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Injury elicits a response from all cells of the immune system in which cytokines and other metabolic products of activated leukocytes can act either beneficially to provide for enhanced host resistance or deleteriously to depress the function of remote organs and cause what has been termed systemic inflammation. These at times antithecal responses of leukocytes that appear to integrate postinjury changes in the neuroendocrine, immune, and coagulation systems have been implicated as principal causative factors in multiple systems organ failure. Numerous investigators have evaluated a variety of therapeutic agents to prevent and control infection by restoring leukocyte function, while others have evaluated antagonists and monoclonal antibodies as a means of controlling the exaggerated and persistent actions of leukocytes and cytokines caused by systemic inflammation. The redundancies of the cell populations and the cytokines and other metabolites produced by the cells predictably limit the effectiveness of any single agent and make clinical evaluation of such agents difficult.

Estimations of total urinary nitrogen from measured urinary urea nitrogen are commonly used in calculating nitrogen balance. Recently published studies suggest the urinary urea nitrogen/total urinary nitrogen relationship is inconstant and total urinary nitrogen must be directly measured in burned patients. This study addresses the relationship of urinary urea nitrogen to total urinary nitrogen after thermal injury. Two hundred random 24-hour urine collections obtained from 45 thermally injured patients (mean burn size 59 +/- 28%, mean age 40.5 +/- 17.2 years) between 1 and 354 days postburn were analyzed for total urinary nitrogen and urinary urea nitrogen. Regression analysis relating total urinary nitrogen to estimated total urinary nitrogen (urinary urea nitrogen x 1.25) revealed a linear relationship (r = .936, p < .001). The mean urinary urea nitrogen/total urinary nitrogen ratio was 0.77 +/- 0.10 and was not significantly correlated with percent burn, age, or postburn day. Mean nitrogen balance calculated from measured urinary urea nitrogen in these patients was -5.7 g, and that calculated from measured total urinary nitrogen was -6.3 g. This difference, although statistically significant, is of little consequence for clinical use. Contrary to recent reports, we found the urinary urea nitrogen to be sufficiently predictive of total urinary nitrogen for practical application, and do not consider routine total urinary nitrogen measurements necessary for the nutritional care of thermally injured patients.

We measured plasma levels of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL-6) following thermal injury. Cytokine levels in the plasma of 27 burned patients were serially screened by ELISA and compared with cytokine levels in 16 healthy laboratory employees. The relationships between cytokine concentrations and patient mortality, burn size, and time postburn were examined. Plasma samples with detectable amounts of IL-1 beta and IL-6 were significantly more frequent in burned patients than in controls, whereas TNF alpha was undetectable in most plasma samples. All nonsurviving burned patients had detectable IL-6 levels; these were significantly higher than those of surviving patients. The IL-1 beta and IL-6 concentrations were highest during the first week after injury and declined over time. The IL-1 beta concentrations were positively correlated with burn size. These findings suggest that IL-1 beta and IL-6 may influence metabolic and immunologic responses in the first few weeks following thermal injury. Tumor necrosis factor alpha was transiently elevated in a small subpopulation of burned patients with no obvious relationship to burn size or time postburn.

Objective: This study compared two forms of high-frequency ventilation (HFV) with conventional volume ventilation (CON) in a primate model of inhalation injury to determine whether ventilatory mode was a determinant of pulmonary damage., Summary Background Data: The authors previously reported that the prophylactic use of high-frequency flow interruption in patients with bronchoscopically diagnosed inhalation injury requiring mechanical ventilatory support resulted in a significant decrement in mortality. They hypothesized that a reduction in ventilatory mode induced pulmonary damage was in part responsible for their clinical results., Methods: Fifteen adult baboons were randomized to one of three ventilatory modes (CON, high-frequency flow interruption [HFFI], or high-frequency oscillatory ventilation [HFO]) after moderate smoke injury. Ventilatory support was tailored to the same physiologic endpoints. After 7 days, the animals were killed and pulmonary pathologic changes were scored and compared. Repetitive physiologic and biochemical data were compared using analysis of variance for repeated measures., Results: Physiologic endpoints were achieved in CON and HFFI, but not in HFO. Hemodynamic variables did not differ between CON and HFFI. The barotrauma index was greater in CON compared to HFFI (p < 0.05), despite similar PO2, FIO2, AA gradient, and PCO2. Animals treated with HFFI had significantly less parenchymal damage than those treated with CON (p = 0.03) or HFO (p = 0.0008)., Conclusions: The prophylactic use of HFFI led to a significant decrement in ventilatory mode induced pulmonary damage and offers an explanation for the decreased mortality in inhalation injury patients treated with HFFI.

