Transcriptome modulation by hydrocortisone in severe burn shock: ancillary analysis of a prospective randomized trial.

BACKGROUND: Despite shortening vasopressor use in shock, hydrocortisone administration remains controversial, with potential harm to the immune system. Few studies have assessed the impact of hydrocortisone on the transcriptional response in shock, and we are lacking data on burn shock. Our objective was to assess the hydrocortisone-induced transcriptional modulation in severe burn shock, particularly modulation of the immune response. METHODS: We collected whole blood samples during a randomized controlled trial assessing the efficacy of hydrocortisone administration in burn shock. Using whole genome microarrays, we first compared burn patients (n = 32) from the placebo group to healthy volunteers to describe the transcriptional modulation induced by burn shock over the first week. Then we compared burn patients randomized for either hydrocortisone administration or placebo, to assess hydrocortisone-induced modulation. RESULTS: Study groups were similar in terms of severity and major outcomes, but shock duration was significantly reduced in the hydrocortisone group. Many genes (n = 1687) were differentially expressed between burn patients and healthy volunteers, with 85% of them exhibiting a profound and persistent modulation over seven days. Interestingly, we showed that hydrocortisone enhanced the shock-associated repression of adaptive, but also innate immunity. CONCLUSIONS: We found that the initial host response to burn shock encompasses wide and persistent modulation of gene expression, with profound modulation of pathways associated with metabolism and immunity. Importantly, hydrocortisone administration may worsen the immunosuppression associated with severe injury. These data should be taken into account in the risk ratio of hydrocortisone administration in patients with inflammatory shock. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00149123 . Registered on 6 September 2005.

Low-dose hydrocortisone reduces norepinephrine duration in severe burn patients: a randomized clinical trial.

INTRODUCTION: The aim of this study was to assess the effect of low-dose corticosteroid therapy in reducing shock duration after severe burn. METHODS: A placebo-controlled, double-blind, randomized clinical trial (RCT) was performed on two parallel groups in the burn intensive care unit (ICU). Patients were randomized to receive either low-dose corticosteroid therapy or placebo for seven days. A corticotropin test was performed at the time of randomization, before the administration of the treatment dose. Thirty-two severely burned patients with refractory shock (>0.5 µg/kg/min of norepinephrine) were prospectively included in the study. RESULTS: We included 12 patients in the hydrocortisone-treated group and 15 patients in the placebo group in the final analysis. Among these patients, 21 were nonresponders to the corticotropin test. Median norepinephrine treatment duration (primary objective) was significantly lower in the corticosteroid-treated versus the placebo group (57 hours versus 120 hours, P = 0.035). The number of patients without norepinephrine 72 hours after inclusion was significantly lower in the treated group (P = 0.003, log-rank test analysis). The total quantities of norepinephrine administered to patients were lower in the hydrocortisone-treated versus the placebo group (1,205 µg/kg (1,079 to 2,167) versus 1,971 µg/kg (1,535 to 3,893), P = 0.067). There was no difference in terms of ICU or hospital length of stay, sepsis incidence, cicatrization or mortality. CONCLUSIONS: In this placebo-controlled, randomized, double-blind clinical trial, we show for the first time that the administration of low-dose hydrocortisone in burn patients with severe shock reduces vasopressor administration. TRIAL REGISTRATION: Clinicaltrial.gov NCT00149123 . Registered 6 September 2005.

Survey on methodologies in the risk assessment of chemical exposures in emergency response situations in Europe.

A scientifically sound assessment of the risk to human health resulting from acute chemical releases is the cornerstone for chemical incident prevention, preparedness and response. Although the general methodology to identify acute toxicity of chemicals has not substantially changed in the last decades, there is ongoing debate on the current approaches for human health risk assessment in scenarios involving acute chemical releases. A survey was conducted to identify: (1) the most important present and potential future chemical incident scenarios and anticipated changes in chemical incidents or their management; (2) information, tools and guidance used in different countries to assess health risks from acute chemical releases; and (3) needs for new information, tools, guidance and expertise to enable the valid and rapid health risk assessment of acute chemical exposures. According to the results, there is an obvious variability in risk assessment practices within Europe. The multiplicity of acute exposure reference values appears to result in variable practices. There is a need for training especially on the practical application of acute exposure reference values. Although acutely toxic and irritating/corrosive chemicals will remain serious risks also in future the development of plausible scenarios for potential emerging risks is also needed. This includes risks from new mixtures and chemicals (e.g. nanoparticles).

Long-term alteration of daily melatonin, 6-sulfatoxymelatonin, cortisol, and temperature profiles in burn patients: a preliminary report.

