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Objective: Glucocorticoids play a major role in the consolidation and retrieval of traumatic information. They act through the glucocorticoid receptor, for which, in humans, several polymorphisms have been described. In particular, the BclI single-nucleotide polymorphism is associated with hypersensitivity to glucocorticoids and with susceptibility to development of major depression. Furthermore, in patients with posttraumatic stress disorder carrying the BclI GG genotype, cortisol levels were lower and showed an inverse relationship to posttraumatic stress disorder symptom intensity. Here, we studied the association of the BclI polymorphism with plasma cortisol levels, traumatic memories, posttraumatic stress disorder symptoms, and health-related quality of life outcomes in 126 patients undergoing cardiac surgery and intensive care unit therapy., Design: Prospective observational study., Setting: Cardiovascular intensive care unit in a university hospital., Patients: A total of 126 patients undergoing cardiac surgery and intensive care unit treatment., Interventions: No interventions were performed., Measurements and Main Results: Validated questionnaires were used to quantify end points. Measurements were taken 1 day before and 1 wk and 6 months after cardiac surgery. Homozygous carriers of the BclI G allele (n = 21) had significantly lower preoperative plasma cortisol levels and more long-term traumatic memories from intensive care unit therapy at 6 months after cardiac surgery than heterozygous carriers or noncarriers (1.9 ± 1.4 vs. 1.0 ± 1.2, p = .01). Anxiety was significantly more common as a long-term traumatic memory in homozygous BclI G allele carriers than in heterozygous carriers or noncarriers (57% vs. 35%, p = .03). Posttraumatic stress disorder symptom scores were significantly higher at discharge from the intensive care unit in homozygous BclI G allele carriers than in heterozygous carriers or noncarriers. Only heterozygous carriers or BclI G allele noncarriers had a significant gain in health-related quality of life physical function at 6 months after cardiac surgery (p < .01). Baseline values were not statistically different between carriers of the different BclI alleles., Conclusion: Homozygous BclI G allele carriers are at risk for traumatic memories, posttraumatic stress disorder symptoms, and lower health-related quality of life after cardiac surgery and intensive care unit therapy. The BclI single-nucleotide polymorphism may help to identify individuals at need for tailored medical care.

The interaction between blood glutathione (GSH) and supplementation of selenium (Se, 2.5 mg/kg diet) on meat colour and fatty acids concentrations was studied. Forty eight Merino lambs selected for high blood GSH (HGSH) or low GSH (LGSH) concentration were used. They were fed individually with or without Se supplement for 8 weeks. There were interactions (P<0.05) between GSH and Se on the colour stability (as w630 nm/w580 nm ratio) of m. longissimus (LD), m. semimembranosus (SM) and m. semitendinosus. Without Se supplementation the ratio was higher in HGSH than LGSH group. However, the difference was reduced with Se supplement. Polyunsaturated and n-3 fatty acids in SM and LD were higher in HGSH than in LGSH group (P<0.05), and did not change with Se supplement. Se supplementation increased Se content in LD (P<0.001) and the lungs (P<0.05), but had no influence in the heart., (Copyright © 2010 The American Meat Science Association. Published by Elsevier Ltd. All rights reserved.)

Cardiac surgery with cardiopulmonary bypass (CPB) is associated with activation of the complement system, platelets, neutrophils, monocytes, and macrophages which may lead to systemic inflammatory response syndrome in several cases. Despite modification of surgical techniques, biocompatibility of the bypass circuit and intensive care procedures after operation, CPB is still associated with post-operative morbidity including reduced cardiac function, capillary leak or multi-organ dysfunction. Corticosteroids are known for their anti-inflammatory effects and therefore, they are beneficial in selected trauma or septic patients. Prophylaxis with corticosteroids in cardiac surgery has been used since decades. The studies for methylprednisolone and hydrocortisone, the most commonly used corticosteroids, show conflicting results. For hydrocortisone, which is the mainstream of corticosteroid treatment in septic patients, the number of studies is low, but will increase in the next years. This article reviews the data concerning its use in patients undergoing cardiac surgery, its contraindications, adverse effects, risks, and benefits.

Objective: To evaluate the feasibility and outcomes of protocol-driven noninvasive mechanical ventilation in patients with acute respiratory failure (ARF) after cardiac surgery., Methods: From 2001 to 2004, a total of 2428 cardiac surgery patients admitted to our intensive care unit were observed. After exclusion of patients who received tracheostomy or were discharged while still on mechanical ventilation, 2261 patients with spontaneous breathing were further evaluated for ARF. Patients diagnosed with ARF were treated with intermittent noninvasive mechanical ventilation (NIV) if possible. Risk factors for the development of postoperative ARF as well as outcomes in patients with and without ARF were analyzed., Results: In 2261 spontaneously breathing postoperative cardiac surgical patients after primarily successful extubation, 799 patients (35%) were diagnosed with ARF. Fifty-six patients (7%) did not tolerate NIV treatment. In 743 patients (33%) intermittent NIV was performed. In patients with ARF, ejection fraction was lower, combined cardiac surgical procedures were more frequent, postoperative mechanical ventilation time was longer, and the severity of illness score (SAPS II) was higher (P < .05). The duration of catecholamine support was longer, and the transfusion rate was higher in the NIV group (P < .05); however, mortality did not differ between patients with ARF treated by NIV and patients without ARF., Conclusion: Our study demonstrates the feasibility of NIV in patients after cardiac surgery. These results might suggest that NIV should be considered as first-line ventilatory support in ARF after cardiac surgery. A large randomized trial is warranted to confirm these findings.

Purpose: To compare inter-laboratory and inter-assay measurements of total cortisol in patients with septic shock and to evaluate current recommendations for diagnosis of corticosteroid insufficiency in septic shock., Methods: In the multinational CORTICUS study duplicate serum samples were taken before and after corticotropin stimulation tests in patients with septic shock. Serum cortisol was measured in paired samples, one being measured by the chemical laboratory of each participating site and the other by a central laboratory using an electrochemiluminescence immunoassay. Cortisol levels measured by tandem mass spectrometry were used as a 'gold standard' reference method in a subset of samples., Results: A total of 425 corticotropin tests (850 cortisol samples) were available for comparison of local and central laboratory measurements. The concordance correlation coefficient between central laboratory immunoassay and local hospital assays was 0.98 (CI 0.97-0.99) when the immunoassay of one manufacturer was used and 0.60 (CI 0.54-0.65) when immunoassays of different manufacturers were used. The comparison with the reference method of mass spectrometry showed concordance correlation coefficients ranging from 0.43 to 0.97 depending on the assay under study. Diagnosis of corticosteroid insufficiency was diverging due to inter-assay variations in up to 27% of cases., Conclusion: In samples taken from patients in septic shock, there was a high inter-assay variation of total serum cortisol. Comparisons with a reference method revealed both over- and underestimations of true cortisol levels. These inter-assay variations in samples of patients with septic shock complicate the diagnosis of corticosteroid insufficiency.

