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Partial Liquid Ventilation in Adult Patients with Acute Respiratory Distress Syndrome

Department of Anesthesia and Critical Care, Harvard Medical School, and Respiratory Care, Massachusetts General Hospital, Boston; Averion, Inc.; Boston Biostatistics Research Foundation, Inc., Framingham, Massachusetts; Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio; Clinical Research Alliance Pharmaceutical Corporation, San Diego, California; and St. Michael's Hospital, and Departments of Medicine, Surgery, and Biomedical Engineering, University of Toronto, Toronto, Canada

Correspondence and requests for reprints should be addressed to Robert M. Kacmarek, Ph.D., R.R.T., Respiratory Care, Ellison 401, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E-mail: rkacmarek{at}partners.org

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 APPENDIX 3 REFERENCES

 
Rationale: Despite recent clinical trials demonstrating improved outcome in acute respiratory distress syndrome (ARDS), mortality remains high. Partial liquid ventilation (PLV) using perfluorocarbons has been shown to improve oxygenation and decrease lung injury in various animal models.

Objective: To determine if PLV would have an impact on outcome in patients with ARDS.

Methods: Patients with ARDS were randomized to (1) conventional mechanical ventilation (CMV; n = 107), (2) "low-dose" perfluorocarbon (10 ml/kg; n = 99), and (3) "high-dose" perfluorocarbon (20 ml/kg; n = 105). Patients in all three groups were ventilated using volume ventilation, VT 10 ml/kg predicted body weight, rate 25/min, inspiratory-to-expiratory ratio 1:1, FI_O2 0.5, and positive end-expiratory pressure 13 cm H₂O.

Results: The 28-d mortality in the CMV group was 15%, versus 26.3% in the low-dose (p = 0.06) and 19.1% in the high-dose (p = 0.39) PLV groups. There were more ventilator-free days in the CMV group (13.0 ± 9.3) compared with both the low-dose (7.4 ± 8.5; p < 0.001) and high-dose (9.9 ± 9.1; p = 0.043) groups. There were more pneumothoraces, hypoxic episodes, and hypotensive episodes in the PLV patients.

Conclusions: PLV at both high and low doses did not improve outcome in ARDS compared with CMV and cannot be recommended for patients with ARDS.

Key Words: acute respiratory distress syndrome • liquid ventilation • mechanical ventilation • partial liquid ventilation

Despite recent clinical trials demonstrating improved outcome in the acute respiratory distress syndrome (ARDS) (1, 2), overall mortality in unselected patients with ARDS remains unacceptably high at 40 to 50% (3–5). As a result, adjuncts and alternatives to standard conventional mechanical ventilation continue to be evaluated in an effort to improve the outcome of these patients (6, 7).

One of these alternatives is partial liquid ventilation (PLV), a nontraditional approach to ventilation that has received considerable attention over the past decade (8). With PLV, the lungs are partially filled with perfluorocarbon (PFC), a clear inert liquid, and mechanical ventilation is provided with a standard ventilator (9). The rationale underlying this approach in patients with ARDS is that PFCs improve gas exchange by recruiting dependent lung regions, by clearing retained secretions, and by redistributing blood flow to ventilated regions (10, 11); and the use of PLV abrogates lung injury due to the low surface tension properties and antiinflammatory properties of PFCs (12, 13). In animal models of acute lung injury (ALI), PLV has been shown to improve gas exchange and decrease lung injury compared with conventional mechanical ventilation (CMV) (14–16). Preliminary studies have demonstrated that PLV can be performed safely in humans (17–21) and a post hoc analysis of a phase II trial demonstrated more rapid discontinuation of mechanical ventilation and a trend to decreased mortality in patients younger than 55 yr who were treated with PLV (20).

On the basis of the strong animal data (14–16) suggesting the efficacy of PLV in models of lung injury, and on the suggestive human data (20), we performed a randomized clinical trial comparing PLV with CMV in patients with ARDS.

