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Intensive care management of severely burned patients demands expertise in several areas. These include airway management, fluid resuscitation, support of the hypermetabolic response, infection control, and treatment of smoke inhalation injury. Surgical management of the burn wound, plastic reconstruction, and long-term rehabilitation are also essential aspects of modern burn care.

The aim of the present investigation was to determine whether there is a net uptake of insulin-like growth factor I (IGF-I) or IGF-binding proteins (IGFBPs) by the leg after burn injury and to elucidate the regulatory role of insulin exerted on this system under in vivo conditions in burn patients. Studies were performed on nine patients after burn injury (approximately 60% body surface area). Each patient was studied twice during a continuous infusion of a carbohydrate-rich enteral diet. Blood was collected simultaneously from the femoral artery and vein for the measurement of various elements of the IGF system after 7 days of enteral diet alone (basal period) and after 7 days of the enteral diet plus the infusion of insulin (insulin period). Data from these patients were compared to values in age-matched fed healthy volunteers. During the basal period, burn patients demonstrated a significant reduction in the venous concentration of IGF-I and an increase in both IGFBP-1 and -2 compared to control values. Insulin produced a significant 15% increase in the IGF-I concentration in burn patients, but decreased the circulating levels of IGFBP-1 by 50%. The IGF-I and IGFBP-1 concentrations at the end of the insulin period were still significantly different from those in control subjects. Burn patients also exhibited a marked reduction in intact IGFBP-3 and the acid-labile subunit under basal conditions, and these alterations were not reversed by insulin. Under basal conditions, all burn patients had a positive arterio-venous (A-V) difference for IGF-I across the leg. The A-V difference was increased 50% in response to insulin. The net uptake of IGF-I by the leg was 2.4 micrograms/min under basal conditions, and as leg blood flow also tended to increase in response to insulin, IGF-I uptake was elevated more than 3-fold during the insulin period. No A-V difference across the leg was detected for IGFBP-1, -2, or -3 in burn patients. In conclusion, burn injury in humans produces dramatic and sustained alterations in various components of the IGF system that persist despite adequate nutritional support. Our data indicate the presence of a net uptake of IGF-I by the leg in burn patients that may serve to counteract the catabolic state.

BACKGROUND: Cultured keratinocyte (CK) and cadaveric skin allografts have prolonged survival in patients with massive thermal injury. It is unclear if this delayed rejection is due to impaired host responsiveness or decreased graft immunogenicity. Although burn injury has been shown to decrease parameters of allograft response, no studies have examined the effect of burn injury on alloantigen expression. This study investigated the effect of burn size on class II antigen expression in CK allografts as well as on tissue levels of interferon-gamma (IFN-gamma), the principle regulator of alloantigen expression. METHODS: Anesthetized CBA mice (n = 64) received a 0%, 20% partial-thickness (PT), 20% full-thickness (FT), or 40% FT contact burn. Forty-eight hours later, wounds were partially excised and covered with CK allografts from C57BL/6 donors. Five days after burn injury, grafts were analyzed for donor-specific class II antigen. Protein expression was determined by Western immunoblotting and quantified with video densitometry. Wound, serum, and unburned skin levels of IFN-gamma were determined by enzyme-linked immunosorbent assay. Groups were compared by Fisher's analysis of variance. RESULTS: As burn size increased, class II antigen expression decreased (p < 0.001). This corresponded with decreased wound and skin levels of IFN-gamma after 40% burn (p < 0.05); however, wound IFN-gamma was significantly elevated after 20% PT and FT burns (p < 0.01). Serum IFN-gamma increased as burn size increased (p < 0.01). CONCLUSIONS: Burn injury decreases the antigenicity of CK allografts, which partly explains delayed allograft rejection after burn injury. Although wound IFN-gamma increases after minor thermal injury, the profound decrease in wound and skin IFN-gamma after a major burn corresponds with diminished class II antigen expression. The decreased availability of IFN-gamma after major thermal injury provides a mechanism for limited allograft tolerance.