Background: Severe systemic inflammation (systemic inflammatory response syndrome) associated with cardiac surgery often leads to a worse short-term and long-term outcome. Stress doses of hydrocortisone have been successfully used to improve outcome of CS. The interleukin (IL)-6 to IL-10 ratio is associated with outcome after trauma and major surgery., Objective: To evaluate immunologic effects (especially IL-6 to IL-10 ratio) of stress doses of hydrocortisone in a high-risk group of patients after cardiac surgery with cardiopulmonary bypass., Design: Prospective, randomized, double-blinded, placebo-controlled trial., Setting: Cardiovascular intensive care unit of a university hospital., Patients: High-risk patients (n = 36) undergoing CS., Intervention: Stress doses of hydrocortisone or placebo., Main Outcome Measures: IL-6 to IL-10 ratio and other markers of systemic inflammation at predefined time points; short-term clinical outcome., Results: The two study groups did not differ with regard to demographic data. The patients from the hydrocortisone group (n = 19) had significantly lower levels of IL-6 and higher levels of IL-10, resulting in an attenuated change in IL-6/IL-10 ratio (28.7 [6.4/128.7] vs. 292.8 [6.5/534.6] 4 hours after cardiopulmonary bypass; p < 0.001). Patients in the hydrocortisone group had a shorter duration of catecholamine support (1 [1/2] vs. 4 [2/4.5] days; p = 0.02), a shorter length of stay in the intensive care unit (2 [2/3] vs. 6 [4/8] days; p = 0.001), and a lower incidence of postoperative atrial fibrillation (26% vs. 59%; p = 0.04)., Conclusions: Stress doses of hydrocortisone attenuate the evolution of IL-6/IL-10 ratio in patients with systemic inflammatory response syndrome after CS, which seems to be associated with an improved outcome. The immunologic effects of hydrocortisone may thus be both, inhibitory (IL-6) and permissive (IL-10), regarding the immune response.

Critically ill patients with severe systemic inflammation can develop critical illness-related corticosteroid insufficiency (CIRCI), which is associated with a poor outcome. A task force of the American College of Critical Care Medicine compiled recommendations for diagnosis and treatment of this clinical entity thereby focusing on patients with septic shock and acute respiratory distress syndrome (ARDS). The results of large scale multi-centre trials gave partially conflicting results arguing against the broad use of corticosteroids in stress doses. However, the task force recommended treatment with stress-dose corticosteroids in patients with septic shock who respond poorly to fluid resuscitation and vasopressor therapy and in patients with early ARDS (<14 days after onset). The dose of corticosteroids should be reduced in a step-wise manner. Corticosteroids at stress doses are currently under investigation in other target populations of critically ill patients potentially suffering from CIRCI. Preliminary data suggest that patients with vasodilatory shock after cardiac surgery and patients with liver cirrhosis and sepsis can benefit from corticosteroids. Critical illness-related corticosteroid insufficiency can also occur in patients with trauma, traumatic brain injury, acute pancreatitis and burn injuries, but data from clinical trials on these target groups are insufficient at present. The therapeutic use of corticosteroids in stress doses reduces the incidence of post-traumatic stress disorder (PTSD) after intensive care treatment.

Background: Healthy vascular endothelium is clothed by the endothelial glycocalyx. This structure plays a key role in the regulation of inflammation and vascular permeability and is known to be degraded by ischemic and inflammatory stress. Our aim was to show whether hydrocortisone and antithrombin stabilize the glycocalyx and, therefore, the vascular barrier, against damage induced by the inflammatory stimulus TNF-alpha, thus improving the cardio-vascular situation., Methods: Isolated guinea pig hearts were perfused with Krebs-Henseleit buffer for 20 min at constant flow (baseline perfusion pressure 70 cmH(2)O). Hydrocortisone in a stress dose (10 microg/ml) or antithrombin in a physiological dose (1 U/ml) were then applied for 15 min before infusion of TNF-alpha (4 ng/ml, 10 min). Coronary net fluid filtration was assessed directly by measuring transudate formation on the epicardial surface. Hearts were perfusion-fixed to visualize the glycocalyx., Results: TNF-alpha induced severe degradation of the glycocalyx, increased coronary resistance, heightened vascular leak and permeability to hydroxyethyl starch and caused mast-cell degranulation. Hydrocortisone and antithrombin both reduced all of these effects. Electron microscopy revealed a mostly intact glycocalyx after treatment with either drug., Conclusions: Both hydrocortisone and antithrombin clearly preserve the endothelial glycocalyx in the face of inflammatory degradation initiated by TNF-alpha, however, with different mechanisms. This is an important new facet in the pathophysiology and therapy of sepsis, since preservation of the glycocalyx should help prevent vasoconstriction, tissue edema as well as leukocyte and platelet adhesion, thus mitigating inflammation and tissue hypoxia.

Object: This prospective longitudinally designed study was conducted to evaluate language functions pre- and postoperatively in patients who underwent microsurgical treatment of tumors in close proximity to or within language areas and to detect those patients at risk for a postoperative aphasic disturbance., Methods: Between 1991 and 2005, 153 awake craniotomies with subsequent cortical mapping of language functions were performed in 149 patients. Language functions were assessed using a standardized test battery. Risk factors were obtained from multivariate logistic regression models., Results: Language mapping was able to be performed in all patients, and complete tumor resection was achieved in 48.4%. Within 21 days after surgery a new language deficit (aphasic disturbance) was observed in 41 (32%) of the 128 cases without preoperative deficits. There were a total of 60 cases involving postoperative aphasic disturbances, including cases both with and without preoperative disturbances. Risk factors for postoperative aphasic disturbance were preoperative aphasia (p<0.0002), intraoperative complications (p<0.02), language-positive sites within the tumor (p<0.001), and nonfrontal lesion location (p<0.001). In patients without a preoperative deficit, a normal (yet submaximal) naming performance was a powerful predictor for an early postoperative aphasic disturbance (p<0.0003). Seven months after treatment 10.9% of the 128 cases without preoperative aphasic disturbances continued to demonstrate new postoperative language disturbances. A total of 17.6% of all cases demonstrated new postoperative language disturbances after 7 months. Risk factors for persistent aphasic disturbance were increased age (>40 years, p<0.02) and preoperative aphasia (p<0.001)., Conclusions: Every attempt should be undertaken to preserve language-relevant areas intraoperatively, even when they are located within the tumor. New postoperative deficits resolve in the majority of patients, which may be a result of cortical mapping as well as functional reorganization.

