Background Traditional approaches to mechanical ventilationuse tidal volumes of 10 to 15 ml per kilogram of body weightand may cause stretch-induced lung injury in patients with acutelung injury and the acute respiratory distress syndrome. Wetherefore conducted a trial to determine whether ventilationwith lower tidal volumes would improve the clinical outcomesin these patients.
Methods Patients with acute lung injury and the acute respiratorydistress syndrome were enrolled in a multicenter, randomizedtrial. The trial compared traditional ventilation treatment,which involved an initial tidal volume of 12 ml per kilogramof predicted body weight and an airway pressure measured aftera 0.5-second pause at the end of inspiration (plateau pressure)of 50 cm of water or less, with ventilation with a lower tidalvolume, which involved an initial tidal volume of 6 ml per kilogramof predicted body weight and a plateau pressure of 30 cm ofwater or less. The first primary outcome was death before apatient was discharged home and was breathing without assistance.The second primary outcome was the number of days without ventilatoruse from day 1 to day 28.
Results The trial was stopped after the enrollment of 861 patientsbecause mortality was lower in the group treated with lowertidal volumes than in the group treated with traditional tidalvolumes (31.0 percent vs. 39.8 percent, P=0.007), and the numberof days without ventilator use during the first 28 days afterrandomization was greater in this group (mean [±SD],12±11 vs. 10±11; P=0.007). The mean tidal volumeson days 1 to 3 were 6.2±0.8 and 11.8±0.8 ml perkilogram of predicted body weight (P<0.001), respectively,and the mean plateau pressures were 25±6 and 33±8cm of water (P<0.001), respectively.
Conclusions In patients with acute lung injury and the acuterespiratory distress syndrome, mechanical ventilation with alower tidal volume than is traditionally used results in decreasedmortality and increases the number of days without ventilatoruse.
The mortality rate from acute lung injury and the acute respiratorydistress syndrome1 is approximately 40 to 50 percent.2,3,4 Althoughsubstantial progress has been made in elucidating the mechanismsof acute lung injury,5 there has been little progress in developingeffective treatments.
Traditional approaches to mechanical ventilation use tidal volumesof 10 to 15 ml per kilogram of body weight.6 These volumes arelarger than those in normal subjects at rest (range, 7 to 8ml per kilogram), but they are frequently necessary to achievenormal values for the partial pressure of arterial carbon dioxideand pH. Since atelectasis and edema reduce aerated lung volumesin patients with acute lung injury and the acute respiratorydistress syndrome,7,8 inspiratory airway pressures are oftenhigh, suggesting the presence of excessive distention, or "stretch,"of the aerated lung. In animals, ventilation with the use oflarge tidal volumes caused the disruption of pulmonary epitheliumand endothelium, lung inflammation, atelectasis, hypoxemia,and the release of inflammatory mediators.9,10,11,12,13,14 Therelease of inflammatory mediators could increase lung inflammationand cause injury to other organs.10,15 Thus, the traditionalapproach to mechanical ventilation may exacerbate or perpetuatelung injury in patients with acute lung injury and the acuterespiratory distress syndrome and increase the risk of nonpulmonaryorgan or system failure.
The use of lower tidal volumes during ventilation in patientswith acute lung injury and the acute respiratory distress syndromemay reduce injurious lung stretch and the release of inflammatorymediators.16,17,18 However, this approach may cause respiratoryacidosis16,17 and decrease arterial oxygenation19,20 and maytherefore require changes in the priority of some objectivesin the care of these patients. With the traditional approach,the attainment of normal partial pressure of arterial carbondioxide and pH is given a higher priority than is protectionof the lung from excessive stretch. With an approach that involveslower tidal volumes, the reverse is true. Uncontrolled studiessuggested that the use of a lower tidal volume would reducemortality in patients with acute lung injury and the acute respiratorydistress syndrome,17 but the results of four randomized trialsof lung-protecting ventilation strategies have been conflicting.21,22,23,24The present trial was conducted to determine whether the useof a lower tidal volume with mechanical ventilation would improveimportant clinical outcomes in such patients.