Important questions for pediatric burn care specialists relate to the quality of life for those children who survive the most severe burn injuries. This study examines the psychological adjustment of 25 children who survived injuries > or = 80% total body surface area and the impact of such injury on the families. Data were analyzed from the most recent assessment, with the Child Behavior Checklist, Teacher Report Form, Piers-Harris Children's Self-Concept Scale, Parenting Stress Index, and a parental questionnaire designed by the authors. As a group, the children's behavioral problems as reported by both parents and teachers were within normal limits. Measures of parental stress, however, clearly differentiated the burn population. These parents attributed more stress to characteristics of their children. Children with > or = 80% TBSA burns develop positive feelings about themselves and appear no more troubled than a comparable group of nonburned children. The impact on the families is significant, however, and must be considered of consequence in the rehabilitation of the burned child. Language: en

Splanchnic ischemia has been associated with bacterial translocation and increased endotoxin absorption from the gut. To study the effects of major burn on splanchnic circulation, minipigs were randomized to receive 40% flame burn and Parkland resuscitation or sham burn and maintenance fluids. Total and fractionated blood flow, O2 delivery and consumption, mucosal pH of the intestine, and endotoxin levels in the superior mesenteric vein were measured for 48 h, and then abdominal organs were harvested for bacteriological culture and histopathological analysis. Total mesenteric blood flow and fractionated blood flow to the mucosa-submucosa of the jejunum, cecum, and colon decreased 2 and 4 h postburn. Although mesenteric O2 consumption was unchanged, mesenteric O2 delivery and intestinal mucosal pH were decreased during the early postburn period. Concomitantly, endotoxin levels in the superior mesenteric vein were significantly elevated during the first 8 h postburn. The bacteriological cultures of the systemic tissue samples showed increased bacterial translocation in the burn group. After major burns, there is a transient selective splanchnic vasoconstriction, which is associated with intestinal mucosal acidosis and increased incidence of bacterial translocation and endotoxin absorption from the gut.

This review article describes the pathophysiological aspects of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), induced by combined burn and smoke inhalation and examines various therapeutic approaches. The injury results in a fall in arterial oxygenation as a result of airway obstruction, increased pulmonary transvascular fluid flux and loss of hypoxic pulmonary vasoconstriction. The changes in cardiopulmonary function are mediated by reactive oxygen and nitrogen species. Nitric oxide (NO) is generated by both inducible and constitutive isoforms of nitric oxide synthase (NOS). Recently, neuronal NOS emerged as a major component within the pathogenesis of ARDS. NO rapidly combines with the oxygen radical superoxide to form reactive and highly toxic nitrogen species such as peroxynitrite. The control of NO formation involves poly(ADP-ribose) polymerase and its ability to up-regulate the activity of nuclear transcription factors through ribosylation. In addition, present data support a major role of the bronchial circulation in the injury, as blockage of bronchial blood flow will also minimize the pulmonary injury. Current data suggest that cytotoxins and activated cells are formed in the airway and carried to the parenchyma.

Toxic effects of sodium hypochlorite on wound healing elements have been confined to a restricted range of sodium hypochlorite concentrations. We investigated concentrations of sodium hypochlorite for antibacterial activity and tissue toxicity at varying time intervals. We attempted to find the efficacious therapeutic concentration that was both microbicidal and nontoxic. Gram-negative and gram-positive isolates (0.1/ml of 1 x 10(8)/ml) were introduced into various concentrations of buffered and unbuffered sodium hypochlorite solutions for determinations of bactericidal activity at 5-, 10-, 15-, and 30-minute intervals. Concentrations of sodium hypochlorite were 0.25%, 0.025%, and 0.0125%. In vitro assays with fibroblasts at the same concentrations were also performed to determine toxicity at the same time intervals. An in vivo incisional model was also used to determine the effects of sodium hypochlorite therapy on wound healing. Bactericidal effects were observed for concentrations as low as 0.025%. Tissue toxicity, both in vitro and in vivo, was observed at concentrations of 0.25% but not at a concentration of 0.025%. Although concentrations below this level were nontoxic, they were not bactericidal. Therefore a modified "Dakin's" solution at a concentration of 0.025% is therapeutically efficacious as a fluid dressing, since it preserves bactericidal properties and eliminates the detrimental potential on wound healing.

Controversies exist over the influence of inhalation anaesthesia on blood flow regulation in response to local alveolar hypoxia. This study investigates the blood flow diversion from a hypoxic to an oxygenated lung in anaesthetized and ventilated animals in comparison to unanaesthetized animals. Chronically instrumented adult ewes (n = 14, 32-45 kg) were intubated one week after surgery with a modified Carlen's tube, allowing separate ventilation of the left and right lung. In the awake state (n = 7) or after one hour of constant anaesthetic conditions (n = 7, halothane 1.6% and 2.4%), cardiac output (thermodilution) and left pulmonary blood flow (ultrasonic transit time) were evaluated. Then, under identical ventilatory conditions, the left or right lung, alternately, was rendered hypoxic for 10 min by ventilation with nitrogen. The contralateral lung was ventilated with oxygen. After 10 min, haemodynamics were again recorded. The changes in left pulmonary blood flow under unilateral lung hypoxia were similar either in the awake or the anaesthetized state. Thus, we conclude that, under these experimental conditions, halothane anaesthesia and mechanical ventilation have no influence on blood flow regulation under unilateral lung hypoxia.

