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Rats with 50% total body surface area full-thickness burn injuries have sustained increases in body temperature without evidence of sepsis. In this animal model, the only known endogenous pyrogen consistently present in plasma is interleukin-6 (IL-6). We investigated the hypothesis that IL-6 acts as an endogenous pyrogen and produces the observed increase in body temperature. Body temperature and activity index were recorded every 5 minutes for control rats and rats with burns (50% total body surface area scald burns) for a period before the burn injuries and through the eighth day after the burn injuries. On the fifth day after the burn injuries, between 8 and 9 AM, control animals and animals with burns were given an intra-arterial dose of IL-6 polyclonal neutralizing antibody (IL-6 pAb) that was equivalent to one half of the neutralizing dose of IL-6 pAb. This calculation was based on plasma levels of IL-6 obtained from rats with burns in previous studies and on the neutralizing capability of the IL-6 used. On the sixth and seventh days after the burn injuries, a full neutralizing dose of IL-6 pAb was given. Blood samples were obtained for IL-6 assays at baseline and after treatment with IL-6 pAb but were lost because of the failure of an ultracold freezer. A one half neutralizing dose of IL-6 pAb produced no discernible effect on the body temperature of the control animals or of the animals with burns. On the sixth and seventh days after the burn injury, IL-6 pAb produced 45% and 34% respective decreases in body temperature compared with the animals with burns that received saline solution (P < .05 for both comparisons). On the eighth day after the burn injuries, the effect had completely dissipated. We concluded that our results support the idea that increased circulating levels of IL-6 may be causally related to fever that occurs in nonseptic rats with large burn wounds.

Introduction: Rats with burn injury to ≥50% of the BSA demonstrate a significant increase in body temperature ( T B ) during light hours, and decrease of circadian variation in T B . This study investigated the hypothesis that part or all of the signal for increased T B in rats with burn injury is transmitted to the central nervous system by way of afferent vagal fibers. Methods: Four groups of animals were studied: Burn-Sham Vagotomy; Control-Sham Vagotomy; Burn-Vagotomy and Control-Vagotomy. Anesthetized animals had bilateral subdiaphragmatic vagotomy (VagX) or sham VagX performed, and AM radio transmitters were implanted in the peritoneal cavity for the purpose of recording T B and activity index (AI). Following a one week recovery period, burn animals received scald burns equal to 50.3±2.5% BSA. Results: The main effect of VagX upon T B was a small but significant reduction in T B during dark hours. At least 87% of this decrease in post-burn T B was also present for the control vagotomy group. Vagotomy had no effect on the increase in T B for the burn groups during light hours. During dark hours, VagX significantly reduced T B in burns and controls, and burn injury significantly reduced activity. Conclusions: One may speculate that afferent vagal signals are partially responsible for maintenance of T B , with or without burn injury, and that the major signal for increase in T B for animals with burn injury is not a neural one via afferent vagal pathways.

This study investigates the hypothesis that continuous administration of indomethacin (a cyclo-oxygenase inhibitor) will chronically reduce body temperature (TB) in burned rats (i.e., modulate "true" fever). Male Sprague-Dawley rats had radio transmitters and osmotic pumps (containing indomethacin) placed in the peritoneal cavity, and 7 days later large full-thickness scald burns were produced. Activity and TB were continually recorded through the 14th postburn day (PBD). There were 4 experimental groups: burn + indomethacin (B-In), n = 9; burn + polyethylene glycol (B-Peg), n = 6; control + indomethacin (C-In), n = 9; and control + polyethylene glycol (C-Peg), n = 6. From PBD 5 through PBD 10, the B-Peg group had consistently and significantly higher TB during light hours than the B-In, C-In, and C-Peg groups. From PBD 7 through PBD 12, the B-In group had an average TB during light hours significantly lower or not different than the C-In and C-Peg groups. These results support the hypothesis that in this burned-rat model chronically increased TB during the light hours may be "fever" (rather than hyperthermia) and that the final effector link could be a prostanoid because changes in activity do not explain the changes in body temperature.