Methods
Patients
Patients were recruited from March 1996 through March 1999 atthe 10 university centers of the Acute Respiratory DistressSyndrome Network of the National Heart, Lung, and Blood Institute(the centers are listed in the Appendix). The protocol was approvedby the institutional review board at each hospital, and informedconsent was obtained from the patients or surrogates at allbut one hospital, where this requirement was waived. A completedescription of the methods is available on the World Wide Web(at www.ardsnet.org) or from the National Auxiliary PublicationsService (*).
Patients who were intubated and receiving mechanical ventilationwere eligible for the study if they had an acute decrease inthe ratio of partial pressure of arterial oxygen to fractionof inspired oxygen to 300 or less (indicating the onset of hypoxemia;values were adjusted for altitude in Denver and Salt Lake City),bilateral pulmonary infiltrates on a chest radiograph consistentwith the presence of edema, and no clinical evidence of leftatrial hypertension or (if measured) a pulmonary-capillary wedgepressure of 18 mm Hg or less.1 Patients were excluded if 36hours had elapsed since they met the first three criteria; theywere younger than 18 years of age; they had participated inother trials within 30 days before the first three criteriawere met; they were pregnant; they had increased intracranialpressure, neuromuscular disease that could impair spontaneousbreathing, sickle cell disease, or severe chronic respiratorydisease; they weighed more than 1 kg per centimeter of height;they had burns over more than 30 percent of their body-surfacearea; they had other conditions with an estimated 6-month mortalityrate of more than 50 percent; they had undergone bone marrowor lung transplantation; they had chronic liver disease (asdefined by Child–Pugh class C)25; or their attending physicianrefused or was unwilling to agree to the use of full life support.
A centralized interactive voice system was used for randomization.Patients were randomly assigned to receive mechanical ventilationinvolving either traditional tidal volumes or lower tidal volumes.
Ventilator Procedures
The volume-assist–control mode was used for the ventilatoruntil the patient was weaned from the device or for 28 daysafter randomization on day 0. Because normal lung volumes arepredicted on the basis of sex and height,26,27 a predicted bodyweight was calculated for each patient from these data.28 Thepredicted body weight of male patients was calculated as equalto 50 + 0.91(centimeters of height – 152.4); that of femalepatients was calculated as equal to 45.5 + 0.91(centimetersof height – 152.4). In the group treated with traditionaltidal volumes, the initial tidal volume was 12 ml per kilogramof predicted body weight. This was subsequently reduced stepwiseby 1 ml per kilogram of predicted body weight if necessary tomaintain the airway pressure measured after a 0.5-second pauseat the end of inspiration (plateau pressure) at a level of 50cm of water or less. The minimal tidal volume was 4 ml per kilogramof predicted body weight. If the plateau pressure dropped below45 cm of water, the tidal volume was increased in steps of 1ml per kilogram of predicted body weight until the plateau pressurewas at least 45 cm of water or the tidal volume was 12 ml perkilogram of predicted body weight.
In the group treated with lower tidal volumes, the tidal volumewas reduced to 6 ml per kilogram of predicted body weight withinfour hours after randomization and was subsequently reducedstepwise by 1 ml per kilogram of predicted body weight if necessaryto maintain plateau pressure at a level of no more than 30 cmof water. The minimal tidal volume was 4 ml per kilogram ofpredicted body weight. If plateau pressure dropped below 25cm of water, tidal volume was increased in steps of 1 ml perkilogram of predicted body weight until the plateau pressurewas at least 25 cm of water or the tidal volume was 6 ml perkilogram of predicted body weight. For patients with severedyspnea, the tidal volume could be increased to 7 to 8 ml perkilogram of predicted body weight if the plateau pressure remained30 cm of water or less.
