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Background The catecholamine-mediated hypermetabolic response to severe burns causes increased energy expenditure and muscle-protein catabolism. We hypothesized that blockade of
Methods Twenty-five children with acute and severe burns (more than 40 percent of total body-surface area) were studied in a randomized trial. Thirteen received oral propranolol for at least two weeks, and 12 served as untreated controls. The dose of propranolol was adjusted to decrease the resting heart rate by 20 percent from each patient's base-line value. Resting energy expenditure and skeletal-muscle protein kinetics were measured before and after two weeks of beta-blockade (or no therapy, in controls). Body composition was measured serially throughout hospitalization.
Results Patients in the control group and the propranolol group were similar with respect to age, weight, percentage of total body-surface area burned, percentage of body-surface area with third-degree burns, and length of time from injury to metabolic study. Beta-blockade decreased the heart rates and resting energy expenditure in the propranolol group, both as compared with the base-line values (P<0.001 and P=0.01, respectively) and as compared with the values in the control group (P=0.03 and P=0.001, respectively). The net muscle-protein balance increased by 82 percent over base-line values in the propranolol group (P=0.002), whereas it decreased by 27 percent in the control group (P not significant). The fat-free mass, as measured by whole-body potassium scanning, did not change substantially in the propranolol group, whereas it decreased by a mean (±SE) of 9±2 percent in the control group (P=0.003).
Conclusions In children with burns, treatment with propranolol during hospitalization attenuates hypermetabolism and reverses muscle-protein catabolism.
-adrenergic stimulation with propranolol would decrease resting energy expenditure and muscle catabolism in patients with severe burns.
Endogenous catecholamines are primary mediators of the hypermetabolic response to trauma or burns.5,6 Shortly after severe trauma or burns, plasma catecholamine levels increase as much as 10-fold.7,8 This systemic response to injury is characterized by the development of a hyperdynamic circulation9 and an increase in basal energy expenditure10 and catabolism of skeletal-muscle protein.3,11 Blockade of -adrenergic stimulation after severe burns decreases supraphysiologic thermogenesis,12 tachycardia,13 cardiac work,14 and resting energy expenditure.15 Decreased rates of cardiac complications and overall mortality have been documented in patients without trauma who are given beta-blockers for the control of tachycardia after major surgical procedures.16 After burns, the elevations in basal energy expenditure and muscle-protein catabolism have been found to be correlated.17 Because beta-blockade decreases energy expenditure after burns,6,13 we hypothesized that long-term beta-blockade with propranolol would decrease the rate of muscle-protein catabolism as well.
Methods
Subjects
This study was approved by the institutional review board of the University of Texas Medical Branch, and written informed consent was obtained from each patient's parent or guardian. Children could be enrolled if they were less than 18 years of age, had burns on more than 40 percent of their total body-surface area, and had been transferred to our hospital within one week after injury. Patients with a history of asthma were excluded.
Within 48 hours after admission, each patient underwent burn-wound excision and grafting with skin autografts and allografts. The patients returned to the operating room in 6 to 10 days, when the autograft sites had healed. Sequential staged grafting procedures were performed until the wounds were closed.
The patients were fed a commercial enteral formula (Vivonex T.E.N., Sandoz Nutritional, Minneapolis) through a nasoduodenal tube. The daily caloric intake was calculated to deliver 1500 kcal per square meter of body-surface area burned plus another 1500 kcal per square meter of total body-surface area. Enteral nutrition was started at admission and continued until the wounds healed. The patients remained in bed for five days after excision and grafting procedures, after which they were allowed to walk daily until the next excision-and-grafting procedure.
Study Design
From January through December 1999, 25 patients were enrolled in this prospective, randomized trial. Thirteen received propranolol, and 12 served as untreated controls. Randomization was performed with use of a random-number–generating scheme.