Hypothesis.IL-10 will reduce morbidity and mortality in murine MODS. Introduction.Intraperitoneal (ip) zymosan causes a triphasic inflammatory process leading to MODS. Phase I is an acute systemic inflammatory response to sterile peritonitis. Phase II is the recovery phase. Phase III is characterized by recurrent illness, progressive organ dysfunction, and elevated proinflammatory cytokines. Methods.Male ICR mice were randomized (on Experiment Day 0, time = 0 h) into four initial groups (A–D): Control Group A received no zymosan and no IL-10. Group B received zymosan (1 mg/g mouse BW,t= 0) and no IL-10. Group C received no zymosan and IL-10 att= 2 h. Group D received zymosan and IL-10 att= 2 h. On Experiment Day 4, mice in Groups B–D were randomized into six further treatment groups (B1 and B2, C1 and C2, D1 and D2). Group B1 received no treatment. Group B2 received IL-10 when clinical signs of recurrent illness developed (Phase III, 12–18 days after zymosan treatment). Mice were sacrificed when they were preterminal (clinical signs of shaking, shivering, or paralysis) or on Experiment Day 28 (survivors). Plasma total bilirubin and creatinine levels were measures of organ function. Terminal pulmonary compliance was measuredin situthrough a physiologic range of tidal volumes. Results.Mice entering Phase III consistently progressed to MODS characterized by elevated bilirubin and hemorrhagic lungs which, if left untreated, was lethal. Mice treated with IL-10 (Group B2) when they entered Phase III had lower mortality (28.6% vs 100%,P< 0.02), longer survival (25 vs 18 days,P< 0.05), and improved lung pulmonary compliance (slope β1= 0.082 ml/mm Hg vs 0.059 ml/mm Hg,P< 0.001) compared to untreated (Group B1) mice in Phase III. Conclusions.IL-10 improves survival even when given after clinical signs of illness are present.

In the medical community, the practice of admitting all electrical burns for 24–48 h of observation, monitoring and laboratory evaluation is widespread. This retrospective review of paediatric electrical burns was conducted to determine which patients may safely be treated as outpatients. Retrospective analysis of all paediatric burns admitted between 1980 and 1991 identified 35 patients with electrical injuries. Patients were divided into two groups for analysis: those burned by exposure to household voltages (120–240 V; n=26) and those exposed to high voltages, in excess of 1000 V (n=9). The majority of household electrical injuries occurred secondary to contact with the household 120 V (2126). Contact with an extremity accounted for the largest number of these injuries (1826). The mouth was the second most frequent site of injury (726). Most of these patients (2026) had < 1 per cent BSA burn. No patient in the household-voltage group had an arrythmia that required treatment, nor were there any identified examples of compartment syndrome or other vascular complications. Seven patients did require minimal skin grafting. No deaths occurred in either group. The patients in the household-voltage group were significantly younger. High-voltage electrical injuries occurred in an older patient population and required more aggressive care and surgical intervention. This was evident at the time of initial evaluation. Based on these data, healthy children with small partial-thickness electrical burns and no initial evidence of cardiac or neurovascular injury do not appear to need hospital admission.

Background : Because severe acidosis is an indicator of poor prognosis in trauma patients, medical records of these patients were analyzed to determine whether aggressive resuscitation was appropriate. Patients and methods : Data from a level 1 trauma center registry were reviewed retrospectively to identify patients with a pH ≤7.0. Thirty-seven patients were identified. Severely acidotic patients were compared to average trauma patients in terms of demographics, resuscitation, injury, and outcome. Surviving acidotic patients were also compared to nonsurviving acidotic patients. Results : Half of the severely acidotic group survived initial resuscitation with approximately one third surviving to leave the hospital. There were no chronically disabled survivors. Nonsurviving acidotic patients were more unstable, more neurologically depressed, and more severely injured. Resuscitation efforts did not consume excessive hospital resources. Conclusion : Severe acidosis alone is not a sufficiently powerful predictor of outcome to justify withholding resuscitation; however, when combined with coma and shock, this condition had no survivors in this small series.