Plateau pressures were measured with a half-second inspiratorypause at four-hour intervals and after changes in the tidalvolume or positive end-expiratory pressure. Plateau pressuresof more than 50 cm of water in the patients in the group treatedwith traditional tidal volumes and of more than 30 cm of waterin patients in the group treated with lower tidal volumes wereallowed if the tidal volume was 4 ml per kilogram of predictedbody weight or if arterial pH was less than 7.15.
All other objectives and ventilation procedures, including weaning,were identical in the two study groups (Table 1). If a patientbecame able to breathe without assistance but subsequently requiredadditional mechanical ventilation within a period of 28 days,the same tidal-volume protocol was resumed.
Patients were monitored daily for 28 days for signs of the failureof nonpulmonary organs and systems.29 Circulatory failure wasdefined as a systolic blood pressure of 90 mm Hg or less orthe need for treatment with any vasopressor; coagulation failureas a platelet count of 80,000 per cubic millimeter or less;hepatic failure as a serum bilirubin concentration of at least2 mg per deciliter (34 µmol per liter); and renal failureas a serum creatinine concentration of at least 2 mg per deciliter(177 µmol per liter). We calculated the number of dayswithout organ or system failure by subtracting the number ofdays with organ failure from the lesser of 28 days or the numberof days to death. Organs and systems were considered failure-freeafter patients were discharged from the hospital.
Plasma Interleukin-6 Concentrations
Blood samples were obtained from 204 of the first 234 patientson day 0 and on day 3 for measurement of plasma interleukin-6by immunoassay (R & D Systems, Minneapolis).30 Blood sampleswere stored in sterile EDTA-treated glass tubes.
Data Collection
Data on demographic, physiologic, and radiographic characteristics,coexisting conditions, and medications were recorded withinfour hours before the ventilator settings were changed on day0. Physiologic and radiographic data, medication use, and useof other investigational treatments were recorded between 6and 10 a.m. on days 1, 2, 3, 4, 7, 14, 21, and 28. Data weretransmitted weekly to the network coordinating center. Patientswere followed until day 180 or until they were breathing ontheir own at home.
Assessment of Compliance
Randomly selected ventilator and blood gas variables were analyzedfor compatibility with the protocol. Quarterly reports of thesedata from each of the 10 centers were used by investigatorsto assess compliance.
Statistical Analysis
The first primary outcome was death before a patient was dischargedhome and was breathing without assistance. Patients who werein other types of health care facilities at 180 days were consideredto have been discharged from the hospital and to be breathingwithout assistance. The second primary outcome was ventilator-freedays, defined as the number of days from day 1 to day 28 onwhich a patient breathed without assistance, if the period ofunassisted breathing lasted at least 48 consecutive hours. Adifference in ventilator-free days could reflect a differencein mortality, ventilator days among survivors, or both. Otheroutcomes were the number of days without organ or system failureand the occurrence of barotrauma, defined as any new pneumothorax,pneumomediastinum, or subcutaneous emphysema, or a pneumatocelethat was more than 2 cm in diameter. Interim analyses were conductedby an independent data and safety monitoring board after theenrollment of each successive group of approximately 200 patients.Stopping boundaries (with a two-sided level of 0.05) were designedto allow early termination of the study if the use of lowertidal volumes was found to be either efficacious31 or ineffective.32
The comparison of traditional with lower tidal volumes was oneof two trials conducted simultaneously in the same patientsin a factorial experimental design. Ketoconazole was comparedwith placebo in the first 234 patients, and lisofylline wascompared with placebo in the last 194 patients; no drugs wereassessed in the middle 433 patients.
We used Student's t-test or Fisher's exact test to compare base-linevariables. We used analysis of covariance to compare log-transformedplasma interleukin-6 values. We used Wilcoxon's test to comparethe day 0 and day 3 plasma interleukin-6 concentrations, ventilator-freedays, and organ-failure–free days, which had skewed distributions.We used the 180-day cumulative incidence of mortality to comparethe proportion of patients in each group who died before beingdischarged home and breathing without assistance,33 after stratificationfor other experimental interventions: treatment with ketoconazole,the ketoconazole placebo, lisofylline, the lisofylline placebo,or no other agent. We used a chi-square test to determine whetherthere was an interaction between the study group and the otherexperimental interventions with respect to the mean (±SE)mortality rates at 180 days. All P values are two-sided.
