Comparison of two fluid-management strategies in acute lung injury. Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. Does ICU-acquired paresis lengthen weaning from mechanical ventilation? Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. Low-dose steroid therapy at an early phase of postoperative acute respiratory distress syndrome. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome* Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature Infections and the inflammatory response in acute respiratory distress syndrome. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Risk of death does not alter the efficacy of hydrocortisone therapy in a mouse E. coli pneumonia model Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Stress doses of hydrocortisone in septic shock: beneficial effects on opsonization-dependent neutrophil functions Critical illness polyneuropathy and myopathy (CIPNM): evidence for local immune activation by cytokine-expression in the muscle tissue Paresis acquired in the intensive care unit: a prospective multicenter study. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome.
BACKGROUND Optimal fluid management in patients with acute lung injury is unknown . Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary-organ perfusion . METHODS In a r and omized study , we compared a conservative and a liberal strategy of fluid management using explicit protocol s applied for seven days in 1000 patients with acute lung injury . The primary end point was death at 60 days . Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology . RESULTS The rate of death at 60 days was 25.5 percent in the conservative- strategy group and 28.4 percent in the liberal- strategy group ( P=0.30 ; 95 percent confidence interval for the difference , -2.6 to 8.4 percent ) . The mean ( + /-SE ) cumulative fluid balance during the first seven days was -136+/-491 ml in the conservative- strategy group and 6992+/-502 ml in the liberal- strategy group ( P<0.001 ) . As compared with the liberal strategy , the conservative strategy improved the oxygenation index ( [ mean airway pressure x the ratio of the fraction of inspired oxygen to the partial pressure of arterial oxygen]x100 ) and the lung injury score and increased the number of ventilator-free days ( 14.6+/-0.5 vs. 12.1+/-0.5 , P<0.001 ) and days not spent in the intensive care unit ( 13.4+/-0.4 vs. 11.2+/-0.4 , P<0.001 ) during the first 28 days but did not increase the incidence or prevalence of shock during the study or the use of dialysis during the first 60 days ( 10 percent vs. 14 percent , P=0.06 ) . CONCLUSIONS Although there was no significant difference in the primary outcome of 60-day mortality , the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures . These results support the use of a conservative strategy of fluid management in patients with acute lung injury . ( Clinical Trials.gov number , NCT00281268 [ Clinical Trials.gov ] . ) Nuclear factor-kappaB ( NF-kappaB ) and glucocorticoid receptor-alpha ( GR-alpha ) have diametrically opposed functions in regulating inflammation . We investigated whether unresolving acute respiratory distress syndrome ( ARDS ) is associated with systemic inflammation- induced glucocorticoid resistance and whether prolonged methylprednisolone administration accelerates the suppression of systemic inflammatory indices and normalizes the sensitivity of the immune system to glucocorticoids . Patients enrolled into a r and omized trial evaluating prolonged methylprednisolone administration in unresolving ARDS had serial plasma sample s collected before and after r and omization . In the plasma , we measured the concentrations of tumor necrosis factor-alpha ( TNF-alpha ) , interleukins ( IL ) IL-1beta and IL-6 , adrenocorticotropic hormone ( ACTH ) , and cortisol . The ability of patient plasma to influence the NF-kappaB and GR-signal transduction systems of normal peripheral blood leukocytes ( PBL ) was examined . Patients treated with methylprednisolone had progressive and sustained reductions of TNF-alpha , IL-1beta , IL-6 , ACTH , and cortisol concentrations over time . Normal PBL exposed to plasma sample s collected during methylprednisolone exhibited significant progressive increases in all aspects of GR-mediated activity and