This study in burned rats studied at two ambient temperatures (22 degrees and 28 degrees C) and housed at 28 degrees C was designed to investigate the role of catecholamines in the maintenance of thermal homeostasis following burn injury. Two weeks prior to burn or sham burn, animals underwent adrenal medullectomy or sham adrenal medullectomy. Between postburn days 9 and 13, simultaneous direct and indirect calorimetry was performed following administration of 2mg/kg of phentolamine (alpha adrenergic blocking agent) via a carotid arterial line. Following administration of phentolamine, heat production and body temperature decreased and heat loss increased immediately. The cooling slopes for the burn groups were significantly steeper than for the control groups, within ambient temperatures. Within ambient temperatures, the presence or absence of the adrenal medulla had no discernible effect on the cooling slope of the burns or the controls. The burned animals cooled 1.9-3.5 times faster at 22 degrees than at 28 degrees C, and controls cooled 2.0-3.9 times faster at 22 degrees than at 28 degrees C. Phentolamine produced a several-fold increase in serum concentrations of both norephinephrine (NE) and epinephrine (E), indicating a gross overlap in alpha and beta adrenergic receptor utilization for E and NE. The progressive cooling of the adrenal demedullated burn group at 22 degrees C following phentolamine administration seems to indicate that norepinephrine is calorigenic for rats under these experimental circumstances. These experimental results indicate a relatively non-essential role for catecholamines in the maintenance of thermal homeostasis within the thermal neutral zone in the rat.

This prospective randomized study was performed to evaluate the metabolic and thermal responsiveness of patients with burns to thermal stress with three protocols of wound care: group I (n = 7) treated with dressings and variable ambient temperature selected for patients subjective comfort; group II (n = 7) treated without dressings and variable ambient temperature for patient comfort; group III (n = 6) treated without dressings and ambient temperature of 25 degrees C, electromagnetic heaters were set to achieve patient subjective comfort; and group IV (n = 6) healthy volunteers. After baseline partitional calorimetry was performed, individual patients were cold-challenged while subjectively comfortable by sequentially lowering either the ambient temperature or the output from the electromagnetic heaters. Heat balance and temperatures were obtained after each perturbation in external energy support. For patients in groups I and II, subjective perception of thermal comfort (warm, neutral, neutral and fed, cool, or cold) was more strongly correlated (p < 0.02) with the changes in the rate of heat production than the actual ambient temperature. For patients treated with electromagnetic heaters, changes in heat production were most strongly correlated with the energy output from the electromagnetic heaters. Even though the environmental conditions required to achieve a particular level of comfort are quite different between treatment groups, the difference in temperature between the patient's surface and ambient is approximately the same for groups I, II, and IV for each subjective state.(ABSTRACT TRUNCATED AT 250 WORDS)

Burn injury in man is characterized by increased body temperature proportional to burn wound size and may represent fever and/or hyperthermia. A nonseptic animal model used to study this phenomena has not been described. To test the hypothesis that large burn injuries in rats would produce increased body temperature, the rectal, skin, and body temperatures were sequentially measured and were calculated for rats in the control group and rats with burn injuries covering 26% to 63% of the body surface area [or = 35%, 36% to 45%, andor = 46% body surface area]. The group with burns coveringor = 46% of the body surface area had significantly higher rectal temperatures than did at least one other group on postburn days 7, 9, 11, 13, 18, and 20. On postburn days 7 and 11 this increase was significantly higher than that of all burn and control groups. Animals did not demonstrate any overt evidence of wound infection. These data do not establish a cause for increased body temperature after burn injury but suggest that a reproducible animal model may be possible for the study of the cause of increased body temperature after burn injury.

Rats with burn injuries demonstrate changes in thermoregulation including an upward shift of the set-point and reference temperatures with no change in sensitivity of the response in heat production to displacement of the temperature of the preoptic anterior hypothalamus. In the present studies, the response in plasma and urinary catecholamines to burn injury after destruction of the preoptic anterior hypothalamus was examined in the rat. Preoptic anterior hypothalamic lesioning impaired the hypermetabolic response to burn injury, and at 22 degrees C, burned lesioned rats were hypothermic. Furthermore, plasma levels and urinary excretion rates for catecholamines were not decreased in burned lesioned rats, but rather showed an inverse relationship with heat production. Burned lesioned rats were capable of maintaining body temperature at an ambient temperature of 28 degrees C. This suggests that a less precise thermoregulation is present in lesioned animals. Rats in which the preoptic anterior hypothalamus has been destroyed have reduced tolerance to burn injury.

