Partial liquid ventilation in critically ill infants receiving extracorporeal life support. Philadelphia Liquid Ventilation Consortium. Reduced mortality in association with the acute respiratory distress syndrome (ARDS) Publication bias and clinical trials. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. Influence of direct and indirect etiology on acute outcome and 6-month functional recovery in acute respiratory distress syndrome. Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis. Acute lung injury in the medical ICU: comorbid conditions, age, etiology, and hospital outcome. Mortality rates and prognostic variables in children with adult respiratory distress syndrome. Partial liquid ventilation in adult patients with ARDS: a multicenter phase I-II trial. Adult PLV Study Group. Initial experience with partial liquid ventilation in pediatric patients with the acute respiratory distress syndrome. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. Underreporting research is scientific misconduct.
OBJECTIVES To demonstrate that a period of partial liquid ventilation ( PLV ) with perflubron improves pulmonary function , without adverse events , in a select group of critically ill infants receiving extracorporeal life support ( ECLS ) with a high likelihood of mortality . METHODS This was an open-label , noncontrolled , phase I and II trial of PLV in two infants with congenital diaphragmatic hernia and four infants with acute respiratory distress syndrome ( ARDS ) who were failing to improve while receiving ECLS .  PLV was performed by instilling and maintaining a functional residual capacity of sterile perflubron for 4 to 96 hours . RESULTS Four infants were successfully weaned off ECLS for at least 3 days , and two infants ( both with ARDS ) are long-term survivors after PLV . All infants demonstrated lung recruitment and improved lung compliance , and there were no adverse events related to PLV . CONCLUSIONS The study suggests that perflubron PLV is safe , improves lung function , and recruits lung volume in critically ill infants receiving ECLS .  PLV therapy for infants with ARDS seems to have a great deal of promise . Based on this and other phase I and II trials , studies of PLV on selected full-term infants before ECLS have been initiated BACKGROUND A study was undertaken to investigate possible reductions in mortality and /or changes in outcome predictive factors in patients with the acute respiratory distress syndrome ( ARDS ) managed in a single centre . METHODS The study was a prospect i ve observational cohort study of two patient population s with ARDS . Group 1 comprised 41 patients enrolled between May 1990 and April 1993 , and group 2 consisted of 78 patients enrolled between June 1993 and March 1997 . The end points of the study were mortality and various factors predictive of death . RESULTS There was a marked reduction in mortality between groups 1 and 2 ( 66 % versus 34 % ; relative risk 1.77 ; CI 1.23 to 2.55 ) . There were no significant differences between the groups in terms of age ( 40.6 ( 3.3 ) versus 45.5 ( 2.2 ) years ) , APACHE score ( 14.5 ( 0.72 ) versus 13.6 ( 0.1 ) ) ,  lung injury score  ( 2.95 ( 0.07 ) versus 2.8 ( 0.1 ) ) , incidence of multi-organ failure ( 29 % versus 32 % ) , incidence of sepsis ( 31 % versus 39 % ) , or Pao 2/Fio 2 ( kPa ) ratio ( 11.8 ( 0.67 ) versus 12.0 ( 0.6 ) ) . There was a significantly lower proportion of men in group 1 ( 51 % versus 74 % ) . The case mix of the two groups was closely matched : following elective surgery 48 % versus 48 % , trauma 17 % versus 16 % , primary lung injury 12 % versus 24 % . Patients in group 1 were supported using several ventilatory and other modes ( volume preset , non-inverse ratio ventilation , n = 15 ; pressure controlled inverse ratio ventilation ( PC-IRV ) , n = 11 ; ultra high frequency jet ventilation ( UHFJV ) , n = 13 ; an intravascular oxygenation device ( IVOX ) and extracorporeal gas exchange ( ECGE ) , n = 2 ) . Within group 1 no significant difference in mortality was observed between the patients on volume controlled ventilation and the remainder . In group 2 all patients received PC-IRV ( n = 78 ) but , in addition , some received other support techniques ( UHFJV n = 4 , ECGE n = 2 ) . In group 1 only sepsis on admission ( 21 % ( survivors ) versus 56 % ( non-survivors ) ) predicted death . In group 2 age of survivors and non-survivors ( 41.2 ( 2.6 ) versus 52.6 ( 3.5 ) ) , APACHE score ( 12.2 ( 0.6 ) versus 15.8 ( 0.9 ) ) , and Pao 2/Fio 2 ( 12.8 ( 0.86 ) versus 10.5 ( 0.72 ) ) predicted survival , but not the incidence of sepsis or multi-organ failure . CONCLUSIONS In recent years a highly significant reduction in mortality associated with ARDS has been observed between two groups of patients well matched for disease severity and case mix . Changes in ICU organisation rather than specific interventions may account for this reduction , although different ventilatory and other management strategies used in the two groups may also be relevant A study was performed to evaluate the extent to which the medical literature may be misleading as a result of selective publication of r and omized clinical trials ( RCTs ) with results showing a statistically significant treatment effect . Three hundred eighteen authors of published trials were asked whether they had participated in any unpublished RCTs .  