Melatonin, which shows a robust nycthemeral rhythm, plays the role of an endogenous synchronizer, able to stabilize and reinforce circadian rhythms and maintain their mutual phase relationships. Additionally, melatonin is a potent antioxidant and displays immunological properties. Because free radical generation, immune dysfunction, and sleep and metabolic disorders are involved in the short- and long-term pathophysiology of the burn syndrome, we undertook the study of daily urine melatonin, 6-sulfatoxymelatonin (aMT6s, the main hepatic melatonin metabolite), and cortisol variations plus temperature profiles in burn patients using a non-invasive protocol. Eight patients (6 males, 2 females) were studied on three occasions after admission to the intensive care unit (early session: days 1 to 3; intermediate session: day 10; late session: days 20 to 30). Melatonin, aMT6s, and free cortisol levels were determined in urine samples collected at 4 h intervals over a continuous 24 h span. Core temperature was recorded daily. Controls consisted of healthy subjects in the same age range. Cosinor analysis of the data provided an evaluation of mesor, amplitude, and acrophase of circadian rhythms. Also, we calculated day (D), night (N), and 24 h hormone excretions, N/D ratio for melatonin and aMT6s, and D/N ratio for cortisol. These data were analyzed using Kruskal-Wallis test followed by multiple comparisons. Cosinor analysis did not detect a circadian rhythm in melatonin, aMT6s, or cortisol in any of the three sessions. D melatonin excretion displayed a major increase, resulting in a decreased N/D melatonin ratio, and the melatonin mesor (24 h mean) was increased in the early session, compared with controls. For aMT6s, only the early N/D ratio was decreased, and the mesor of the intermediate session increased. These results were not the consequence of hepatic and/or kidney alteration, as the patients' hepatic and renal parameters were in the normal range. The D and N melatonin/aMT6s ratios of controls and patients were similar, and the aMT6s profiles were superimposed on the melatonin ones, mainly during the day. The D, N, and 24 h cortisol values were increased in all sessions, except for the D level of the early session. The consistently increased mesors in the three sessions provided confirmation. The core temperature profiles were abnormal in all three sessions, mainly during the night, although there was a tendency toward normalization with time. The individual mesors were consistently increased compared with controls. Globally, the abnormalities we report could participate in the pathophysiology of short- and long-term alterations observed in burn syndrome, especially disturbances of sleep, metabolism, and immune function.

Decreased monocyte human leukocyte antigen-DR expression after severe burn injury: Correlation with severity and secondary septic shock.

OBJECTIVE: Severe thermal injury causes immune dysfunctions involving both pro- and anti-inflammatory mechanisms. It subsequently leads to a state of immune deficiency that shares some similarities with sepsis-induced immunosuppression. A hallmark of the latter is established by decreased monocyte human leukocyte antigen-DR (mHLA-DR) measurements. The main objective of the current study was to characterize the appearance and the duration of low mHLA-DR expression after severe burn as well as to determine its correlation with mortality and septic complications. DESIGN: Observational study. SETTING: Burn unit (intensive care unit) in a university hospital. PATIENTS: Severe burn patients (total burn surface area >30%, n = 14) and healthy individuals (n = 29). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were immunologically monitored during 15 days. We quantified mHLA-DR expression with a standardized flow cytometry protocol. Every patient presented with decreased mHLA-DR expression at days 2-3 after burn. Then, from days 4-6, this expression increased in patients who would survive whereas it remained low in nonsurvivors. As early as days 7-10 after burn, patients who were going to develop secondary septic shock exhibited significantly lower mHLA-DR expression in comparison with patients recovering without severe septic complications. Using quantitative reverse transcriptase-polymerase chain reaction, at days 4-6, we found that the RNA level of the nonpolymorphic HLA-DRA chain and the transcription factor class II transactivator were also significantly decreased compared with healthy controls; however, plasma cytokines (interleukin-6, tumor necrosis factor-alpha, and interleukin-10) did not provide any significant prognostic information. CONCLUSIONS: Severe burn injury induced a marked reduction in mHLA-DR expression at both protein and messenger RNA levels. Its persistent decrease was associated with mortality and the development of septic complications.

Methemoglobinemia by cerium nitrate poisoning.

Cerium nitrate is a topical antiseptic used with silver sulfadiazine (Flammacerium) for the treatment of serious burns. This topical agent can induce methemoglobinemia, but no cases have been reported in the recent literature. In this article, we present the case of a 16-year old girl, with third-degree burns over 95% of her body. After daily dressings of Flammacerium, on the sixth day she developed a bluish skin coloring. When tested for methemoglobinemia, levels of 31.8% were found. These returned to normal after classic treatment with Methylene blue.

The AETL methodology as a potential solution to current challenges associated with the development and use of acute exposure levels in Seveso II applications.

This paper analyses current trends in the development and use of acute exposure levels in Europe for the implementation of the Seveso II Directive [Council Directive 96/82/EC of December 9, 1996 on the control of major-accident hazards involving dangerous substances. Official Journal of the European Communities, vol. L 10, January 14, 1997, Luxembourg, pp. 13-33]. It also describes a new initiative to develop a European methodology for deriving acute exposure threshold levels that responds to emerging needs in this area. The need for acute exposure values to predict human health effects of potential accidents on exposed populations has burgeoned in recent years. As the driving legislation for managing industrial hazards in Europe, the Seveso II Directive has particularly influenced this trend. Yet at this time it is questionable whether the availability and range of acute exposure values for toxic substances has kept apace with the growing need. Results of a survey of Seveso II competent authorities in the EU-15 revealed that a variety of different types of acute exposure values (AEGLs, EPRGs, etc.) are used for Seveso II applications. Moreover, a comparison of these values indicates gaps in coverage of substances as well as inconsistencies in terms of how health effects and exposure periods are defined for each type. These findings highlight an opportunity for greater collaboration on scientific inputs to application of the Directive in Europe. The ACUTEX project is an EU-funded research project aimed at furthering scientific exchange and collaboration in support of the development of acute exposure levels for toxic substances in Europe. Its goal is to develop a European methodology for deriving acute exposure threshold levels (AETLs). In particular, it provides the possibility for a common European platform for developing additional acute exposure values to meet emerging needs and cover more chemical substances. To maximise success, the work plan is designed to meet two very important challenges, the need to complement and add value to the existing array of acute exposure methodologies and the necessity of meeting requirements of a diverse range of European stakeholders. As such the project will draw on collaboration among European scientists and process of deliberation among stakeholders to deliver the following key results: (1) to facilitate wide acceptance of the methodology in Europe by both the scientific community and communities of different end-users; (2) to provide greater equivalence and transparency in implementation of the Seveso II Directive across the Member States, specifically through the development of common scientific bases for assessing risks and making risk management decisions related to toxic releases; (3) to produce a methodology that remains open to future collaboration on derivation of acute exposure levels on a European and a global basis.