The renal effects of low-dose dopamine (LDD) therapy in hyperdynamic thermally injured patients are unknown. We investigated the renal effects of LDD in ten burn patients (mean +/- SEM age and % total body surface burned: 30.2 +/- 3.3 years and 53.4% +/- 7%) and six controls (mean age; 20.2 +/- 0.5 years). Administration of LDD significantly increased glomerular filtration rate, effective renal plasma flow, sodium excretion, and urine flow in the controls and effective renal plasma flow, urine flow, heart rate, and cardiac index in the patients. The chronotropic effect of dopamine appears to be a principal contributor to the patients' increased effective renal plasma flow. Sodium excretion was increased by LDD only in the patients in whom the predopamine sodium excretion exceeded 5 mEq/h. Lack of a consistent natriuretic effect and the consistent chronotropic effect suggest that the routine use of low-dose dopamine in burn patients is unwarranted. The side effects that attend the desired response determine clinical use, i.e., the potential for blood flow redistribution and increased cardiac work demands must be balanced against increased renal plasma flow and natriuresis.

Objective: The relationship of plasma cytokine levels to infection, core temperature, and to one another in patients with thermal injury was examined., Summary Background Data: The response to infection has been associated with cytokines such as interleukin 1 beta (IL1 beta), interleukin 6 (IL6), and tumor necrosis factor alpha (TNF alpha), and these cytokines have been studied in various inflammatory diseases. The authors previously reported that patients with thermal injury have elevated IL1 beta and IL6 plasma levels and that these cytokines may play different roles in the response to thermal injury., Methods: IL1 beta, IL6, and TNF alpha were measured by enzyme-linked immunosorbent assay (ELISA) in serial samples of plasma from 27 patients., Results: IL6 and TNF alpha levels were increased in severely infected patients as compared to patients who remained free of infection, and the IL6 level was higher in infected patients who died than those who survived. There was no apparent relationship between IL1 beta levels and infection. IL6 and IL1 beta were positively correlated with core temperature. The correlations between IL6 and IL1 beta, between IL6 and TNF alpha, and between TNF alpha and IL1 beta were significant., Conclusions: These results suggest that IL6 and TNF alpha play a role in the response of burned patients to infection.

Objective: To study a cohort of patients treated at the same institution and to compare that patient population with that of a previous report documenting the comorbidity of inhalation injury and pneumonia. Specifically, we wanted to determine whether there had been an improvement in survival of patients suffering inhalation injury., Design: A retrospective review., Setting: The US Army Institute of Surgical Research, Ft Sam Houston, Tex, a 40-bed burn intensive care referral unit., Subjects: One thousand two hundred fifty-six thermally injured patients treated between January 1985 and December 1990., Main Outcome Measure: A comparison of pneumonia frequency and ultimate survival of the current cohort of patients as compared with a previously generated stepwise logistic analysis predicting mortality on the basis of 1980 to 1984 patient data., Results: Of 1256 burned patients admitted between 1985 and 1990, there were 330 identified as having inhalation injury. These patients were older (35.0 vs 26.6 years) and had more extensive burns (41.1% vs 18.3%) and a higher mortality (29.4% vs 5.0%) than did the patients without inhalation injury. When compared with a mortality predictor generated from 1980 through 1984 patient data, patients in the most recent period had a lower mortality than predicted (29.4% vs 41.4%). Patients with less severe injury (positive xenon scan, negative results of bronchoscopy; n = 85), although having a similar incidence of pneumonia (13.1% vs 19.5%) as the same group from 1980 through 1984, accounted for the most improvement in survival. The 3.6% mortality was significantly less than the predicted rate of 15.7%. Patients with positive results of bronchoscopy (n = 245) also showed some improvement in outcome from that predicted (38.3% vs 50.2%) despite no change in the rate of pneumonia (46.9% vs 48.5%). Further improvement in survival was realized in those patients supported with high-frequency ventilation. Although their age (33.9 vs 36.3 years), burn size (46.0% vs 45.5%), and duration of intubation (16.8 vs 15.1 days) were similar to those of conventionally treated patients, mortality was significantly less than predicted (16.4% vs 40.9%) and less than that in patients treated with conventional ventilation (16.4% vs 42.7%)., Conclusions: The improvement in survival of patients with inhalation injury represents the aggregate effects of the general improvement and outcome of all burned patients, the prevention of pneumonia by high-frequency ventilation, and the reduced mortality from the pneumonias that did occur.

Nitric oxide is biosynthesized from the amino acid L-arginine by the enzyme nitric oxide synthase. Nitric oxide is a vasodilator, a neurotransmitter, and may modulate immune function. The experiments presented here were performed to determine whether the synthesis of nitric oxide is increased following experimental burn injury in rats. After a 30% total body surface area burn in 300-g Lewis rats, the urinary output of nitrate, a stable metabolite of nitric oxide, was significantly increased for 8 days postburn compared with that in sham-burned control rats. The origin of the urinary nitrate from L-arginine was demonstrated by administering the stable isotope 15N2-guanido-arginine to burned and sham-burned rats and observing an immediate enrichment of 15N in nitrate. The amount of administered 15N recovered as 15NO3 was < 1% of the administered arginine isotope in both the burned and unburned rats; the recovery of the isotope increased tenfold over baseline recovery in burned rats. The arginine analog N-monomethyl-arginine, an inhibitor of the enzyme nitric oxide synthase, blocked the postburn rise in urinary NO3 output in burned rats, but did not completely inhibit the output of NO3 in burn wound-infected rats. Experimental burn injury in rats results in an increase in L-arginine-dependent nitric oxide production and urinary nitrate output.