The 156 respondents reported 271 unpublished and 1041 published trials . Of the 178 completed unpublished RCTs with a trend specified , 26 ( 14 % ) favored the new therapy compared to 423 of 767 ( 55 % ) published reports ( p less than 0.001 ) . For trials that were completed but not published , the major reasons for nonpublication were " negative " results and lack of interest . From the data provided , it appears that nonpublication was primarily a result of failure to write up and su bmi t the trial results rather than rejection of su bmi tted manuscripts . The results of this study imply the existence of a publication bias of importance both to meta- analysis and the interpretation of statistically significant positive trials 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 OBJECTIVE To assess the possibility that acute respiratory distress syndrome ( ARDS ) of pulmonary and nonpulmonary origins represent two distinct syndromes . DESIGN Analysis of data collected prospect ively from an inception cohort of 117 patients with ARDS . SETTING Adult intensive care unit ( ICU ) , university/postgraduate hospital . MEASUREMENTS AND MAIN RESULTS Differences were sought in mortality and 6-month functional outcome between patients developing ARDS due to pulmonary ( group 1 ) and nonpulmonary ( group 2 ) pathology . Group 1 patients displayed a trend toward increased ICU and in-hospital mortality ( 42.1 % vs. 23.2 % , p = .10 , and 47.4 % vs. 27.9 % , p = .11 , respectively ) . No difference was found in ICU length of stay ( 46.3 + /- 4.9 vs. 39.0 + /- 4.8 days for groups 1 and 2 , respectively ) nor in duration of positive-pressure ventilation ( 26.2 + /- 4.3 vs. 20.6 + /- 3.2 days ) . However , the need for pressure-controlled inverse ratio ventilation was significantly greater in group 1 ( 16.9 + /- 3.2 vs. 9.1 + /- 1.3 days ; p = .033 ) . In survivors , reductions in total lung capacity at 6 months ( 68.1 + /- 4.6 vs. 61.8 + /- 4.6 % predicted for groups 1 and 2 , respectively ; p = .4 ) , accessible lung volume ( 74.4 + /- 4.4 vs. 68.9 + /- 4.9 % predicted ; p = .56 ) , and forced expiratory volume ( 77.8 + /- 2.9 vs. 80.3 + /- 2.4 % predicted ; p = .57 ) did not differ between groups . Gas transfer coefficient was well preserved ( 84.5 + /- 4.6 vs. 86.6 + /- 4.7 % predicted ; p = .80 ) . CONCLUSIONS These data suggest a trend toward higher mortality and ventilatory requirements in ARDS of direct etiology , generating a hypothesis worthy of further exploration To identify the potential impact of novel therapeutic approaches , we studied the early predictive factors of survival at the onset of acute respiratory distress syndrome ( ARDS ) in a 24-bed medical ICU of an academic tertiary care hospital . Over a 48-mo period , a total of 3,511 adult patients were admitted and 259 mechanically ventilated patients met ARDS criteria , as defined by American-European consensus conference , i.e. , bilateral pulmonary infiltrates and PaO2/FIO2 lower than 200 without left atrial hypertension . These patients were r and omly included in a developmental sample ( 177 patients ) and a validation sample ( 82 patients ) . Demographic variables , hemodynamic and respiratory parameters , underlying diseases , as well as several severity scores ( SAPS , SAPS-II , OSF ) and Lung Injury Score ( LIS ) were collected . These variables were compared between survivors and nonsurvivors and entered into a stepwise logistic regression model to evaluate their independent prognostic roles . The overall mortality rate was 65 % . SAPS-II , the severity of the underlying medical conditions , the oxygenation index ( mean airway pressure x FIO2 x 100/PaO2 ) , the length of mechanical ventilation prior to ARDS , the mechanism of lung injury , cirrhosis , and occurrence of right ventricular dysfunction were independently associated with an elevated risk of death . Model calibration was very good in the developmental and validation sample s ( p = 0.84 and p = 0.72 , respectively ) , as was model discrimination ( area under the ROC curves of 0.95 and 0.92 , respectively ) . Thus , the prognosis of ARDS seems to be related to the triggering risk factor , the severity of the respiratory illness , and the occurrence of a right ventricle dysfunction , after adjustment for a general severity score The independent effects of chronic disease , age , severity of illness , lung injury score ( LIS ) and etiology , and preceding nonpulmonary organ-system dysfunction ( OSD ) on the outcome of acute lung injury ( ALI ) have not been examined in an exclusively medical-intensive-care-unit ( MICU ) population . Therefore , 107 consecutive MICU patients with ALI ( 76 % with acute respiratory distress