Objective: To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients., Participants: A multidisciplinary, multispecialty task force of experts in critical care medicine was convened from the membership of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. In addition, international experts in endocrinology were invited to participate., Design/methods: The task force members reviewed published literature and provided expert opinion from which the consensus was derived. The consensus statements were developed using a modified Delphi methodology. The strength of each recommendation was quantified using the Modified GRADE system, which classifies recommendations as strong (grade 1) or weak (grade 2) and the quality of evidence as high (grade A), moderate (grade B), or low (grade C) based on factors that include the study design, the consistency of the results, and the directness of the evidence., Results: The task force coined the term critical illness-related corticosteroid insufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axis that occurs during critical illness. Critical illness-related corticosteroid insufficiency is caused by adrenal insufficiency together with tissue corticosteroid resistance and is characterized by an exaggerated and protracted proinflammatory response. Critical illness-related corticosteroid insufficiency should be suspected in hypotensive patients who have responded poorly to fluids and vasopressor agents, particularly in the setting of sepsis. At this time, the diagnosis of tissue corticosteroid resistance remains problematic. Adrenal insufficiency in critically ill patients is best made by a delta total serum cortisol of < 9 microg/dL after adrenocorticotrophic hormone (250 microg) administration or a random total cortisol of < 10 microg/dL. The benefit of treatment with glucocorticoids at this time seems to be limited to patients with vasopressor-dependent septic shock and patients with early severe acute respiratory distress syndrome (PaO2/FiO2 of < 200 and within 14 days of onset). The adrenocorticotrophic hormone stimulation test should not be used to identify those patients with septic shock or acute respiratory distress syndrome who should receive glucocorticoids. Hydrocortisone in a dose of 200 mg/day in four divided doses or as a continuous infusion in a dose of 240 mg/day (10 mg/hr) for > or = 7 days is recommended for septic shock. Methylprednisolone in a dose of 1 mg x kg(-1) x day(-1) for > or = 14 days is recommended in patients with severe early acute respiratory distress syndrome. Glucocorticoids should be weaned and not stopped abruptly. Reinstitution of treatment should be considered with recurrence of signs of sepsis, hypotension, or worsening oxygenation. Dexamethasone is not recommended to treat critical illness-related corticosteroid insufficiency. The role of glucocorticoids in the management of patients with community-acquired pneumonia, liver failure, pancreatitis, those undergoing cardiac surgery, and other groups of critically ill patients requires further investigation., Conclusion: Evidence-linked consensus statements with regard to the diagnosis and management of corticosteroid deficiency in critically ill patients have been developed by a multidisciplinary, multispecialty task force.

Objective: To assess the effects of stress doses of hydrocortisone (HC) on clinical parameters and neutrophil functions in patients with septic shock., Design: Prospective, double-blind, randomized, placebo-controlled study., Setting: Intensive care units of a university hospital., Patients and Participants: 30 adult patients with septic shock., Interventions: Patients were allocated to receive either HC (intravenous bolus of 100 mg preceding a continuous infusion 10 mg/h, n = 15) or placebo (n = 15), respectively. The effects of HC were assessed at baseline and after 24 h., Measurements and Results: As compared with placebo-treated patients, administration of HC significantly decreased norepinephrine requirements (from 1.5 to 0.8 mg/h; p < 0.001), interleukin-6 serum concentrations (from 388.8 to 88.8 pg/ml; p < 0.02), and the spontaneous release of hydrogen peroxide (H2O2) by neutrophils (-33.0%; p < 0.05). Additionally, HC treatment preserved the autologous plasma-induced amplification of phagocytosis of zymosan particles [factor of opsonin-induced amplification of phagocytosis of unopsonized particles: 1.80 for placebo vs. 1.75 for HC at baseline (not significant between groups) and 0.50 for placebo vs. 1.75 for HC after 24 h of treatment (p < 0.05)]. These effects were paralleled by respective changes in the phagocytosis-associated H2O2 production., Conclusions: In patients with septic shock stress doses of HC exert beneficial effects in terms of improvements in hemodynamics, decrease in pro-inflammatory mediators, and oxidative stress without the compromise of opsonization-dependent phagocytic neutrophil functions; thus, HC treatment does not aggravate non-specific immunosuppression but instead improves innate immunity in the early stage of septic shock.

Background: Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin., Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test., Results: Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock., Conclusions: Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. (ClinicalTrials.gov number, NCT00147004.), (2008 Massachusetts Medical Society)

Objectives: Biological effects of cortisol are substantially determined by protein binding of the hormone. The aim of our study was to characterize temperature effects on cortisol protein binding by use of an equilibrium dialysis method., Design and Methods: Serum samples obtained from ten healthy volunteers were submitted to equilibrium dialysis. Each sample from the individuals was incubated for 16 h at 37 degrees C, 38 degrees C, 39 degrees C, 40 degrees C and 41 degrees C, respectively. In the dialysate samples obtained, cortisol concentrations were measured by immunoassay., Results: For samples incubated at 37 degrees C, a mean dialysate cortisol concentration of 0.41 microg/dL (SD=0.14) was found. Gradual increase of dialysate cortisol concentration was observed with increasing incubation temperatures. For samples incubated at 41 degrees C, a mean dialysate cortisol of 0.75 microg/dL (SD=0.24) was found. Thus, the mean percentage of free-to-total cortisol increased by about 80% from 3.7% (SD=1.1) at 37 degrees C to 6.7% (SD=1.8) at 41 degrees C., Conclusions: The results of our in vitro experiments suggest that during fever the free-to-total ratio of cortisol is increased substantially compared to normal conditions, and that administration of antipyretic drugs might potentially be associated with substantial changes in the bioavailability of cortisol.

