Lyle D. Broemeling

Effects of Recombinant Human Growth Hormone on Donor-site Healing in Severely Burned Children

The beneficial effects of growth hormone on wound healing in severely burned children were studied. Forty patients who were 2 to 18 years old, with 40% or more total body surface area (TBSA) and 20% or more TBSA full-thickness flame or scald burns, were randomized in a double-blind study to receive placebo or 0.1 mg/kg/day recombinant human growth hormone (rHGH) until the first donor site healed or to receive 0.2 mg/kg/day rHGH or placebo from admission throughout hospitalization. Patients receiving 0.2 mg/kg/day rHGH demonstrated significantly higher serum IGF-1 levels at 4.8 +/- 1.7 U/mL compared to placebos at 1.6 +/- 0.4 U/mL (p less than 0.05) and a significant decrease in donor-site healing times compared to placebo (p less than 0.05). Length of hospital stay (LOS/%TBSA) was decreased from 0.80 +/- 0.10 days/%TBSA burned in the placebo group to 0.54 +/- 0.04 days/%TBSA burned in the 0.2 mg/kg/day treatment group (p less than 0.05). This translates, for the average 60% TBSA burned patient, to a decrease in LOS from 46 to 32 days.

The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores.

The first randomized, blinded, placebo-controlled human trials of recombinant basic fibroblast growth factor (bFGF) for pressure sore treatment were performed. Three different concentrations of bFGF in five dosing schedules were tested for safety using hematology, serum chemistries, urinalysis, absorption, antibody formation, and signs of toxicity. Efficacy was evaluated by wound volumes, histology, and photography. No toxicity, significant serum absorption, or antibody formation occurred. In six of eight subgroups, there was a trend toward efficacy with bFGF treatment. When all subgroups were combined, comparison of the slopes of the regression curves of volume decrease over initial pressure sore volume demonstrated a greater healing effect for the bFGF-treated patients (p < 0.05). Histologically, bFGF-treated wound sections demonstrated increased fibroblasts and capillaries. More patients treated with bFGF achieved >70% wound closure (p < 0.05). Blinded observers were able to distinguish differences in visual wound improvement between bFGF and placebo groups. These data suggest that bFGF may be effective in the treatment of chronic wounds.

Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns.

ObjectiveTwo forms of recombinant growth hormone that accelerate the healing of skin graft donor sites in severely burned children were evaluated. Summary Background DataGrowth hormone has been shown to reduce wound healing times in burned pediatric patients. Through genetic engineering, several different forms have been synthesized; however, not all are marketed currently. Two forms of growth hormone were used in these studies, Protropin (Genentech, Inc., San Francisco, GA), a commercially available product that possesses a N-terminal methionine residue not found in the second form Nutropin (Genentech, Inc., San Francisco, CA), which, as yet, is not commercially available. Through the use of recombinant human growth hormone, rapid wound healing may reduce the hypermetabolic period, the risk of infection, and accelerate the healing of donor sites used for grafting onto burned areas. The two structurally different forms of growth hormone were tested for their efficacy in healing donor sites in severely burned children. MethodsForty-six children, with a > 40% total body surface area and > 20% total body surface area full-thickness burn were entered in a double-bind, randomized study to receive rhGH within 8 days of injury. Twenty received (0.2 mg/kg/day) Nutropin or placebo by subcutaneous or intramuscular injection beginning on the morning of the initial excision. Eighteen patients who failed the entry criteria for receiving Nutropin received Protropin therapeutically (0.2 mg/kg/day). Donor sites were harvested at 0.006 to 0.010 inches in depth and dressed with Scarlet Red impregnated fine mesh gauze (Sherwood Medical, St. Louis, MO). The initial donor site healing time, in days, was reached when the gauze could be removed without any trauma to the healed site. ResultsDonor sites in patients receiving Nutropin (n = 20) or Protropin (n = 18) healed at 6.8 ± 1.5 and 6.0 ± 1.5 (mean ± SD) days, respectively, whereas those receiving placebo (n = 26) had a first donor site healing time of 8.5 ± 2.3 days. Both groups receiving rhGH showed a significant reduction in donor site healing time compared with placebo at p < 0.01. When subgroups were compared, no difference in healing times could be shown with regards to age or time of admission after injury.

Early burn wound excision significantly reduces blood loss.

The hypothesis that near-total early excision of large burns in children can be performed safely with a reduction in blood loss was tested. Of 1662 acutely burned patients admitted to this institution between 1982 and 1989, 594 underwent near-total excision of cutaneous flame or scald burn injuries in a single procedure. Operations took less than 3 hours and there were no operative deaths. Blood losses in burns of more than 30% total body surface area (TBSA) were significantly less at 0.40 +/- 0.06 mL/cm2 and 0.49 +/- 0.49 mL/cm2 excised when surgery was performed within the first 24 hours or after the 16th day after burn, respectively, when compared to 0.75 +/- 0.02 mL/cm2 for those excised between 2 and 16 days after burn (p less than 0.05). Blood loss for burns of less than 30% TBSA was of 1.19 +/- 0.13 mL/cm2. Early excision did not increase mortality rate when compared to later excision times. We suggest that near-total excision of large burns within the first 24 hours reduces blood requirements and morbidity without adversely altering hemodynamic stability or increasing mortality risks.

Long-term reduction in bone mass after severe burn injury in children.

