Noe A. Rodriguez

Long-term propranolol use in severely burned pediatric patients: A randomized controlled study

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. Background:Severe burns trigger a hypermetabolic response that persists for up to 2 years postburn. Propranolol given for 1 month postburn 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 more than 30% total body surface area burns were randomized to control (n = 89) or 4 mg/kg/d propranolol (n = 90) for 12 months postburn. 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 adjusted for non-normality, repeated-measures, and regression analyses. P < 0.05 was considered significant. Results:Long-term propranolol treatment significantly reduced the percentage of the predicted heart rate and percentage 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 after thermal injury, ameliorates the hyperdynamic, hypermetabolic, hypercatabolic, and osteopenic responses in pediatric patients. This study is registered at clinicaltrials.gov: NCT00675714.

Five-Year Outcomes after Oxandrolone Administration in Severely Burned Children: A Randomized Clinical Trial of Safety and Efficacy

BACKGROUND Oxandrolone, an anabolic agent, has been administered for 1 year post burn with beneficial effects in pediatric patients. However, the long-lasting effects of this treatment have not been studied. This single-center prospective trial determined the long-term effects of 1 year of oxandrolone administration in severely burned children; assessments were continued for up to 4 years post therapy. STUDY DESIGN Patients 0 to 18 years old with burns covering >30% of the total body surface area were randomized to receive placebo (n = 152) or oxandrolone, 0.1 mg/kg twice daily for 12 months (n = 70). At hospital discharge, patients were randomized to a 12-week exercise program or to standard of care. Resting energy expenditure, standing height, weight, lean body mass, muscle strength, bone mineral content (BMC), cardiac work, rate pressure product, sexual maturation, and concentrations of serum inflammatory cytokines, hormones, and liver enzymes were monitored. RESULTS Oxandrolone substantially decreased resting energy expenditure and rate pressure product, increased insulin-like growth factor-1 secretion during the first year after burn injury, and, in combination with exercise, increased lean body mass and muscle strength considerably. Oxandrolone-treated children exhibited improved height percentile and BMC content compared with controls. The maximal effect of oxandrolone was found in children aged 7 to 18 years. No deleterious side effects were attributed to long-term administration. CONCLUSIONS Administration of oxandrolone improves long-term recovery of severely burned children in height, BMC, cardiac work, and muscle strength; the increase in BMC is likely to occur by means of insulin-like growth factor-1. These benefits persist for up to 5 years post burn.

The Effect of Ketoconazole on Post-Burn Inflammation, Hypermetabolism and Clinical Outcomes

Background Hypercortisolemia has been suggested as a primary hormonal mediator of whole-body catabolism following severe burn injury. Ketoconazole, an anti-fungal agent, inhibits cortisol synthesis. We, therefore, studied the effect of ketoconazole on post-burn cortisol levels and the hyper-catabolic response in a prospective randomized trial (block randomization 2∶1). Methodology/Principal Findings Fifty-five severely burned pediatric patients with >30% total body surface area (TBSA) burns were enrolled in this trial. Patients were randomized to receive standard care plus either placebo (controls, n = 38) or ketoconazole (n = 23). Demographics, clinical data, serum hormone levels, serum cytokine expression profiles, organ function, hypermetabolism measures, muscle protein synthesis, incidence of wound infection sepsis, and body composition were obtained throughout the acute hospital course. Statistical analysis was performed using Fisher’s exact test, Student’s t-test, and parametric and non-parametric two-way repeated measures analysis of variance where applicable. Patients were similar in demographics, age, and TBSA burned. Ketoconazole effectively blocked cortisol production, as indicated by normalization of the 8-fold elevation in urine cortisol levels [F(1, 376) = 85.34, p<.001] with the initiation of treatment. However, there were no significant differences in the inflammatory response, acute-phase proteins, body composition, muscle protein breakdown or synthesis, or organ function between groups. Conclusions Both groups were markedly hypermetabolic and catabolic throughout the acute hospital stay. Normalization of hypercortisolemia with ketoconazole therapy had no effect on whole-body catabolism or the post-burn inflammatory or hypermetabolic response, suggesting that hypercortisolemia does not play a central role in the post-burn hypermetabolic catabolic response. Trial Registration ClinicalTrials.gov NCT00675714; and NCT00673309

Measurement of precursor enrichment for calculating intramuscular triglyceride fractional synthetic rate

Our goal was to assess the validity of the enrichments of plasma free palmitate and intramuscular (IM) fatty acid metabolites as precursors for calculating the IM triglyceride fractional synthetic rate. We infused U-13C16-palmitate in anesthetized rabbits for 3 h and sampled adductor muscle of legs using both freeze-cut and cut-freeze approaches. We found that IM free palmitate enrichment (0.70 ± 0.07%) was lower (P < 0.0001) than IM palmitoyl-CoA enrichment (2.13 ± 0.17%) in samples taken by the freeze-cut approach. The latter was close (P = 0.33) to IM palmitoyl-carnitine enrichment (2.42 ± 0.16%). The same results were obtained from the muscle samples taken by the cut-freeze approach, except the enrichment of palmitoyl-CoA (2.21 ± 0.08%) was lower (P = 0.02) than that of palmitoyl-carnitine (2.77 ± 0.17%). Plasma free palmitate enrichment was ∼2-fold that of IM palmitoyl-CoA enrichment and palmitoyl-carnitine enrichment (P < 0.001). These findings indicate that plasma free palmitate overestimated IM precursor enrichment owing to in vivo IM lipid breakdown, whereas IM free palmitate enrichment underestimated the precursor enrichment because of lipid breakdown during muscle sampling and processing. IM palmitoyl-carnitine enrichment was an acceptable surrogate of the precursor enrichment because it was less affected by in vitro lipid breakdown after sampling.