significant reductions in NF-kappaB DNA-binding and transcription of TNF-alpha and IL-1beta . These findings provide support for the presence of endogenous glucocorticoid inadequacy in the control of inflammation and systemic inflammation-induced peripheral glucocorticoid resistance in ARDS . Prolonged methylprednisolone administration accelerated the resolution of both systemic inflammation and peripheral acquired glucocorticoid resistance in ARDS Objective To determine whether ICU-acquired paresis ( ICUAP ) is an independent risk factor of prolonged weaning . Design Second study of a prospect i ve cohort of 95 patients who were enrolled in an incidence and risk factor study of ICUAP . Setting Three medical and two surgical ICUs in four hospitals . Patients and participants Ninety-five patients without pre-existing neuromuscular disease recovering from the acute phase of critical illness after ≥7 days of mechanical ventilation . Interventions None . Measurements and results Duration of weaning from mechanical ventilation  was defined as the duration of mechanical ventilation between awakening ( day 1 ) and successful weaning . Muscle strength was evaluated at day 7 after awakening using the Medical Research Council ( MRC ) score . Patients with an MRC < 48 were considered to have ICUAP . Among the 95 patients ( mean age 62.0±15.3 years , SAPS 2 on admission 48.7±17.4 ) who regained satisfactory awakening after 7 or more days of mechanical ventilation , 67 ( 70.5 % ) were hospitalized in a medical ICU and 28 ( 29.5 % ) in a surgical ICU . Median duration ( 25th–75th percentiles ) of weaning was longer in patients with ICUAP than in those without ICUAP : 6 days ( 1–22 days ) vs 3 days ( 1–7 days ) ; p=0.01 ; log-rank analysis . In multivariate analysis , the two independent predictors of prolonged weaning were ICUAP [ hazard ratio ( HR ) : 2.4 ; 95 % confidence interval ( CI ) : 1.4–4.2 ] and chronic obstructive pulmonary disease ( HR : 2.7 ; 95 % CI : 1.6–4.5 ) Conclusions ICU-acquired paresis is an independent predictor of prolonged weaning . Prevention of ICU-acquired neuromuscular abnormalities in patients recovering from severe acute illness should result in shorter weaning duration BACKGROUND Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome . We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients . METHODS Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter , r and omized trial . The trial compared traditional ventilation treatment , which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration ( plateau pressure ) of 50 cm of water or less , with ventilation with a lower tidal volume , which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less . The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28 . RESULTS The trial was stopped after the enrollment of 861 patients because  mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes ( 31.0 percent vs. 39.8 percent , P=0.007 ) , and the number of days without ventilator use during the first 28 days after r and omization was greater in this group ( mean [ + /-SD ] , 12+/-11 vs. 10+/-11 ; P=0.007 ) . The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight ( P<0.001 ) , respectively , and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water ( P<0.001 ) , respectively . CONCLUSIONS In patients with acute lung injury and the acute respiratory distress syndrome , mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use BACKGROUND The acute respiratory distress syndrome ( ARDS ) that develops after thoracic surgery is usually lethal . The use of corticosteroids to treat ARDS has been the subject of great controversy . METHODS Therefore we compared conventional therapy with early low-dose steroid therapy in the treatment of postoperative ARDS . Methylprednisolone was given daily as an intravenous push every 6 hours and was changed to a single oral dose or discontinued , with a loading dose of 2 mg/kg followed by 2 mg/kg per day . RESULTS Over 2.5 years , 523 major thoracic operations were performed with postoperative ARDS developing in 20 patients ( 3.8 % ) , of which 8 were treated with conventional therapy  and 12 with early low-dose steroid therapy . Early low-dose steroid therapy significantly reduced postoperative mortality , with 7 patients ( 58.3 % ) recovering