Cultured autologous keratinocytes (CAK) have been heralded as a means to achieve more rapid closure of massive burn wounds. Despite the claimed benefits of this technology, we have failed to identify its positive impact on wound closure in extensively burned patients. Sixteen patients with a mean age of 29.7 years (range, 10-56 years) and a mean total body surface area burn of 68.2% (range, 42%-85%) underwent 22 applications of CAK supplied by a private laboratory. The keratinocyte grafts were applied to a mean of 15.9% of the body surface area (range, 4%-59%) at an average cost per patient of $43,705 (range, $9,800 to $161,000). The mean body surface area of definitive wound coverage by these grafts was 4.7% (range, 0%-18.6%). The mean length of hospitalization was 132 days (range, 50-275 days). The observed mortality was 12.5% (two patients). Our experience with this wound care approach has been assessed with respect to the extent of burn, the level of wound excision, and the site of CAK application.

In the course of developing a model of inhalation injury, the relationship between the severity of pulmonary injury and specific techniques and doses of smoke exposure was examined in pairs of rabbits simultaneously exposed to smoke. In group I (5 pairs), one animal in each pair was exposed to smoke with a breath hold (BH) at the end of each exposure; the second animal received an exposure producing the same level of carboxyhemoglobin without BH. In group II (6 pairs), both animals were exposed to 25 units of smoke simultaneously, with BH. In group III (3 pairs), one animal received a 20-unit exposure and the other a 25-unit exposure, both with BH. In group IV, 9 animals received 25-unit exposures with BH and were observed for 4 days. Groups V and VI served as controls. Smoke exposure with BH regularly produced severe injury in terms of decreased PaO2 and histopathologic changes, while exposure without BH did not, despite high levels of carboxyhemoglobin after smoke inhalation. The mean differences in percent residual PaO2 (PaO2 at 48 hours x 100/pre-injury PaO2) and in extravascular lung water (EVLW) at 48 hours within pairs of animals receiving 25 units with BH were 12.3% +/- 5.33%, and 0.271 +/- 0.157 mL/g, respectively. Histologic findings such as necrotic tracheobronchitis with pseudomembrane were consistently present. No differences were observed between animals receiving exposure of 20 and 25 units. During the 4 days of observation, three animals in group IV died. PaO2 was lowest on the second day and rose thereafter in all surviving animals except in one that had massive pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been estimated that 26% of Americans are obese. A very small subset of this group can be categorized as morbidly obese, fulfilling the criteria of being 100 pounds, or 100%, over ideal body weight. The clinical records of seven morbidly obese burn patients treated over a 20-year period are reviewed. Particularly notable was a 43% incidence of fatal pulmonary embolism.

The frequency of thromboembolic complications in burn patients has been estimated to range from 0.4% to 7%. The clinical significance of these events is often debated and has prompted some centers to adopt the routine prophylactic use of low dose heparin prophylaxis. A 10 year review of 2,103 burn patients treated at this institution was undertaken. Twenty-five (1.2%) patients, with a mean age of 40.0 years and an average burn size of 49.3% total body surface area (TBSA), were identified as having significant pulmonary thromboembolism (PTE). In only 3 (0.14%) patients was the thromboembolism considered to be a cause of death. Nineteen (0.9%) patients, with an average age of 36.7 years and a mean burn size of 48.3% TBSA, developed clinically evident deep venous thrombosis (DVT); however, in only 1 (0.05%) patient did the disease progress to fatal PTE. A review of the literature reveals a 0.6% to 5% incidence of complications related to low dose heparin therapy which includes bleeding, thrombocytopenia, and arterial thrombosis. We feel that the infrequency of clinically significant PTE and DVT in burn patients and the comparable or greater rate of complications associated with heparin prophylaxis mitigate against the routine use of low dose heparin therapy except in patients at high risk for these events.

Background: Alterations in granulocyte function after thermal injury have been described. We have serially studied the level of granulocyte cytosolic peroxidase activity in 23 thermally injured patients during the first 6 weeks after injury. The patients' mean age and burn size were 35.1 +/- 15.7 years and 41.6% +/- 16.8% (range, 18% to 88%), respectively. Fourteen patients had concomitant inhalation injury, and the overall mortality rate was 4.3%., Methods: Purified granulocytes were obtained from peripheral blood after red cell lysis and Ficoll-Hypaque (Pharmacia Inc., Piscataway, N.J.) gradient separation. Cells were loaded with dichlorofluorescin diacetate, and baseline fluorescence was measured by flow cytometry. After phorbol myristate acetate stimulation, fluorescence was measured again. Cells from unburned normal subjects were used as daily controls., Results: The data are expressed as percent of stimulated control granulocyte fluorescence. Unstimulated patient granulocytes demonstrated a significantly higher baseline activity than did unstimulated controls (22.9% vs 15.4%; p < 0.05). Mean fluorescence from stimulated granulocytes was 114% of the control values (p < 0.05)., Conclusions: Granulocytes from thermally injured patients exhibited a baseline increase in cytosolic oxidase activity, suggesting in vivo activation and a greater than normal oxidase activity after in vitro stimulation.