Results
The trial was stopped after the fourth interim analysis becausethe use of lower tidal volumes was found to be efficacious (P=0.005for the difference in mortality between groups; P value forthe stopping boundary, 0.023). The base-line characteristicsof the 861 patients who were enrolled were similar, except thatminute ventilation was slightly but significantly higher (P=0.01)in the group treated with lower tidal volumes (Table 2).
Table 2. Base-Line Characteristics of the Patients.
The tidal volumes and plateau pressures were significantly loweron days 1, 3, and 7 in the group treated with lower tidal volumesthan in the group treated with traditional tidal volumes (Table 3).The mean (±SD) tidal volumes on days 1 to 3 were6.2± 0.8 and 11.8±0.8 ml per kilogram of predictedbody weight (P<0.001), respectively, and the mean plateaupressures were 25±6 and 33±8 cm of water (P<0.001),respectively. The partial pressure of arterial oxygen was similarin the two groups at all three times, but the positive end-expiratorypressure and fraction of inspired oxygen were significantlyhigher and the ratio of partial pressure of arterial oxygento fraction of inspired oxygen was significantly lower in thegroup treated with lower tidal volumes on days 1 and 3. On day7, positive end-expiratory pressure and the fraction of inspiredoxygen were significantly higher in the group treated with traditionaltidal volumes. The respiratory rate was significantly higherin the group treated with lower tidal volumes on days 1 and3, but minute ventilation was similar in the two groups on thesedays. The partial pressure of arterial carbon dioxide was significantlyhigher on days 1, 3, and 7 and arterial pH was significantlylower on days 1 and 3 in the group treated with lower tidalvolumes.
Table 3. Respiratory Values during the First Seven Days of Treatment in Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome.
The probability of survival and of being discharged home andbreathing without assistance during the first 180 days afterrandomization is shown in Figure 1. The mortality rate was 39.8percent in the group treated with traditional tidal volumesand 31.0 percent in the group treated with lower tidal volumes(P=0.007; 95 percent confidence interval for the differencebetween groups, 2.4 to 15.3 percent). The interaction betweenthe study group and stratification for other experimental interventionswas not significant (P=0.16).
Figure 1. Probability of Survival and of Being Discharged Home and Breathing without Assistance during the First 180 Days after Randomization in Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome.
The status at 180 days or at the end of the study was known for all but nine patients. Data on these 9 patients and on 22 additional patients who were hospitalized at the time of the fourth interim analysis were censored.
Data were available to calculate the static compliance of therespiratory system at base line in 517 patients (Figure 2).The interaction between the quartile of static compliance atbase line and the study group with respect to the risk of deathwas not significant (P=0.49).
Figure 2. Mean (+SE) Mortality Rate among 257 Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome Who Were Assigned to Receive Traditional Tidal Volumes and 260 Such Patients Who Were Assigned to Receive Lower Tidal Volumes, According to the Quartile of Static Compliance of the Respiratory System before Randomization.
The interaction between the study group and the quartile of static compliance at base line was not significant (P=0.49).
The number of ventilator-free days was significantly higherin the group treated with lower tidal volumes than in the grouptreated with traditional tidal volumes (Table 4). The medianduration of ventilation was 8 days among patients in both groupswho were discharged from the hospital after weaning and 10.5and 10 days, respectively, among those who died in the grouptreated with lower tidal volumes and the group treated withtraditional tidal volumes. The number of days without nonpulmonaryorgan or system failure was significantly higher in the grouptreated with lower tidal volumes (P=0.006). This group had moredays without circulatory failure (mean [±SD], 19±10vs. 17±11 days; P=0.004), coagulation failure (21±10vs. 19±11 days, P=0.004), and renal failure (20±11vs. 18±11 days, P=0.005) than did the group treated withtraditional tidal volumes. The incidence of barotrauma afterrandomization was similar in the two groups.