	METHODS

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Between 1998 and 2000, patients with ARDS were randomized from 56 centers (Appendix 1). Inclusion criteria were as follows: risk factor for ALI/ARDS; prior mechanical ventilation for 120 h or less; acute, bilateral infiltrates on chest radiograph; and a Pa_O2/FI_O2 of 200 mm Hg or less with an FI_O2 of 0.5 or greater, and positive end-expiratory pressure (PEEP) of 5 cm H₂O or more. Patients were excluded if their age was younger than 16 or older than 65 yr, their Acute Physiology and Chronic Health Evaluation (APACHE) II score was 30 or more, it had been more than 48 h since meeting inclusion criteria, and there was presence of serious nonpulmonary organ dysfunction (Appendix 2). To ensure persistent hypoxemia, only patients with Pa_O2/FI_O2 greater than 70 and less than 300 mm Hg on PEEP of 13 cm H₂O or greater and FI_O2 of 0.5 or more were included.

Patients were randomly assigned to one of four groups using a block design (22) that ensured a balance of distribution of patients with respect to four strata (ARDS etiology, age, APACHE II score, and alternative therapies). Group assignment was performed using a computerized randomization system. The control group received CMV with no PFC; the low-dose PLV group had their lungs filled with PFC (Perflubron, Alliance Pharmaceutical, San Diego, CA) to the carina in the supine position. This was accomplished by slowly instilling two separate aliquots (5 ml/kg predicted body weight [PBW] per aliquot) of PFC into the lungs. A "suction catheter check" was performed by inserting a suction catheter to the carina while the patient was on zero PEEP. Suction was then applied to the catheter; if PFC was suctioned, then suctioning was continued until no PFC was removed. If no PFC was suctioned, then 5-ml/kg aliquots of PFC were administered, followed by suction catheter checks until some PFC was suctioned. The protocol for high-dose PLV group was similar to that described above, except dosing was to obtain PFC to a level 5 cm caudal to the incisors. Supplemental dosing was provided every 3 h; a suction catheter fluid level check was performed every 6 h, and dosing adjusted. In the control group, sham suctioning checks (insertion of the catheter) were mandated every 3 h; however, suctioning occurred only if required clinically. The two treatment groups received PLV for a minimum of 48 h. Supplemental dosing was continued for up to another 72 h if the FI_O2 was greater than 0.5.

All groups received standardized ventilatory support: volume control, VT of 10 ml/kg PBW or less, rate of 25/min or less, inspiratory-to-expiratory ratio of 1:1, FI_O2 of 0.5 or greater, and PEEP of 13 cm H₂O or more. End-inspiratory plateau pressure was maintained at 35 cm H₂O or lower. PEEP in the treatment groups was maintained at 13 cm H₂O or higher until dosing was stopped. When patients met target gas exchange criteria with PEEP of 8 cm H₂O or less, FI_O2 of 0.5 or less, patients were weaned using spontaneous breathing trials (23, 24).

The primary study outcome was ventilator-free days during the 28 d after randomization. The secondary outcomes were mortality, time to unassisted ventilation, percentage of patients alive and off ventilation at Day 28, and time to ARDS resolution defined as the time to a Pa_O2/FI_O2 of 200 mm Hg or greater with a PEEP of 5 cm H₂O or less, and an FI_O2 of 0.5 or less. Data on demographic, physiologic, laboratory and radiographic characteristics, and coexisting conditions were recorded. Arterial blood gases, ventilator, physiologic, laboratory, and radiographic data were obtained after stabilization on standardized ventilator settings, 12, 24, 48, 72, 96, and 120 h, and at 7, 14, and 28 d after randomization. See online supplement for statistical analysis. The trial was monitored by a data safety monitoring board (Appendix 3).

	RESULTS

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A total of 3,817 patients were screened between December 1998 and December 2000, from which 311 patients were enrolled: 107 patients were randomized to CMV, 99 were randomized to low-dose PLV, and 105 were randomized to high-dose PLV. Five patients randomized to PLV (two randomized to low-dose and three randomized to high-dose) never received PLV. These five patients were included in all analyses except for ventilator settings at 24, 72, and 168 h postrandomization. All patients were monitored for the 28-d study period.