Resting energy expenditures (REE) were measured using indirect calorimetric techniques in 62 patients with burn injuries admitted during 1987 to 1989 and compared with similar measurements made during 1972 to 1973. Energy requirements were related to burn size in both populations, but were greater in the earlier population. In the present study, data from some patients were obtained using a canopy system and from others during mechanical ventilation and were analyzed separately. The regression of REE on burn size was linear for the canopy measurements (r = 0.724) and for the ventilator measurements (r = 0.579). REE data were corrected for the expected basal metabolic rate (BMR) for each patient, with appropriate adjustment for age and sex. The regression of REE per BMR on burn size was linear (r = 0.724), differing from the curvilinear relationship found during 1972 to 1973. These data suggest a change in postburn energy requirements, probably related to differences in patient management. Predictive equations based on older data can be expected to overestimate energy requirements in patients receiving modern burn therapy.

Skin grafts can be used effectively to inhibit wound contraction. A critical element of this inhibition is the adherence of the graft to the wound bed. Fibrin glue has been shown to increase the adherence of skin grafts to wound beds. We therefore devised an experiment to determine the effect of fibrin glue on skin graft inhibition of wound contraction. Two 2.5 x 2.5-cm full-thickness defects were created on the dorsa of 15 Sprague-Dawley rats. Thirty partial-thickness grafts were harvested from isogeneric donor animals using a brown dermatome. Prior to grafting, one full-thickness defect, each animal received 0.2 mL of fibrin glue (Immuno AG, Vienna, Austria). The adjacent wound served as the control and received 0.2 mL of normal saline. Grafts were applied, sutured, and protected with an occlusive dressing. The size of graft sites treated with fibrin glue or normal saline was determined at the time of graft application and thereafter at 3-day intervals for 21 days using standardized photographic techniques. The percentage of change from initial wound size at each point was recorded for each group. Graft sites treated with fibrin glue contracted less than the controls from the ninth postgraft day to the completion of the study. The mechanism by which fibrin glue inhibits wound contraction may be related to increased adherence of grafts to the underlying wound bed. As an adjunct in skin grafting, fibrin glue may offer certain advantages that are not achieved by suturing alone.

Several fluorescent substances are present in the supernatants of acid-precipitated whole blood or plasma from burned patients. Perchloric acid supernatants of sera from infected, but not uninfected, burned rats contained a fluorescent substance with maximum emission at 420 nm at 355-nm excitation (355 ex/420 em). In this study of serum from burned human patients, several fluorescent substances were resolved by reverse-phase high-pressure liquid chromatography. One of these fluorescent components had an high-pressure liquid chromatography retention time and fluorescent characteristics identical to those of neopterin. The identification of this component as neopterin was verified by thermospray mass spectrometry. Serum neopterin concentrations were then determined in supernatants of patient serum samples having various levels of 355 ex/420 em fluorescence. A correlation was found between the concentrations of neopterin determined by high-pressure liquid chromatography and the presence of bacteremia in burned patients. These findings suggest that neopterin, which is a useful indicator of infection in other clinical settings, may also be an indicator of infection in burned patients.

The role of platelet-activating factor (PAF) in inhalation injury was studied in sheep, using CV-3988, a PAF antagonist. Following smoke exposure, 15 sheep were divided into three groups of five. Group I animals were untreated; group II animals were treated with CV-3988 before and after exposure; group III animals were treated only after exposure. In group I, platelet and WBC counts were markedly changed within 6 hours (p less than 0.05); in the treated groups, alteration of cell counts was not obvious. Blood malondialdehyde (MDA) levels were increased significantly only in group I. Blood PGE2 and TXB2 levels did not differ among the groups. Mean tissue MDA and mean bronchoalveolar lavage fluid (BALF) MDA concentrations were significantly increased in group I (p less than 0.01); mean BALF TXB2 levels were significantly decreased in group I (p less than 0.01). These data suggest that PAF affects inhalation injury through modulation of lipid oxygenation and that PAF antagonists may offer therapeutic benefit in the management of this injury.

Previous studies have demonstrated that human malignancies can synthesize large amounts of thromboxane. It has also been reported that thromboxane can significantly alter multiple components of physiologic and immunologic function. We investigated the effect of elevated levels of thromboxane on host response to tumor using multiple rat models, and the long acting thromboxane analogue U-46619. Administration of the thromboxane analogue was not found to significantly alter the growth of primary tumors or peritoneal metastases. The analogue was found to significantly decrease mean survival time with a pulmonary metastases model. The thromboxane analogue failed to alter macrophage cytotoxicity, lymphocyte cytotoxicity, T lymphocyte subset numbers, or lymphocyte blastogenic response. Administration of the thromboxane analogue decreased the rate of lymphocyte metabolism of glucose and decreased lymphocyte intracellular adenosine deaminase activity. In conclusion, elevated thromboxane levels do not appear to alter primary tumor growth or host immune function, but do decrease resistance to pulmonary metastases.

