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Original Research: Critical Care |

The Adult Calfactant in Acute Respiratory Distress Syndrome TrialCARDS Adult Trial FREE TO VIEW

Douglas F. Willson, MD; Jonathon D. Truwit, MD, MBA; Mark R. Conaway, PhD; Christine S. Traul, MD; Edmund E. Egan, MD
Author and Funding Information

From the Department of Pediatrics (Dr Willson), Medical College of Virginia, Virginia Commonwealth University, Richmond, VA; Division of Pulmonary and Critical Care Medicine (Dr Truwit), Froedtert & the Medical College of Wisconsin, Milwaukee, WI; Department of Health Evaluation Sciences (Dr Conaway), University of Virginia Health Sciences System, Charlottesville, VA; Department of Pediatrics (Dr Traul), Cleveland Clinic Children’s, Cleveland, OH; Pneuma Pharmaceuticals (Dr Egan), Amherst, NY; and University at Buffalo (Dr Egan), The State University of New York, Buffalo, NY.

CORRESPONDENCE TO: Douglas F. Willson, MD, Department of Pediatrics, Children’s Hospital of Richmond at VCU, Old City Hall, 2nd Fl, Ste 205A, 1001 E Broad St, Richmond, VA 23219; e-mail: dwillson@mcvh-vcu.edu


Drs Willson and Truwit are co-first authors.

FUNDING/SUPPORT: This work was supported by Pneuma Pharmaceuticals (Amherst, NY).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(2):356-364. doi:10.1378/chest.14-1139
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BACKGROUND:  Surfactant has been shown to be dysfunctional in ARDS, and exogenous surfactant has proven effective in many forms of neonatal and pediatric acute lung injury (ALI). In view of the positive results of our studies in children along with evidence that surfactant-associated protein B containing pharmaceutical surfactants might be more effective, we designed a multiinstitutional, randomized, controlled, and masked trial of calfactant, a calf lung surfactant, in adults and children with ALI/ARDS due to direct lung injury.

METHODS:  Adult subjects within 48 h of initiation of mechanical ventilation for direct ARDS were randomized to receive up to three interventions with instilled calfactant vs air placebo. The primary outcome was 90-day all-cause mortality.

RESULTS:  Three hundred seventeen subjects were enrolled, 308 of whom could be evaluated. There were no significant baseline differences between groups. Calfactant administration was not associated with improved survival, lengths of stay, or oxygenation. Calfactant instillation was frequently associated with transient hypoxia and hypotension. The study was stopped at the first interim analysis at the sponsor’s request.

CONCLUSIONS:  Administration of calfactant was not associated with improved oxygenation or longer-term benefits relative to placebo in this randomized, controlled, and masked trial. At present, exogenous surfactant cannot be recommended for routine clinical use in ARDS.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00682500; URL: www.clinicaltrials.gov.

Figures in this Article

ARDS is a highly lethal form of acute respiratory failure that currently has no proven effective therapy beyond mechanical ventilation.1 Despite both animal and human evidence for surfactant dysfunction in ARDS213 and early success in pilot studies,1418 five randomized clinical trials of exogenous surfactant in adults with ARDS failed to demonstrate sustained benefit.1923 The first trial used an aerosol delivery technique and a synthetic surfactant with no apoprotein activity, colfosceril palmitate (Exosurf), and observed no improvement in oxygenation or longer-term outcomes.19 A second trial used instillation of a semisynthetic surfactant with subthreshold levels of surfactant-associated protein B (SP-B), beractant (Survanta), and showed transiently improved oxygenation but no change in outcomes.20 Two more recent trials used an instillation of a synthetic surfactant, lusupultide (Venticute), with a recombinant surfactant-associated protein C (SP-C) but no SP-B protein.22,23 Post hoc analysis of the initial Venticute trial suggested benefit in patients with direct lung injury but in a subsequent trial focused on this patient population, the administration of lusupultide (Venticute) failed to provide benefit. Finally, a trial with a natural porcine surfactant also failed to demonstrate benefit and suggested the instillation technique may have been injurious.21

In contrast, pediatric studies have generally demonstrated benefit.2432 Surfactant replacement is clearly beneficial in surfactant-deficient preterm infants; studies in term infants with pneumonia and meconium aspiration have consistently shown improved oxygenation, shortened duration of ventilation, and better survival with surfactant administration.3337 Outside of the neonatal period, studies in children have been smaller in scale with more diverse patient populations but have consistently shown initial improvement in oxygenation with surfactant administration and at least one study demonstrated improved survival.31 As in the study by Spragg et al,22 the survival benefit in that study appeared confined to those subjects with direct lung injury on post hoc analysis.