There were no significant differences between groups in thepercentages of days on which neuromuscular-blocking drugs wereused among patients who were discharged home and breathing withoutassistance (6±14 percent in the group treated with lowertidal volumes and 6±15 percent in the group treated withtraditional tidal volumes) or among those who died (20±32percent and 16±28 percent, respectively), or in the percentagesof days on which sedatives were used among patients who weredischarged home and breathing without assistance (65±26percent and 65±24 percent, respectively) or those whodied (73±24 percent and 71±28 percent, respectively).Investigational treatments for acute lung injury and the acuterespiratory distress syndrome that were not included in thefactorial design of the experimental interventions were givento 15 patients in the group treated with lower tidal volumesand 12 patients in the group treated with traditional tidalvolumes. These included prone positioning in 14 and 9 patients,respectively.
The mean log-transformed plasma interleukin-6 values decreasedfrom 2.5±0.7 pg per milliliter on day 0 to 2.3±0.7pg per milliliter on day 3 in the group treated with traditionaltidal volumes and from 2.5±0.7 pg per milliliter to 2.0±0.5pg per milliliter in the group treated with lower tidal volumes.The decrease was greater in the group treated with lower tidalvolumes (P<0.001), and the day 3 plasma interleukin-6 concentrationswere also lower in this group (P=0.002).
Discussion
In this large study of patients with acute lung injury and theacute respiratory distress syndrome, mortality was reduced by22 percent and the number of ventilator-free days was greaterin the group treated with lower tidal volumes than in the grouptreated with traditional tidal volumes. These results are consistentwith the results of experiments in animals9,10,11,12,13,14 andobservational studies in humans.16,17
These benefits occurred despite the higher requirements forpositive end-expiratory pressure and fraction of inspired oxygenand the lower ratio of partial pressure of arterial oxygen tofraction of inspired oxygen in the group treated with lowertidal volumes on days 1 and 3. These results, coupled with thegreater reductions in plasma interleukin-6 concentrations, suggestthat the group treated with lower tidal volumes had less lunginflammation.35 The greater reductions in plasma interleukin-6concentrations may also reflect a reduced systemic inflammatoryresponse to lung injury, which could contribute to the highernumber of days without organ or system failure and the lowermortality in the group treated with lower tidal volumes.15
Several factors could explain the difference in results betweenour trial and other trials of ventilation using lower tidalvolumes in patients with acute lung injury and the acute respiratorydistress syndrome.22,23,24 First, our study had a greater differencein tidal volumes between groups. In one earlier trial, the traditionaltidal volume was equivalent to approximately 12.2 ml per kilogramof predicted body weight and the lower tidal volume was equivalentto approximately 8.1 ml per kilogram of predicted body weight.23In a second study, the traditional and lower tidal volumes wereapproximately 10.3 and 7.1 ml per kilogram of dry body weight(calculated as the measured weight minus the estimated weightgain from fluid retention), respectively.22 In the present trial,measured weight exceeded predicted body weight by approximately20 percent. Assuming a similar difference, and assuming thathalf the difference was dry weight in excess of predicted bodyweight, tidal volumes in the second trial would have been approximately11.3 and 7.8 ml per kilogram of predicted body weight. Therefore,the traditional tidal volume of 11.8 ml per kilogram of predictedbody weight in our study was similar to the values in the previoustwo trials. However, the tidal volume of 6.2 ml per kilogramof predicted body weight in the group receiving lower tidalvolumes was lower than the values in the previous two trials.
If one assumes that measured weights also exceeded predictedbody weights by 20 percent in the earlier trials, the tidalvolumes in the traditional groups were approximately 10.2 and9.4 ml per kilogram of measured weight, respectively, as comparedwith 9.9 ml per kilogram of measured weight in our study. Therefore,the tidal volumes in the traditional groups in each of the threetrials were consistent with traditional recommendations.6,36
A second possible explanation for the different results is thatthe previous trials were designed to detect larger differencesin mortality between groups.22,23,24 Hence, they lacked thestatistical power to demonstrate the moderate effects of lowertidal volumes that we found.