Baseline demographic characteristics, disease severity, and ventilator management were similar in the three groups (Table 1). The duration of PLV treatment was 92 ± 39.2 h in the low-dose group (n = 97) and 85 ± 39.5 h in the high-dose group (n = 102). Nine patients (five in the low-dose and four in the high-dose PLV groups) received PLV therapy for more than 5 d. The total volume of Perflubron instilled into the lungs was 82 ± 32.8 ml/kg PBW (5,179 ± 2,150 ml) in the low-dose PLV group and 107 ± 45.8 ml/kg PBW (6,910 ± 3,278 ml) in the high-dose group.

Efficacy
Ventilatory and gas exchange variables at 24, 72, and 168 h after randomization are provided in Table 2. At 24 and 72 h, the CMV group had a lower plateau pressure, peak inspiratory pressure, mean airway pressure, respiratory rate, FI_O2, total PEEP, and Pa_CO2 (p < 0.05), and a higher Pa_O2/FI_O2 and pH (p < 0.05) than both PLV groups. VT was lower (p < 0.05) in the low-dose PLV group at 24 and 72 h than in the CMV group. At 168 h, the mean airway pressure was higher and the Pa_O2/FI_O2 lower in the low-dose group than in the CMV group (p < 0.05), and the minute ventilation and total PEEP were higher in the high-dose PLV group than in the CMV group (p < 0.05).

View larger version (7K): [in this window] [in a new window]   Figure 1. All-cause mortality for all patients enrolled into the three studied groups over the first 28 d of the study. Treatment groups: solid line, low-dose; dotted line, high-dose; dashed line, conventional mechanical ventilation.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 APPENDIX 3 REFERENCES

The results of this trial are disappointing. The hypothesis of the current study was based on animal data and a post hoc analysis of a phase II trial comparing PLV with a non-PLV control group (20). In the previous study, the PLV group had a significantly greater number of ventilator-free days and a trend toward a lower mortality rate compared with control in patients younger than 55 yr (20). The plateau pressures in the phase II trial for all groups were 35 to 39 cm H₂O, and in the current study they were 26 to 30 cm H₂O in the CMV group. This difference may have contributed to the CMV mortality benefit in our trial versus the phase II trial. Outcome data for the PLV groups in this study were similar to those from the post hoc analysis of the phase II trial; however, in the present study, the control group had a much improved outcome. This study joins a large group of negative studies that were based on promising post hoc analyses (7, 25, 26). The reason for the large number of negative post hoc trials is likely related to the statistical issue of multiple testing in which "false positives" occur by chance alone. However, it should also be understood that it is still unclear how to optimally dose PFCs and adjust ventilator settings in patients receiving PLV. Therefore, the overall role, if any, of PFCs in ventilator management of ARDS remains to be determined despite this negative study.

Why the Negative Results?
Given the putative benefits of PLV, which include decreased surface tension (9), antiinflammatory properties (12), "liquid PEEP," and redistribution of blood flow to better ventilated areas (10, 11), and given the promising animal data (14–16), why was this trial negative? There are a number of possibilities, including the heavy sedation and paralysis required in many patients on PLV, the requirement for at least 48 h of PLV before discontinuation, the fact that PLV requires about 24 h for the PFC to evaporate, and possible repeated derecruitment of unstable lung units since patients in the PLV arm had to be disconnected from the mechanical ventilator every 3 h for either redosing or evaluation of the PFC level. However, the negative results may have been a result of the ventilatory strategy used in all groups. As we now know, a low VT ( 6 ml/kg) is ideal in ARDS (1, 2). This study used VTs of about 9 ml/kg PBW, lower than those used in the animal studies cited above. These lower VTs may have prevented the beneficial effects of PLV from being observed. In addition, plateau pressures were higher in the PLV groups by about 3 cm H₂O throughout the study. It may be that the benefits of adjunctive therapies demonstrated in animals ventilated with large VTs are simply overshadowed by the benefits of low ventilating pressures and VTs currently used in patients with ARDS. This combined with the unexpectedly low mortality in the control group were the primary reasons why we believe the trial results were negative.