In view of the positive results of our studies in children along with evidence that SP-B containing pharmaceutical surfactants might be more effective,3845 we designed a multiinstitutional, randomized, controlled, and blinded study of calfactant, an extract of natural surfactant recovered rinsing calf lungs, in adults and children with acute lung injury (ALI)/ARDS due to direct lung injury. The pediatric arm of the study has already been reported.46 This is a report of the adult arm of the study.

Patient Population

Adult subjects were recruited from July 2008 to July 2010 from the ICUs of 34 medical centers in six countries (e-Appendix 1, e-Tables 1, 2). The study was performed in accordance with the Declaration of Helsinki (1996) and the rules of the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use—Good Clinical Practice Consolidated Guideline. All patients or their legal representatives provided written informed consent; independent ethics committees or institutional review boards at each participating center approved the study protocol. An independent Data and Safety Monitoring Board monitored the study, and interim analyses were planned after the enrollment of 200, 400, and 600 subjects.

Study coordinators at each site screened all admissions. Patients were eligible for the adult arm of the study if they were age 18 to 85 years of age, met the American-European Consensus Conference definition of ALI/ARDS due to direct lung injury (injury originating on the alveolar side of the alveolar capillary membrane), were within 48 h of initiation of mechanical ventilation, did not have significant other organ failure or chronic lung disease, and/or their care was not limited. In the event of a question regarding eligibility, participating investigators were encouraged to contact the study primary investigator or study coordinator on call. All enrolled subjects were also subsequently reviewed by the study Data and Safety Monitoring Board to ascertain eligibility. If arterial blood gas measurements were not obtained, oxygen saturation (Spo2) could be substituted for Pao2 in the entry criteria but an Spo2/Fio2 < 250 (when Spo2 < 97%) was necessary to qualify for study entry. A log of patients who were intubated with ALI/ARDS was maintained, and the primary reason for not enrolling a potentially eligible patient was recorded.

This study was a part of a combined adult and pediatric trial. Many of the participating hospitals admitted both adult and pediatric patients. A single research assistant commonly performed screening in those hospitals, but each hospital had separate adult and pediatric ICUs and separate adult and pediatric primary investigators. Patients received care from adult and pediatric specialists as appropriate to their age and ICU.

Investigators were naive to the randomization scheme. Randomization was performed via the study website in blocks of four. Subjects with an initial Pao2/Fio2 or Spo2/Fio2 < 100 (or an oxygenation index > 30) or who were immune compromised were considered higher risk and were independently randomized to assure an even distribution of more severely ill subjects in both groups.

Pneumasurf

Calfactant (Pneumasurf) is a lung wash extract of natural surfactant from calf lungs that includes phospholipids, neutral lipids, and hydrophobic SP-B and SP-C. It contains no preservatives. It contains 60 mg/mL phospholipids (compared with the neonatal formulation calfactant [Infasurf] which contains 30 mg/mL) and approximately 1 mg% SP-B and SP-C.

Study Intervention

The study intervention consisted of direct instillation of up to three doses of calfactant 12 h apart vs sham treatment with air placebo. The dose was 30 mg of calfactant (60 mg/mL) per centimeter of height delivered in two equal divided aliquots. Subjects were sequentially turned right side down and then left side down during active drug or placebo administration. Fio2 was increased to 1.0 during instillation but ventilator settings were otherwise unchanged unless there were difficulties during the intervention. Blinding was accomplished by having the intervention performed by a nurse and/or respiratory therapist not otherwise involved in the subject’s care and who agreed to not divulge treatment assignment. To qualify for a subsequent dose the subject was required to have at least a 25% improvement in Pao2/Fio2 (or Spo2/Fio2) in the 12 h following the previous dose with no significant adverse effects. BP, heart rate, and Spo2 were continuously monitored and recorded every 5 min for 30 min after the intervention.