Background: The physicochemical properties of propofol could allow diffusion across the alveolocapillary membrane and a measurable degree of pulmonary propofol elimination. The authors tested this hypothesis and showed that propofol can be quantified in expiratory air and that propofol breath concentrations reflect blood concentrations. This could allow real-time monitoring of relative changes in the propofol concentration in arterial blood during total intravenous anesthesia., Methods: The authors measured gas-phase propofol using a mass spectrometry system based on ion-molecule reactions coupled with quadrupole mass spectrometry which provides a highly sensitive method for on-line and off-line measurements of organic and inorganic compounds in gases. In a first sequence of experiments, the authors sampled blood from neurosurgery patients undergoing total intravenous anesthesia and performed propofol headspace determination above the blood sample using an auto-sampler connected to the mass spectrometry system. In a second set of experiments, the mass spectrometry system was connected directly to neurosurgery patients undergoing target-controlled infusion via a T piece inserted between the endotracheal tube and the Y connector of the anesthesia machine, and end-expiratory propofol concentrations were measured on-line., Results: A close correlation between propofol whole blood concentration and propofol headspace was found (range of Pearson r, 0.846-0.957; P < 0.01; n = 6). End-expiratory propofol signals mirrored whole blood values with close intraindividual correlations between both parameters (range of Pearson r, 0.784-0.985; n = 11)., Conclusion: Ion-molecule reaction mass spectrometry may allow the continuous and noninvasive monitoring of expiratory propofol levels in patients undergoing general anesthesia.

Background: Quantification of bioactive, free serum cortisol concentrations can characterize adrenocortical function more appropriately compared to total serum cortisol measurement. Ultrafiltration or equilibrium dialysis of serum samples allow direct measurement of free serum cortisol concentrations but respective methods have poorly been validated so far. The aim of our study was to investigate the analytical performance of free serum cortisol measurement employing equilibrium dialysis and ultrafiltration., Methods: Two commercially available ultrafiltration devices and self-assembled dialysis cells, respectively, were studied. Cortisol was quantified in filtrate or dialysate using an automated immunoassay system. Using two serum pools, the inter-assay coefficient of variation was determined for the three methods and a method comparison was performed., Results: Inter-assay coefficients of variation (n=10) between 3.2% and 14.8% were observed in the imprecision study. Method comparison demonstrated close agreement between free serum cortisol results obtained by ultrafiltration and equilibrium dialysis, respectively (equilibrium dialysis=1.2xultrafiltration+3.9 nmol/L; r=0.99; n=35)., Conclusions: Direct quantification of free serum cortisol after equilibrium dialysis or ultrafiltration of the samples offers acceptable reproducibility and results in close agreement can be obtained. Both methods can potentially be introduced into a routine laboratory setting.

Like other humans exposed to extreme trauma, patients who have been treated in an intensive care unit (ICU) often report traumatic memories. Extremely traumatic memories from the ICU in some of these patients are associated with the development of posttraumatic stress disorder (PTSD), which results in significant impairments in health-related quality of life (HRQL) outcomes of ICU therapy. Severely ill patients in the ICU often show insufficient endogenous glucocorticoid signaling, which has recently been termed critical illness-related corticosteroid insufficiency (CIRCI). We performed several controlled trials in ICU patients with suspected CIRCI from septic shock or cardiac surgery, which indicated that the administration of glucocorticoids (stress doses of hydrocortisone) during ICU treatment results in a significant reduction of PTSD symptoms in long-term survivors as well as improvements in HRQL outcomes. Stress doses of hydrocortisone could help to surmount impaired glucocorticoid signaling from CIRCI during critical illness resulting in a downregulation of the stress response as well as inhibition of traumatic memory retrieval and facilitated extinction of aversive information.

Objective: The prophylactic use of nimodipine in patients with aneurysmal subarachnoid hemorrhage reduces the risk of ischemic brain damage. However, its efficacy seems to be rather moderate. The question arises whether other types of calcium antagonists offer better protection. Magnesium, nature's physiological calcium antagonist, is neuroprotective in animal models, promotes dilatation of cerebral arteries, and has an established safety profile. The aim of the current pilot study is to evaluate the efficacy of magnesium versus nimodipine to prevent delayed ischemic deficits after aneurysmal subarachnoid hemorrhage., Methods: One hundred and thirteen patients with aneurysmal subarachnoid hemorrhage were enrolled in the study and were randomized to receive either magnesium sulfate (loading 10 mg/kg followed by 30 mg/kg daily) or nimodipine (48 mg/d) intravenously until at least postoperative Day 7. Primary outcome parameters were incidence of clinical vasospasm and infarction. Secondary outcome measures were the incidence of transcranial Doppler/angiographic vasospasm, the neuronal markers (neuron-specific enolase, S-100), and the patients' Glasgow Outcome Scale scores at discharge and after 1 year., Results: One hundred and four patients met the study requirements. In the magnesium group (n = 53), eight patients (15%) experienced clinical vasospasm and 20 (38%) experienced transcranial Doppler/angiographic vasospasm compared with 14 (27%) and 17 (33%) patients in the nimodipine group (n = 51). If clinical vasospasm occurred, 75% of the magnesium-treated versus 50% of the nimodipine-treated patients experienced cerebral infarction resulting in fatal outcome in 37 and 14%, respectively. Overall, the rate of infarction attributable to vasospasm was virtually the same (19 versus 22%). There was no difference in outcome between groups., Conclusion: The efficacy of magnesium in preventing delayed ischemic neurological deficits in patients with aneurysmal subarachnoid hemorrhage seems to be comparable with that of nimodipine. The difference in their pharmacological properties makes studies on the combined administration of magnesium and nimodipine seem promising.

A randomised, prospective, placebo-controlled phase III multicentre clinical trial (KyberSept) has been performed to test the efficacy of high-dose antithrombin therapy in patients with severe sepsis. Concomitant low-dose heparin has been routinely given in two thirds of patients for deep vein thrombosis prophylaxis. This study analyses heparin - antithrombin interactions in terms of long-term mortality, adverse events, and thromboembolic events. From a total of 2,314 patients with severe sepsis (placebo: n = 1,157; antithrombin: n = 1,157) 1,616 patients (placebo: 811, antithrombin: 805) received heparin concomitantly with study drug (antithrombin 30,000 IU) over four days, whereas 698 patients (346 and 352, respectively) did not. In patients with no concomitant heparin, 28-day mortality was lower with antithrombin than with placebo (37.8% vs. 43.6%; absolute reduction: 5.8%; risk ratio: 0.860 [0.725-1.019]), which increased until day-90 (44.9% vs. 52.5%; absolute reduction: 7.6%; risk ratio: 0.851 [0.735-0.987]). In patients with concomitant heparin, no effect of antithrombin on mortality was seen (28-day mortality: 39.4% vs. 36.6%; absolute increase: 2.8%; risk ratio: 1.08 [0.96-1.22]). Frequency of use of concomitant heparin increased during conduct of the study. Increased bleeding incidences were reported with antithrombin plus concomitant heparin as compared to antithrombin alone. Rates of thromboembolic events were similar when antithrombin was given with or without concomitant heparin. In the treatment of severe sepsis, high-dose antithrombin may sufficiently protect against development of venous thromboembolism when no concomitant heparin is given. Combined administration of the two increases bleeding risk and probably abolishes efficacy of antithrombin.