Topical chemotherapy, prompt excision, and timely closure of the burn wound have significantly reduced the occurrence of invasive burn wound infection and its related mortality. Since wound protection is imperfect and invasive wound infection may still occur in patients with massive burns in whom wound closure is delayed, scheduled wound surveillance and biopsy monitoring are necessary to assess the microbial status of the burn wound and identify wound infections caused by resistant bacteria or non-bacterial opportunists at a stage when therapeutic intervention can control the process. As a reflection of the systemic immunosuppressive effects of burn injury, infection remains the most common cause of morbidity and mortality even though the occurrence of wound infections has been significantly decreased. Pneumonia is the most frequent infection occurring in burn patients today but the improvements in patient management, wound care, and infection control have made bronchopneumonia the most common form of this infection and gram-positive organisms the most common causative agents. The organisms causing bacteremia that exert a species specific effect on the mortality related to extent of burn injury and patient age have changed in concert with changes in wound flora. Infection control procedures, including scheduled surveillance cultures, utilization of cohort patient care methodology, strict enforcement of patient and staff hygiene, and patient monitoring have been effective in eliminating endemic resistant microbial strains, preventing the establishment of newly introduced resistant organisms, diagnosing infection in a timely fashion, instituting antibiotic and other necessary therapy in a prompt manner, and documenting the effectiveness of present day burn patient care and the improved survival of burn patients.

Alterations in intestinal permeability have been postulated to occur after thermal injury. We evaluated the status of intestinal permeability during the first 2 postburn weeks in 15 subjects by measuring the differential excretion of enterally administered lactulose and mannitol. The mean age and burn size of the patients were 32.7 +/- 3.6 years and 53.3% +/- 5.1% of the total body surface area, respectively. Ten healthy volunteers were also studied. The lactulose-mannitol excretion ratio was 0.159 +/- 0.017 for the patients and 0.017 +/- 0.003 for controls. The increased ratio did not correlate with burn size or postburn day. Patients who developed significant clinical infections during their first 2 postburn weeks had lactulose-mannitol ratios on postburn day 2 that were significantly higher than those of controls and patients who did not develop infections. This suggests a relationship between susceptibility to infection and early alterations in intestinal permeability.

Prostaglandin E (PGE) is produced by certain tumors and is reported to decrease primary tumor growth. We evaluated its effect in multiple tumor models utilizing a 1 week course of the long acting PGE derivative dimethyl-PGE (dPGE) at a dosage of 100 micrograms/kg/day vs. a lactated Ringers control. For all tumor models, a suspension of 1 x 10(6) colon carcinoma cells were injected into Wistar-Furth rats. When the suspension was injected subcutaneously and the drug was begun at the time of tumor challenge, there was no effect on survival. When the tumor was injected intraperitoneally or intravenously and the drug begun at the time of tumor challenge, dPGE decreased survival time. When the tumor was administered intravenously but dPGE was delayed for 5 days, there was no effect on survival time. When rats were given a 1 week course of dPGE or saline, dPGE was found not to alter natural killer (NK) cell cytotoxicity, macrophage cytotoxicity, spontaneous lymphocyte blastogenesis, or mitogen stimulated blastogenesis. dPGE failed to alter lymphocyte metabolism of glucose in nonstimulated lymphocytes, but decreased the rate of glucose metabolism and adenosine deaminase activity in mitogen stimulated lymphocytes. In conclusion, PGE appears to enhance metastatic growth of tumor lines where it does not alter primary tumor growth. This effect does not appear immunologically mediated.

Pulmonary injury resulting from inhalation of chemical and particulate products of incomplete combustion is one of the principal determinants of mortality following burn injury. In this study, the histopathology of inhalation injury was examined in sheep. Mild, moderate, or severe smoke injury was produced in anesthetized sheep by insufflation with various doses of ambient temperature smoke, generated by burning polyethylene, wood pulp, and nonwoven cellulose pads. A total of 64 sheep were exposed and evaluated at times ranging from 15 minutes to 4 weeks after exposure. Morphologic changes in the lungs were studied using light microscopy and both transmission and scanning electron microscopy. The primary, dose-responsive injury observed was acute cell membrane damage in the trachea and bronchi leading to edema, progressive necrotic tracheobronchitis with pseudomembrane formation, and airway obstruction. These inflammatory and occlusive effects were followed by congestion, alveolar space edema, atelectasis, and bronchopneumonia. Morphologic changes occurring in the alveolar epithelium following high smoke dosage included intracellular edema in type-I cells, changes in the membrane-bound vacuoles of type-II cells, and septal thickening caused by interstitial edema. No capillary endothelial changes were observed.