without mechanical ventilation . CONCLUSIONS We believe this is the first clinical study of low-dose methylprednisolone at an early phase of postoperative ARDS . The beneficial effects of the use of early low-dose steroids in ARDS are consistent with the hypothesis that fibroproliferation is an early response to lung injury , which is inhibited by early low-dose steroid therapy without disturbing operative wound healing BACKGROUND Persistent acute respiratory distress syndrome ( ARDS ) is characterized by excessive fibroproliferation , ongoing inflammation , prolonged mechanical ventilation , and a substantial risk of death . Because previous reports suggested that corticosteroids may improve survival , we performed a multicenter , r and omized controlled trial of corticosteroids in patients with persistent ARDS . METHODS We r and omly assigned 180 patients with ARDS of at least seven days ' duration to receive either methylprednisolone or placebo in a double-blind fashion . The primary end point was mortality at 60 days . Secondary end points included the number of ventilator-free days and organ-failure-free days , biochemical markers of inflammation and fibroproliferation , and infectious complications . RESULTS At 60 days , the hospital mortality rate was 28.6 percent in the placebo group ( 95 percent confidence interval , 20.3 to 38.6 percent ) and 29.2 percent in the methylprednisolone group ( 95 percent confidence interval , 20.8 to 39.4 percent ; P=1.0 ) ; at 180 days , the rates were 31.9 percent ( 95 percent confidence interval , 23.2 to 42.0 percent ) and 31.5 percent ( 95 percent confidence interval , 22.8 to 41.7 percent ; P=1.0 ) , respectively . Methylprednisolone was associated with significantly increased 60- and 180-day mortality rates among patients enrolled at least 14 days after the onset of ARDS . Methylprednisolone increased the number of ventilator-free and shock-free days during the first 28 days in association with an improvement in oxygenation , respiratory-system compliance , and blood pressure with fewer days of vasopressor therapy . As compared with placebo , methylprednisolone did not increase the rate of infectious complications but was associated with a higher rate of neuromuscular weakness . CONCLUSIONS These results do not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology . In addition , starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death . ( Clinical Trials.gov number , NCT00295269 . ) Within the last few years , increasing evidence of relative adrenal insufficiency in septic shock evoked a re assessment of hydrocortisone therapy . To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation , 40 patients with septic shock were r and omized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 ( n = 20 ) or placebo ( n = 20 ) , followed by the opposite medication until Day 6 . Hydrocortisone infusion induced an increase of mean arterial pressure , systemic vascular resistance , and a decline of heart rate , cardiac index , and norepinephrine requirement . A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support . The inflammatory response ( interleukin-6 and interleukin-8 ) , endothelial ( soluble E-selectin ) and neutrophil activation ( expression of CD11b , CD64 ) , and antiinflammatory response ( soluble tumor necrosis factor receptors I and II and interleukin-10 ) were attenuated . In peripheral blood monocytes , human leukocyte antigen-DR expression was only slightly depressed , whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased . Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects . In conclusion , hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression We hypothesize that hydrocortisone infusion in severe community-acquired pneumonia attenuates systemic inflammation and leads to earlier resolution of pneumonia and a reduction in sepsis-related complications . In a multicenter trial , patients admitted to the Intensive Care Unit ( ICU ) with severe community-acquired pneumonia received protocol -guided antibiotic treatment and were r and omly assigned to hydrocortisone infusion or placebo . Hydrocortisone was given as an intravenous 200-mg bolus followed by infusion at a rate of 10 mg/hour for 7 days . Primary end-points of the study were improvement in Pa(O(2)):FI(O(2 ) ) ( Pa(O(2)):FI(O(2 ) ) > 300 or > /= 100 increase from study entry ) and multiple organ dysfunction syndrome ( MODS ) score by Study Day 8 and reduction in delayed septic shock .  