Arthur D. Mason

Catecholamines: Mediator of the Hypermetabolic Response to Thermal Injury

Hypermetabolism characterizes the metabolic response to thermal injury and the extent of energy production is positively related to the rate of urinary catecholamine excretion. Alpha and beta adrenergic blockade decreased metabolism from 69.6 +/- 5.3 Kcal/m(2)/hr to 57.4 +/- 5.2 (p < 0.01), and infusion of 6 microgm epinephrine/minute in normal man significantly increased metabolic rate. Twenty noninfected burned adults with a mean burn size of 45% total body surface (range 7-84%) and four normal controls were studied in an environmental chamber at two or more temperatures between 19 and 33 C with vapor pressure constant at 11.88 mm Hg. All burn patients were hypermetabolic at all temperatures studied and their core and mean skin temperatures were significantly elevated above control values. Between 25 and 33 C ambient, metabolism was unchanged in controls and burns of less than 40% total body surface (48.9 +/- 4.6 Kcal/m(2)/hr vs. 48.9 +/- 4.5), but metabolic rate decreased in larger burns in the warmer environment (72.0 +/- 1.9 vs. 65.8 +/- 1.7, p < 0.001). At 21 C, metabolism and catecholamines increased, except in four nonsurvivors who became hypothermic with decreased catechol elaboration. Metabolic rate in ten patients with bacteremia was below predicted levels while catecholamines were markedly elevated suggesting interference with tissue uptake of the neurohormonal transmitters. Feeding burn patients or administering glucose and insulin improved nitrogen retention and altered substrate flow but did not significantly reduce urinary catecholamines or metabolic rate. Burned patients are internally warm, not externally cold, and catecholamines appear to mediate their increased heat production. Hypermetabolism may be modified by ambient temperature, infection, and pharmacologic means. Alterations in hypothalamic function due to injury, resulting in increased catecholamine elaboration, would explain the metabolic response to thermal injury.

The Influence of Inhalation Injury and Pneumonia on Burn Mortality

In order to assess the specific effects of inhalation injury and pneumonia on mortality in burn patients, the records of 1058 patients treated at a single institution over a five-year period, 1980-1984, were reviewed. Of these patients, 373 (35%) had inhalation injury diagnosed by bronchoscopy and/or ventilation perfusion lung scan. Of the 373 patients, 141 (38%) had subsequent pneumonia. Among the patients without inhalation injury, pneumonia occurred in 60 of 685 (8.8%). A multiple logistic equation was developed to estimate expected mortality at any age and burn size for patients without either inhalation injury or pneumonia, with either alone, or with both. Subtraction of the expected mortality without either inhalation injury or pneumonia from the expected mortality in the presence of either or both permitted the estimation of additional mortality attributable to these complications. Inhalation injury alone increased mortality by a maximum of 20% and pneumonia by a maximum of 40%, with a maximum increase of approximately 60% when both were present. The influence on mortality was maximal in the midrange of expected mortality without these complications for any age group. These data indicate that inhalation injury and pneumonia have significant, independent, additive effects on burn mortality and that these effects vary with age and burn size in a predictable manner.

Plasma cytokines following thermal injury and their relationship with patient mortality, burn size, and time postburn.

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.

Influence of the burn wound on local and systemic responses to injury.

Total resting leg blood flow, measured by venous occlusion plethysmography; leg oxygen consumption; substrate turnover; and leg surface temperature were determined in 21 nonseptic burn patients and four normals. The patients studied during the second to third week postinjury sustained total body surface injuries averaging 45% (range 12–86%) and leg injuries of 35% total leg surface (0–82.5%). To integrate the peripheral metabolic and circulatory events with the systemic responses to injury, total body oxygen consumption, cardiac output, rectal and mean skin temperatures were also measured. Leg blood flow and leg surface temperature generally increased with total burn size but did not correlate with cardiac output, total body oxygen consumption, or body temperature. However, leg blood flow was closely related to the extent of the leg burn (r2 = 0.73). To evaluate the metabolic determinants of the wound blood flow, patients were matched for burn size (40.5% total body surface in one group vs. 42%), resulting in similar systemic responses to injury (cardiac index 7.8 ± 0.7 L/min·m2 vs. 7.5 ± 0.8, &OV0312;O2 204 ± 12 ml/min·m2 vs. 241 ± 22, rectal temperature 38.5 ± 0.3° vs. 38.3 ± 0.3°, NS). One group (n = 7) had extensive leg burns (58% of the leg surface), the other (n = 9) minimal leg injuries (9.5%). Leg oxygen consumption was similar in the two groups (0.24 ± 0.01 ml/100 ml leg·min vs. 0.19 ± 0.04, NS), although leg blood flow was markedly increased in the injured extremities (8.0 ± 0.5 ml/100 ml leg·min vs. 4.2 ± 0.4, p < 0.001). Glucose uptake and lactate production were enhanced in the burned extremities (glucose 0.34 ± 0.08 mg/100 ml leg·min vs. 0.04 ± 0.03, p < 0.01, lactate 0.30 ± 0.08 mg/100 ml leg·min vs. 0.06 ± 0.06, p < 0.05) and related in a general manner with size of the leg burn. Increased peripheral blood flow following injury is directed to the wound and unrelated to aerobic metabolic demands of the extremity. The selectively perfused wound consumes glucose and produces lactate. The increased systemic cardiovascular and metabolic responses to thermal injury are essential for the enhanced culatory and anaerobic demands of the healing wound.