The relationship between effective blood volume and related hormones in burn patients following resuscitation is not well understood. Previous reports have suggested that hormone secretion is altered by a resetting of neural control mechanisms. Serum and urine sodium, plasma renin activity, serum ADH, cardiac index, effective renal plasma flow, and total blood volume were measured in seven burn patients (mean age, total burn size, and postburn day: 32 years, 56%, and 9 days, respectively). The same values (with the exception of cardiac index and blood volume) were measured in 10 control patients (mean age, 24 years). The blood volume of patients was measured by 51chromium red blood cell (RBC) labeling and compared to normal predicted values based on body surface area and sex. Mean serum sodium and osmolality were 138 mmol/L (millimolar) and 286 mosm/kg, respectively, in both patients and control subjects. Mean +/- standard error of the mean total blood volume in the patients was low, 81% +/- 4% of predicted values. Cardiac index and renal plasma flow were significantly elevated. Plasma renin activity and antidiuretic hormone (ADH) levels were elevated and altered in the direction expected from blood volume measurements despite the findings of increased blood flow. Dissociation of organ flow and hormonal response suggests that simultaneous direct blood volume measurements are necessary to elucidate factors other than altered neural control settings to explain hormonal changes in the flow phase of injury. Depressed total blood volume appears to promote elevated ADH levels in burn patients following resuscitation. Whether there is an additional role of altered neural control settings remains to be established.

We have examined the effects of direct current (DC) conducted through silver-nylon dressings on the healing time and morphologic maturation of split-thickness grafts placed on tangentially excised deep partial-thickness burn wounds. Male guinea pigs (n = 120) were used as the experimental hosts. The DC-treated animals required 2 days for complete revascularization of their grafts; control animals required 7 days (p less than 0.01). The DC-treated animals had increased epithelial proliferation at the graft-wound interface as compared with controls (p less than 0.01). Grafts from DC-treated animals were firmly adherent within 4 days, whereas graft adherence in controls was weak before 7 days after grafting. At 3 months after grafting, control animal grafts had mild contraction with moderate hair loss and thick subepidermal fibrosis; the grafts in DC-treated animals expanded with the growth of the animals and had abundant hair growth and significantly reduced dermal fibrosis (p less than 0.01).

The use of serum visceral protein concentrations as predictors of nitrogen balance was assessed during the first 4 weeks following thermal injury. The correlation between nitrogen balance and serum albumin was not significant. Statistically significant correlations were found between nitrogen balance and serum prealbumin, retinol-binding protein, and transferrin. However, even the best correlation (retinol-binding protein, r = 0.388) was too weak to permit prediction of nitrogen balance on the basis of the visceral protein concentration. The correlation between change in direction of nitrogen balance and change in direction of protein concentration over time showed all four visceral proteins to be poor predictors of change in nitrogen balance. The efficiency was less than 50% for each visceral protein. Stepwise multiple regression analysis performed to determine which indices were most closely correlated with nitrogen balance showed that a calculation using readily available information (nitrogen intake, postburn day, percent total body surface burned, and age) provided better prediction of nitrogen balance (r = 0.765) than any of the visceral protein concentrations. In view of these findings, measurement of serum visceral protein concentrations to monitor adequacy of nutritional support seems an unwarranted expense in patients with thermal injury.

Death and the incidence of pneumonia are significantly increased in burn patients with inhalation injury, despite application of conventional ventilatory support techniques. The effect of high-frequency percussive ventilation on mortality rate, incidence of pulmonary infection, and barotrauma were studied in 54 burn patients with documented inhalation injury admitted between March 1987 and September 1990 as compared to an historic cohort treated between 1980 and 1984. All patients satisfied clinical criteria for mechanical ventilation. High-frequency percussive ventilation was initiated within 24 hours of intubation. The patients' mean age and burn size were 32.2 years and 47.8%, respectively (ranges, 15 to 88 years; 0% to 90%). The mean number of ventilator days was 15.3 +/- 16.7 (range, 1 to 150 days), with 26% of patients ventilated for more than 2 weeks. Fourteen patients (25.9%) developed pneumonia compared to an historic frequency of 45.8% (p less than 0.005). Mortality rate was 18.5% (10 patients) with an expected historic number of deaths of 23 (95% confidence limits of 17 to 28 deaths). The documented improvement in survival rate and decrease in the incidence of pneumonia in patients treated with prophylactic high-frequency ventilation (HFV), as compared to a cohort of patients treated in the 7 years before the trial, indicates the importance of small airway patency in the pathogenesis of inhalation injury sequelae and supports further use and evaluation of HFV.

We studied the effects of granulocyte-macrophage colony-stimulating factor in burn patients. Serial measurements of granulocyte oxidative function were obtained in treated patients and in a group of controls matched for age and total burn size. The administration of granulocyte-macrophage colony-stimulating factor resulted in a 50% increase in mean leukocyte counts. Both groups showed significant baseline increases in granulocytic cytosolic oxidative function. Treated patients showed normal stimulated cytosolic oxidative function, which was significantly depressed compared with that of untreated patients. Myeloperoxidase activity was increased in treated patients during the first postburn week but then declined to normal levels. Untreated patients had a significant increase in myeloperoxidase activity for the first 3 weeks following injury. Untreated patients exhibited a significant decrease in superoxide activity during the second 3 weeks following injury. Treated patients demonstrated normal superoxide activity.