On the fifth day after the first surgical procedure, all patients underwent metabolic examination. Resting energy expenditure and net protein balance across one of the patient's legs (randomly determined) were the main outcome variables. In addition, all patients underwent whole-body potassium scanning at base line to determine the fat-free mass. Immediately after the next operation, the patients in the propranolol group began to receive propranolol by nasogastric tube at a dose of 0.33 mg per kilogram of body weight every four hours (total dose, 1.98 mg per kilogram per day). This dose was adjusted to achieve a 20 percent decrease in the heart rate of each patient, as compared with the 24-hour average heart rate immediately before drug treatment. Heart rate and blood pressure were monitored continuously throughout the study. When the mean blood pressure fell below 65 mm Hg, the dose of propranolol was withheld or decreased. The dose was then increased incrementally to meet the study goal of a decrease in heart rate by 20 percent from established base-line levels as tolerated. Propranolol was given as scheduled during surgical procedures.
Two weeks after treatment was started, a second series of metabolic and protein-kinetics studies was performed. Patients who had received at least a four-week treatment course underwent a second measurement of whole-body potassium. At discharge, the patients underwent body-composition scanning with use of dual-image x-ray absorptiometry.
Measurement of Vital Signs
Temperature, heart rate, and systolic and diastolic blood pressure were measured hourly with use of a standard bladder-temperature monitor, electrocardiographic monitor, and arterial catheter, respectively. The average for each 24-hour period was determined. The heart rate was compared between groups for the duration of the study. Other analyses of changes with treatment were made between groups with data gathered on the day of the stable-isotope study.
Measurement of Serum Glucose, Potassium, and Hormone Values
Serum levels of glucose and potassium were determined (Stat-5 analyzer, Novel Biomedical, Waltham, Mass.) on the morning of the stable-isotope studies. On the same morning, serum levels of insulin-like growth factor I were determined by ethanol extraction, and serum levels of growth hormone, cortisol, and insulin were determined by enzyme-linked immunosorbent assay or enzyme immunoassay (Diagnostic Systems Laboratories, Webster, Tex.).
Determination of Infections and Energy Expenditure
Infection was defined throughout hospitalization by the presence of burn sepsis, which we have previously described.17 Between midnight and 5 a.m. on the day of the stable-isotope study, oxygen consumption, carbon dioxide production, the respiratory quotient, and the resting energy expenditure were determined with use of a metabolic cart (model 2900, Sensormedics, Yorba Linda, Calif.) at an ambient temperature of 30°C during continuous feeding.
Kinetics Study
On the fifth day after the first and third operations, all patients underwent a five-hour protein-kinetics study, as previously described,18 while receiving a continuous feeding. Briefly, an infusion of L-[ring-2H5]phenylalanine (Cambridge Isotopes, Andover, Mass.) was given intravenously for five hours: the initial, or priming, dose was 2 µmol per kilogram and was followed by a dose of 0.08 µmol per kilogram per minute. Biopsy of the vastus lateralis muscle of the study leg was performed two and five hours after the commencement of the infusion. To determine blood flow in the leg, indocyanine green was infused into the femoral artery. Cross-leg amino-acid kinetics were calculated according to a three-compartment model described by Biolo et al.18
The blood levels of unlabeled phenylalanine and its isotopic counterpart were simultaneously determined by gas chromatography–mass spectrometry with the use of the internal-standard approach and N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide, as previously described.19 Levels of indocyanine green were determined spectrophotometrically at a wavelength of 805 nm (Spectronic 1001, Bausch and Lomb, Rochester, N.Y.).
