Glenn D. Warden

Differential Effects of Three Enteral Dietary Regimens on Selected Outcome Variables in Burn Patients

A modular tube feeding recipe (MTF) was designed to meet the unique nutritional needs of burn patients, applying principles previously documented in our burned guinea pig model. MTF, a high-protein, low-fat, linoleic acid-restricted formulation is enriched with omega-3 fatty acids, arginine, cysteine, histidine, vitamin A, zinc, and ascorbic acid. Fifty patients, 3 to 76 years of age with burns ranging from 10 to 89% total body surface area were prospectively randomized into three groups which blindly compared MTF to two enteral regimens widely utilized in the nutritional support of burns. Age, percent total and third-degree burn, resting energy expenditure, and calorie and protein intake were similar in all groups. Data analysis demonstrated significant superiority of MTF in the reduction of wound infection (p less than 0.03) and length of stay/percent burn (p less than 0.02). MTF was also associated with a decreased incidence of diarrhea, improved glucose tolerance, lower serum triglycerides, reduced total number of infectious episodes and trends toward improved preservation of muscle mass, although statistical significance was not achieved. Seventy percent of deaths occurred in the group supported with an inherently large dose of fat and linoleic acid. Combining these observations, it is believed that MTF is effective in modulating an improved response to burn injury.

Multicenter postapproval clinical trial of Integra dermal regeneration template for burn treatment.

The safety and effectiveness of Integra Dermal Regeneration Template was evaluated in a postapproval study involving 216 burn injury patients who were treated at 13 burn care facilities in the United States. The mean total body surface area burned was 36.5% (range, 1-95%). Integra was applied to fresh, clean, surgically excised burn wounds. Within 2 to 3 weeks, the dermal layer regenerated, and a thin epidermal autograft was placed. The incidence of invasive infection at Integra-treated sites was 3.1% (95% confidence interval, 2.0-4.5%) and that of superficial infection 13.2% (95% confidence interval, 11.0-15.7%). Mean take rate of Integra was 76.2%; the median take rate was 95%. The mean take rate of epidermal autograft was 87.7%; the median take rate was 98%. This postapproval study further supports the conclusion that Integra is a safe and effective treatment modality in the hands of properly trained clinicians under conditions of routine clinical use at burn centers.

Comparative assessment of cultured skin substitutes and native skin autograft for treatment of full-thickness burns.

ObjectiveComparison of cultured skin substitutes (CSSs) and split-thickness autograft (STAG) was performed to assess whether the requirement for autologous skin grafts may be reduced in the treatment of massive bums. Summary Background DataCultured skiasubstitutes consisting of collagen-glycosaminoglycan substrates populated with autologous fibroblasts and keratinocytes have been demonstrated to close full-thickness skin wounds in athymic mice and to express normal skin antigens after closure of excised wounds in burn patients. MethodsData were collected from 17 patients between days 2 and 14 to determine incidence of exudate, incidence of regrafting, coloration, keratinization, and percentage of site covered by graft (n = 17). Outcome was evaluated on an ordinal scale (0 = worst; 10 = best) beginning at day 14, with primary analyses at 28 days (n = 10) and 1 year (n = 4) for erythema, pigmentation, epithelial blistering, surface roughness, skin suppleness, and raised scar. ResultsSites treated with CSSs had increased incidence of exudate (p = 0.06) and decreased percentage of engraftment (p < 0.05) compared with STAG. Outcome parameters during the first year showed no differences in erythema, blistering, or suppleness. Pigmentation was greater, scar was less raised, but regrafting was more frequent in CSS sites than STAG. No differences in qualtative outcomes were found after 1 year, and antibodes to bovine collagen were not detected in patientsera. ConclusionsThese results suggest that outcome of engrafted CSSs is not different from STAG and that increased incidence is related to decreased percentage of initial engraftment. Increased rates of CSSs may lead to improved outcome for closure of burn wounds, allow greater availability of materials for grafting, and reduce requirements for donor skin autogratt.

The 1999 clinical research award. Cultured skin substitutes combined with Integra Artificial Skin to replace native skin autograft and allograft for the closure of excised full-thickness burns.