A blood culture is an essential laboratory procedure necessary to confirm a septic episode. However, it is important to collect the blood sample at the appropriate time with an acceptable technique. The standard method is to collect at least 5 to 10 ml blood per culture bottle from patients with fevers. However, this volume of blood is an unrealistic amount to take from the frequently febrile pediatric patient. Alternatively, the pediatric blood culture bottle allows the collection of 1 ml blood per bottle to perform the same evaluation. We evaluated the two techniques of blood-culture collection over a 9-month period and compared the results between adult and pediatric blood culture bottles. Seventy-six patients, from November 1988 through February 1989, had blood cultures performed with the adult culture bottles, which produced a total of 1314 samples. A total of 113 patients, from March through July 1989, had blood cultures performed with the pediatric culture bottles, which produced a total of 758 samples. Percent recovery for the adult bottles versus the pediatric bottles was 13.95% versus 22.8% (p less than 0.0001). Since the amount of blood necessary to isolate an infectious agent is critical not only for laboratory identification but also for the volume of blood of pediatric patients, these data clearly establish the efficacy of pediatric blood culture bottles and the utilization of smaller amounts of blood. Not only did this approach significantly enhance organism recovery rate, but it may well be more cost-effective because fewer cultures need to be performed to isolate the infectious organism.

Most fatalities from fires are not due to burns, but are a result of inhalation of toxic gases produced during combustion. Fire produces a complex toxic environment, involving flame, heat, oxygen depletion, smoke and toxic gases such as carbon monoxide and cyanide. As a wide variety of synthetic materials is used in buildings, such as insulation, furniture, carpeting, electric wiring covering as well as decorative items, the potential for poisoning from inhalation of products of combustion is continuously increasing. The present review describes the pathophysiologic effects from smoke inhalation injury as well as strategies for emergency treatment on scene and in the intensive care setting.

Endotoxin is known to be a primary initiator of sepsis and septic shock. Migration of immunocompetent cells due to chemotactic attraction plays a central role in the initiation of the immune response. Two major groups of chemokines can be distinguished: C-x-C chemokines like Interleukin-8 attract mainly neutrophils, C-C chemokines (e.g. RANTES) attract monocytes and T-cells. The aim of this study was to get further insight into chemokine profiles after a single endotoxin bolus in man.We investigated the effect of systemically administered endotoxin (4ng/kg BW i.v.) in 8 healthy volunteers. Clinical data (heart rate, mean arterial pressure, temperature), serum levels of IL-8, and RANTES, as well as white blood cell count were obtained before and hourly for five hours after endotoxin administration.Heart rate and MAP showed significant changes (p0.05) after 2-3 hours. All volunteers presented with low-grade fever after 2 hours. WBC was elevated 43% and 63% after 4 and 5 hours, respectively. Both chemokines were significantly different from baseline two hours after endotoxin challenge: While IL-8 was significantly increased RANTES serum levels were diminished.From our data we conclude that this endotoxin model was effective to mimic the clinical appearance of sepsis. Chemokines like IL-8 and RANTES are integrated in the early immune response to endotoxin challenge in man.

Severe burn incites metabolic disturbances which last up to one year post injury. Persistent profound catabolism after severe burn hampers rehabilitative efforts delaying meaningful return of individuals to society. The simplest effective anabolic strategies for severe burn injuries are early excision and grafting of the burn wound, prompt treament of sepsis, maintenance of environmental temperature at 30-32 inverted exclamation mark C, continuous enteral feeding of a high carbohydrate, high protein diet, early institution of vigorous resistive and aerobic resistive exercise programs. To further minimize erosion of lean body mass administration of recombinant human growth hormone, insulin, oxandrolone or propranolol are all reasonable approaches. Exogenous continuous low dose insulin infusion, beta blockade with propranolol and the use of the synthetic testosterone analog, oxandrolone are the most cost effective and least toxic pharmaco therapies to date.

Toxic epidermal necrolysis is a rare but life-threatening exfoliating disease of the skin and mucous membranes, commonly considered a drug sensitivity reaction. In this review of the literature we discuss the epidemiology, etiology, and pathology. We show diagnostic problems and current treatment strategies. Many of the problems associated with the disease, such as wound infection, sepsis, nutritional support, and pain management, are similar to problems in severely burned patients. Burn centers provide optimal logistics and knowledge to diagnose and treat this serious disease entity.