Hypermetabolism proportional to wound size is the expected response in patients who sustain large burns. This metabolic response persists until wound closure is achieved. The value of this response to the injured host remains unproven. Between 1978 and 1991, 104 patients with burns covering 30% or more of the body surface area underwent partitional calorimetry as a component of various research protocols. Thirteen of these patients failed to demonstrate an increase in metabolic rate as compared with a control group. These patients without hypermetabolism were compared with case-matched patients who demonstrated the expected increase in metabolic rate. Although they were not hypermetabolic in response to the burn injury, five of these patients were exposed to a cold stress and were able to increase their metabolic rate appropriately. The failure to mount a hypermetabolic response did not impact the clinical course as measured by survival, length of hospital stay, or maximum weight loss.

This study investigates the hypothesis that indomethacin's ability to prevent "fever" following burn injury in rats is mediated via decreased plasma concentrations of IL-6, the putative mediator of increased body temperature. Sprague-Dawley rats had radio transmitters and osmotic pumps containing indomethacin placed in the peritoneal cavity. Seven days later full thickness scald burns to 50% of the body surface area were produced. Following burn injuries, daily blood samples were obtained from a carotid catheter for assay of lipopolysaccharide (LPS), interleukin-1alpha (IL-1alpha), IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and IL-6. In addition, body temperature (T(B)) and activity index were obtained every five minutes by telemetry. There were four experimental groups: burn + indomethacin (B-In); burn + polyethylene glycol (Peg) (B-Peg); control + indomethacin (C-In); and control + Peg (C-Peg). Burned animals demonstrated a significant two-fold increase in plasma IL-1alpha levels (p=0.004) and a seven-fold increment in IL-6 (p=0.0001) through the 7th PBD, and indomethacin administration had no significant effect upon the cytokine plasma levels. There were no significant increases in IL-1beta, TNF-alpha or LPS in any group. Indomethacin eliminated the chronic increase in T(B) following burn injury, and this effect was not produced by changes in plasma levels of the endogenous pyrogens IL-1alpha and IL-6.

In previous studies, we established that circulating epinephrine (E) is not essential for a normal hypermetabolic response to burn injury in the rat, within the zone of thermal neutrality. In other studies, burned rats with adrenal medullectomy (AdxB) studied at 22 degrees C were unable to maintain rectal temperature (TR) after alpha-adrenergic blockage. These data suggest that norepinephrine (NE) is calorigenic in such animals without formal cold acclimation. These studies investigate the hypothesis that, contrary to the usual belief, norepinephrine might be calorigenic in rats without formal cold acclimation. Burned (B) and control (C) rats with adrenal medullectomies (Adx) and Sham (S) Adx (AdxB, SAdxB, AdxC, and SAdxC) were housed at either 22 degrees C or 28 degrees C. Calorimetry was performed during the eighth to eleventh days after the burn. For groups housed at 22 degrees C and studied at 28 degrees C, NE given intravenously (iv) produced an average 16.5%+/-3.3% increment in heat production (HP) for the four groups, which was significant for AdxB, SAdxB, and SAdxC. Intravenous administration of E produced an average increment in HP of 4.44%+/-4.1%, which was not significant. HP was significantly higher after NE than E in three cases. Studies with animals housed at 28 degrees C and studied at 28 degrees C produced intermediate but similar results. For groups housed at 28 degrees C and studied at 22 degrees C, iv administration of E and NE produced average decreases in He of 18%+/-6.7% for E and 10.75%+/-4.7% for NE. Except for the AdxC group, these differences were significant. These data suggest that chronic exposure to an ambient temperature of 22 degrees C produces an enhanced calorigenic response to NE in burn and control rats. Based on the data presented here, combined with earlier studies, NE must be considered as a facilitator for hypermetabolic response to burn injury in the rat. It is interesting to speculate whether NE is calorigenic for patients with large burn wounds, which are managed without dressings at ambient temperatures below thermal neutrality.