Ventilator settings, arterial blood gas results (if performed), and Spo2 and end-tidal CO2 values were recorded at 1, 2, 4, 8, and 12 h after each intervention and daily at approximately 8:00 am for the first 7 days after study enrollment. Daily fluid balance was collected for the first 7 days as previously described. Demographics as well as dates and times of intubation and extubation, and ICU and hospital admission and discharge, were also collected. The duration of ventilation was calculated, with successful extubation defined as 24 h off mechanical ventilation, and was computed as “ventilator-free days (VFDs) at 28 days” (28 − days of ventilation). For subjects undergoing tracheostomy, cessation of ventilation was defined as the time at which positive pressure was discontinued. Subjects dying before hospital discharge were designated as having 0 VFDs.

As a precondition of trial participation all investigators agreed to follow the ARDSNet ventilator and general fluid guidelines (e-Figs 1, 2). These guidelines were reviewed at the study initiation visit, and investigators and study coordinators were given a supply of laminated cards for distribution to their colleagues to facilitate following these guidelines. While no attempt was made to direct the conduct of this aspect of the study, ventilator settings and fluid balances were collected the first 7 days after enrollment to determine whether calfactant and placebo subjects were managed comparably.

Subjects were followed daily until hospital discharge, and all adverse events (AEs) were recorded. All other aspects of care were left to the judgment of the attending physicians. Discharged patients were contacted by phone at 90 days to determine their health status.

Study Outcomes

The primary study outcome was all-cause mortality at 90 days after study entry. Secondary outcomes included VFDs at 90 days, durations of ICU, hospital stay and oxygen use, and changes in oxygenation after the study intervention. AEs were followed throughout the period of hospitalization and assigned a relationship to the study intervention by the primary investigator at each site.

Statistical Methods

Sample size was calculated with the assumption of a 90-day mortality of 25% in the placebo group and 18% mortality in the calfactant group. Enrolling 540 subjects in each group was calculated to yield an 80% power using an α (two sided) of 0.05.

An interim analysis for the primary efficacy end point was performed at the midpoint of accrual for the first study (n = 240 adult subjects) with a planned α = 0.005 based on the method of O’Brien and Fleming.47 If the P value was less than α = 0.005, the trial was to be stopped due to efficacy. In addition, conditional power calculations were performed to provide a probability for futility. If the conditional power was < 0.20, the trial was to be terminated due to futility.

For comparing the placebo and surfactant groups, the χ2 test was used for categorical variables, and the Mann-Whitney nonparametric test was used for continuous variables. Logistic regression was used to compare mortality between groups, adjusting for age, sex, risk strata, immune status, fluid balance, and APACHE (Acute Physiology and Chronic Health Evaluation) score. Repeated measures models were used to compare the groups with respect to oxygenation measures taken 0, 1, 2, 4, 8, and 12 h postintervention.

The planned interim review at 400 subjects (combined children and adults) suggested little likelihood of benefit from calfactant in any of the outcomes at hospital discharge and the study was stopped at the request of the sponsor. Three hundred seventeen adult subjects had been enrolled when the study was stopped. Two of these subjects had consent withdrawn before randomization, and no data for these subjects are available. Seven subjects were deemed ineligible after initial randomization, did not receive treatment, and none of their data are included in the analysis.

In all 97,135 patients were screened, 34,971 (36%) of whom were intubated and on mechanical ventilation. Of the patients who were intubated, 17% met definitional criteria for ALI/ARDS and one-half (2,948) of those were due to direct lung injury (Fig 1). Only 11% of patients with direct lung injury were enrolled in the study. Reasons for exclusion are shown in Figure 1. In total, only 0.5% of screened patients were enrolled in the study.

Figure Jump LinkFigure 1 –  Flowchart for subject entry into the Calfactant in Acute Respiratory Distress Syndrome (CARDS) Trial. ALI = acute lung injury; DNR = do not resuscitate; GCS = Glasgow Coma Scale.Grahic Jump Location

Fifty percent of subjects (154 of 308) received a second intervention, 76 placebo subjects (47%) and 78 surfactant subjects (53%). Only nine subjects (six placebo, three surfactant) received a third intervention.