A third difference in the trials was in the treatment of acidosis.Increases in the ventilator rate were required and bicarbonateinfusions were allowed to correct mild-to-moderate acidosisin our study, which resulted in smaller differences in the partialpressure of arterial carbon dioxide and pH between the studygroups than in the previous trials.22,23,24 The deleteriouseffects of acidosis in the previous studies may have counteracteda protective effect of the lower tidal volumes.
In addition to being caused by excessive stretch, lung injurymay also result from repeated opening and closing of small airwaysor from excessive stress at margins between aerated and atelectaticregions of the lungs.37 These types of lung injury may be preventedby the use of a higher positive end-expiratory pressure.10,13,37,38A slightly higher positive end-expiratory pressure was necessaryin the group treated with lower tidal volumes during the firstfew days to maintain arterial oxygenation at a level similarto that in the group treated with traditional tidal volumes,but positive end-expiratory pressure was not increased as ameans of protecting the lungs.
In a recent trial in 53 patients with acute respiratory distresssyndrome, 28-day mortality was significantly lower with a ventilationstrategy that used a higher positive end-expiratory pressurecombined with limited peak inspiratory pressure than with astrategy of traditional ventilation.21 These results suggestthat both increased positive end-expiratory pressure and reducedinspiratory stretch could have beneficial effects.
Stretch-induced lung injury may not occur if lung complianceis not greatly reduced. However, the benefit of ventilationwith a lower tidal volume was independent of the static complianceof the respiratory system at base line, suggesting that thelower tidal volume was advantageous regardless of lung compliance.Variations in chest-wall compliance, which contributes to complianceof the respiratory system and is reduced in many patients withacute lung injury and the acute respiratory distress syndrome,39may have obscured a true interaction between tidal volume andbase-line lung compliance.
Barotrauma occurred with similar frequency in the two studygroups, a finding consistent with the results of other studiesin which the incidence of barotrauma was independent of airwaypressures.22,23,24,40,41 The most common manifestation of barotraumawas pneumothorax, which could have been the result of invasiveprocedures. Pneumothorax is not a sensitive or specific markerof stretch-induced injury with the tidal volumes used in thisstudy.
The similarity in the number of days of ventilator use amongthe survivors in both groups suggests that the higher numberof ventilator-free days in the group treated with lower tidalvolumes resulted from reduced mortality rather than from a reducednumber of days of ventilation among the survivors. However,the comparison of the number of days of ventilator use amongthe survivors could be misleading.42 Some patients who wouldhave survived in the group treated with traditional tidal volumesmight have needed the ventilator on fewer days had they beenin the group treated with lower tidal volumes. This beneficialeffect would have been obscured if prolonged ventilation wasrequired before recovery among patients who otherwise wouldhave died in the group treated with traditional tidal volumes.For similar reasons, it is also difficult to compare the numberof days with organ or system failure among the survivors inthe two study groups.
We found that treatment with a ventilation approach designedto protect the lungs from excessive stretch resulted in improvementsin several important clinical outcomes in patients with acutelung injury and the acute respiratory distress syndrome. Onthe basis of these results, high priority should be given topreventing excessive lung stretch during adjustments to mechanicalventilation, and this lower-tidal-volume protocol should beused in patients with acute lung injury and the acute respiratorydistress syndrome.
Supported by contracts (NO1-HR 46054, 46055, 46056, 46057, 46058,46059, 46060, 46061, 46062, 46063, and 46064) with the NationalHeart, Lung, and Blood Institute.
We are indebted to the intensive care unit nurses, respiratorytherapists, and physicians, as well as our patients and theirfamilies, who supported this trial.
* Members of the Acute Respiratory Distress Syndrome (ARDS) Networkare listed in the Appendix.