Hypermetabolic Low Triiodothyronine Syndrome of Burn Injury

The free tetraiodothyronine index (FT4I) and free triiodothyronine index (FT3I) in burn patients represented the serum levels of free (dialyzable) T4 and free T3, respectively. FT4I and FT3I were lower with greater burn size and were lower in nonsurvivors than expected for the burn size. There was no compensatory elevation of basal or releasing hormone-stimulated thyrotrophin (TSH) concentrations. Reverse T3 was higher with greater burn size. T3 treatment restored FT3I but did not affect mortality or resting metabolic rate (MR) measured in survivors, compared with placebo therapy. Whereas the hypermetabolic response to burn injury appeared to be independent of thyroid hormones, MR was correlated positively with burn size and with elevated plasma nor-epinephrine and epinephrine concentrations for several weeks after injury. Lack of augmented TSH concentrations, absence of low plasma reverse T3, and presence of hypermetabolism suggest that the reduced plasma free T3 does not indicate functional hypothyroidism, but may represent an adaptation to the assumption of metabolic control by the sympathetic nervous system.

Effect of carbohydrate and fat intake on nitrogen excretion during total intravenous feeding.

Recent availability of intravenous soy bean oil emulsion for clinical trials in the United States prompted infusion of intravenous diets containing a constant nitrogen level (11.7 grams/m2/day) and 13 different combinations of carbohydrate (110-2300 kcal/m2/day) and fat (0-1100 kcal/m2/day) during 34 three-day studies in 5 patients who were clinically stable after injury or operation. Urea nitrogen excretion was inversely related to carbohydrate intake (P less than 0.01) and directly related to resting metabolic rate (P less than 0.01). Fat infusion did not affect nitrogen excretion at any level of carbohydrate intake. This study suggests that, when a primary clinical goal is nitrogen conservation, carbohydrate calories should be given in amounts approximating the resting metabolic rate. Additional calories and essential fatty acids now can be safely given as intravenous fat emulsion, but fat did not affect nitrogen conservation under the conditions of this study.

Development and analysis of a small animal model simulating the human postburn hypermetabolic response

Growing guinea pigs and mature rats are good models of the human metabolic response to thermal injury demonstrating a dose-response relationship between burn size and metabolic rate, an elevation in metabolic rate related to the stage of convalescence and hypermetabolism that may be altered but not abated by external heating. A 50% total body surface burn must be produced before reliable elevations in metabolic rate are observed. The mature rat is the best of the three animal models and is suitable for evaluation of the mediators and modulators of the hypermetabolic response to thermal injury.

Cortisol and Corticotrophin in Burned Patients

In a study of 36 men burned in a fire, based on sequential early morning samples, plasma cortisol concentration was elevated in proportion to burn size. Plasma corticotrophin (ACTH) was not correlated with burn size, suggesting that factors other than ACTH contribute to the elevated cortisol. Cortisol levels did not fall on the days preceding death in nonsurvivors. During 24-hr sampling, burned patients exhibited a fitted cortisol curve mean that was elevated in proportion to burn size, a rhythm amplitude that was significantly less than that in uninjured controls, and a normal peak time. Metabolic rate, rectal temperature, and urinary catecholamine excretion were also elevated in proportion to burn size. Although plasma cortisol was positively correlated with metabolic rate and with temperature, this appeared to result from a common relationship of these variables with burn size. On the other hand, urinary catecholamine values significantly reduced the residual variance of metabolic rate and temperature after accounting for variance related to burn size. Cortisol appears to be less prominent than catecholamines as a possible mediator of the elevated thermogenesis.

Plasma cytokines after thermal injury and their relationship to infection.

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.

PSEUDOMONAS BURN WOUND SEPSIS. I PATHOGENESIS OF EXPERIMENTAL PSEUDOMONAS BURN WOUND SEPSIS.

Summary The bacteriologic and clinicopathologic features of experimental Pseudomonas burn wound sepsis display an orderly sequence of progression. There is initial supraeschar and intrafollicular (hair) bacillary localization followed by more widespread intraeschar colonization. By the fourth and fifth days, bacilli have invaded to the junction of the burned and viable tissue, and at this time a low grade bacteremia becomes evident. Bacteria then invade to the zone of viable granulation tissue. During the terminal phase of the disease, the bacterial invasion front destroys the granulation tissue zone and invades the deeper tissues. This is associated with a rise in pseudomonad count in the blood stream and the appearance of visceral hematogenous lesions, leukopenia and hypothermia. The hematogenous lesions not infrequently show Pseudomonas vasculitis similar to that seen in the human disease. The details of the bacteriologic and clinicopathologic findings of burn wound sepsis in the rat are discussed in relation to its human counterpart.