We investigated the possible causal relationship between interleukin-6 (IL-6) and increased body temperature (T(B)) in a rat burn model. Transmitters for measuring core temperature and estimating activity were implanted in the abdominal cavity. Animals in the burn group were clipped and received full-thickness scald burns to 45% to 55% of the body surface area, and control animals were clipped. T(B) and activity were measured continuously through the tenth postburn day. Carotid lines were placed, and serial blood samples obtained for lipopolysaccharide, IL-6, and tumor necrosis factor-alpha assay. From the third through the tenth postburn day, the burn group had a consistently significantly higher T(B) during light hours than the control group did (average, 0.45 degrees C +/- 10 degrees C, p = 0.0001). Differences in activity during light hours were not significant between the two groups, therefore, do not account for the observed significant difference in T(B). The average IL-6 serum levels were 3.5-fold higher for the burned animals. In this study, burn and control serum levels of IL-6 demonstrated positive correlation with T(B). These data suggest, but do not prove, a causal relationship between IL-6 and fever in the rat burn model, and make it unlikely that circulating systemic lipopolysaccharide is the cause.

Burn (B) and control (C) rats with and without adrenal medullectomy (Adx) 9-11 days postburn underwent warning and cooling of the preoptic anterior hypothalamus (POAH) during calorimetry at 22 degrees and 28 degrees C ambient. Blood was drawn for catecholamine assay during each displacement of the POAH temperature (Thy). The heat production (Hp) for the AdxB group at 22 degrees and 28 degrees C was not different from the Hp for the sham AdxB group (80 +/- 4 vs 86 +/- 8 at 22 degrees C, 58 +/- 8 vs 64 +/- 7 W/m2 at 28 degrees C) in spite of there being no detectable circulating epinephrine (E) for the AdxB groups. Cooling of the POAH of the AdxB 22 degrees C group, however, did not induce a further increment in Hp, in contrast to all other groups. Thy demonstrated good significant negative linear correlation with Hp for all groups. The resulting slopes were not significantly different from one another, indicating no difference in thermal sensitivity of the POAH between the groups. In four of eight groups plasma norepinephrine (NE) demonstrated positive correlation with Hp and in five of eight groups negative correlation with Thy, Plasma E values did not correlate with Hp and demonstrated negative correlation with Thy in two of four possible groups. These data show that postburn hypermetabolism is not dependent on E in the rat and suggest that NE may be calorigenic in burned rats.

Rats, with the preoptic anterior hypothalamus implanted with two thermodes and a thermocouple reentry tube, had simultaneous direct and indirect calorimetry performed [during the ninth to eleventh postburn day interval] at ambient temperatures of 22 degrees and 28 degrees C. During calorimetry, blood was drawn at baseline and near the end of each period of displacement of the preoptic anterior hypothalamus temperature for catecholamine assay. Cooling the preoptic anterior hypothalamus resulted in a significant increase in heat production and plasma epinephrine and norepinephrine concentrations for both burn and control groups at 22 degrees C and 28 degrees C (p < 0.05 for all comparisons). Heat production demonstrated consistent negative linear correlation with preoptic anterior hypothalamic temperature. Plasma epinephrine values correlated with preoptic anterior hypothalamic temperature for only the controls at 28 degrees C ambient, whereas norepinephrine had significant linear correlation with heat production for all groups and significant negative linear correlation with preoptic anterior hypothalamic temperature. These data indicate norepinephrine may be more important than epinephrine in the maintenance of postburn hypermetabolism in this rat burn model while demonstrating that the hypermetabolism is appropriately responsive to perturbation of preoptic anterior hypothalamic temperature.

This study was conducted to examine the guinea pig as a suitable model for the study of the postburn hypermetabolic response and the febrile response that accompanies burn injury in man. Thirty animals were randomly assigned to four groups:50% body surface area burn (n = 6); 45% to 50% body surface area burn (n = 10);45% body surface area burn (n = 6); and controls (n = 8). On postburn days 3, 7, 11, 13, and 15, sequential temperature measurements were made. On postburn days 7 to 15, the randomly selected burn group (n = 12) and the control group (n = 8) had calorimetry studies performed. Sequential rectal temperature data demonstrate that the guinea pig does not mount a prolonged or consistent febrile response after burn injury (p0.05 for burn group vs control group on postburn days 7 to 13; p0.05 for postburn days 3 and 15 only). However, the burned guinea pig is significantly hypermetabolic after burn injury, with significant increases in dry and evaporative heat loss. The hypermetabolic response was proportional to burn wound size. Guinea pigs are not an ideal model for the study of the postburn febrile response; however, this is an excellent model for the study of postburn hypermetabolism.