Forty-six patients entered the study . At study entry , the  hydrocortisone group had lower Pa(O(2)):FI(O(2 ) ) , and higher chest radiograph score and C-reactive protein level . By Study Day 8 , treated patients had , compared with control subjects , a significant improvement in Pa(O(2)):FI(O(2 ) ) ( p = 0.002 ) and chest radiograph score ( p < 0.0001 ) , and a significant reduction in C-reactive protein levels ( p = 0.01 ) , MODS score ( p = 0.003 ) , and delayed septic shock ( p = 0.001 ) . Hydrocortisone treatment was associated with a significant reduction in length of hospital stay ( p = 0.03 ) and mortality ( p = 0.009 ) Objective : We investigated the efficacy of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome ( ARDS ) by post hoc analysis of a previously completed clinical trial . Design : Retrospective analysis of a placebo-controlled , r and omized , double-blind trial of low doses of corticosteroids in septic shock . Setting : Nineteen intensive care units in France . Patients : Among the 300 septic shock patients enrolled , we selected those meeting st and ard criteria for ARDS at inclusion . Interventions : Seven-day treatment with 50 mg of hydrocortisone every 6 hrs and 50 & mgr;g of 9-α-fludrocortisone once a day . Measurements and Main Results : There were 177 patients with ARDS ( placebo , n = 92 ; corticosteroids , n = 85 ) including 129 ( placebo , n = 67 ; corticosteroids , n = 62 ) nonresponders and 48 (  placebo , n = 25 ; corticosteroids , n = 23 ) responders . In nonresponders , there were 50 deaths ( 75 % ) in the placebo group and 33 deaths ( 53 % ) in the steroid group ( hazard ratio 0.57 , 95 % confidence interval 0.36–0.89 , p = .013 ; relative risk 0.71 , 95 % confidence interval 0.54–0.94 , p = .011 ) . The number of days alive and off the ventilator was 2.6 ± 6.6 in the placebo group and 5.7 ± 8.6 in the steroid group ( p = .006 ) . There was no significant difference between groups in responders . There was no significant difference between groups in the two subsets of patients without ARDS . Adverse events rates were similar in the two groups . Conclusions : This post hoc analysis shows that a 7-day treatment with low doses of corticosteroids was associated with better outcomes in septic shock-associated early ARDS nonresponders , but not in responders and not in septic shock patients without ARDS Objectives To compare the design and results of r and omized trials investigating  prolonged glucocorticoid treatment ( ≥ 7 days ) in patients with acute lung injury – acute respiratory distress syndrome ( ALI – ARDS ) , and review factors affecting response to therapy , including the role of secondary prevention . Design Trials were retrieved from the Cochrane Central Register of Controlled Trials ( CENTRAL ) . Two investigators collected data on study characteristics , treatment intervention , and outcomes . The method ological quality of trials was determined and data were analyzed with Review Manager 4.2.3 . Measurements and results Five selected trials ( n = 518 ) consistently reported significant improvement in gas exchange , reduction in markers of inflammation , and decreased duration of mechanical ventilation and intensive care unit stay ( all p < 0.05 ) . Two early small clinical trials showed marked reductions in the relative risk ( RR ) of death  with glucocorticoid therapy ( RR = 0.14 , 95 % CI 0.04–0.53 ; p = 0.004 , I2 = 0 % ) . Three subsequent larger trials , when combined , although nominally beneficial , did not reproduce the marked reductions observed in the earlier trials ( RR = 0.84 ; 95 % CI 0.68–1.03 ; p = 0.09 , I2 = 9.1 % ) , but achieved a distinct reduction in the RR of death in the larger subgroup of patients ( n = 400 ) treated before day 14 of ARDS [ 82/214 ( 38 % ) vs. 98/186 ( 52.5 % ) , RR = 0.78 ; 95 % CI 0.64–0.96 ; p = 0.02 , I2 = 0 % ] . Conclusions Prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcome variables , and has a distinct survival benefit when initiated before day 14 of ARDS STUDY OBJECTIVE Systemic inflammatory response syndrome ( SIRS ) and infections