The effect of blood transfusions and anesthesia on host response to endotoxin was evaluated in multiple Lewis rat models. The rats were randomized to receive A'Sogaloff Cancer Institute rat blood, pentobarbital sodium, or lactated Ringer's solution and, at either 2 or 7 days following administration of these agents, were challenged with intravenous endotoxin. Neither blood transfusions nor anesthesia altered mortality when administered 2 days before endotoxin challenge. However, blood transfusions administered 7 days before endotoxin challenge were found to prolong survival, to prevent endotoxin-induced alterations in T-lymphocyte subsets, and to decrease plasma tumor necrosis factor levels. In conclusion, blood transfusions appear to depress immune function in a beneficial manner in endotoxin shock.

To evaluate our experience with fungal burn wound infection, we performed a 10-year review for comparison with our experience with bacterial burn wound infection. During the study period, a marked decline occurred in bacterial wound infection but not in fungal wound infection. Patients with either bacterial or fungal burn wound infection had massive injury, with burn size averaging greater than 50% of the total body surface area. Factors that appear to have markedly reduced bacterial burn wound infection, including patient isolation, topical chemotherapeutic agents, and burn wound excision, do not appear to have had a similar effect on fungal wound infection. The mechanism of spread and colonization of fungi, and the lack of effective topical chemotherapeutic antifungal agents, may explain in part our findings.

Inhalation injury, present in approximately one third of burned patients treated at burn centers, increases mortality by a maximum of 20% in relation to age and extent of burn. The development of animal models of inhalation injury has made possible the identification of both the airway and vascular responses evoked by smoke inhalation. Inflammatory occlusion of terminal bronchioles and necrosis of the endobronchial mucosa render the airway and pulmonary parenchyma susceptible to infection and the resulting pneumonitis further increases mortality. Early diagnosis, best achieved by endoscopic bronchoscopy and 133xeon ventilation perfusion scan, permits timely application of high-frequency ventilation that appears to reduce the incidence of pneumonia and to decrease mortality. Pharmacologic agents give promise of ameliorating the deleterious changes of the vasculature. The recent advances in understanding inhalation injury have identified the research needed to further improve patient salvage.

The United States Army Institute of Surgical Research was asked to provide burn care assistance in June 1989 following the explosion of leaking methane/propane gas in the Central Soviet Union, which destroyed two passenger trains and injured 800 passengers. A 17-member burn team flew from San Antonio, Texas, to Ufa, USSR and assisted in the management of 150 burn patients in a general medical-surgical hospital. Early problems included heavily colonized burn wounds, with a microbial flora that demonstrated broad antibiotic resistance. As wound complications were controlled, 28 operative procedures were performed to excise and graft the burn wounds. The recommendations for burn disaster management, based on our experience in Ufa, should be of assistance to other groups that may be asked to provide similar assistance in the future.

Administration of a long-acting prostaglandin E, 16,16-dimethyl-PGE (dPGE), to rats improves their survival of bacterial peritonitis. We examined the mechanism of this protective effect with reference to its interaction with the release of cachectin (TNF). Sixty rats received saline, 20 micrograms/kg dPGE, or 80 micrograms/kg dPGE 12 hr prior to endotoxin and continuing for 48 hr. Survival rates for the saline, 20 micrograms/kg dPGE, and 80 micrograms/kg dPGE groups were 0, 40, and 85%, respectively. Forty rats received saline or 80 micrograms/kg dPGE, with the initial dose being 3 hr following endotoxin challenge and continuing for 48 hr. Survival rates for both groups were 0%. Sixty rats received saline or 80 micrograms/kg dPGE at 12 and 1 hr prior to endotoxin. Two hours after challenge, they were sacrificed and plasma TNF levels were assayed. The plasma TNF level in saline-treated rats was 22.72 +/- 0.83 ng/ml and in the dPGE-treated group, 16.03 +/- 1.13 ng/ml (P less than 0.001).

Transfusions are reported to increase the incidence of tumor metastasis in clinical studies and primary tumor growth in animal studies. We evaluated the effect of transfusions on immunologic response to primary and metastatic tumors in multiple rat models. One half of the animals were administered lactated Ringer's solution and one half ACI rat blood at the time of tumor challenge. In 80 rats a slow-growing colon tumor was implanted subcutaneously. At 4 months there were no significant differences in tumor size or leukocyte infiltration of the tumor. Similar results were obtained with a rapidly growing colon cancer. Analysis of T-lymphocyte subpopulations in both groups showed no differences. Rats transfused at the time of intravenous challenge with a suspension of 1 x 10(6) tumor cells had a mean survival time of 38.3 +/- 0.8 days and the control group had a mean survival time of 41.1 +/- 0.8 days (p = 0.016). One week after transfusion, natural killer cell lysis of tumor cells at a 100:1 effector/target cell ratio was 18.0% +/- 1.8% in the transfusion group and 23.0% +/- 1.3% in the control group (p = 0.034). In conclusion, transfusions in multiple rat cancer models did not affect primary tumor growth or the host's immunologic response to it but did significantly impair natural killer cell function and survival with tumor metastases.