Baseline characteristics between calfactant and placebo groups are shown in Table 1. There were no significant differences in age, race, sex, diagnostic categories, or the distribution of higher-risk subjects.

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics

Data are given as No. (%) unless otherwise indicated. APACHE = Acute Physiology and Chronic Health Evaluation.

Outcomes

Calfactant therapy did not reduce hospital mortality (calfactant, 27.8% vs placebo, 25.5%). Mortality at 90 days was similar (27.8% in the calfactant group and 26.1% in the placebo group). Secondary outcomes were not different between groups (Table 2). Because of the large number of participating sites relative to the number of subjects it was not possible to compare outcomes across sites. Interestingly, there were 42 adult subjects with ALI/ARDS secondary to H1N1, only eight of whom died (19%).

Table Graphic Jump Location
TABLE 2 ]  Study Outcomes

Data are given as No. (%) unless otherwise indicated. Ventilator-free, ICU-free, and hospital-free days are set to 0 for patients who died. P value for categorical outcomes by χ2 test; P values for continuous outcomes by Wilcoxon test.

Survival was better in subjects deemed to be at lower risk of death (younger, higher initial Pao2/Fio2 ratios, and immune competent). However, no differences in survival between study arms in this subgroup was found (e-Table 3). APACHE score and “first subject enrolled at site” did not significantly impact mortality.

No improvement in oxygenation was observed with calfactant compared with placebo (Fig 2). As arterial blood gas measurements were not required, calculation of Pao2/Fio2 was not possible for all subjects. Changes in Spo2/Fio2, however, followed a similar pattern and the results are not different between the calfactant and placebo groups.

Figure Jump LinkFigure 2 –  A, B, Change in oxygenation after intervention. A, Change in the Pao2 to Fio2 ratio when Pao2 is estimated from SpO2 (using the same formula as in the pediatrics article for SpO2 > 80% and SpO2 < 97%). Time 0: surfactant, n = 135; placebo, n = 147. Time 1 h: surfactant, n = 133; placebo, n = 145. Time 2 h: surfactant, n = 129; placebo, n = 140. Time 4 h: surfactant, n = 134; placebo, n = 142. Time 8 h: surfactant, n = 138; placebo, n = 147. Time 12 h: surfactant, n = 136; placebo, n = 143. B, Change in the ratio of Pao2 to Fio2 when the ratio was available. Time 0: surfactant, n = 82; placebo, n = 88. Time 1 h: surfactant, n = 74; placebo, n = 76. Time 2 h: surfactant, n = 80; placebo, n = 73. Time 4 h: surfactant, n = 87; placebo, n = 76. Time 8 h: surfactant, n = 84; placebo, n = 90. Time 12 h: surfactant, n = 84; placebo, n = 86. SpO2 = oxygen saturation.Grahic Jump Location

Compliance with the ventilator algorithm was not different between surfactant and placebo groups. Peak inspiratory settings > 30 cm H2O were exceeded in 23% and 18% of recorded ventilator parameters in placebo and surfactant subjects (P = .93), respectively. Tidal volumes exceeded 8 mL/kg predicted body weight (PBW) of recorded ventilator settings in 17.6% of patients receiving placebo and 12.5% of subjects receiving surfactant (P = .12).

Seven-day fluid accumulation was not significantly different between surfactant and placebo group subjects but, as was seen in the pediatric subjects, there was a strong relationship between fluid accumulation and mortality (Fig 3). There was a statistically significant association between APACHE score and day 7 fluid balance but the effect was small (r = 0.15; CI, 0.04, 0.26; P = .01). Variation in APACHE score accounted for only 2.3% of the variation in day 7 cumulative fluid balance.