An additional reason for this negative trial may have been the population of patients studied; it may be that a different population of patients would have benefited from PLV. Finally, it may be that the high peak alveolar pressure in the most gravity-dependent lung in the PLV group when applied over time enhanced injury in this group. Although plateau pressures were about 30 to 32 cm H₂O in the PLV groups, plateau pressure does not reflect the impact of the PFCs on the dependent lung. The combined effect of pressure exerted by the PFC and the airway gas pressure may have enhanced injury over time in the PLV groups. Finally, the overall volume of fluid plus gas in the PLV groups may have markedly over distended lung, increasing susceptibility to injury.

The ARDSNet data (2) became available during the conduct of this trial. This brings up the question of whether this study should have changed to a lower VT strategy in the control group. This is a complex issue. The current study was almost completed when the ARDSNet results were published. The VTs used in our study were about midway between those of the control arm and the conventional arm of the ARDSNet trial, and the mortality rates that were seen by the Data Safety Monitoring Board (albeit in a blinded fashion) were comparable to the 6-ml/kg group in the ARDSNet trial. When entry criteria differ and outcomes of the study being conducted are good, decisions are frequently made to continue the trial as designed. A good example of this is the recent prone-positioning trial by Guerin and coworkers (27), which used a VT of about 10 ml/kg PBW.

High Dose versus Low Dose
Two dosing levels of PLV were tested based on efficacy data available at the time the study was initiated. Most clinical studies using PLV have used dosing to full FRC (17–20). However, nonclinical data in various lung-injury models have indicated that PLV with less than a full FRC dose may be as effective as a full FRC dose (14, 15). Specifically, in large animals, lung compliance only improves up to a dose of 10 ml/kg (15). Although oxygenation in animal models improves in a dose-dependent manner, the use of moderate levels of PEEP during PLV results in a similar benefit to that of large PFC dosing at low PEEP levels (28, 29). The dosing level of approximately 20 ml/kg was chosen based on the volume of PFC used in a previous phase II trial (22 ± 0.8 ml/kg) (20) and the lower dose of 10 ml/kg was based on previous studies in which this dose appeared to be effective (14, 15).

Adverse Events
The increased numbers of hypoxic and hypotensive episodes in the PLV groups were primarily related to the interruption of ventilatory support that was required for initial dosing and subsequent dosing of PFC. In addition, the greater distending pressure in the dependent lung regions may have contributed to the higher pneumothorax rate in the PLV groups (9.3 vs. 29.4 and 28%) (10, 11). Although all of the short-term preclinical data indicated less lung injury with PLV (30, 31), it is easy to speculate how the long-term application of PLV might have induced this level of barotrauma.

Conventional Ventilation
Although direct comparison of mortality among different studies is fraught with uncertainty due to a number of factors, it is interesting to compare the mortality in our control group with those of other studies. The mortality rate of 15% in our control group is the lowest mortality reported in any reported randomized controlled trial of mechanical ventilation in ARDS (1, 2, 7, 25, 26, 32–35). This low mortality rate may be due to a number of factors. First, patients enrolled in our trial had fewer organ failures than many other ARDS trials and were ventilated for less than 48 h after the diagnosis of ARDS was made. In addition, the inclusion criteria only included patients younger than 65 yr; increased age is a well-known determinant of increased mortality in patients with ARDS (36, 37). However, our patients may have had more severe lung injury at the time of enrollment based on oxygenation criteria, since we assessed oxygenation using a relatively high PEEP of 13 cm H₂O or greater, and only patients with an FI_O2 of 0.5 or more and a Pa_O2/FI_O2 less than 300 mm Hg were randomized. When the ventilation strategy used in our study is compared with that of the ARDSNet trial (2), striking differences exist. VT in our CMV arm was about 9.0 ml/kg PBW, somewhat lower than those used in Stewart and coworkers' (32) and Brochard and colleagues' (33) studies, but greater than the 6.0 ml/kg PBW in the ARDSNet treatment arm. However, we used a PEEP level that was about 14 cm H₂O at randomization, a value greater than that used in the three previously mentioned trials. A number of animal studies have demonstrated that higher levels of PEEP produce marked protection from ventilator-induced lung injury. Plateau pressures in both the present study and in the ARDSNet study (2) were about 28 cm H₂O. Given that we used a higher VT and a higher PEEP level, this would suggest that there was marked recruitment of the lung by the application of PEEP of 13 cm H₂O or greater from the first or second day of ARDS in our study. This leads one to speculate on the relative importance of volume, PEEP, and plateau pressure on outcome in ARDS.