Muscle samples were stored at –70°C. Each sample was weighed, and protein was precipitated out with 5 percent perchloric acid solution. An internal standard containing 5.9 µmol of L-[ring-13C6]phenylalanine per liter was added and thoroughly mixed. The level of bound-protein precipitate was determined by comparison with a set of isotopically labeled phenylalanine dilution-calibration standards, with correction for the various weights of the labeled compounds.18
We calculated the fractional rate of synthesis of skeletal-muscle protein by determining the rate of incorporation of labeled phenylalanine into protein and then measuring the level of bound protein in the intracellular pool, as previously described.19
Determination of Body Composition
The fat-free mass was determined by whole-body potassium-40 scintillation counting in a heavily shielded counting room with a low level of background noise, a 32NaI detector array, and a computed data-analysis method that has been validated for use in children.20,21 The counting precision of the instrument used is within less than 1.5 percent, and it was calibrated daily by using a bottle-manikin absorption phantom (Canberra Industries, Meriden, Conn.) with simulated fat overlays. Feeding and intravenous fluids were discontinued during the studies to minimize exogenous potassium contamination.
The total-body lean mass and fat mass were measured with use of a dual-image x-ray absorptiometer (model QDR-4500W, Hologic, Waltham, Mass.) with a pediatric software package. This system has a minimal mean error rate with respect to the measurement of fat-free mass in children.22 To minimize systematic deviations, the system was calibrated daily against a spinal phantom (Hologic) in the anteroposterior, lateral, and single-beam modes for quality control of the measurements.
Statistical Analysis
Data are presented as means ±SE. The distribution of the data was normal, and the degree of variation within individual subjects was similar. We did not control for differences between the groups in sex, age, or weight. Two-sided paired t-tests were used to compare data within groups. Comparisons between groups were made by unpaired t-tests. Fisher's exact test was used for frequency data. P values of less than 0.05 were considered to indicate statistical significance.
Results
The characteristics of the patients are shown in Table 1. One of the 25 patients chose not to participate in the stable-isotope studies. Three patients (two in the control group and one in the propranolol group) were fully healed and discharged before receiving four weeks of treatment. These subjects did not undergo a second whole-body potassium-counting study.
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Concurrently with the decline in energy expenditure, beta-blockade also improved the kinetics of skeletal-muscle protein. Treatment with propranolol improved the net muscle-protein balance as compared with base-line values (P=0.002) and with values in the control group (P=0.001) (Figure 2). The remainder of the model-derived values for the studies comparing the propranolol group with the control group are listed in Table 3. In one of the studies in one patient, a steady state (in which the ratio of unlabeled to labeled phenylalanine was 1) was not reached, and thus this study was not included in the analysis. As a result of an increase in the efficiency of protein synthesis, there was an increase in protein synthesis, as measured by the rate of incorporation of the tracer into muscle over time, with long-term beta-blockade.
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Discussion
During catabolism, muscle protein is degraded faster than it is synthesized, resulting in a negative net protein balance. We used stable-isotope methods and serial body-composition scanning to determine that beta-blockade with propranolol diminishes wasting of skeletal-muscle protein after severe burns. Thirteen severely burned children were given propranolol for up to four weeks and had a decrease in resting energy expenditure, without any adverse effects. Twelve of these patients had an improvement in net muscle-protein balance. Beta-blockade given over a period of weeks after severe burn led to an increase in lean body mass.
Catecholamines are the primary mediators of elevated energy expenditure after burns.5,6,15 Both direct5,6 and indirect15 calorimetry have been used to demonstrate that energy expenditure is decreased by beta-blockade after severe burns. Other studies have also demonstrated that urinary nitrogen losses23 and whole-body urea production24 are decreased by beta-blockade. Interestingly, -agonists have been shown to stimulate muscle-protein synthesis in unstressed animals,25,26 although the relevance of such animal models to the physiological state of critically ill patients is unclear.
The net balance of protein synthesis and breakdown achieved anabolic levels during treatment with propranolol. Propranolol has a greater anabolic effect on muscle than other agents that have been evaluated in burn victims by methods similar to ours.27,28,29
To corroborate the results of our stable-isotope measurements, we used two independent body-composition tests. Fat-free mass, which corresponds to the sum of lean mass and bone mass, was measured by whole-body potassium scanning before and after four weeks of treatment. In the propranolol group, fat-free mass was preserved (the change was statistically no different from zero). In comparison, 10 control patients lost 9 percent of their fat-free mass over this period. These results were confirmed by the results of dual-image x-ray absorptiometry, performed at the time of discharge in 16 patients.