Figure Jump LinkFigure 3 –  The relationship of fluid balance and mortality. Day 7 cumulative balance is in units of L/M2. For patients who died before d 7, the cumulative fluid balance was taken as the last recorded cumulative balance (based on 80 deaths and 223 survivors; fluid balance missing in five subjects). The results indicate that each 1,000 mL of cumulative fluid balance is associated with and increased odds of death by a factor of 1.19.Grahic Jump Location

Eleven thousand fifty-one AEs were reported. One percent of AEs were categorized by the site investigator as possibly related (116), probably related (99), or related (17) to the study intervention. Hypoxia, hypotension, or both during the study intervention were the most common (e-Table 4). Most of these AEs were rated as “mild” but there were seven “severe” AEs felt possibly or probably related to the intervention, six in the surfactant group and one in the placebo group. In the placebo group, one subject had severe hypoxia during the intervention; in the surfactant group, there were three episodes of severe hypoxia, one episode of severe bronchospasm, one subject suffered a cardiac arrest, and one subject developed atrial fibrillation during surfactant administration. All subjects recovered without sequelae.

There was no immediate or longer-term benefit with calfactant administration. This contrasts with our previous pediatric studies3032 but is consistent with the pediatric arm of this trial.46 The study 90-day mortality was 26.1% (placebo) and 27.8% (calfactant), which is consistent with that reported for ALI/ARDS.1,4851 There were no differences between study arms in secondary outcomes, VFDs, or lengths of ICU or hospital stay.

The major correlates of mortality in our study were age, immune status, and severity of the lung injury as judged by the initial Pao2/Fio2 ratio. While age and immune status have well-established impact on mortality, the influence of initial oxygenation has been variably reported. The Berlin Consensus Conference divided patients into “mild, moderate, and severe” based on initial oxygenation disturbance and demonstrated a significant correlation with mortality in subjects from a database composed from previous studies.48 Because of the importance of using a standardized ventilator setting in judging severity of lung injury,52,53 a minimum of 5 cm H2O of positive end-expiratory pressure (PEEP) was required for study entry and investigators agreed to follow the ARDSNet ventilator protocol (including the Fio2/PEEP grid). Our results are consistent with findings in the Berlin Consensus Conference and others.48,5457

It is tempting to speculate that the lack of response in this study could relate to insufficient dosing of surfactant. The initial dose chosen followed the standard approach taken by neonatologists and our previous pediatric studies to replace the estimated surfactant component in the normal lung. Our previous studies generally did not demonstrate benefit with additional dosing when the initial dose was ineffective, although our data are limited to the 29 subjects from our first open label trial.13 The optimal dose and timing of therapeutic surfactant in ALI has not been studied. Given the expense and possibility of adverse effects, we chose not to administer a second dose of surfactant if the first was without clear benefit or was associated with adverse effects.

We chose to accept the Spo2/Fio2 ratio in place of the Pao2/Fio2 ratio when arterial blood gas measurements were not available in deference to the decreasing use of invasive monitoring and arterial blood gases, particularly in pediatric subjects. The relationship of the Spo2/Fio2 to Pao2/Fio2 is essentially linear below an Spo2 of 97%.4 This potentially allowed earlier study entry in the event that arterial catheter placement was delayed, as well as qualification of subjects without such catheters.

Unlike our previous pediatric studies3032 but consistent with the pediatric arm of this study,46 there was no oxygenation benefit with calfactant administration. We chose to forego a recruitment maneuver during instillation in this study because of the limited adult experience with this intervention. This may explain both the lack of improvement in oxygenation along with the significant adverse effects (hypoxia, respiratory acidosis, increased ventilator requirements). Administration of a viscous fluid bolus into the airway might have created an obstruction resulting in transient hypoxia and hypotension, necessitating a higher ventilator pressure until the bolus is cleared. The diminished inspiratory volume (6 mL/kg PBW) may also compromise surfactant distribution. Recruitment maneuvers alone have been reported to transiently improve oxygenation but with little sustained effect.5860 In a previous study, when the intervention was delivered using 10 cm H2O pressure above peak ventilator pressure, both surfactant and placebo subjects demonstrated improved oxygenation but the improvement was sustained only in the surfactant group.32 It is not established whether surfactant distribution is affected by a recruitment maneuver, but Lu et al61 reported increased lung aeration relative to placebo on CT scan when instillation was accompanied by a recruitment maneuver, increasing tidal volume to 12 mL/kg PBW and PEEP by 5 cm H2O for 30 min after instillation.61 In future studies, it would be of interest to investigate surfactant distribution when instilled with and without such a recruitment maneuver.

