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Micafungin (MCFG) concentrations in the plasma and in burn eschar were investigated after daily intravenous infusion (1 h) of MCFG (200 mg) in three patients with severe burns. MCFG treatment was initiated more than 72 h after the burn injuries. The MCFG concentrations in the plasma were determined at the end of the first administration of MCFG, immediately before the second dosing, at the end of the MCFG infusion after at least 4 days from the initial treatment, and immediately before the subsequent dosing using high-performance liquid chromatography. In addition, the trough levels in burn eschar after both the initial administration and repeated administration were measured. The peak and trough levels in the plasma were comparable to or slightly lower than the reported values in healthy volunteers. The mean (range) MCFG concentrations in the burn eschar after initial administration and repeated administration were 1.41 μg/mL (<0.1-3.98 μg/mL) and 6.65 μg/mL (1.10-14.81 μg/mL), respectively. In most cases, the MCFG concentrations in the burn eschar, especially after repeated administration, were higher than the reported MIC90 of MCFG against the clinically important pathogenic species of Candida and Aspergillus. These results suggest that MCFG is capable of penetrating burn eschar.

Hypermetabolism is a prominent feature of burn injury, and altered mitochondria function is presumed to contribute to this state. Recently, brown adipose tissue (BAT) was found to be present not only in rodents but also in humans, and its activity is associated with resting metabolic rate. In this report, we elucidate the relationship between burn injury-induced hypermetabolism and BAT activity and the possible role of the mitochondria-targeted peptide SS31 in attenuating burn injury-induced hypermetabolism by using a rat burn injury model. We demonstrate that burn injury induces morphological changes in interscapular BAT (iBAT). Burn injury was associated with iBAT activation, and this effect was positively correlated with increased energy expenditure. BAT activation was associated with augmentation of mitochondria biogenesis, and UCP1 expression in the isolated iBAT mitochondria. In addition, the mitochondria-targeted peptide SS31 attenuated burn injury-induced hypermetabolism, which was accompanied by suppression of UCP1 expression in isolated mitochondria. Our results suggest that BAT plays an important role in burn injury-induced hypermetabolism through its morphological changes and expression of UCP1.

Micafungin concentrations in plasma and burn eschar after daily intravenous infusion (1 h) of micafungin (200 to 300 mg) were investigated for six patients with severe burns. Micafungin treatment was initiated more than 72 h after the burn injuries. The peak and trough levels in the plasma after the initial administration and repeated administrations for more than 4 days were comparable with or slightly lower than the reported values for healthy volunteers. Micafungin concentrations in the plasma and burn eschar were between 3.6 and >1,000 times higher than the reported MIC(90)s of micafungin against clinically important Candida and Aspergillus species.

We compared the effects of Ringer's lactate (RL) and acetate (RA) solutions on parameters of splanchnic dysoxia such as PgCO(2) (PCO(2) of gastric mucosa) and pH(i) (pH of gastric mucosa) using a gastric tonometer, in addition to blood markers such as the serum arterial level of lactate, base excess, ketone body ratio, and antithrombin during the first 72h of the resuscitation period in patients with burns covering 30% or more of their body surface. A prospective study was conducted in the university tertiary referral centers. There were no significant differences in the average age, TBSA (total burn surface area), and resuscitative fluid volume during the first and second 24h between the two groups. In the RA group, PCO(2) gap values calculated employing the formula: PgCO(2)-PaCO(2) (arterial PCO(2)), and pH gap calculated by: pH(a) (arterial pH)-pH(i), improved to the normal ranges at 24 h postburn, which was significantly faster than in the RL group. On the other hand, there were no significant differences in blood parameters between the two groups over the course. These results suggest that fluid resuscitation with RA may more rapidly ameliorate splanchnic dysoxia, as evidenced by gastric tonometry, compared to that with RL., (Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.)