See NAPS document no. 05542 for 15 pages of supplementary material.To order, contact NAPS c/o Microfiche Publications, 248 HempsteadTpk., West Hempstead, NY 11552.
Source Information
The writing committee (Roy G. Brower, M.D., Johns Hopkins University, Baltimore; Michael A. Matthay, M.D., University of California, San Francisco; Alan Morris, M.D., LDS Hospital, Salt Lake City; David Schoenfeld, Ph.D., and B. Taylor Thompson, M.D., Massachusetts General Hospital, Boston; and Arthur Wheeler, M.D., Vanderbilt University, Nashville) assumes responsibility for the overall content and integrity of the manuscript. Presented in part at the International Conference of the American Lung Association and the American Thoracic Society, San Diego, Calif., April 26, 1999.
Address reprint requests to Dr. Brower at the Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 600 N. Wolfe St., Baltimore, MD 21287.
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Appendix
In addition to the members of the Writing Committee, the membersof the National Heart, Lung, and Blood Institute ARDS Networkwere as follows: Network Participants: Cleveland Clinic Foundation— H.P. Wiedemann, A.C. Arroliga, C.J. Fisher, Jr., J.J.Komara, Jr., P. Perez-Trepichio; Denver Health Medical Center— P.E. Parsons, R. Wolkin; Denver Veterans Affairs MedicalCenter — C. Welsh; Duke University Medical Center —W.J. Fulkerson, Jr., N. MacIntyre, L. Mallatratt, M. Sebastian,R. McConnell, C. Wilcox, J. Govert; Johns Hopkins University— D. Thompson; LDS Hospital — T. Clemmer, R. Davis,J. Orme, Jr., L. Weaver, C. Grissom, M. Eskelson; McKay–DeeHospital — M. Young, V. Gooder, K. McBride, C. Lawton,J. d'Hulst; MetroHealth Medical Center of Cleveland —J.R. Peerless, C. Smith, J. Brownlee; Rose Medical Center —W. Pluss; San Francisco General Hospital Medical Center —R. Kallet, J.M. Luce; Jefferson Medical College — J. Gottlieb,M. Elmer, A. Girod, P. Park; University of California, San Francisco— B. Daniel, M. Gropper; University of Colorado HealthSciences Center — E. Abraham, F. Piedalue, J. Glodowski,J. Lockrem, R. McIntyre, K. Reid, C. Stevens, D. Kalous; Universityof Maryland — H.J. Silverman, C. Shanholtz, W. Corral;University of Michigan — G.B. Toews, D. Arnoldi, R.H.Bartlett, R. Dechert, C. Watts; University of Pennsylvania —P.N. Lanken, H. Anderson III, B. Finkel, C.W. Hanson; Universityof Utah Hospital — R. Barton, M. Mone; University of Washington–HarborviewMedical Center — L.D. Hudson, C. Lee, G. Carter, R.V.Maier, K.P. Steinberg; Vanderbilt University — G. Bernard,M. Stroud, B. Swindell, L. Stone, L. Collins, S. Mogan; ClinicalCoordinating Center: Massachusetts General Hospital and HarvardMedical School — M. Ancukiewicz, D. Hayden, F. Molay,N. Ringwood, G. Wenzlow, A.S. Kazeroonian; National Heart, Lung,and Blood Institute Staff: D.B. Gail, C.H. Bosken, P. Randall,M. Waclawiw; Data and Safety Monitoring Board: R.G. Spragg,J. Boyett, J. Kelley, K. Leeper, M. Gray Secundy, A. Slutsky;Protocol Review Committee:T.M. Hyers, S.S. Emerson, J.G.N.Garcia, J.J. Marini, S.K. Pingleton, M.D. Shasby, W.J. Sibbald.
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level of 0.05) were designed to allow early termination of the study if the use of lower tidal volumes was found to be either efficacious31 or ineffective.32 
See NAPS document no. 05542 for 15 pages of supplementary material. To order, contact NAPS c/o Microfiche Publications, 248 Hempstead Tpk., West Hempstead, NY 11552. 