Two additional possible explanations for the lack of improvement in oxygenation relative to our previous studies include the use of a smaller volume concentrated surfactant (60 mg/mL compared with 30 mg/mL) and the limited use of position changes to facilitate distribution of surfactant. The smaller volume, more concentrated formulation of surfactant was specifically chosen because of our concern that inexperienced clinicians would have difficulty in instilling large volumes of liquid down the endotracheal tube. This may have been a poor decision because neonatal data suggest that larger volumes of more dilute surfactant distribute more homogeneously.5 The decision not to place subjects in four different positions during administration of surfactant as is done commonly with neonates (right side down, head up then down; left side down, head up then down) was a practical one. Maneuvering large adults into four different positions and dividing the administration into four rather than two aliquots was felt to be too cumbersome, particularly in the absence of evidence that this was helpful. What, if any, contribution this made to the lack of improvement seen in this study relative to previous studies is unclear but it is possible that this also compromised the distribution of the administered surfactant.

The large number of AEs documented in the study reflected the severity of illness in the study population; only 1% were felt to be possibly or probably related to the study intervention. Hypoxia and hypotension were most common and may be consequent to the transient airways obstruction and increased intrathoracic pressure with diminished venous return accompanying instillation of a large fluid bolus. It was seen to a lesser extent in the placebo group, however, so simple changes in positioning in these critical patients may have contributed as well. It is also likely that AEs were more commonly reported for the surfactant group because individuals performing the intervention could not actually be blinded. Immediate AEs such as hypoxia, hypotension, or increased ventilator requirements are naturally more likely to be directly attributed to the witnessed instillation of surfactant compared with the placebo instillation of air. These observed adverse effects are well described in neonatal surfactant administration.6,7 The study by Kesecioglu et al21 was stopped early for similar concerns of hypoxia and hypotension during surfactant administration. The lack of reported problems with surfactant administration in the neonatal population suggests there may be a learning curve with this therapy.

Despite the encouragement to use the ARDSNet fluid conservative management strategy, many subjects were net fluid positive over the first 7 days after study entry. The relationship of fluid accumulation and mortality observed in this arm of the study was similar to that seen in our pediatric population.62 On this post hoc analysis, it is not possible to ascertain whether such fluid accumulation is a cause or consequence of the severity of ALI. These subjects were more severely ill as judged by initial APACHE scores but differences in severity of illness accounted for only an estimated 2.3% of the variation in fluid accumulation seen. There was a numerical but nonstatistical difference in fluid accumulation between surfactant and placebo groups (Table 2) not accounted for by differences in surfactant fluid volume, which at most would have been 200 mL. Other studies have demonstrated an antiinflammatory effect of exogenous surfactants8,9 so this in unlikely to relate to a proinflammatory effect of surfactant. Nonetheless, it is clear that the lung inflammation in ALI is associated with capillary leak and, in the presence of pulmonary endothelial injury, lung water increases in direct proportion to venous pressure.63,64 The ARDSNet Fluid and Catheter Treatment Trial (FACTT) demonstrated that a conservative approach to fluid management after stabilization was associated with improved oxygenation, shorter duration of ventilation, and decreased length of ICU stay in adult subjects with ALI.51 Whether more aggressive fluid management would have impacted mortality in our subjects is unknown, and no difference with mortality was seen between the conservative and liberal study arms in FACTT.51

Unlike infantile respiratory distress syndrome, surfactant deficiency is not the primary pathology in ARDS but, rather, an initially functional pulmonary surfactant system becomes “collateral damage” from both the cause of the respiratory failure and the resulting lung injury. The pathophysiology of the respiratory failure in ARDS indicates that the normal alveolar surfactant film is dysfunctional. Animal and our earlier pediatric studies showed exogenous surfactant can improve surfactant function and allow decreased ventilator settings and improve oxygenation.3032,65,66 The lack of oxygenation benefit with surfactant administration in this study may be our use of ineffective instillation timing and techniques rather than a lack of efficacy of exogenous surfactant. Before restoration of surfactant function is abandoned as a potential therapy for ARDS there should be further study to identify the optimal techniques for treatment. We continue to believe that delivery of an inhibition-resistant exogenous surfactant that contains physiologic levels of SP-B and SP-C (distributed evenly throughout the lung, and at a sufficient dose and at a time in the course of ARDS when restoration of surfactant function can reverse the course of the respiratory failure) could be of benefit to these patients.