Anatomic predisposition to ligamentous lisfranc injury: A matched case-control study

BACKGROUND Subtle, or ligamentous, Lisfranc injuries occur following low-energy trauma to the midfoot and can be debilitating. Since they are ligamentous, they may not heal, requiring arthrodesis in some cases. Certain mortise anatomic characteristics on radiographs have been shown to be associated with a predisposition to the ligamentous subtype of Lisfranc injuries. It is not known whether there are other morphometric characteristics, such as arch height or the relative length of the second metatarsal, that can similarly influence the predisposition to these injuries. METHODS The present retrospective matched case-control study involved fifty-two control subjects and twenty-six patients with ligamentous Lisfranc injuries treated from 2006 to 2010 at two institutions. Clinical and radiographic data (second metatarsal length relative to foot length, first intermetatarsal angle, navicular-cuboid overlap relative to cuboid vertical height, first metatarsal-talus angle, and calcaneal pitch angle) were examined for the existence of significant differences between control and Lisfranc subjects. Logistic regression analysis was then performed to evaluate potential risk for injury on the basis of these anatomic variables. RESULTS Compared with matched controls, patients with a ligamentous Lisfranc injury were found to have a significantly smaller ratio of second metatarsal length to foot length (p < 0.001) on weight-bearing radiographs. CONCLUSIONS Occurrence of a ligamentous Lisfranc injury was shown to be associated with a smaller ratio of second metatarsal length to foot length; >50% of patients in the injury group had a ratio of <29%.

Acute hyperinsulinemia and reduced plasma free fatty acid levels decrease intramuscular triglyceride synthesis

OBJECTIVE To investigate the effect of acute hyperinsulinemia and the resulting decrease in plasma free fatty acid (FFA) concentrations on intramuscular TG synthesis. MATERIALS/METHODS U-(13)C(16)-palmitate was infused for 3 h in anesthetized rabbits after overnight food deprivation. Arterial blood and leg muscle were sampled during the tracer infusion. Plasma samples were analyzed for free and TG-bound palmitate enrichments and concentrations. The enrichments and concentrations of palmitoyl-CoA and palmitoyl-carnitine as well as the enrichment of palmitate bound to TG were measured in muscle samples. Fractional synthetic rate (FSR) of intramuscular TG was calculated using the tracer incorporation method. The rabbits were divided into a control group and a hyperinsulinemic euglycemic clamp group. Insulin infusion decreased the rate of appearance of plasma free palmitate (2.00±0.15 vs 0.68±0.20 μmol⋅kg(-1)⋅min(-1); P<.001), decreased plasma FFA concentration (327±61 vs 72±25 nmol/mL; P<.01), decreased the total concentration of intramuscular fatty acyl-CoA plus fatty acyl-carnitine (12.1±1.6 vs 7.0±0.7 nmol/g; P<.05), and decreased intramuscular TG FSR (0.48±0.05 vs 0.21±0.06%/h; P<.01) in comparison with the control group. Intramuscular TG FSR was correlated (P<.01) with both plasma FFA concentrations and intramuscular fatty acyl-CoA concentrations. CONCLUSIONS Fatty acid availability is a determinant of intramuscular TG synthesis. Insulin infusion decreases plasma and intramuscular fatty acid availability and thereby decreases TG synthesis.

Triglycerides produced in the livers of fasting rabbits are predominantly stored as opposed to secreted into the plasma

OBJECTIVE The liver plays a central role in regulating fat metabolism; however, it is not clear how the liver distributes the synthesized triglycerides (TGs) to storage and to the plasma. MATERIALS AND METHODS We have measured the relative distribution of TGs produced in the liver to storage and the plasma by means of U-(13)C(16)-palmitate infusion in anesthetized rabbits after an overnight fast. RESULTS The fractional synthesis rates of TGs stored in the liver and secreted into the plasma were not significantly different (stored vs. secreted: 31.9 ± 0.8 vs. 27.7 ± 2.6%∙h(-1), p > 0.05). However, the absolute synthesis rates of hepatic stored and secreted TGs were 543 ± 158 and 27 ± 7 nmol∙kg(-1)∙min(-1) respectively, indicating that in fasting rabbits the TGs produced in the liver were predominately stored (92 ± 3%) rather than secreted (8 ± 3%) into the plasma. This large difference was mainly due to the larger pool size of the hepatic TGs which was 21 ± 9-fold that of plasma TGs. Plasma free fatty acids (FFAs) contributed 47 ± 1% of the FA precursor for hepatic TG synthesis, and the remaining 53 ± 1% was derived from hepatic lipid breakdown and possibly plasma TGs depending on the activity of hepatic lipase. Plasma palmitate concentration significantly correlated with hepatic palmitoyl-CoA and TG synthesis. CONCLUSION In rabbits, after an overnight fast, the absolute synthesis rate of hepatic stored TGs was significantly higher than that of secreted due to the larger pool size of hepatic TGs. The net synthesis rate of TG was approximately half the absolute rate. Plasma FFA is a major determinant of hepatic TG synthesis, and therefore hepatic TG storage.