Prompt and permanent closure of excised full-thickness burns remains a critical factor in a patients recovery from massive burn injuries. Hypothetically, Integra Artificial Skin (Integra) may replace the need for allografts for immediate wound coverage, and cultured skin substitutes (CSS) that contain stratified epithelium may replace the need for autografts for definitive wound closure. To test this hypothesis, 3 patients with full-thickness burns of greater than 60% of their total body surface areas had their eschar excised within 14 days of admission. Integra was applied, and a skin biopsy was collected from each patient for the preparation of CSS. At 3 weeks or more after the application of the Integra and the collection of skin biopsies, the outer silastic cover of the Integra was removed and CSS were grafted. The CSS were irrigated with nutrients and antimicrobials for 6 days and then dressed with antimicrobial ointment and cotton gauze. Treated wounds were traced on days 14 and 28 after the grafting of CSS for determination of engraftment and wound closure, respectively. Cost analysis was not performed. Engraftment on postoperative day (POD) 14 was 98%+/-1% (mean +/- standard error of the mean), the ratio of closed:donor areas on POD 28 was 52.3+/-5.2, and no treated sites required regrafting. The histology of the closed wounds showed stable epithelium that covered a layer of newly formed fibrovascular tissue above the reticulated structure of the degrading Integra. The clinical outcomes of the closed wounds after POD 28 demonstrated smooth, pliable, and hypopigmented skin. Two patients who had received CSS grafts over Integra on their backs were positioned supine on air beds from POD 8 or POD 9 with minimal graft loss because of mechanical loading. One patient with a full-thickness burn of 88% of the total body surface area was covered definitively at 55 days postburn. These results demonstrate that the combination of CSS and Integra can accomplish functionally stable and cosmetically acceptable wound closure in patients with extensive full-thickness burns. This combination of alternatives to the conventional grafting of split-thickness skin permits the substitution of cadaveric allograft with Integra and the substitution of donor autograft with CSS. This approach to the closure of excised full-thickness burns is expected to reduce greatly the time to definitive closure of burn wounds and to reduce the morbidity associated with the harvesting of donor sites for split-thickness skin autografts.

Principles and practices for treatment of cutaneous wounds with cultured skin substitutes

BACKGROUND Skin substitutes prepared from cultured skin cells and biopolymers may reduce requirements for donor skin autograft, and have been shown to be effective in treatment of excised burns, burn scars, and congenital skin lesions. DATA SOURCES Cultured skin substitutes (CSS) generate skin phenotypes (epidermal barrier, basement membrane) in the laboratory, and restore tissue function and systemic homeostasis. Healed skin is smooth, soft and strong, but develops irregular degrees of pigmentation. Quantitative analysis demonstrates that CSS closes 67 times the area of the donor skin, compared to less than 4 times for split-thickness skin autograft. CONCLUSIONS CSS reduce requirements for donor skin autograft for closure of excised, full-thickness cutaneous wounds, and demonstrate qualitative outcome that is not different from meshed, split-thickness autograft. These results offer reductions in morbidity and mortality for the treatment of burns and chronic wounds, and for cutaneous reconstruction.

Effect of inhalation injury on fluid resuscitation requirements after thermal injury

The presence of inhalation injury has been reported to increase fluid requirements for resuscitation from burn shock after thermal injury. To evaluate the effect of inhalation injury on the magnitude of burn-induced shock, the characteristics of resuscitation of 171 patients with burns covering at least 25 percent of the total body surface area were reviewed. When inhalation injury was suspected, confirmation by xenon-133 scanning, bronchoscopy, or both was obtained. Initial fluid resuscitation was calculated according to the Parkland formula, and titration was initiated to maintain a urine output of 30 to 50 ml/hour. Fifty-one patients had inhalation injuries. Patients with inhalation injuries had a mean fluid requirement of 5.76 ml/kg per percentage of total body surface area burned and a mean sodium requirement of 0.94 mEq/kg per percentage of total body surface area burned to achieve successful resuscitation, compared with a fluid requirement of 3.98 ml/kg per percentage of total body surface area burned and a sodium requirement of 0.68 mEq/kg per percentage of total body surface area burned for the group without inhalation injury (p < 0.05). These data confirm and quantitate that inhalation injury accompanying thermal trauma increases the magnitude of total body injury and requires increased volumes of fluid and sodium to achieve resuscitation from early burn shock.

Cultured Skin Substitutes Reduce Donor Skin Harvesting for Closure of Excised, Full-Thickness Burns

ObjectiveComparison of cultured skin substitutes (CSS) and split-thickness skin autograft (AG) was performed to assess whether donor-site harvesting can be reduced quantitatively and whether functional and cosmetic outcome is similar qualitatively in the treatment of patients with massive cutaneous burns. Summary Background DataCultured skin substitutes consisting of collagen-glycosaminoglycan substrates populated with autologous fibroblasts and keratinocytes have been shown to close full-thickness skin wounds in preclinical and clinical studies with acceptable functional and cosmetic results. MethodsQualitative outcome was compared between CSS and AG in 45 patients on an ordinal scale (0, worst; 10, best) with primary analyses at postoperative day 28 and after about 1 year for erythema, pigmentation, pliability, raised scar, epithelial blistering, and surface texture. In the latest 12 of the 45 patients, tracings were performed of donor skin biopsies and wounds treated with CSS at postoperative days 14 and 28 to calculate percentage engraftment, the ratio of closed wound:donor skin areas, and the percentage of total body surface area closed with CSS. ResultsMeasures of qualitative outcome of CSS or AG were not different statistically at 1 year after grafting. Engraftment at postoperative day 14 exceeded 75% in the 12 patients evaluated. The ratio of closed wound:donor skin areas for CSS at postoperative day 28 was significantly greater than for conventional 4:1 meshed autografts. The percentage of total body surface area closed with CSS at postoperative day 28 was significantly less than with AG. ConclusionsThe requirement for harvesting of donor skin for CSS was less than for conventional skin autografts. These results suggest that acute-phase recovery of patients with extensive burns is facilitated and that complications are reduced by the use of CSS together with conventional skin grafting.