OBJECTIVE Because burn victims are at risk of having bone loss, a cross-sectional study was undertaken to determine whether severe burn injury had acute and long-term effects on bone mass or on the incidence of fractures in children. METHODS Dual-energy x-ray absorptiometry of the lumbar portion of the spine was performed on 68 children: 16 moderately burned (15% to 36% of total body surface area) and 52 age-matched severely burned (> or = 40% of total body surface area). Twenty-two severely burned children were hospitalized and studied within 8 weeks of their burn, and 30 others were studied approximately 5 years after discharge. In the severely burned group, both hospitalized and discharged, serum and urine were analyzed for calcium, phosphorus, intact parathyroid hormone, osteocalcin, and type I collagen telopeptide. RESULTS Sixty percent of severely burned patients had age-related z scores for bone density less than -1, and 27% of severely burned patients had age-related z scores for bone density less than -2 (p < 0.005, for each). In the moderately burned group, 31% of patients had z scores less than -1 (p < 0.005 vs normal distribution), but only 6% had z scores less than -2 (p value not significant). There was evidence of increased incidence of fractures after discharge in the severely burned patients. Biochemical studies were compatible with a reduction in bone formation and an increase in resorption initially, and with a long-term persistence of low formation. CONCLUSION We conclude that acute burn injury leads to profound and long-term bone loss, which may adversely affect peak bone mass accumulation.

Current Treatment Reduces Calories Required to Maintain Weight in Pediatric Patients with Burns

A previous study indicated that formulas for determining caloric requirements of severely burned children overestimated their needs. This study was undertaken to determine the caloric intake required to maintain weight in patients under 12 years of age with burns over more than 30% total body surface area. The 102 patients studied were divided into two groups according to weight changes. A comparison of the actual caloric intakes of these groups was conducted. Multivariate regression analysis indicated that body surface area in square meters and burn surface were significant predictors of caloric requirements to maintain weight in these patients. It was determined that 1800 kcal was a plausible value for the calories per body surface area. Therefore the regression was formed with 1800 kcal as the multiplier of body surface area, and the multiplier of burn surface area was estimated. The resulting formula provides 1300 kcal/m2 burned, which is 900 kcal/m2 burned less than our previously suggested formula.

Application of basic fibroblast growth factor may reverse diabetic wound healing impairment

This study examines the effect of application of basic fibroblast growth factor (bFGF) on the wound healing impairment seen in streptozotocin-induced diabetic (SD) rats compared with control nondiabetic (NL) animals. Under general anesthesia, a 6-cm dorsal incision was made through the skin and panniculus carnosus. Both the NL and SD wounds were injected with 0.1 ml of one of the following three solutions: saline, vehicle, and 10 μg of bFGF. The wounds were closed with interrupted sutures of 4-0 nylon. The animals were returned to their cages and sacrificed at 7, 10, 14, or 21 days later. Breaking strength of the wound was analyzed by using an Instron Tensiometer 4201 to assay for relative collagen maturation. Data among groups were compared using an analysis of variance. At 7 and 10 days, all NL wounds were stronger than all SD wounds. By 14 days there was no statistically significant difference in breaking strength between the bFGF-SD wounds and all subgroups of NL wounds. The bFGF-SD subgroup was statistically significantly stronger than the saline-SD (p < 0.02) and vehicle-SD (p < 0.01) wounds. At 21 days the bFGF-SD wounds were statistically significantly stronger than the vehicle-SD wounds to a confidence level of p < 0.001. These findings indicate that application of bFGF may reverse the impairment seen in diabetic wound healing.

A comparison of bayes and maximum likelihood estimation of the intraclass correlation coefficient

Two methods of estimating the intraclass correlation coefficient (p) for the one-way random effects model were compared in several simulation experiments using balanced and unbalanced designs. Estimates based on a Bayes approach and a maximum likelihood approach were compared on the basis of their biases (differences between estimates and true values of p) and mean square errors (mean square errors of estimates of p) in each of the simulation experiments. The Bayes approach used the median of a conditional posterior density as its estimator.

In vivo characterization of interleukin-4 as a potential wound healing agent.

Interleukin‐4 increases the synthesis of extracellular matrix proteins, including types I and III collagen and fibronectin, by both human and rat fibroblasts. Because fibroblasts are the final common effector cells of most phases of tissue repair, this study set out to investigate the effects of interleukin‐4 on the healing of three different types of wounds. Acute excisional and chronic granulating wounds inoculated with Escherichia coli and incisional wounds in streptozotocin‐induced diabetic Sprague‐Dawley rats were used. Recombinant murine or human interleukin‐4 was applied topically to the open wounds at doses of 0.1, 1.0, or 10.0 µg/cm2/wound for 5 or 10 days. Incisional wounds received the same doses once—at the time of wounding. The time taken to achieve wound closure or wound breaking strength measurements of wounds was recorded and compared with relevant untreated control groups. Wound contraction was impaired in the presence of bacteria, and this was reversed by all doses of recombinant murine interleukin‐4. Recombinant murine interleukin‐4 had no effect on the wound closure of noncontaminated wounds; it reduced wound breaking strength in acute excisional wounds, except in a contaminated setting when wounds were treated with 1.0 pg/cm2/wound. Recombinant interleukin‐4 (1.0 µg) improved breaking strength of both diabetic and normal incisional wounds. The apparent pleiotropic effect of interleukin‐4 on wound breaking strength under different wound conditions may be related not only to the activity of the fibroblast but also the ratio of cross‐linked collagen/total collagen content of wounds. This study suggests that interleukin‐4 may be a useful agent for accelerating closure of wounds, particularly where healing is impaired.

Bayesian Statistics Using Mathematica

Abstract We illustrate the use of the Mathematica software system (programming language) for performing Bayesian calculations of the sort encountered in introductory presentations of Bayesian statistics. In particular, we show the ease with which one can do numerical computation, graphics, and symbolic computation to analyze one- and two-dimensional probability density functions. Our illustrations involve a time series problem using oxygen uptake data taken from a burn patient.