Glutamine is synthesized primarily in skeletal muscle, and enables transfer of nitrogen to the liver, as well as serving other functions. There is increasing evidence for beneficial clinical effects of glutamine supplementation in critically ill patients. However, the response of endogenous glutamine formation to severe stress is poorly understood. The rates of net protein balance, leucine oxidative decarboxylation, and alanine and glutamine synthesis de novo were determined in leg skeletal muscle of 20 severely burned patients and 19 normal controls in the post-absorptive state. Patients were studied at 14+/-5 days post-burn, and their mean burn size was 66+/-18% of total body surface area. Methods were based on the leg arteriovenous balance technique in combination with biopsies of the vastus lateralis muscle. In the post-absorptive state, patients with severe burns, as compared with healthy control subjects, exhibited accelerated muscle loss (+150%) (i.e. proteolysis minus synthesis) and leucine oxidative decarboxylation (+117%), and depletion of the intramuscular free glutamine pool (-63%). The average rate of glutamine synthesis de novo was decreased by 48%, whereas net alanine synthesis de novo was increased by 174%, in skeletal muscle of burned patients. In conclusion, in severely hypercatabolic burned patients, muscle glutamine formation was suppressed, whereas alanine was the major vehicle for inter-organ nitrogen transport. These changes account for a decreased glutamine availability during prolonged severe stress.

Severe cutaneous burn causes transient mesenteric vasoconstriction and altered gut mucosal integrity. We recently showed that burn also increases gut epithelial cell death by apoptosis. The goal of this study was to determine whether changes in gut perfusion after burn contribute to burn-associated gut apoptosis.We first correlated superior mesenteric artery blood flow with measurement of gut perfusion at the tissue level by laser doppler in four nonburned rats before, during, and after arterial clamping to validate our measurements of gut perfusion. We then characterized gut perfusion sequentially over time after burn; gut perfusion was measured 3 cm from the ligament of Treitz before burn and hourly for 6 hours. A group of control rats underwent the exact same protocol without the burn to exclude effects of anesthesia and laparotomy on tissue perfusion (n = 4). We studied a third group of rats with hypoperfusion of the same duration and magnitude induced mechanically without burn (n = 7). Sections of the proximal gut from all three groups (control without burn, burn, and hypoperfusion without burn) were examined for epithelial apoptosis.Linear regression analysis demonstrated a strong correlation between superior mesenteric artery blood flow and intestinal tissue perfusion measured by laser doppler under both low and high flow conditions (r = 0.85). Laser doppler measurements of gut perfusion after burn showed deceased gut perfusion that was maximal at 2 hours postburn (p0.05), and that persisted for 4 hours (p0.05). By 6 hours, gut perfusion returned to baseline. Apoptosis increased significantly in the burn group (2.11 +/- 0.17%) compared with control (0.52 +/- 0.2%) and the mechanically decreased perfusion group (0.51 +/- .03) (p0.001).We conclude that burn-induced gut hypoperfusion is insufficient to cause burn-related increased gut epithelial apoptosis. We speculate that the signal for increased gut epithelial apoptosis is primarily related to proinflammatory mediators induced by the burn wound.

Short term administration of testosterone stimulates net protein synthesis in healthy men. We investigated whether oxandrolone [Oxandrin (OX)], a synthetic analog of testosterone, would improve net muscle protein synthesis and transport of amino acids across the leg. Six healthy men [22+/-1 (+/-SE) yr] were studied in the postabsorptive state before and after 5 days of oral OX (15 mg/day). Muscle protein synthesis and breakdown were determined by a three-compartment model using stable isotopic data obtained from femoral arterio-venous sampling and muscle biopsy. The precursor-product method was used to determine muscle protein fractional synthetic rates. Fractional breakdown rates were also directly calculated. Total messenger ribonucleic acid (mRNA) concentrations of skeletal muscle insulin-like growth factor I and androgen receptor (AR) were determined using RT-PCR. Model-derived muscle protein synthesis increased from 53.5+/-3 to 68.3+/-5 (mean+/-SE) nmol/min.100 mL/leg (P0.05), whereas protein breakdown was unchanged. Inward transport of amino acids remained unchanged with OX, whereas outward transport decreased (P0.05). The fractional synthetic rate increased 44% (P0.05) after OX administration, with no change in fractional breakdown rate. Therefore, the net balance between synthesis and breakdown became more positive with both methodologies (P0.05) and was not different from zero. Further, RT-PCR showed that OX administration significantly increased mRNA concentrations of skeletal muscle AR without changing insulin-like growth factor I mRNA concentrations. We conclude that short term OX administration stimulated an increase in skeletal muscle protein synthesis and improved intracellular reutilization of amino acids. The mechanism for this stimulation may be related to an OX-induced increase in AR expression in skeletal muscle.