syndrome [ ARDS ] ) were prospect ively investigated . The impact of comorbidities , age > 65 yr , acute physiology score ( APS ) , LIS , etiology of ALI  , and OSD  on hospital survival were studied . The overall mortality was 62 of 107 patients ( 58 % ) , including 47 ( 58 % ) with ARDS . With univariate analysis , age > 65 yr , organ transplantation , human immunodeficiency virus ( HIV ) infection , active malignancy , chronic steroid use , and a septic or aspiration-related etiology of ALI were associated with a > or = 1.2-fold greater relative risk ( RR ) of hospital mortality . With multiple logistic regression , independent predictors of hospital death were age > 65 yr , organ transplantation , HIV infection , cirrhosis , active malignancy , and sepsis . APS , LIS , aspiration-related etiology of ALI , preceding OSD , and other comorbidities were not independently predictive of hospital death . Multivariate analysis of the ARDS cohort showed similar results , although cirrhosis and malignancy did not reach statistical significance . We conclude that comorbid conditions , older age , and sepsis etiology are independent predictors of hospital death in exclusively MICU patients with ALI ( 76 % of whom satisfied criteria for ARDS ) . These factors should be considered in analyzing studies of new therapies and interpreting trends in mortality for ALI and ARDS In a retrospective chart review of cases of adult respiratory distress syndrome in our pediatric intensive care unit from 1987 to 1990 , we attempted to identify the physiologic variables predictive of death . We identified 44 children with adult respiratory distress syndrome ; the mortality rate was 75 % . We found significant differences between survivors and nonsurvivors in intrapulmonary venous admixture ( Qsp/Qt ) , mean airway pressure ( Paw ) , alveolar-arterial oxygen tension difference ( P(A-a)O2 ) , oxygenation index , and peak inspirator pressure ; Qsp/Qt greater than 0.5 , Paw greater than 23 cm H2O , and P(A-a)O2 greater than 470 mm Hg were 93 % , 90 % , and 81 % predictive of death , respectively , in this study population . Sensitivity and specificity were enhanced when we linked multiple predictors , but this linkage was seldom successful because few patients had more than one positive predictor . We propose to use the individual predictors that we have identified as r and omization criteria in a future trial of extracorporeal membrane oxygenation for pediatric cases of adult respiratory distress syndrome OBJECTIVE To evaluate the safety and efficacy of partial liquid ventilation ( PLV ) in adult patients with the acute respiratory distress syndrome ( ARDS ) . SUMMARY BACKGROUND DATA Previous studies have evaluated gas exchange and the safety of PLV in adult patients with severe respiratory failure whose gas exchange was partially provided by extracorporeal life support ( ECLS ) . This is the first experience with adult patients who were not on ECLS . METHODS Intratracheal perflubron in a total dose of 30.1 + /- 7.1 ml/kg was administered over a period of 45 + /- 9 hours to nine adult patients with mean age = 49 + /- 4 years and mean PaO2/FiO2 ratio = 128 + /- 7 as part of a prospect i ve , multicenter , phase I-II noncontrolled trial . RESULTS Significant decreases in mean (A-a)DO2 ( baseline = 430 + /- 47 , 48 hour = 229 + /- 17 , p = 0.0127 by ANOVA ) and FiO2 ( baseline = 0.82 + /- 0.08 , 48 hour = 0.54 + /- 0.06 , p = 0.025 ) , along with an increase in mean SvO2 ( baseline = 75 + /- 3 , 48 hour = 85 + /- 2 , p = 0.018 by ANOVA ) were observed . No significant changes in pulmonary compliance or hemodynamic variables were noted . Seven of the nine patients in this study survived beyond 28 days after initiation of partial liquid ventilation whereas 5 patients survived to discharge . Three adverse events [ hypoxia ( 2 ) and hyperbilirubinemia ( 1 ) ] were determined to be severe in nature . CONCLUSIONS These data suggest that PLV may be performed safely with few related severe adverse effects . Improvement in gas exchange was observed in this series of adult patients over the 48 hours after initiation of PLV OBJECTIVE Liquid ventilation with perfluorocarbon previously has not been reported in pediatric patients with respiratory failure beyond the neonatal period . We evaluated the technique of partial liquid ventilation in six pediatric patients with the acute respiratory distress syndrome of sufficient severity to require extracorporeal life support ( ECLS ) .  