Limitations
The major limitation of this study was the methodology used to check whether further dosing of PFC was required. The repetitive disconnection of the mechanical ventilator may have disadvantaged patients in the PLV groups. Only two dosing levels were used; it is possible that a much lower dose of PFC may have been more advantageous. The approach to ventilation used during PLV may not have been ideal. The use of a smaller well-defined VT in all groups may have affected outcome. It is possible that use of high-frequency ventilation during PLV would have been more advantageous than CMV. It can be argued that this trial, similar to many other trials of innovative medical approaches, was conducted too soon. However, the results of animal studies (14–16) were positive, a phase II trial (20) identified a group of patients that might benefit from PLV, and much of the human lung protective mechanical ventilation data we know today were not available in 1998. In addition, ventilator adjustments were not guided by specific algorithms. Ranges (i.e., VT 10 ml/kg PBW) were defined but the clinician was free to adjust settings within the defined range as they considered clinically appropriate.

In addition, the delay between study completion and study publication must be addressed. Multiple factors clearly affect the speed of publication. Positive results are embraced by everyone and enthusiasm for publication is high. However, negative trials are not as enthusiastically embraced. The investigators' interest in pursuing the effort required to publish is diminished, and journals overall are less interested in publishing negative trials than positive trials. Despite this, it is critical that data from negative trials be available for the entire medical community to evaluate to help guide future studies. Finally, as with all studies, our results can only be generalized to others meeting our inclusion criteria including a Pa_O2/FI_O2 of 300 mm Hg or less at a PEEP of 13 cm H₂O or greater and FI_O2 of 0.5 or greater.

In conclusion, the use of PLV as applied in this study results in a greater number of serious adverse outcomes than CMV and does not improve outcome compared with CMV. PLV is not indicated in patients with severe ARDS.

	APPENDIX 1

TOP ABSTRACT METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 APPENDIX 3 REFERENCES