Objectives: Improvement in health-related quality of life is a major object of cardiac surgery. However, high stress exposure during the perioperative period of cardiac surgery can result in the formation of traumatic memories and symptoms of chronic stress or even posttraumatic stress disorder, which can have negative effects on health-related quality-of-life outcome. In this controlled study we examined whether exogenously administered stress doses of hydrocortisone during cardiac surgery reduce perioperative stress exposure and the long-term incidence of chronic stress symptoms and improve health-related quality of life after cardiac surgery., Methods: Thirty-six high-risk patients undergoing cardiac surgery were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Of 28 available patients at 6 months after cardiac surgery, 14 had received hydrocortisone, and 14 had received placebo. Traumatic memories, chronic stress symptoms (posttraumatic stress disorder scores), and health-related quality of life were measured by using validated questionnaires., Results: Compared with patients from the placebo group, patients from the hydrocortisone group had a significantly shorter duration of intensive care unit treatment, required lower doses of the stress hormone norepinephrine during cardiac surgery, and had significantly fewer stress symptoms and a better health-related quality of life regarding physical function, chronic pain, general health, vitality, and mental health during follow-up. The groups did not differ with regard to the number or type of intensive care unit-related traumatic memories., Conclusions: The use of stress doses of hydrocortisone in high-risk cardiac surgical patients reduces perioperative stress exposure, decreases chronic stress symptoms, and improves health-related quality of life at 6 months after cardiac surgery.

Background: The prognosis in patients with hyperdynamic septic shock correlates with the presence and the severity of septic encephalopathy. However, the neurological evaluation is considerably influenced by the use of analgesia sedation during mechanical ventilation. An early concentration peak of the neuroprotein S-100B in serum reflects both cellular damage at an increased permeability of the blood-brain-barrier and a delayed renal elimination. Thus, the objective of this study was to analyze the effect of continuous veno-venous hemofiltration (CVVH) on early S-100B serum levels in septic shock patients, who were treated with either stress doses of hydrocortisone or placebo., Methods: Twenty-four consecutive patients, who met the ACCP / SCCM criteria for septic shock, were enrolled in this prospective, randomised, double-blind, single-center trial. The severity of illness at recruitment was graded using the APACHE II and SAPS II scoring systems; the MODS was described by the SOFA score. All patients were prospectively randomised to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days., Results: Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/ml (0.19-3.60) at study entry to 0.07 ng/ml (0.04 - 0.32) 6 days later without significant differences compared to the placebo group. Patients undergoing CVVH showed significantly higher S-100B serum values compared to patients without CVVH (p<0.001). However, initial median S-100B serum levels of the CVVH group even increased from 0.92 ng/ml (0.16 - 4.63) to 2.33 ng/ml (0.59 - 2.44) 30 hours after study entry, reaching data ranges already known in patients with out-of-hospital cardiac arrest or severe traumatic brain injury., Conclusion: Early S-100B serum levels in septic shock patients receiving either stress doses of hydrocortisone or placebo were not influenced by CVVH. For the first time, we observed a similar extent of S-100B serum increase in CVVH patients, who had significantly higher S-100B serum values compared to those without CVVH, as reported for out-of-hospital cardiac arrest or severe traumatic brain injury. Hypercortisolemia induced by the infusion of stress doses of hydrocortisone did not significantly reduce early S-100B serum concentrations with time.

Stress doses of hydrocortisone are known to have immunomodulatory effects in patients with hyperdynamic septic shock. The prognosis correlates with the presence and severity of septic encephalopathy. However, neurological evaluation is influenced by the use of analgesia sedation during artificial ventilation. The objective of this study was to demonstrate the effect of stress doses of hydrocortisone during the initial phase of human septic shock on the serum values of the neurospecific protein S-100B in comparison to the inflammation markers interleukin (IL)-8 in serum and polymorphonuclear (PMN) elastase in plasma. A total of 24 consecutive patients, who met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock, were enrolled in this prospective, randomized, double-blind, single-center trial. The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. Multi-organ dysfunction syndrome was described by the Sepsis-related Organ Failure Assessment (SOFA) score. All patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days. Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/mL at study entry to 0.07 ng/mL 6 days later without significant differences compared to the placebo group. Initial IL-8 serum levels were significantly higher in the hydrocortisone group up to 12 h after study entry, and significantly decreased from 715 to 17 pg/mL at the end of the observation period. Median PMN elastase plasma levels were not affected by hydrocortisone infusion. Patients with initial S-100B serum levels > 0.50 ng/mL revealed significantly higher SOFA scores up to 30 h, IL-8 serum levels up to 12 h, and PMN elastase plasma levels up to 36 h after study entry than those patients with < or = 0.50 ng/mL. These effects were independent of the amount of fluid correction for hemodilution. Starting S-100B, IL-8 and PMN elastase values of the hydrocortisone group were within the ranges already known in patients with out-of-hospital cardiac arrest or severe traumatic brain injury. Stress doses of hydrocortisone resulted in a significant reduction in IL-8 serum, but not in S-100B serum and PMN elastase plasma concentrations in patients with hyperdynamic septic shock. For the first time, a similar extent of S-100B increase in serum of septic patients at the time of diagnosis was shown as reported for cardiac arrest or severe traumatic brain injury.