Previously, we have found that a prior burn insult induces lethal acute lung injury (ALI) and overproduction of proinflammatory cytokines after LPS challenge in mice. The current study was aimed to determine the role of IL-18 in burn-induced LPS hypersensitivity. Except sham group, mice were subjected to a 15% total body surface area full-thickness burn and either untreated or treated with IL-18 alone, IL-18 + anti-IL-10 antibody or IL-18 + isotype immunoglobulin G. LPS was intravenously administered to all mice on the 11th day, and the mice were killed at the indicated time point, or survival was examined. We additionally examined cytokine production by splenic cells in vitro for the elucidation of immunologic mechanisms. Unexpectedly, the liver IL-18 decreased transiently after burn injury, and in vivo IL-18 supplementation improved survival and ameliorated ALI, as well as reducing the lung contents of all cytokines examined, except IL-10. Neutralization of IL-10 cancelled the protective effect of IL-18. In splenic macrophages obtained from burned mice, the production of macrophage inflammatory protein 2 (MIP-2), TNF-alpha, and IL-10 was augmented, whereas in vivo IL-18 supplementation decreased MIP-2 production, but increased IL-10 production. Furthermore, a physiological concentration of IL-18 directly attenuated MIP-2 production by splenic cells in vitro. Burn injury induces LPS hypersensitivity through augmented production of proinflammatory cytokines by systemic macrophages. IL-18 supplementation is protective for LPS-induced lethal ALI through the direct anti-inflammatory effect on macrophages as well as by in vivo acceleration of IL-10 production, and could thus be an effective prophylactic strategy against septic complications in critically ill patients.

Many patients who experience surgical stress, including burn injury, become susceptible to severe sepsis and septic organ dysfunction, which remains the primary contributor to morbidity and mortality in burn patients. In the present study, we developed a murine model of burn-primed sublethal endotoxemia by producing a 15% BSA full-thickness burn on the dorsum of BALB/c mice under ether anesthesia and administering 10 mg/kg of LPS intravenously on day 11 to model endotoxemia. The prior burn injury in this model induced two-peaked production of cytokines, TNF-alpha, and macrophage inflammatory protein-2 at 2 and 12 h after LPS administration, and it was associated with increased mortality. We also assessed the effect of pharmacological modulation with cytokine synthesis inhibitors prednisolone and JTE-607 and found that pretreatment with them attenuated later cytokine production and decreased mortality after LPS administration. We speculate that the prior burn injury primed the mice for the secondary insult via cytokine production. These results also suggested that an anticytokine strategy might serve as a novel prophylactic therapy for septic organ dysfunction in burn-primed patients.

QT dispersion, defined as the maximal-minus-minimal QT interval on a 12-lead electrocardiogram, has emerged as a non-invasive measurement for quantifying the spatial inhomogeneity of ventricular repolarization under various conditions, including acute stress. Because burn injuries elicit acute stress reactions, it was hypothesized that QT dispersion increases with the severity of the burn injury. To test the hypothesis, 13 burned patients (age range of 22-76 years, nine males, ranging from 4.0 to 75.0% of total body surface area burned) in whom a measurable 12-lead electrocardiogram had been obtained within 4h after arrival at the emergency department were identified retrospectively, and their QTc intervals, i.e. QT intervals corrected for heart rate by the standard Bazett formula, were measured. QTc dispersion (QTcd) was then calculated, and correlations were assessed with burn severity (burn index, BI; prognostic burn index, PBI). Of the 13 patients, nine patients had a prolonged QTcd (>40 ms), and linear correlation analyses showed significant positive correlations between QTcd and both BI and PBI (r=0.61 and 0.62, respectively). In conclusion, QT dispersion was greater in the burned patients, and although the pathophysiology was unclear from the present study, the findings suggested that acute stress contributed to the spatial inhomogeneity of ventricular repolarization.

Abstract: Inhalation injury has recently emerged as the major cause of mortality in burn patients. However, the prognostic value of inhalation injury has not been thoroughly assessed in Japanese burn facilities. The aim of the present study was to evaluate the impact of inhalation injury on burn patients’ mortality in Tokyo. Of 6416 patients admitted to 13 burn facilities of the Tokyo Burn Unit Association between 1984 and 2002; the 5560 eligible patients were included in this study (mean age, 40±20 years; male, 61.6%; mean partial- and full-thickness burn size, 10.7±13.0% and 9.6±20.5%). Of the 5560 patients, 1690 patients (30.4%) had experienced inhalation injury. The overall in-hospital mortality rate of the patients with inhalation injury was higher than that of those without inhalation injury (33.6% versus 8.1%, odds ratio, 5.72 [95% CI, 4.91–6.67]). The results of the multivariate analysis indicated that inhalation injury; full- and partial-thickness burn size, and age were independent predictors of outcome (relative risk, 2.58 [2.03–3.29], 1.10 [1.09–1.11], 1.06 [1.06–1.07], 1.05 [1.05–1.06], respectively). In conclusion, inhalation injury was the most important predictor of overall mortality among burned patients in Tokyo. [Copyright &y& Elsevier]