 
PLV Study Investigators

Principal Investigator Institution Sivak, Edward, M.D. SUNY Health Sciences Center, Syracuse, NY Williams, Glenn, M.D. Baptist Memorial Health Care Foundation, Memphis, TN Blosser, Sandralee, M.D. Hershey Medical Center, Hershey, PA Conrad, Steven, M.D. Louisianna State University Medical Center, Shreveport, LA Crain, Michael, M.D. Princeton Pulmonary Group PC, Birmingham, AL Croce, Martin, M.D. University of Tennessee, Memphis, TN Davis, Ken, M.D. University of Cincinnati Medical Center, Cincinnati, OH Fessler, Henry, M.D. Johns Hopkins University, Baltimore, MD Hirschl, Ronald, M.D. University of Michigan Medical Center, Ann Arbor, MI Lamberti, James, M.D. Inova Fairfax Hospital, Falls Church, VA Ray, Daniel, M.D. Lehigh Valley Hospital, Allentown, PA Mette, Stephen, M.D. Maine Medical Center, Portland, ME McKibben, Andrew, M.D. University of Missouri–Columbia School of Medicine, Columbia, MO Habashi, Nader, M.D. R.A. Cowley Shock Trauma Center, Baltimore, MD Sandifer, Dean, M.D. Lakeland Regional Medical Center Watson Clinic, Lakeland, FL Schein, Roland, M.D. Veterans Affairs Medical Center, University of Miami, Miami, FL Schuster, Daniel, M.D. Washington University School of Medicine, St. Louis, MO Mallampalli, Antara, M.D. University of Louisville Health Sciences Center, Louisville, KY Thompson, Taylor, M.D. Massachusetts General Hospital, Boston, MA Wiedemann, Herbert, M.D. Cleveland Clinic Foundation, Cleveland, OH Woda, Russell, M.D. Ohio State University Medical Center, Columbus, OH James Allen, M.D. Ohio State University Medical Center, Columbus, OH Zwischenberger, Jay, M.D. University of Texas Medical Center, Galveston, TX Johnson, Steven, M.D. University of Arizona Health Sciences Center, Tucson, AZ Tsuei, Betty, M.D. University of Kentucky Chandler Medical Center, Lexington, KY Moncure, Michael, M.D. University of Kansas Medical Center, Kansas City, KS Rouben, Lawrence, M.D. Jewish Hospital, Heart and Lung Institute, Louisville, KY Senkowski, Michael, M.D. Memorial Medical Center, Savannah, GA Heard, Stephen, M.D. University of Massachusetts, Worcester, MA Shapiro, Michael, M.D. University of Pennsylvania, Philadelphia, PA Strange, Charlie, M.D. Medical University of South Carolina, Charleston, SC Raoff, Suhail, M.D. Nassau County Medical Center, East Meadow, NY Garland, Alan, M.D. Robert Wood Johnson Medical School, New Brunswick, NJ Cardinal, Pierre, M.D. Ottawa General Hospital, Ottawa, ON, Canada Fenwick, John, M.D. Vancouver Hospital and Health Sciences Center, Vancouver, BC, Canada Goldberg, Peter, M.D. Royal Victoria Hospital, Montreal, PQ, Canada Hamielec, Cindy, M.D. Hamilton Health Sciences, Hamilton, ON, Canada Laporta, Denny, M.D. Jewish General Hospital, Montreal, PQ, Canada Mazer, David, M.D. St. Michael's Hospital, Toronto, ON, Canada Sandham, Dean, M.D. Foothills Hospital, Calgary, Alberta Smith, Terry, M.D. Sunnybrook Health Sciences Center, Toronto, ON Laufer, Brian, M.D. Hospital Maisonneuve-Rosemont, Montreal, PQ, Canada Berthiaume, Yves, M.D. Campus Hotel-Dieu, Montreal, PQ, Canada Lesur, Olivier, M.D. Universite de Sherbrooke, Sherbrooke, PQ, Canada Chiche, Jean-Daniel, M.D. Hopital Cochin, Paris, France Chastre, Jean, M.D. Hospitalier Bichat-Claude Bernard, Paris, France Damas, Pierre, M.D. Centre Hospitalier Universitaire de Liege, Leige, Belgium Dreyfuss, Didier, M.D. Hopital Louis Mourier, Paris, France Falke, Konrad, M.D. Charity Campus Virchow Klimikun Universitatklinikum, Berlin, Germany Lemaire, Francois, M.D. Hopital Henri Mondor, Paris, France Papazian, Laurent, M.D. Hopital Sainte Marguerite, Marseille, France Rouby, Jean-Jacques, M.D. Hospitalier Pitie-Salpetriere, Paris, France Suter, Peter, M.D. Hopital Cantonal de Geneve, Geneva, Switzerland Vincent, Jean Louis, M.D. Hopital Erasme, Brussels, Belgium Quintel, Michael MD Klinikum Mannheim, Mannheim, Germany LeGall, Jean-Roger, M.D. Hopital St. Louis, Paris, France

	APPENDIX 2

TOP ABSTRACT METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 APPENDIX 3 REFERENCES

 
Summary of Exclusion Criteria

• Age < 16 and > 65 yr
  
• Inability to obtain informed consent
  
• APACHE II score 30
  
• Time window for inclusion exceeded (> 48 h)
  
• Significant nonpulmonary organ dysfunction as defined by the following:
  1. Chronic renal failure requiring dialysis
     
  2. Acute liver disease with significant hepatocellular or cholestatic liver injury (acute hepatitis or acute cholestasis)
     