Data derived from our stable-isotope studies provide insight into the physiological changes induced by beta-blockade at the tissue level. We found an acceleration in the rate of protein synthesis in the propranolol-treated patients. The post-traumatic increase in proteolysis is primarily the result of a large increase in protein degradation, which outweighs the increase in total protein synthesis.27,30,31 We found that propranolol induced an increase in the intracellular recycling of free amino acids. In the process of substrate reuse, free intracellular amino acids derived from stimulated protein breakdown were incorporated back into bound protein without leaving the myocyte.
Each of the methods we used to measure changes has limitations. For instance, we used labeled phenylalanine as the only tracer in the stable-isotope studies, assuming that since phenylalanine is neither synthesized nor degraded in the leg, any changes in the net balance reflect the total protein balance. This assumption has been verified in normal subjects but not in stressed, hypermetabolic subjects.32 Whole-body potassium scanning is based on the assumption that the ratios of potassium to nitrogen in skeletal muscle and nonskeletal muscle are constant. Wang et al. showed that this method may underestimate total lean body mass during conditions of muscle wasting.33 A limitation of dual-image x-ray absorptiometry is that it overestimates lean body mass in patients with edema. However, all three methods demonstrated significant improvements in lean body mass with propranolol treatment, despite the different assumptions and shortcomings of each method, thus supporting the conclusion that propranolol treatment improves the accretion of lean body mass in severely burned children.
Any pharmacotherapy carries risks. Given carelessly, propranolol could cause hypoperfusion as a result of decreased cardiac output, particularly in patients with sepsis. In patients with other conditions, it could induce severe bronchospasm.
We had a specific therapeutic goal of decreasing the heart rate by 20 percent, a decrease that we have previously shown to be safe.12,13,14 The patients underwent continuous hemodynamic and respiratory monitoring, and there were no complications related to therapy. We found no significant decrease in blood pressure with propranolol treatment at these doses. However, propranolol was withheld temporarily from 3 of the 13 patients at some time during therapy because of a low mean arterial pressure, which indicates that patients receiving this treatment should be closely monitored. We have previously shown that propranolol treatment does not reduce the ability of patients with burns to respond to cold-induced stress.34
We can only speculate on the possible mechanisms underlying the changes associated with propranolol treatment. Decreased catecholamine activity caused by beta-blockade could have direct effects on protein-flux machinery or could act indirectly by changing endogenous insulin responsiveness, cortisol activity, or regional blood flow. Larger studies will be required to make such determinations.
In summary, we have used indirect calorimetry, stable-isotope methods, whole-body potassium scanning, and dual-image x-ray absorptiometry to show that long-term beta-blockade decreases lean-mass catabolism in severely burned children. These changes would presumably improve the patients' strength and ability to recuperate. When it is given in doses that decrease the heart rate by approximately 20 percent from the base-line values and with careful monitoring, propranolol is safe, easily administered, and effective. This therapy may benefit a wide variety of patients who may have a negative nitrogen balance, such as those with trauma and those who are undergoing general surgery.
Supported by grants from Shriners Hospitals for Children (8660 and 8490) and the National Institutes of Health (2T32GM0825611, 1P50GM60338-01, GM56687-02, and MO1 RR 00073).
Presented at the 30th annual meeting of the Western Trauma Association, Squaw Valley, Calif., February 27–March 4, 2000.
We are indebted to Deb Benjamin, Gordon Klein, M.D., and Martin Esch, Ph.D., for assistance in the performance of this study.
Source Information
From the Department of Surgery, University of Texas Medical Branch, Shriners Hospitals for Children, Galveston.
Address reprint requests to Dr. Herndon at Shriners Hospitals for Children, 815 Market St., Galveston, TX 77550, or at dherndon{at}utmb.edu.
References
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