Objective: To assess the effects of corticosteroids on mortality in patients with severe sepsis and septic shock., Data Sources: Randomised and quasi-randomised trials of corticosteroids versus placebo (or supportive treatment alone) retrieved from the Cochrane infectious diseases group's trials register, the Cochrane central register of controlled trials, Medline, Embase, and LILACS., Review Method: Two pairs of reviewers agreed on eligibility of trials. One reviewer entered data on to the computer and four reviewers checked them. We obtained some missing data from authors of trials and assessed methodological quality of trials., Results: 16/23 trials (n = 2063) were selected. Corticosteroids did not change 28 day mortality (15 trials, n = 2022; relative risk 0.92, 95% confidence interval 0.75 to 1.14) or hospital mortality (13 trials, n = 1418; 0.89, 0.71 to 1.11). There was significant heterogeneity. Subgroup analysis on long courses (> or = 5 days) with low dose (< or = 300 mg hydrocortisone or equivalent) corticosteroids showed no more heterogeneity. The relative risk for mortality was 0.80 at 28 days (five trials, n = 465; 0.67 to 0.95) and 0.83 at hospital discharge (five trials, n = 465, 0.71 to 0.97). Use of corticosteroids reduced mortality in intensive care units (four trials, n = 425, 0.83, 0.70 to 0.97), increased shock reversal at 7 days (four trials, n = 425; 1.60, 1.27 to 2.03) and 28 days (four trials, n = 425, 1.26, 1.04 to 1.52) without inducing side effects., Conclusions: For all trials, regardless of duration of treatment and dose, use of corticosteroids did not significantly affect mortality. With long courses of low doses of corticosteroids, however, mortality at 28 days and hospital morality was reduced.

Background: Traumatic experiences associated with cardiac surgery (CS) can result in traumatic memories and posttraumatic stress disorder (PTSD). Because it is known that subjects who develop PTSD often show sustained reductions in circulating cortisol concentrations, we performed a prospective, randomized study to examine whether exogenously administered stress doses of hydrocortisone during the perioperative period of CS reduces the long-term incidence of chronic stress and PTSD symptoms., Methods: Patients (n = 91) were prospectively randomized to receive either stress doses of hydrocortisone or standard treatment during the perioperative period of CS. Of 48 available patients at 6 months after CS, 26 had received stress doses of hydrocortisone and 22 standard treatment. Traumatic memories and PTSD symptoms were diagnosed with previously validated questionnaires., Results: As compared with patients after standard therapy, patients from the hydrocortisone group had significantly lower chronic stress symptom scores (p <.05). There was no significant difference regarding the number or type of traumatic memories between the hydrocortisone and the standard treatment groups., Conclusions: Stress doses of hydrocortisone in patients undergoing CS are associated with a lower intensity of chronic stress and PTSD symptoms at 6 months after CS.

Background: Sepsis may be complicated by impaired corticosteroid production. Giving corticosteroids could potentially benefit patients., Objectives: To examine the effects of corticosteroids on death at one month in patients with severe sepsis and septic shock., Search Strategy: We searched the Cochrane Infectious Diseases Group's trial register (August 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2003), MEDLINE (August 2003), EMBASE (August 2003), LILACS (August 2003), reference lists of articles, and also contacted trial authors., Selection Criteria: Randomized and quasi-randomized controlled trials of corticosteroids versus placebo or supportive treatment in severe sepsis and septic shock., Data Collection and Analysis: Two pairs of reviewers agreed the eligibility of trials. One reviewer extracted data, which was checked by the other reviewers and the primary author of the paper whenever possible. We obtained some missing data from the trial authors. We assessed trial methodological quality., Main Results: We identified 15 trials (n =2023). Corticosteroids did not change 28-day all-cause mortality (15 trials, n = 2022, relative risk (RR) 0.92, 95% confidence interval (CI) 0.75 to 1.14; random effects model) and hospital mortality (13 trials, n = 1418, RR 0.89, 95% CI 0.71 to 1.11; random effects model); however, there was statistically significant heterogeneity, with some evidence that this was related to the dosing strategy. Corticosteroids reduced intensive care unit mortality (4 trials, n = 425, RR 0.83, 95% CI 0.70 to 0.97), increased the proportion of shock reversal by day 7 (6 trials, n = 728, RR 1.22, 95% CI 1.06 to 1.40) and by day 28 (4 trials, n = 425, RR 1.26, 95% CI 1.04 to 1.52), without increasing the rate of gastroduodenal bleeding (10 trials, n = 1321, RR 1.16, 95% CI 0.82 to 1.65), superinfection (12 trials, n = 1705, RR 0.93, 95% CI 0.73 to 1.18), and of hyperglycaemia (6 trials, n = 608, RR 1.22, 0.84 to 1.78)., Reviewer's Conclusions: Overall, corticosteroids did not change 28-day mortality and hospital mortality in severe sepsis and septic shock. Long course of low dose corticosteroids reduced 28-day all-cause mortality, and intensive care unit and hospital mortality.

Objective: Severe systemic inflammation with a vasodilatory syndrome occurs in about one third of all patients after cardiac surgery with cardiopulmonary bypass. Hydrocortisone has been used successfully to reverse vasodilation in septic patients. We evaluated if stress doses of hydrocortisone attenuate severe systemic inflammatory response syndrome in a predefined risk group of patients after cardiac surgery with cardiopulmonary bypass., Design: Randomized, nonblinded, controlled trial., Setting: Anesthesiologic intensive care unit for cardiac surgical patients of an university hospital., Patients: After a risk analysis, we enrolled 91 patients into a prospective randomized trial. Patients were included according to the evaluated criteria (preoperative ejection fraction, duration of cardiopulmonary bypass, type of surgery)., Interventions: The treatment group received stress doses of hydrocortisone perioperatively: 100 mg before induction of anesthesia, then 10 mg/hr for 24 hrs, 5 mg/hr for 24 hrs, 3 x 20 mg/day, and 3 x 10 mg/day., Measurements and Main Results: We measured various laboratory (e.g., lactate) and clinical variables (e.g., duration of ventilation and length of stay in the intensive care unit), characterizing the patients' outcome. The two study groups did not differ regarding age, preoperative medication, duration of the cardiopulmonary bypass, and type of surgery. The patients in the treatment group had significantly lower concentrations of IL-6 and lactate, higher antithrombin III concentration, lower need for circulatory and ventilatory support and for transfusions, lower Therapeutic Intervention Scoring System values, and shorter length of stay in the intensive care unit and in the hospital. The mortality rate did not differ significantly between the groups., Conclusions: Although we acknowledge the limitations of a nonblinded interventional trial, stress doses of hydrocortisone seem to attenuate systemic inflammation in a predefined risk group of patients after cardiac surgery with cardiopulmonary bypass and improve early outcome.