The scalp is a useful and reliable donor site in pediatric burn patients that can be multiply harvested with minimal morbidity. Healing complications, however, may include alopecia and chronic folliculitis. To investigate scalp donor-site morbidity, a consecutive series of 2478 pediatric burn patients treated over a 10-year period were reviewed. A total of 450 of these patients had scalp donor sites for wound closure. Percent of total body surface area burned was 46+/-23 percent (mean+/-standard deviation), and the mean number of sequential scalp donor-site harvests was 2.2+/-2 (range, 1 to 10) with mean intervals between harvesting of 6+/-0.6 days. Ten patients (2.2 percent) had related complications. Eight patients developed scalp folliculitis, with Staphylococcus sp as the predominant organism (80 percent). Two patients were managed successfully with wound care alone; the other six patients required surgical debridement and split-thickness skin grafting to achieve wound healing. These eight patients developed varying degrees of alopecia. Two patients developed alopecia without previous folliculitis. Six patients required reconstructive surgery, which consisted of primary closure (3), staged excision (1), and tissue expansion (2). A number of variables were examined to determine any differences in the group that had complications compared with the group of patients that did not. No differences in age, sex, race, burn type, burn size, septic episodes, time to wound closure, or number of times the scalp was harvested were detected. Healed second-degree burns to the scalp that were subsequently taken as donor sites seemed to be a risk factor (p0.05) for folliculitis and alopecia. Our study confirms that scalp donor sites are reliable with low morbidity. Complications include alopecia and chronic folliculitis that can be avoided by meticulous technique and avoidance of previously burned areas.

If ECMO is to be used effectively in pediatric patients, specifically in those with burns, the candidates must be chosen with care. Unlike the situation in neonates, when ECMO is being considered for use in a pediatric patient, no clear set of inclusion or exclusion criteria exists. Evaluation of a pediatric patient for ECMO support is largely based on an assessment of the patient's condition and a center's previous experience with pediatric ECMO. The data that are available through ELSO indicate that survival decreases as the number of days a patient receives mechanical ventilation before the initiation of ECMO increases. The effect of burns on patients' outcomes is unknown. Age, duration of mechanical ventilation, and excision with allografting or homografting of the burns should all be considered before the patient is offered ECMO support. The remaining prognostic signs--duration of ECMO support, frequency of complications, and blood product requirements--are available only after the ECMO course is under way or completed. The success of our center and others in using ECMO to treat respiratory failure associated with burns shows that some patients with burns may benefit from ECMO. Unfortunately, no specific set of criteria exists that would enable ECMO centers to differentiate good candidates from poor ones and thus be able to offer ECMO support with confidence in its benefit for the patient.

Children and adults who are severely burned develop magnesium(Mg) depletion, hypocalcemia, hypoparathyroidism and renal resistance to the administration of exogenous parathyroid hormone(PTH). This same spectrum of findings is seen with both Mg depletion and hypermagnesemia. We reported that in a group of ten children burned at least 30 per cent of total body surface area that 70-80 per cent of serum levels of ionized calcium and Mg were low. In three of the patients studies when serum Mg returned to normal, retention of a standard Mg infusion was abnormally high in two of them, suggesting persistence of Mg depletion despite normal serum Mg levels. Mg intake in these children conforms to the recommended dietary intake for age suggesting that excessive Mg losses may contribute to the observed Mg depletion. These losses are through the burn wound and possibly through abnormal intestinal secretion. Increased metabolic rate seen in burn patients may also promote intracellular Mg uptake to support the increased energy requirements of cells. It is hypothesized that since Mg is an important cofactor in the production of cyclic AMP, Mg deficiency may block intracellular cyclic AMP generation in parathyroid cells to block the secretion of parathyroid hormone and in renal tubular cells to block the renal generation may improve PTH secretion and hypocalcemia in non-burned patients, preliminary data in burned children suggest that the cause of hypocalcemia and hypoparathyroidism is more complex.