The Importance Of Intra-abdominal Pressure Measurements In Burned Children

Four burned children suffering complications from elevated intra-abdominal pressures prompted initiation of a prospective study to determine the value of intra-abdominal pressure measurements in 30 children with large burns. Intra-abdominal pressures were measured every 4 hours during burn shock or sepsis, or daily during periods of stability. Patients were arbitrarily divided into those having one or more measurements > or = 30 mm Hg or all values < 30 mm Hg. Patients in the > or = 30 mm Hg group had significantly larger burns, higher mortality, and increased instances of sepsis. Five patients had elevated intra-abdominal pressures during burn shock, with two requiring abdominal escharotomies. Seven were at > 30 mm Hg during sepsis, with three requiring paralysis, and one each requiring placement of a peritoneal catheter or laparotomy. Significant intra-abdominal pressure elevations may occur in patients with extensive burns and are associated with a poorer prognosis. Elevation of intra-abdominal pressure should be considered in severely burned patients with oliguria, hypoventilation, or hypotension.

Skin anatomy and antigen expression after burn wound closure with composite grafts of cultured skin cells and biopolymers.

Closure of large skin wounds (i.e., burns, congenital giant nevus, reconstruction of traumatic injury) with split-thickness skin grafts requires extensive harvesting of autologous skin. Composite grafts consisting of collagen-glycosaminoglycan (GAG) substrates populated with cultured dermal fibroblasts and epidermal keratinocytes were tested in a pilot study on full-thickness burn wounds of three patients as an alternative to split-thickness skin. Light microscopy and transmission electron microscopy showed regeneration of epidermal and dermal tissue by 2 weeks, with degradation of the collagen-GAG implant associated with low numbers of leukocytes, and deposition of new collagen by fibroblasts. Complete basement membrane, including anchoring fibrils and anchoring plaques, is formed by 2 weeks, is mature by 3 months, and accounts for the absence of blistering of healed epidermis. All skin antigens tested (involucrin, filaggrin, laminin, collagens IV and VII, fibronectin, and chondroitin-sulfate) were expressed by 16 days after grafting. This cultured skin analogue provides an experimental alternative to split-thickness skin graft that develops histiotypic markers of skin anatomy and antigen expression after wound closure.

Increased survival after major thermal injury: The effect of growth hormone therapy in adults

BACKGROUND Advances in the management of patients with major thermal injury have resulted in a progressive increase in survival rates. We report preliminary data evaluating the safety and potential efficacy of human growth hormone (HGH) administration in a high-risk population of burned patients. METHODS From 1989 to 1993, 69 patients sustaining major burns (defined as patient age plus percentage of body surface area with deep second- and third-degree burns > or = 90) were evaluated. Patients routinely received anti-inflammatory pharmacotherapy including antioxidants, an endotoxin binder, and cyclooxygenase blockade. Half of the 54 patients who survived more than 7 days received HGH to enhance wound healing. Injury severity, morbidity, and mortality for patients receiving HGH was compared to the 27 patients not receiving HGH. RESULTS For the entire population (n = 69), average age was 56 +/- 23 years, body surface area burned was 58% +/- 24%, and 30% sustained smoke inhalation. Actual mortality was 41%, significantly less than the more than 70% mortality rate predicted from reported outcome data. Patients receiving HGH were well matched with the group not receiving HGH with respect to extent of injury, burn management, pharmacotherapy, and in-hospital morbidity. Mortality of the patients receiving HGH was 11%, significantly less than the 37% mortality rate of the patients without HGH (p = 0.027). CONCLUSION Compared to standard predictors of burn mortality our small patient group appears to have an improved survival rate, suggesting that the use of anti-inflammatory agents appears safe and potentially beneficial. Patients receiving HGH exhibited minimal drug-related complications and mortality rates were improved when this population was compared with both predicted mortality rates and a well-matched control population of concurrently treated patients. Prospective blinded trials are now necessary to confirm these findings in a larger patient group.