are frequently associated with the development and progression of acute respiratory distress syndrome ( ARDS ) and multiple organ dysfunction syndrome ( MODS ) . We investigated , at onset and during the progression of ARDS , the relationships among ( 1 ) clinical variables and biological markers of SIRS , ( 2 ) infections defined by strict criteria , and ( 3 ) patient outcome . Biological markers of SIRS included serial measurements of inflammatory cytokines (IC)-tumor necrosis factor-alpha ( TNF-alpha ) and interleukins ( IL ) 1 beta , 2 , 4 , 6 , and 8-in plasma and BAL fluid . METHODS We prospect ively studied two groups of ARDS patients : 34 patients treated conventionally ( group 1 ) and nine patients who received glucocorticoid rescue treatment for unresolving ARDS ( group 2 ) . Individual SIRS criteria and SIRS composite score were recorded daily for all patients . Plasma IC levels were measured by enzyme-linked immunosorbent assay on days 1 , 2 , 3 , 5 , 7 , 10 , and 12 of ARDS and every third day thereafter while patients received mechanical ventilation . Unless contraindicated , bilateral BAL was performed on day 1 , weekly , and when ventilator-associated pneumonia was suspected . Patients were closely monitored for the development of nosocomial infections ( NIs ) . RESULTS ICU mortality was similar among patients with and without sepsis on admission ( 54 % vs 40 % ; p < 0.45 ) . Among patients with sepsis-induced ARDS , mortality was higher in those who subsequently developed NIs ( 71 % vs 18 % ; p < 0.05 ) . At the onset of ARDS , plasma TNF-alpha , IL-1 beta , IL-6 , and IL-8 levels were significantly higher ( p < 0.0001 ) in nonsurvivors ( NS ) and in those with sepsis ( p < 0.0001 ) . The NS group , contrary to survivors ( S ) , had persistently elevated plasma IC levels over time . In 17 patients , 36 definitive NIs ( 17 in group 1 and 19 in group 2 ) were diagnosed by strict criteria . No definitive or presumed NIs caused an increase in plasma IC levels above patients ' preinfection baseline . Daily SIRS components and SIRS composite scores were similar among S and NS and among patients with and without sepsis-induced ARDS , were unaffected by the development of NI , and did not correlate with plasma IC levels . CONCLUSIONS Sepsis as a precipitating cause of ARDS was associated with higher plasma IC levels . However , NIs were not associated with an increase in SIRS composite scores , individual SIRS criteria , or plasma IC levels above patients ' preinfection baseline . SIRS composite scores over time were similar in S and NS . SIRS criteria , including fever , were found to be nonspecific for NI . Irrespective of etiology of ARDS , plasma IC levels , but not clinical criteria , correlated with patient outcome . These findings suggest that final outcome in patients with ARDS is related to the magnitude and duration of the host inflammatory response and is independent of the precipitating cause of ARDS or the development of intercurrent NIs OBJECTIVE To determine the effects of low-dose prolonged methylprednisolone infusion on lung function in patients with early severe ARDS . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING ICUs of five hospitals in Memphis . PARTICIPANTS Ninety-one patients with severe early ARDS ( < /= 72 h ) , 66 % with sepsis . INTERVENTIONS Patients were r and omized ( 2:1 fashion ) to methylprednisolone infusion ( 1 mg/kg/d ) vs placebo . The duration of treatment was up to 28 days . Infection surveillance and avoidance of paralysis were integral components of the protocol . MAIN OUTCOME MEASURE The predefined primary end point was a 1-point reduction in lung injury score ( LIS ) or successful extubation by day 7 . RESULTS In intention-to-treat analysis , the response of the two groups ( 63 treated and 28 control ) clearly diverged by day 7 , with twice the proportion of treated patients achieving a 1-point reduction in LIS ( 69.8 % vs 35.7 % ; p = 0.002 ) and breathing without assistance ( 53.9 % vs 25.0 % ; p = 0.01 ) . Treated patients had significant reduction in C-reactive protein levels , and by day 7 had lower LIS and multiple organ dysfunction syndrome scores . Treatment was associated with a reduction in the duration of mechanical ventilation ( p = 0.002 ) , ICU stay ( p = 0.007 ) , and ICU mortality ( 20.6 % vs 42.9 % ; p = 0.03 ) . Treated patients had a lower rate of infections ( p = 0.0002 ) , and infection surveillance identified 56 % of nosocomial infections in patients without fever . CONCLUSIONS Methylprednisolone-induced down-regulation of systemic inflammation was associated with significant improvement in pulmonary and extrapulmonary organ dysfunction and reduction in duration of mechanical ventilation and ICU length of stay Background Risk of death may influence the efficacy of anti-inflammatory agents in sepsis . “ Physiologic ” dose corticosteroids , while improving survival in earlier trials with higher control mortality rates ( > 50 % ) , were not beneficial in the recent CORTICUS trial with lower control mortality ( 31 % ) . We investigated whether risk of death altered the effects of hydrocortisone in a mouse pneumonia model . Methods Mice ( n = 637 ) challenged with high , medium or low intratracheal E. coli doses were r and omized to receive one of three hydrocortisone doses ( 5 , 25 or 125 mg/kg ) or normal saline ( NS ) only ( control ) for 4 days . All animals were treated with similar volumes of ceftriaxone and NS support following E. coli and were observed for 168 h. Results Decreasing E. coli doses reduced control mortality rates ( from 94 to 12 % ) . In similar patterns ( not significant ) each hydrocortisone dose increased the odds ratio ( OR ) of survival ( 95 % confidence interval ) with each E. coli dose ( ORs ranging from 1.2 [ 0.4 , 3.7 ] to 6.1 [ 0.6 , 61.0 ] ) . The effect of hydrocortisone on the OR was not related to control mortality rate ( r = –0.13 , p = 0.29 ) and overall was highly significant ( 2.04 [ 1.37 , 3.03 ] , p = 0.0004 ) . In r and omly selected animals 48 h after the highest E. coli dose , compared with the control , hydrocortisone ( 125 mg/kg ) significantly decreased IL-6 , INFγ , and nitric oxide levels . Conclusions In this mouse model the beneficial effects of hydrocortisone were independent of risk of death . These findings suggest that factors other than risk of death may underlie the differing effects of corticosteroids in recent sepsis trials BACKGROUND Inflammatory cytokines have been related to the development of adult respiratory distress syndrome ( ARDS ) , shock , and multiple organ dysfunction syndrome ( MODS ) . We tested the hypothesis that unfavorable outcome in patients with ARDS is related to the presence of a persistent inflammatory response . For this purpose , we evaluated the behavior of inflammatory cytokines during progression of ARDS and the relationship of plasma inflammatory cytokines with clinical variables and outcome . METHODS We prospect ively studied 27 consecutive patients with severe medical ARDS . Plasma levels of  tumor necrosis factor alpha ( TNF-alpha ) and interleukins ( ILs ) 1 beta , 2 , 4 , 6 , and 8 were measured ( enzyme-linked immunosorbent assay [ ELISA ] method ) on days 1 , 2 , 3 , 5 , 7 , 10 , and 12 of ARDS and every third day thereafter while patients were receiving mechanical ventilation . Subgroups of patients were identified based on outcome , cause of ARDS , presence or absence of sepsis , shock , and MODS at the time ARDS developed . Subgroups were compared for levels of plasma inflammatory cytokines on day 1 of ARDS and over time . RESULTS Of the 27 patients , 13 survived ICU admission and 14 died ( a mortality rate of 52 % ) . Overall mortality was higher in patients with sepsis ( 86 vs 38 % , p < 0.02 ) . The mean initial plasma levels of TNF-alpha , IL-1 beta , IL-6 , and IL-8 were significantly higher in nonsurvivors ( p < 0.0001 ) and in those patients with sepsis ( p < 0.0001 ) . Plasma levels of IL-1 beta ( p < 0.01 ) and IL-6 ( p = 0.03 ) were more strongly associated with patient outcome than cause of ARDS ( p = 0.8 ) , lung injury score ( LIS ) , APACHE II score , sepsis ( p = 0.16 ) , shock , or MODS score . Plasma levels of TNF-alpha , IL-1 beta , IL-6 , and IL-8 remained significantly elevated over time ( p < 0.0001 ) in those who died . Although it was the best early predictor of death ( p < 0.001 ) , plasma IL-2 > 200 pg/mL lost its usefulness after the first 48 h. A plasma IL-1 beta or IL-6 level > 400 pg/mL on any day in the first week of ARDS was associated with a low likelihood of survival . CONCLUSIONS Our findings indicate that unfavorable outcome in acute lung injury is related to the degree of inflammatory response at the onset and during the course of ARDS . Patients with higher plasma levels of TNF-alpha , IL-1 beta , IL-6 , and IL-8 on day 1 of ARDS had persistent elevation of these inflammatory cytokines over time and died . Survivors had lesser elevations of plasma inflammatory cytokines on day 1 of ARDS and a rapid reduction over time . Plasma IL-1 beta and IL-6 levels were consistent and efficient predictors of outcome Objective To assess the effects of stress doses of hydrocortisone ( HC ) on clinical parameters and neutrophil functions in patients with septic shock . Design Prospect i ve , double-blind , r and omized , 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 In a longitudinal prospect i ve study a muscle biopsy was taken from 30/32 ( 33 % ) of the 98 patients who developed critical illness polyneuropathy and myopathy ( CIPNM ) .  Neuropathic changes were found in 37 % , myopathic in 40 % , and a combination in 23 % of the biopsies . The immunohistopathology showed macrophages and Th-cells in 40 % and 60 % of the muscle biopsies respectively . Small mainly perivascular infiltrates contained macrophages and Th-cells . ICAM-1 , VCAM and MAC were found on the vascular endothelium in 58 % , 53 % and 79 % respectively . In all biopsies there was an upregulation of both HLA-I and HLA-DR . Proinflammatory cytokines and TNFalphaR75 were also produced locally ( IL-1beta in 71 % , IFN-gamma in 40 % , IL-12 in 73 % , TNFalphaR75 in 90 % ) . The anti-inflammatory cytokine IL-10 was simultaneously expressed in 96 % of the biopsies . HLA-DR , TNFalphaR75 and IL-10 differed significantly when compared with control muscle biopsies . Our data provide evidence that small numbers of activated leukocytes producing both pro- and anti-inflammatory cytokines infiltrate skeletal muscle of CIPNM patients . We propose that the local balance of leukocyte activities is of importance in the pathophysiology of muscle weakness in CIPNM CONTEXT Although electrophysiologic and histologic neuromuscular abnormalities are common in intensive care unit ( ICU ) patients , the clinical incidence of ICU-acquired neuromuscular disorders in patients recovering from severe illness remains unknown . OBJECTIVES To assess the clinical incidence , risk factors , and outcomes of ICU-acquired paresis ( ICUAP ) during recovery from critical illness in the ICU and to determine the electrophysiologic and histologic patterns in patients with ICUAP . DESIGN Prospect i ve cohort study conducted from March 1999 to June 2000 . SETTING Three medical and 2 surgical ICUs in 4 hospitals in France . PARTICIPANTS All consecutive ICU patients without preexisting neuromuscular disease who underwent mechanical ventilation for 7 or more days were screened daily for awakening . The first day a patient was considered awake was day 1 . Patients with severe muscle weakness on day 7 were considered to have ICUAP . MAIN OUTCOME MEASURES Incidence and duration of ICUAP , risk factors for ICUAP , and comparative duration of mechanical ventilation between ICUAP and control patients . RESULTS Among the 95 patients who achieved satisfactory awakening , the incidence of ICUAP was 25.3 % ( 95 % confidence interval [ CI ] , 16.9%-35.2 % ) . All ICUAP patients had a sensorimotor axonopathy , and all patients who underwent a muscle biopsy had specific muscle involvement not related to nerve involvement . The median duration of ICUAP after day 1 was 21 days . Mean ( SD ) duration of mechanical ventilation after day 1 was significantly longer in patients with ICUAP compared with those without ( 18.2 [ 36.3 ] vs 7.6 [ 19.2 ] days ; P = .03 ) . Independent predictors of ICUAP were female sex ( odds ratio [ OR ] , 4.66 ; 95 % CI , 1.19 - 18.30 ) , the number of days with dysfunction of 2 or more organs ( OR , 1.28 ; 95 % CI , 1.11 - 1.49 ) , duration of mechanical ventilation ( OR , 1.10 ; 95 % CI , 1.00 - 1.22 ) , and administration of corticosteroids  ( OR , 14.90 ; 95 % CI , 3.20 - 69.80 ) before day 1 . CONCLUSIONS Identified using simple bedside clinical criteria , ICUAP was frequent during recovery from critical illness and was associated with a prolonged duration of mechanical