Burn injury in children is associated with low bone formation and long-term bone loss. Because recombinant human GH (rHGH) may accelerate burn wound healing, and because rHGH increases bone formation and density in GH-deficient patients, we studied the short-term effects of rHGH on bone fomation, reflected by osteocalcin and type I procollagen propeptide levels in a randomized, double-blind, placebo-controlled study. Nineteen patients were enrolled and received either rHGH (0.2 mg/kg.day) or an equal volume of saline. Mean burn size and age were not different between the groups, and test substances were given from admission to time of wound healing (mean: 43 +/- 22 days). At wound healing, serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 in the rHGH group rose to mean values of 229% and 187% of the respective means of the placebo group (P0.025). Serum osteocalcin concentrations remained below normal in both groups, and type I procollagen propeptide levels achieved a low normal level IGFBR-4 levels were twice that of normal on admission and doubled further at wound healing; IGFBP-5 levels were low on admission but rose to normal at wound healing. We conclude that large doses of rHGH were ineffective in improving disordered bone formation despite increasing serum IGF-1 and IGFBP-3. The rHGH-independent rise in serum levels of the inhibitory binding protein IGFBP-4 suggests a mechanism by which improved bone formation is prevented despite successful elevation of IGF-1 and IGFBP-3 in the burned child.

The pathogenic methicillin-resistant Staphylococcus aureus (MRSA) has received a voluminous amount of notoriety. The four major reasons are its morbidity, mortality rate, cost of treatment, and constant appearance in intensive care units. Both Staphylococcus aureus and S. epidermidis (MRSE) account for 82% of our gram-positive wound isolates, whereas the gram-negative account for 34% of all isolates. Therefore we compared the morbidity, mortality rate, and cost factors related to MRSA-MRSE and gram-negative infections for a 4-year period, assessing more than 214 documented infections. Morbidity and mortality rates were minor for MRSA. Pseudomonas aeruginosa and Escherichia coli accounted for 57.5% of the total gram-negative isolates. Gram-negative antimicrobial therapy usually requires two therapeutic drugs, which increases morbidity and costs, whereas the staphylococci usually can be treated by one antimicrobial. During this period there were 47 gram-negative infections requiring 10 to 15 additional days of hospital stay, with a daily antibiotic cost of $293.40. Costs for MRSA or MRSE are 28% less. Therefore our preoccupation with MRSA or MRSE infections is unwarranted and unsubstantiated.

We have described previously that CD8+ CD11b+ TCR gamma/delta+ type 2 T cells (BA-type 2 T cells) and suppressor macrophages (Sup-Mł) are generated in spleens of mice 3 to 5 days (Sup-Mł) and 4 to 9 days (BA-type 2 T cells) after thermal injury. In the present study, an additional suppressor T cell, characterized as CD3+ CD4- CD8- TCR alpha/beta+ T cells (double negative suppressor T cells, DN Sup-T cells), was demonstrated in mice 1 day after thermal injury. DN Sup-T cells inhibited the proliferation of lymphocytes stimulated with allogeneic cells or a lectin in a mixed lymphocyte reaction, and produced both type 1 and type 2 cytokines (interferon-gamma, interleukin-2, interleukin-4, and interleukin-10) when they were stimulated in vitro with anti-CD3 monoclonal antibody. These results suggest that DN Sup-T cells express phenotypic properties similar to natural suppressor cells and cytokine-producing profiles different from type 1 (Th1 cells and CTLs) and type 2 T cells (Th2 cells and CD8+ type 2 T cells). DN Sup-T cells may play a role on the burn-associated immunosuppression appearing in the acute phase of thermally injured individuals.

Monocyte/T-cell interactions play a critical role in the systemic response to infection. Distinct patterns of cytokines are produced by two different types of T-helper cells (Th). Th1 cells secrete interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13. In volunteers systemic endotoxin administration initiates many features of gram-negative sepsis including cytokine release, but the patterns (i.e., Th1/Th2 patterns) have not yet been studied. In this institutional review board-approved study we investigated the effect of an intravenous bolus of endotoxin from Escherichia coli (4 ng/kg body weight) on the Th1/Th2 response in four female and four male volunteers (mean age 27.1 +/- 0.8 years). Plasma cytokine levels for IL-2, IL-4, IL-10, IL-12, and IFN-gamma and heart rate, mean arterial pressure, temperature, white blood cell, and differential blood count were determined before and hourly for 5 hours after endotoxin administration. All volunteers had tachycardia, decreased mean arterial pressure, fever, and leukocytosis. IL-10 was significantly (p0.05) elevated (9.4 +/- 3.9 pg/ml vs 60.9 +/- 19.3 pg/ml) 3 hours after endotoxin was administered, whereas IL-2 levels were decreased (69 +/- 26 U/ml vs 30.6 +/- 14.9 U/ml). IL-4 and IFN-gamma were not detectable in plasma. No changes were seen in the plasma levels of IL-12. Systemic responses did not correlate with changes in cytokine levels. Cytokine patterns found in this study suggest that after low-dose endotoxin administration the T-cell immune response is shifted towards the Th2 cell type response. This early shift towards a Th2 cell response may contribute to the depressed cell-mediated immune response associated with sepsis.

