients. The aim of this study was to determine the effects of low and high tidal volume on the number of ventilator days, ventilation pressures, and incidence of atelectasis, pneumonia, and ARDS in pediatric burned patients with inhalation injury within 1 year post burn injury. METHODS: From 1986 to 2014, inhalation injury was diagnosed by bronchoscopy in pediatric burned patients (n = 932). Patients were divided into 3 groups: unventilated (n = 241), high tidal volume (HTV, 15 ± 3 mL/kg, n = 190), and low tidal volume (LTV, 9 ± 3 mL/kg, n = 501). RESULTS: High tidal volume was associated with significantly decreased ventilator days (p < 0.005) and maximum positive end expiratory pressure (p < 0.0001) and significantly increased maximum peak inspiratory pressure (p < 0.02) and plateau pressure (p < 0.02) compared with those in patients with LTV. The incidence of atelectasis (p < 0.0001) and ARDS (p < 0.02) was significantly decreased with HTV compared with LTV. However, the incidence of pneumothorax was significantly increased in the HTV group compared with the LTV group (p < 0.03). CONCLUSIONS: High tidal volume significantly decreases ventilator days and the incidence of both atelectasis and ARDS compared with low tidal volume in pediatric burned patients with inhalation injury. Therefore, the use of HTV may interrupt sequences leading to lung injury in our patient population.

Pulmonary histopathologic abnormalities and predictor variables in autopsies of burned pediatric patients.

UNLABELLED: Pulmonary abnormalities occur in 30-80% of fatalities after burn. The objective of our study is to investigate lung pathology in autopsy tissues of pediatric burn patients. METHODS: Three scientists with pathology training in pediatric burn care reviewed masked autopsy slides of burned children who died after admission to a burn center from 2002 to 2012 (n=43). Autopsy lung tissue was assigned scores for histologic abnormalities in 9 categories, including alveolar and interstitial fibrosis, hyaline membranes, and type II epithelial cell proliferation. Scores were then tested for correlation with age, TBSA burn, number of days between burn and death, time between burn and admission, and the presence of inhalation injury using analyses with linear models. RESULTS: Type II epithelial cell proliferation was significantly more common in cases with a longer time between burn and admission (p<0.02). Interstitial fibrosis was significantly more severe in cases with longer survival after burn (p<0.01). The scores for protein were significantly higher in cases with longer survival after burn (p<0.03). Enlarged air spaces were significantly more prominent in cases with longer survival after burn (p<0.01), and in cases with the presence of inhalation injury (p<0.01). CONCLUSIONS: Histological findings associated with diffuse alveolar damage (DAD), which is the pathological correlate of the acute respiratory distress syndrome (ARDS), were seen in approximately 42% of autopsies studied. Protein-rich alveolar edema, which is the abnormality that leads to ARDS, may occur from multiple causes, including inhalation injury.

Influence of inhalation injury on energy expenditure in severely burned children.

OBJECTIVE: Determine the effect of inhalation injury on burn-induced hypermetabolism in children. DESIGN: Prospective study comparing hypermetabolism (i.e., resting energy expenditure and oxygen consumption) in burned children with and without inhalation injury during acute hospitalization. SETTING: Single pediatric burn center. PATIENTS: Eighty-six children (1-18 years) with ≥40% total body surface area burns were stratified to two groups: no inhalation injury and inhalation injury. INTERVENTIONS: None. MAIN MEASUREMENTS AND RESULTS: Inhalation injury was diagnosed based on bronchoscopic evaluation. At admission, PaO2:FiO2 ratios (an index of respiratory distress) were significantly higher in patients with no inhalation injury than in patients with inhalation injury. No differences were detected in resting energy expenditure or percent of the predicted basal metabolic rate between groups. Additionally, oxygen consumption did not significantly differ between groups. CONCLUSIONS: Inhalation injury does not augment the burn-induced hypermetabolic stress response in children, as reflected by resting energy expenditure and oxygen consumption.

Impact of stress-induced diabetes on outcomes in severely burned children.

BACKGROUND: Post-burn hyperglycemia leads to graft failure, multiple organ failure, and death. A hyperinsulinemic-euglycemic clamp is used to keep serum glucose between 60 and 110 mg/dL. Because of frequent hypoglycemic episodes, a less-stringent sliding scale insulin protocol is used to maintain serum glucose levels between 80 and 160 mg/dL after elevations >180 mg/dL. STUDY DESIGN: We randomized pediatric patients with massive burns into 2 groups, patients receiving sliding scale insulin to lower blood glucose levels (n = 145) and those receiving no insulin (n = 98), to determine the differences in morbidity and mortality. Patients 0 to 18 years old with burns covering ≥ 30% of the total body surface area and not randomized to receive anabolic agents were included in this study. End points included glucose levels, infections, resting energy expenditure, lean body mass, bone mineral content, fat mass, muscle strength, and serum inflammatory cytokines, hormones, and liver enzymes. RESULTS: Maximal glucose levels occurred within 6 days of burn injury. Blood glucose levels were age dependent, with older children requiring more insulin (p < 0.05). Daily maximum and daily minimum, but not 6 am, glucose levels were significantly different based on treatment group (p < 0.05). Insulin significantly increased resting energy expenditure and improved bone mineral content (p < 0.05). Each additional wound infection increased incidence of hyperglycemia (p = 0.004). There was no mortality in patients not receiving insulin, only in patients who received insulin (p < 0.004). Muscle strength was increased in patients receiving insulin (p < 0.05). CONCLUSIONS: Burn-induced hyperglycemia develops in a subset of severely burned children. Length of stay was reduced in the no insulin group, and there were no deaths in this group. Administration of insulin positively impacted bone mineral content and muscle strength, but increased resting energy expenditure, hypoglycemic episodes, and mortality. New glucose-lowering strategies might be needed.