  3. Severe chronic liver disease (bilirubin > 3 mg/dl and serum albumin < 3 g/dl)
     
  4. Hematologic dysfunction, defined by either a total polymorphonuclear leukocyte (PMN) count < 0 or 5 x 10³/m
     
  
  
• Systolic blood pressure < 90 mm Hg, unresponsive to treatment with fluids and vasopressors
  
• Congestive heart failure, defined by either a pulmonary arterial occlusion pressure of >18 mm Hg or by clinical examination
  
• Clinical history of decompensated left ventricular dysfunction as indicated by New York Heart Association class III or IV or left ventricular ejection fraction < 30%
  
• Documented myocardial infarction within the last 3 mo; or life threatening arrhythmia during the present hospital admission
  
• Glasgow Coma Score < 10 determined before the administration of confounding medications, such as narcotics, sedatives, or neuromuscular blockers
  
• Active air leak from the lung into the pleural space in the 24 h before randomization (chest tube to pleuravac with water seal without leak and not requiring suction for a minimum of 24 h was allowed)
  
• Evidence for increased intracranial pressure or history of an intracerebral hemorrhage within the past 3 mo
  
• Status asthmaticus or severe asthma currently under treatment with pharmacologic doses of intravenous corticosteroids
  
• Chronic lung disease requiring chronic oxygen therapy or presenting with a baseline FEV₁ < 700 ml
  
• Spinal cord injury above T-1
  
• Myasthenia gravis or Guillain-Barré syndrome or other neurologic disorder that impairs the patient's ability to breath spontaneously
  
• Organ transplantation (i.e., bone marrow, heart, lung, liver, kidney, pancreas)
  
• Seizures refractory to anticonvulsant therapy
  
• Acute parenchymal lung injury secondary to suspected overdose of narcotics
  
• Burn injury (2° or 3°) with greater than 30% of total body surface area or with a restrictive chest injury
  
• Life expectancy of less than 3 mo for other than ALI/ARDS-associated complications
  
• Positive blood test for HIV with CD-4 count < 200
  
• Received chemotherapy within 30 d before enrollment
  
• Morbid obesity (> twice ideal body weight).
  
• Tracheostomy
  
• Vascular lung disease with alveolar hemorrhage or pulmonary hypertension (e.g., lupus, scleroderma, Wegener's)
  
• Hypersensitivity to PFCs
  
• Positive serum -human chorionic gonadotrophin indicating pregnancy (test was required for females who were not surgically sterile or who were not postmenopausal for at least 6 mo)
  
• Received any other experimental therapy within 30 d before screening (except nitric oxide, provided nitric oxide had been discontinued at least 4 h before initiation of standardized mechanical ventilation)
  

	APPENDIX 3

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Members of the Data Safety Monitoring Board
Kenneth Steinberg, M.D., University of Washington School of Medicine, Seattle, WA

Avi Nahum, M.D., Regents Hospital, St. Paul, MN

Jesus Villar, M.D., Hospital del la Candeleria, Canary Islands

David Schoenfeld, Ph.D., Boston Biostatics, Inc., Boston, MA

	FOOTNOTES

 
Supported by Alliance Pharmaceutical Corp., San Diego, California.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200508-1196OC on October 27, 2005

Conflict of Interest Statement: R.M.K. received a $65,000 grant from Alliance Pharmaceuticals in 1999 to support studies on the approach to mechanical ventilation during partial liquid ventilation. H.P.W. served as a consultant for Alliance Pharmaceuticals prior to and during the conduct of this clinical trial, for which he received at most $10,000/yr during 1994–2000. P.T.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.K.W. was a full-time employee of Alliance Pharmaceuticals at the time of the study. A.S.T. was an employee of Alliance Pharmaceuticals, which sponsored the clinical trial. A.S.S. has been a paid consultant to Maquet in the field of mechanical ventilation (> $10,000/yr), chaired a DSMB for Leo Pharma in relation to a surfactant trial (> $10,000/yr), and was on the Alliance Advisory Board for the trial presented in this publication, but received no financial compensation for this.

Received in original form August 3, 2005; accepted in final form October 24, 2005

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