The process of wound healing represents a series of complex physicochemical reactions requiring different nutritional microcomponents at each stage. In patients with extremely grave diseases and injuries the course of wound healing is impaired because of a hypermetabolic reaction to stress, leading to protein catabolism. The hypothalamus responds to cytokine stimulation by changes of thermoregulation (increase of heat production) and increased production of stress hormones (catecholamines, hydrocortisone, and glucagon). In turn, stress hormones trigger the thermogenous (unproductive) metabolic cycle and the lipolysis and proteolysis processes. Hyperproduction of glucose at the expense of skeletal muscle tissue degradation leads to the formation of amino acid substrate for liver glyconeogenesis. Additional nutrients are obligatory for wound healing in such patients. Protein catabolism cannot be arrested by amino, acids alone partly because amino acid transport is impaired; it can be normalized by anabolics, such as growth hormone and insulin-like growth factor 1. Treatment with growth hormone yields a dramatic positive effect in severely burned children. Proteins and vitamins, specifically arginine and vitamins A, B, and C provide the optimal nutritive support during wound treatment.

The acute response to skin injury following burn is characterized by hypermetabolism, increased cardiac output, lipolysis, gluconeogenesis, and proteolysis. This review will describe the early responses to thermal trauma and potential methods for modulating deleterious consequences of these responses.

Pediatric patients with severe burns exhibit growth delays. This study investigates weight history after discharge. Twenty-seven children with burns covering more than 40% of their total body surface area were studied from admission until 2 to 4 years after injury. Younger children decreased their weights for height; older patients mainly increased theirs. Alterations during the first year of follow-up correlated with alterations until 2 and 3 years (r = 0.91 and r = 0.76, respectively). Once initiated, net weight gain continued, whereas net weight losses diminished with time. Preburn equivalent weights, however, could not be reached within 3 years. Special attention must be paid to children who are close to or less than their ideal body weights at the time of injury, especially if they are young, because further weight loss may be critical. Outpatient nutritional therapy should be focused to control these developments.

The early catabolic phase of severe injury is associated with acute growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) deficiency. The metabolic half-life of circulating IGF-1 is prolonged by its binding to IGFBP-3. The role of this binding protein in nutritionally repleted multiple-injury patients has not been previously evaluated. We have measured plasma levels of these polypeptides and nitrogen (N) balance in 18 adult (15 males/3 females ; mean age, 45 years), severely injured, hypermetabolic, and highly catabolic trauma patients within 48 to 60 hours after injury, when they were receiving maintenance fluids without calories or N and during 6 days of total parenteral nutrition (TPN). Before instituting TPN, the patients were randomized to receive (group H, n = 9) or not to receive (group C, n = 9) daily recombinant human growth hormone (rhGH), 0.15 mg/kg IM. Adjuvant rhGH significantly increases plasma levels of GH, IGF-1, IGFBP-3, and insulin. In addition, it shows better improvement in N balance. The bioavailability of IGF-1 is increased, as indicated by the decrease in IGFBP-3 :IGF-1 ratio. A significant correlation between IGF-1 and IGFBP-3 levels is present in the trauma patients who received TPN and rhGH. A GH/IGF-1/IGFBP-3 axis that closely regulates the metabolic status of the patient is established in trauma.

Arginine-glycine-aspartic acid (RGD) peptide matrix is designed to promote dermal healing by providing a molecular scaffold that facilitates cell ingrowth and establishment of normal tissue architecture. This study investigated the effectiveness and safety of RGD peptide matrix in the treatment of partial-thickness scald burns in pediatric patients. Either topical RGD peptide matrix or control treatment with silver sulfadiazine was applied to matched burn sites daily for up to 21 days. With RGD peptide matrix application under synthetic occlusive dressing, the incidence of healing was nearly threefold higher, average time to healing 2.5 days shorter (regression estimation), extent burn closure at all treated sites 37% greater, and number of needed grafting procedures fourfold lower compared with control treatment. All these differences were statistically significant. RGD peptide matrix was well tolerated. RGD peptide matrix promoted and accelerated healing in this study and thus may be able to reduce morbidity and treatment costs of partial-thickness burns in pediatric patients.