DESIGN This study was a noncontrolled , phase I/II experimental study with a single group pretest/posttest design . SETTING All studies were performed at a tertiary , pediatric referral hospital at the University of Michigan Medical School . PATIENTS Six pediatric patients , from 8 wks to 5 1/2 yrs of age , with severe respiratory failure requiring ECLS to support gas exchange . INTERVENTIONS After 2 to 9 days on ECLS , perfluorocarbon was administered into the trachea until the dependent zone of each lung was filled . The initial administered was 12.9 + /- 2.3 mL/kg ( range 5 to 20 ) . Gas ventilation of the perfluorocarbon-filled lungs ( partial liquid ventilation ) was then performed . The perfluorocarbon dose was repeated daily for a total of 3 to 7 days , with a cumulative dose of 45.2 + /- 6.1 mL/kg ( range 30 to 72.5 ) . MEASUREMENTS AND MAIN RESULTS All measurements of native gas exchange were made during brief periods of discontinuation of ECLS and include PaO2 and the alveolar-arterial oxygen gradient , P(A-a)O2 . Static pulmonary compliance , corrected for weight , was also measured directly . The mean PaO2 increased from 39 + /- 6 to 92 + /- 29 torr ( 5.2 + /- 0.8 to 12.2 + /- 3.9 kPa ) over the 96 hrs after the initial dose ( p = .021 by repeated- measures analysis of variance ) . The average P(A-a)O2 decreased from 635 + /- 10 to 499 + /- 77 torr ( 84.7 + /- 1.3 to 66.5 + /- 10.3 kPa ) over the same time period ( p = .059 ) , while the mean static pulmonary compliance ( normalized for patient weight ) increased from 0.12 + /- 0.02 to 0.28 + /- 0.08 mL/cm H2O/kg ( p = .01 ) . All six patients survived . Complications potentially associated with partial liquid ventilation were limited to pneumothoraces in two of six patients . CONCLUSIONS Perfluorocarbon may be safely administered into the lungs of pediatric patients with severe respiratory failure on ECLS and may be associated with improvement in gas exchange and pulmonary compliance BACKGROUND In patients with the acute respiratory distress syndrome , massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury . We determined whether a ventilatory strategy design ed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome . METHODS We r and omly assigned 53 patients with early acute respiratory distress syndrome ( including 28 described previously ) , all of whom were receiving identical hemodynamic and general support , to conventional or protective mechanical ventilation . Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure ( PEEP ) for acceptable oxygenation , with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels ( 35 to 38 mm Hg ) . Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure-volume curve , a tidal volume of less than 6 ml per kilogram , driving pressures of less than 20 cm of water above the PEEP value , permissive hypercapnia , and preferential use of pressure-limited ventilatory modes . RESULTS After 28 days , 11 of 29 patients ( 38 percent ) in the protective-ventilation group had died , as compared with 17 of 24 ( 71 percent ) in the conventional-ventilation group ( P<0.001 ) . The rates of weaning from mechanical ventilation were 66 percent in the protective-ventilation group and 29 percent in the conventional-ventilation group ( P=0.005 ) : the rates of clinical barotrauma were 7 percent and 42 percent , respectively ( P=0.02 ) , despite the use of higher PEEP and mean airway pressures in the protective-ventilation group . The difference in survival to hospital discharge was not significant ; 13 of 29 patients ( 45 percent ) in the protective-ventilation group died in the hospital , as compared with 17 of 24 in the conventional-ventilation group ( 71 percent , P=0.37 ) . CONCLUSIONS As compared with conventional ventilation , the protective strategy was associated with improved survival at 28 days , a higher rate of weaning from mechanical ventilation , and a lower rate of barotrauma in patients with the acute respiratory distress syndrome .  Protective ventilation was not associated with a higher rate of survival to hospital discharge Substantial numbers of clinical trials are never reported in print , and among those that are , many are not reported in sufficient detail to enable judgments to be made about the validity of their results . Failure to publish an adequate account of a well- design ed clinical trial is a form of scientific misconduct that can lead those caring for patients to make inappropriate treatment decisions . Investigators , research ethics committees , funding bodies , and scientific editors all have responsibilities to reduce underreporting of clinical trials . An extended use of prospect i ve registration of trials at inception , as well as benefiting clinical research in other ways , could help people to play their respective roles in reducing underreporting of clinical trials
BACKGROUND Acute lung injury and acute respiratory distress syndrome are syndromes of severe respiratory failure .
Children with acute lung injury or acute respiratory distress syndrome have high mortality and the survivors have significant morbidity .
Partial liquid ventilation is proposed as a less injurious form of respiratory support for these children .
Uncontrolled studies in adults have shown improvements in gas exchange and lung compliance with partial liquid ventilation .
This review was originally published in 2004 , up date d in 2009 and again in 2012 .
OBJECTIVES To assess whether partial liquid ventilation reduces mortality or morbidity , or both , in children with acute lung injury or acute respiratory distress syndrome .