To study the regulation of leptin secretion in sheep, we infused glucose (0.32 g/h/kg for 12 h) into GH-transgenic animals (n = 8) that have chronically high plasma concentrations of ovine GH and insulin, but low body condition and low plasma leptin concentrations, and compared the responses with those in controls (n = 8). In both groups, the infusion increased plasma concentrations of glucose and insulin within 1 h and maintained high levels throughout the infusion period (P < 0.0001). Compared with controls, GH-transgenics had higher concentrations of insulin, IGF-1, GH (all P < 0.0001) and cortisol (P < 0.05), but lower GH pulse frequency (P < 0.0001). Overall, leptin concentrations were lower in GH-transgenics than in controls (P < 0.01). A postprandial increase in leptin concentrations was observed in both groups, independently of glucose treatment, after which the values remained elevated in animals infused with glucose, but returned to basal levels in those infused with saline, independently of transgene status. In both GH-transgenics and controls, glucose infusion did not affect the concentrations of GH, IGF-1, or cortisol. In conclusion, GH-transgenic and control sheep show similar responses to glucose infusion for leptin and other metabolic hormones, despite differences between them in body condition and basal levels of these hormones. Glucose, insulin, GH, IGF-1 and cortisol are probably not major factors in the acute control of leptin secretion in sheep, although sustained high concentrations of GH and IGF-1 might reduce adipose tissue mass or inhibit leptin gene expression., (Copyright 2002 Elsevier Science Inc.)

In severely ill patients low concentrations of the corticosteroid binding globulin are typically found; the aim of this study was to quantify directly free bioactive cortisol concentrations in the sera of postoperative cardiosurgical patients. Serum samples of 12 consecutive patients undergoing aortocoronary bypass surgery taken preoperatively and on the postoperative days 1 to 4 were analyzed. Total serum cortisol was quantified using liquid chromatography-tandem mass spectrometry with an on-line sample extraction system and tri-deuterated cortisol as the internal standard, and free serum cortisol was measured after over-night equilibrium dialysis. Whereas on the first postoperative day, the median total serum cortisol concentration was approximately two-fold increased compared to preoperative samples (preoperatively, 245 nmol/l (interquartile range (IQR) 203-293 nmol/l); first postoperative day, 512 nmol/l (IQR 410-611 nmol/l)), median dialyzable free cortisol concentration was almost seven-fold increased (preoperatively, 14.2 nmol/l (IOR 10.9-20.7 nmol/l); first postoperative day, 98.3 nmol/l (IQR 81.3-134 nmol/l)). On the fourth postoperative day, median free cortisol was still significantly increased compared to baseline sampling (p < 0.05), whereas median total cortisol was not. A median of 5.7% (IQR 5.4-7.0%) of total cortisol was found as free cortisol on the preoperative day, 21.2% (IQR 18.9-23.5%) on the first postoperative day and 10.5% (IQR 9.8-14.0%) on the fourth postoperative day. It is concluded that during the postoperative period the free-to-bound ratio of cortisol is highly variable and that during the acute phase response direct quantification of free bioactive cortisol concentrations seems to be biologically more appropriate than the measurement of total cortisol concentrations.

Objectives: To compare the changes in free vs. total serum cortisol concentrations after acute stimulation of the adrenal cortex., Design and Methods: Paired serum samples of ten individuals taken immediately before and 1 h after stimulation with 250 microg ACTH (1-24) (Synacthen) given i.v. were analyzed. Total cortisol was quantified using liquid chromatography tandem-mass spectrometry with an online sample extraction system and tri-deuterated cortisol as the internal standard. Free cortisol was measured with the same method after equilibrium dialysis. Concentrations of the corticosteroid-binding globulin (CBG) were determined by radioimmuno assay., Results: Total cortisol increased by a mean of 106% (mean basal cortisol 312 nmol/L (SD 140 nmol/L), stimulated 686 nmol/L (SD 163 nmol/L); p < 0.001, paired t-test for differences); no significant change of CBG concentrations was found (874 nmol/L (SD 179 nmol/L) before stimulation, 869 nmol/L (SD 225 nmol/L) after stimulation). The mean increase of free cortisol was 263% (mean basal free cortisol 20.3 nmol/L (SD 13.2 nmol/L), stimulated 73.8 nmol/L (SD 26.7 nmol/L); p < 0.001) and thus substantially more pronounced compared to the increase of total cortisol (p < 0.01). The ratio of free to total serum cortisol was significantly increased after stimulation (6.1% (SD 1.7%) before stimulation, 10.6% (SD 1.9%) after stimulation; p < 0.001)., Conclusions: After acute neuroendocrine stimulation of the adrenal cortex the relative increase of free bioactive cortisol concentrations is substantially more pronounced than the increase of total cortisol concentrations.

Modern immunology reveals that cortisol interacts with the immune response at virtually all levels exerting suppressive and permissive effects. A prerequisite for the defense of severe infections is the functional integrity of the hypothalamic-pituitary-adrenal axis (HPAA) resulting in adequate cortisol production. There is increasing evidence that cortisol physiology and regulation substantially change in the course of septic shock. Patients with septic shock may suffer from relative adrenocortical insufficiency resulting in a relative deficiency of cortisol. In addition, the number and the affinity of cellular glucocorticoid receptors are decreased which may reduce the cortisol action at the cellular level. Since septic shock and adrenal insufficiency are sharing hemodynamic abnormalities such as hyperdynamic shock and peripheral vasodilation, the administration of stress doses of hydrocortisone appears to be a rational therapeutic approach in patients with septic shock. Controlled studies reveal that stress doses of hydrocortisone attenuate the systemic inflammatory response. Recently, two double-blind studies demonstrated that stress doses of hydrocortisone given in patients with septic shock reduce the time to shock reversal. The most important hemodynamic effect was an increase in the systemic vascular resistance. The earlier weaning from vasopressor therapy was associated with a trend towards improvements in organ dysfunction and mortality, respectively. Large-scale trials are on the way to investigate the benefit of stress doses of hydrocortisone on mortality of septic shock. This paper will focus on changes in glucocorticoid physiology and regulation during septic shock and will discuss the effects of stress doses of hydrocortisone on immune response and vascular tone in the course of septic shock.

A liquid chromatographic-mass spectrometric method for the determination of cortisol in serum using atmospheric pressure electrospray ionization and tandem mass spectrometry is described. During sample preparation, 150 microl of serum were deproteinized with methanol/zinc sulfate followed by on-line solid phase extraction employing column switching. Tri-deuterated cortisol was used as the internal standard. The following transitions were monitored: cortisol, 363>309 m/z; d3-cortisol, 366>312 m/z. The total run-time was 5 minutes. The method proved linear (0-500 microg/l; r=0.999), precise (total coefficient of variation between 5.0% and 3.2% at a mean cortisol concentration of 15.1 microg/l and 269 microg/l, respectively; n=16) and specific with regard to relevant endogenous and exogenous steroids.