Thromboxane A2 (TxA2) is a key mediator in the pathophysiology of severe burns and sepsis. This study was performed to assess the potential benefits of TxA2 synthetase inhibition and TxA2 receptor blockade in sepsis after severe thermal injury.Pigs with left atrial, aortic, and pulmonary artery catheters received a 40 percent third-degree burn and, 24 hours later, 100 micrograms per kg Escherichia coli endotoxin. The antagonist treatment (BM) group was treated with the TxA2 receptor antagonist BM 13.177, the synthetase treatment (OKY) group with the TxA2 synthetase inhibitor OKY-046, and the control group received saline solution placebo. Another group without burn or endotoxin was used to assess the side effects of BM 13.177.Both drugs significantly attenuated the changes in pulmonary vascular resistance index, cardiac index, arterial PO2, shunt, oxygen delivery, and oxygen consumption seen after endotoxin. However, cardiac index was significantly decreased in group BM before endotoxin. In healthy pigs, BM 13.177 decreased cardiac index and oxygen delivery and increased the pulmonary vascular resistance index.TxA2 synthetase inhibitors and TxA2 receptor blockers are potentially useful in sepsis after severe burns. Comparison between drugs was complicated by the adverse effects of the antagonist, and further investigation with other antagonists is needed.

Wound healing is a series of complex physicochemical interactions that require various micronutrients at every step. In the critically ill or severely injured patient, wound healing is impaired by the protein-catabolic, hypermetabolic response to stress. The hypothalamus responds to cytokine stimulation by increasing the thermoregulatory set-point and by augmenting elaboration of stress hormones (catecholamines, cortisol, and glucagon). In turn, the stress hormones induce thermogenic futile substrate cycling, lipolysis, and proteolysis. Increased glucose production results at the expense of skeletal muscle degradation, producing amino acid substrate for hepatic gluconeogenesis. Nutritional support of the hypermetabolic state is an essential part of ensuring efficient wound healing in these patients. Protein catabolism cannot be reversed by increased amino acid availability alone, due partly to a defect in amino acid transport. This defect can be reversed by anabolic agents, such as growth hormone and insulin-like growth factor-1. Growth hormone treatment dramatically improves wound healing in severely burned children. Supplementation with protein and vitamins, specifically arginine and vitamins A, B, and C, provides optimum nutrient support of the healing wound.

Inhalation injury is a dominant cause of mortality in thermally injured individuals. After acute lung injury induced by smoke inhalation, lung lymph flow (QL) increased and pulmonary microvascular reflection coefficient to protein (sigma) decreased. alpha-Trinositol (PP56, 1D-myo-inositol 1,2,6-trisphosphate) can decrease edema formation after thermal injury. We therefore tested the hypothesis that alpha-trinositol could decrease the pulmonary edema noted with inhalation injury. Seven days after surgical preparation, sheep were insufflated with smoke from burning cotton towels. The alpha-trinositol group (n = 8) were treated with alpha-trinositol (2 mg/kg + 3.5 mg.kg-1 x h-1). The sham group (n = 7) received an equal volume of 0.9% NaCl. The sham group showed a large increase in QL (9.3 +/- 1.7 to 54.1 +/- 8.8 ml/h) and a decrease in sigma (0.79 +/- 0.03 to 0.48 +/- 0.03) 24 h after smoke inhalation. alpha-Trinositol attenuated the increase in QL (8.1 +/- 1.2 to 25.6 +/- 6.9 ml/h) and the decrease in sigma (0.76 +/- 0.03 to 0.60 +/- 0.03) noted with smoke inhalation. alpha-Trinositol thus decreased the changes in pulmonary microvascular permeability and transvascular fluid flux noted with inhalation injury.

Blood transfusions have been repeatedly shown to be immunosuppressive in nature. The intracellular mechanisms of this immunosuppression have not been extensively investigated. We investigated the effect of blood transfusions on lymphocyte intracellular metabolism of glucose and amino acids, as well as levels of adenosine deaminase activity and nucleotide triphosphate concentrations. Blood transfusions were found to increase the rate of glucose and glutamine metabolism, to increase nucleotide triphosphate concentrations, and to increase the level of adenosine deaminase activity. This increased level of lymphocyte metabolism in the face of immunosuppression would appear to indicate that the transfusion-induced immunosuppression is an active dynamic process.