ventilation . Our findings suggest an important role of corticosteroids in the development of ICUAP BACKGROUND  Inflammatory cytokines ( ICs ) are important modulators of injury and repair . ICs have been found to be elevated in the BAL of patients with both early and late ARDS . We tested the hypothesis that recurrent injury to the alveolocapillary barrier and amplification of intra-alveolar fibroproliferation observed in nonresolving ARDS is related to a persistent inflammatory response . For this purpose , we obtained serial measurements of BAL IC and correlated these levels with lung injury score ( LIS ) , BAL indexes of endothelial permeability ( albumin , total protein [ TP ] ) , and outcome . METHODS We prospect ively studied 27 consecutive patients with severe medical ARDS . Using enzyme-linked immunosorbent assay methods , levels of tumor necrosis factor-alpha ( TNF-alpha ) and interleukins ( IL ) 1 beta , 2 , 4 , 6 , and 8 were measured at frequent intervals in both plasma and BAL . In 22 patients , bilateral BAL was obtained on day 1 of ARDS and at weekly intervals when possible . Right and left BALs were analyzed separately for IC levels , total cell count and differential , albumin , TP , and quantitative bacterial cultures . RESULTS On day 1 of ARDS , the 10 nonsurvivors had significantly higher ( p = 0.0002 ) BAL TNF-alpha , IL-1 beta , IL-6 , and IL-8 levels , which remained persistently elevated over time , indicating a continuous injury process . In contrast , the 12 survivors had a lesser elevation and a rapid reduction over time . Initial BAL IL-2 and IL-4 levels were significantly higher in patients with sepsis ( p = 0.006 ) ; both increased over time in survivors and nonsurvivors . BAL levels of TNF-alpha , IL-1 beta , IL-6 , and IL-8 correlated with BAL albumin and TP concentrations but not with LIS or ratio of arterial oxygen tension to inspired oxygen concentration . BAL : plasma ratios were elevated for all measured cytokines , suggesting a pulmonary origin . On day 1 of ARDS , nonsurvivors had significantly higher ( p = 0.04 ) BAL : plasma ratios for TNF-alpha , IL-1 beta , IL-6 , and IL-8 . Over time , BAL : plasma ratios for TNF-alpha , IL-1 beta and IL-6 remained elevated in nonsurvivors and decreased in survivors . CONCLUSIONS Our findings indicate that an unfavorable outcome in ARDS is associated with an initial , exaggerated , pulmonary inflammatory response that persists unabated over time . Plasma IC levels parallel changes in BAL IC levels . The BAL : plasma ratio results suggest , but do not prove , a pulmonary origin for IC production . BAL TNF-alpha , IL-1 beta , and IL-8 levels correlated with BAL indices of endothelial permeability . In survivors , reduction in BAL IC levels over time was associated with a decline in BAL albumin and TP levels , suggesting effective repair of the endothelial surface . These findings support a causal relationship between degree and duration of lung inflammation and progression of fibroproliferation in ARDS
While awaiting a larger confirmatory trial in early acute lung injury and ARDS , this meta- analysis provides evidence of a sizable reduction in duration of mechanical ventilation and intensive care unit stay and a considerable survival benefit with the potential saving of one life for every four treated patients ( 1 ) .
In the United States alone , this could translate to tens of thous and s of lives saved per year and several billion dollars in reduced healthcare expenditures ( 17 ) .
Furthermore , the low cost of off-patent methylprednisolone — in the United States approximately $ 240 for 28 days of intravenous therapy (5)—makes this treatment globally and equitably available .
Most misconceptions originate from the findings of sepsis and ARDS trials conducted in the 1980s that investigated a massive daily dose of glucocorticoids ( methylprednisolone , up to 120 mg/kg/day ) over a short time interval ( 24–48 hours ) .
Since then , longitudinal measurements of inflammatory cytokines in ARDS patients have clearly shown that significant systemic and pulmonary inflammation persists 28 days into the disease process ( 21–24 ) and that PGCT ( 14–21 days ) followed by slow tapering is essential to achieve and sustain biological resolution of the disease process ( 21 , 25 ) .