The time required for wound healing, contraction, and hypertrophic scarring often limit the use of deep partial-thickness burn wounds as donor sites for split-thickness grafts. We have examined the effects of weak direct current and silver nylon dressings on the healing of partial-thickness scald burns, split-thickness grafts taken from these wounds when healed, and the resulting donor sites in a guinea pig model. Dorsal scald wounds treated with weak direct current reepithealized by 12 days postinjury. Split-thickness grafts taken from healed scald wounds showed more rapid revascularization with direct current treatment than did control grafts. Grafts and donor sites treated with direct current showed more rapid reepithelialization, decreased contraction, improved hair survival, and decreased dermal fibrosis when compared to controls not treated with direct current. Only donor wounds treated with weak direct current were reusable as donor sites.

The use of blood transfusions has been a art of medical practice for over half a century. The efficacy of blood and blood products in patients in hypovolemic shock from trauma or operative procedures has been well established. During the past quarter century, it has been demonstrated that blood transfusions administered prior to transplantation decrease the frequency and severity of allograft rejection. More recent work has indicated that this beneficial effect is the result of the transfusion inducing a state of immunosuppression in the recipient. A number of reports have suggested that this posttransfusion immunosuppression may result in an increased susceptibility to bacterial infections.

The role of carbon monoxide (CO) in causing the physiologic and anatomic changes characteristic of smoke inhalation injury was evaluated in 34 sheep. The smoke-exposed group received a dose of smoke known to produce mild inhalation injury. The CO group received a pure gas mixture that contained concentrations of oxygen, carbon dioxide, and CO similar to those in the smoke. Cardiopulmonary function was measured immediately after exposure, and 24 and 72 hours after exposure. The CO group showed a transient increase in cardiac output, but the smoke group showed no such response. The CO group maintained normal PaO2 levels during the 72-hour study period; the smoke group gradually developed hypoxemia. The lungs of the CO exposed animals had no discernible histologic changes; lungs of the smoke group showed progressive inflammatory changes. These results indicate that CO per se is not the primary etiologic agent of smoke inhalation injury.

The immunosuppression seen following burn injury has frequently been attributed to elevated prostaglandin E levels. We evaluated the contribution of elevated prostaglandin E levels on susceptibility to infectious complications utilizing multiple mouse models. The administration of 100 micrograms/kg of the long-acting derivative of prostaglandin E, 16,16-dimethyl-prostaglandin E, was found to improve survival in C3/HEN mice challenged with 1 x 10(8) Escherichia coli organisms intraperitoneally. The administration of indomethacin was found to decrease survival in the same model. With C3/HEJ (endotoxin-resistant) mice, indomethacin was found to increase mortality rates in animals challenged with 1 x 10(8), 1 x 10(9) or 1 x 10(10) Escherichia coli organisms. These findings suggest that elevated prostaglandin E levels seen in burn patients may not be responsible for the postburn increased susceptibility to infectious complications.

Heterotopic bone formation about joints and in soft tissues is known to cause joint immobilization and permanent physical impairment in burned patients. Despite aggressive physical therapy aimed at prevention, heterotopic bone formation still occurs in a small percentage of patients. Prolonged immobilization in concert with trauma or burn about the involved joint is recognized as being responsible for this heterotopic bone formation. Specifically, immobilization of extremities, particularly the elbow and upper extremity, should be minimized by early grafting for preservation of function. As burn therapy has enabled increasing numbers of patients to survive extensive burns, it is imperative that preservation of function not be ignored and that attention be directed at improved function early in the postburn course.

Sever thermal injury is often complicated by infection. Moreover, the injury itself render the early detection of infection more difficult. Rapid early detection of infection would thus aid in the treatment of severely burned patients. PCA filtrates of whole blood from burned-infected rats contain three substances that appear to be early indicators of infection in the thermally injured animal. These factors are only slightly affected by the extent of injury. These factors do not appear to be microorganism-specific in that they are found in rats infected with Proteus mirabilis as well as with Pseudomonas aeruginosa. One factor absorbs light at 398 nm and seems to be associated with some cellular component of blood. The other two substances are fluorescent, one gamma ex 280 nm gamma em 340 nm, the other gamma 355 nm gamma em 420 nm, and are detectable in PCA filtrates of plasma as well as of whole blood. All factors are retained by filters with a 25,000 dalton pore size. All factors are precipitable from PCA filtrates by phosphotungstic acid, suggesting that they may be proteins. The 355/420 factor increases with oxidation, whereas both the 280/340 substance and 398 nm material decrease.

The quantitative swab culture is a reliable method for quantifying the number of viable bacteria colonizing open wounds. For open wounds in burn patients, the swab bacterial count is linearly related to biopsy quantification of viable bacteria in the underlying tissue. This technique is simple and requires no surgical manipulation of the wound. For a wound of uniform appearance, the standard deviation of a single swab culture from the mean log bacterial count for a series of cultures from widely spaced areas on the wound is +/- 0.85 logs; 95% confidence limits are +/- 1.7 logs from the mean. A Gram-stained smear from a wound swab requires less than 10 minutes to prepare. Visualization of bacteria on the smear indicates that 106 or more bacteria per swab are present. The value of the smear and swab techniques for predicting safe wound closure may be inferred from the published reports of others and the direct relationship between the swab and biopsy counts of viable bacteria for open wounds.