We report the case of a 23-year-old rower who suffered from an exertional heatstroke while trying to lose 2 kg in weight by jogging before a competition. The development of this illness was favoured by clothes that were inappropriate for the environmental conditions and which the sportsman wore intentionally to enhance sweating. The maximum core temperature was over 43 degrees C. As a consequence the comatose patient developed a fulminant multi-organ failure with the liver ceasing its function, renal failure, massive rhabdomyolysis, and disseminated intravascular coagulation. In addition, he suffered from pericardial effusion and acute pulmonary failure (ARDS). In spite of maximum intensive care with an extensive substitution of blood products, continuous hemodiafiltration, and inhalative administration of nitrous oxide the young sportsman died 48 h after his admission to the intensive care unit. This tragic course demonstrates the danger of the widespread habit of losing weight by vigorously exercising with inappropriate clothes. In this article, potential risk factors, symptomatology, therapy, and methods of preventing an exertional heatstroke are shown and discussed.

Cortisol is known to be an immunomodulatory hormone that exerts suppressive and permissive effects on the immune response. Little is known regarding the evolution of the cytokine response in human septic shock in the presence of hypercortisolemia induced by infusion of stress doses of hydrocortisone. Twenty-four consecutive patients with high-out-put circulatory failure (cardiac index, >4 liters/min per m(2)) who met the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee criteria for septic shock were enrolled in a prospective, double-blind study. The severity of illness at the time of enrollment was graded using the Acute Physiology and Chronic Health Evaluation II system, and the evolution of sepsis-induced organ dysfunction syndrome was assessed using Sepsis-Related Organ Failure Assessment scores. After randomization, hyper-cortisolemia was induced in 12 patients by infusion of 100 mg of hydrocortisone, followed by continuous infusion of 0.18 mg/kg per h. Levels of the circulating cytokines tumor necrosis factor alpha (TNF), interleukin 6 (IL-6), IL-8, and IL-10 were serially measured at prospectively defined time points during the first 5 d after randomization. The infusion of hydrocortisone was associated with significant reductions in serum IL-6 and IL-8 levels and with earlier resolution of the sepsis-induced organ dysfunction syndrome. IL-6 levels started to differ between the groups on day 5. The TNF and IL-10 responses were not altered by hydrocortisone infusion. Hydrocortisone infusion in septic shock differentially regulated the cytokine responses. IL-6 and IL-8 levels decreased significantly and IL-6 levels differed between the groups, whereas TNF and IL-10 levels were not affected by hydrocortisone. Stress doses of hydrocortisone may be a valuable immunomodulatory therapy for septic shock.

Objective: We performed a follow-up cohort analysis in order to delineate the correlation between pulmonary function (PF) and health-related quality of life (HRQL) in patients after ARDS., Design: Follow-up cohort study., Setting: A 20-bed ICU of a university teaching hospital., Patients: A cohort of 50 long-term survivors of ARDS., Measurements and Results: Measurements of PF (FVC, FEV1, TLC, D(LCO)) and HRQL (SF-36 Health Status Questionnaire) were made 5.5 years (median value) after discharge from the ICU. Impairments in PF (defined as PF results below 80% of the predicted value) were frequent but generally mild. Twenty patients had a single PF impairment (with limitations in FEV1/FVC ratio in 12 patients being the most common), four patients had two (with D(LCO) and FEV1/FVC ratio impairment the most common) and three patients had pathologic results in three PF tests (FEV1/FVC ratio, TLC and capillary pO2 during exercise in one case, FVC, TLC and capillary pO2 during exercise in the second patient and FVC, TLC and D(LCO) in the third). Compared to normal controls, survivors of ARDS showed impairments in all SF-36 health dimensions (p < 0.001). Patients with multiple (> 1) PF impairments described the lowest HRQL with major limitations in all SF-36 categories (p < 0.037) including physical and mental summary scores (36.5 vs 46.9, p = 0.037 and 31.3 vs 51.4, p = 0.003) when compared to patients with no or only one PF impairment., Conclusions: Long-term survivors of ARDS have a significant reduction in HRQL and the presence of multiple PF impairments is associated with maximal decrements in HRQL.

Background: Obliterative bronchiolitis (OB), the most important long-term complication after lung transplantation, is thought to be a manifestation of chronic rejection within the airways, with the hallmarks inflammation and fibroproliferation., Methods: To characterize the inflammatory process in the context of OB we quantified tumor necrosis factor-alpha, interleukin (IL)-8, IL-10, and transforming growth factor (TGF)-beta on the protein and mRNA level in bronchoalveolar lavage fluid samples obtained from patients with bronchiolitis obliterans syndrome (BOS) and without BOS. In addition, bronchial cells sampled by bronchial brushing were analyzed for mRNA expression., Results: In respiratory epithelial lining fluid (ELF) from BOS patients the protein levels of IL-8 (52.4+/-22.2 vs. 4.4+/-0.9 pg/ml ELF, P<0.005) and TGF-beta (5.6+/-1.9 vs. 0.9+/-0.2 ng/ml ELF, P<0.005) were significantly elevated. In addition, bronchoalveolar lavage fluid cells of BOS patients showed increased expression of TGF-beta (1.13+/-0.44 vs. 0.45+/-0.16, optical density [O.D.]/O.D. glyceraldehyde-3-phosphate dehydrogenase [GAPDH], P=0.11) and IL-8 (0.25+/-0.13 vs. 0.09+/-0.03 O.D/O.D. GAPDH, P=0.53) without the differences reaching statistical significance. In contrast, IL-8 mRNA expression of bronchial cells was significantly higher in the BOS group (0.85+/-0.40 vs. 0.22+/-0.10 O.D./O.D. GAPDH, P<0.05)., Conclusions: We assume that IL-8 and TGF-beta may act as key mediators for airway inflammation and fibroproliferation in the pathogenesis of OB, with bronchial epithelial cells serving as a relevant source of IL-8.

Introduction: Liver transplantation is the method of choice for metabolic diseases and end-stage liver failure., Methods: At the Klinikum Grosshadern we have performed liver transplantation for inborn errors of metabolism in 24 patients (5.3% of all transplantations, 16 adults, age 39 +/- 13 years; 8 children, age 9 +/- 3 years); 19 patients received a transplant for end-stage liver disease, and in 5 cases because of fulminant hepatic failure., Results: Twenty-four patients received 27 transplants. In 3 cases, a split-liver transplantation was performed; one patient received a combined lung-liver graft. The 5-year survival rate for children is 100% and for adults 68%., Conclusions: Liver transplantation for inborn errors of metabolism not only replaces the diseased organ, but also leads to complete reversal of the metabolic defect.