Ibuprofen is an effective antipyretic in the postburn period and produces associated decrements in the hypermetabolic response. Burn injury is capable of altering the kinetics of many drugs, making the predictable use of agents such as ibuprofen difficult. Ten patients with serious burns were studied after the administration of 10 mg/kg ibuprofen suspension. The half-life varied from 1.4 to 5.1 hours, depending on the site of administration and/or the presence of solid food. The reported half-life for ibuprofen suspension is 1.8 to 2 hours. Burn size did not alter ibuprofen half-life or area under the time-concentration curve. Maximum ibuprofen concentration varied greatly, depending on route of administration. Time to maximal temperature reduction was between 2 and 3 hours after drug administration. Although the precise level of ibuprofen needed for cyclooxygenase inhibition is unknown, enteral administration results in levels below the targeted 10 to 20 mcg/ml for much of the traditional 6-hour dosing interval. Future studies with ibuprofen in the burn population must standardize more than just total dose.

A group of 15 burned children and young adults with large burns (mean, 41% +/- 15% BSA) were administered ibuprofen (40 mg/kg for 3 days). Each patient served as his or her own control in this crossover study (with and without ibuprofen). Paired calorimetric and temperature studies and urinary nitrogen measurements were performed. No nitrogen-sparing effect was identified for this dose of ibuprofen. However, patients demonstrated a statistically significant reduction in average rectal temperature (0.67 degrees C decreases) (p less than 0.01) and in metabolic rate (11.4% decreases) (p less than 0.01) while taking ibuprofen. Linear regression analysis of the reduction in temperature versus the reduction in metabolic rate yielded a statistically significant correlation (p less than 0.01) with a slope of 13.6% reduction in metabolic rate per degree centigrade reduction in the 72-hour average rectal temperature. These results support the hypothesis that ibuprofen attenuates the hypermetabolic response to thermal injury by blunting the temperature elevation that is usually seen.

The preoptic anterior hypothalamus (POAH) of rats housed at three ambient temperatures was implanted with perfusion apparatuses. Response of heat production to displacement of POAH temperature was determined for control animals and animals with burns (31% +/- 3% total body surface area). At an ambient temperature of 22 degrees C there was a significant increase in thermosensitivity of the POAH for both control rats and rats with burns compared with thermosensitivity at 32 degrees C. Within ambient temperatures there was no effect on thermosensitivity detected for rats with burns compared with control rats. The threshold temperature for heat production was shifted significantly upward (p less than 0.05) both by a lower ambient temperature and by burn injury. The reference temperature for heat production was also shifted to the right by burn injury (p less than 0.05). The significant shifts to the right for threshold temperature and reference temperature for heat production enhance the organisms's ability to meet the stress of the hypermetabolic response. At a warm ambient temperature (32 degrees C) there are no significant differences in thermoregulation detected in animals with burns or control animals.

The sequential metabolic studies of nine severely burned patients were examined retrospectively. Information analyzed included heat production (M), partitioned heat loss (HL), the percentage of the body surface area open wound (% open wound) and skin (TS) and rectal (TR) temperatures. The reduction in the hypermetabolic response correlated with the number of days postburn (DPB), % open wound, average body temperature (TB = 0.8TR + 0.2TS) and evaporative heat loss (EV) (r = 0.62, 0.55, 0.56, 0.63, respectively). However, decrements in metabolic rate between sequential studies correlated only with the change in % open wound and the change in EV (r = 0.41 and 0.49, respectively). While changes in heat loss are not capable of predicting all of the variation in metabolic rate, burned patients demonstrate an increase in heat production largely secondary to the inability to conserve heat effectively in the periphery. This response is compounded by an altered central thermoregulation.