This study also demonstrates that a large number of patients must be screened to identify an adequate number of study patients. Approximately 17% of patients who were intubated met criteria for ALI/ARDS, somewhat lower than the 26% from the Kings County study by Rubenfeld et al.67 Similar to the Kings County population, about one-half of the patients suffered from “direct” causes of ALI/ARDS. Many of these could not be recruited because of the coexistence of preexisting lung disease (17%), significant other organ dysfunction (13%), or limitations of care/do not resuscitate orders (10%).

Administration of calfactant was not associated with improved oxygenation or longer-term benefits relative to placebo in this randomized, controlled, blinded trial. Surfactant instillation was associated with significant but transient adverse effects, primarily hypoxia and hypotension. Further studies of exogenous surfactant administration should consider using recruitment maneuvers during instillation. At present, exogenous surfactant cannot be recommended for routine clinical use in ARDS.

Author contributions: D. F. W. and J. D. T. were study co-chairs and take responsibility for the integrity of the work as a whole, from inception to published article. D. F. W. and J. D. T. contributed to the conceptualization and design of the study, composed the first drafts of the manuscript, and participated in manuscript revisions; M. R. C. contributed to the conceptualization and design of the study, was responsible for the statistical design and analysis of study results, and participated in manuscript revisions; C. S. T. contributed to the conceptualization and design of the study, coordinated data collection and oversaw study conduct at all study sites, and participated in manuscript revisions; and E. E. E. contributed to the conceptualization and design of the study, was responsible for overall study coordination and interaction with the clinical research organization, and participated in manuscript revisions.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Egan is CEO of Pneuma Pharmaceuticals. The University of Virginia received compensation from Pneuma Pharmaceuticals to support in part the salaries of Drs Willson, Truwit, Conaway, and Traul. Collaborating investigators were paid compensation for subjects successfully enrolled in the study as well as support for the work of their research assistants.

Role of sponsors: The sponsor approved the design of the study but did not participate in data collection or analysis. The sponsor reviewed and made suggestions regarding the manuscript but by prior agreement the writing and content of the final manuscript was the purview of the primary investigators Drs Willson and Truwit.

Additional information: The e-Appendix, e-Figures, and e-Tables can be found in the Supplemental Materials section of the online article.

AE

adverse event

ALI

acute lung injury

APACHE

Acute Physiology and Chronic Health Evaluation

PBW

predicted body weight

PEEP

positive end-expiratory pressure

SP-B

surfactant-associated protein B

SP-C

surfactant-associated protein C

Spo2

oxygen saturation

VFD

ventilator-free day

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Wiswell TE, Smith RM, Katz LB, et al. Bronchopulmonary segmental lavage with Surfaxin (KL(4)-surfactant) for acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;160(4):1188-1195. [CrossRef] [PubMed]
 
Anzueto A, Baughman RP, Guntupalli KK, et al; Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med. 1996;334(22):1417-1421. [CrossRef] [PubMed]
 
Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155(4):1309-1315. [CrossRef] [PubMed]
 
Kesecioglu J, Beale R, Stewart TE, et al. Exogenous natural surfactant for treatment of acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2009;180(10):989-994. [CrossRef] [PubMed]
 
Spragg RG, Lewis JF, Walmrath H-D, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med. 2004;351(9):884-892. [CrossRef] [PubMed]
 
Spragg RG, Taut FJH, Lewis JF, et al. Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury. Am J Respir Crit Care Med. 2011;183(8):1055-1061. [CrossRef] [PubMed]
 
Hermon MM, Golej J, Burda G, et al. Surfactant therapy in infants and children: three years experience in a pediatric intensive care unit. Shock. 2002;17(4):247-251. [CrossRef] [PubMed]
 
Herting E, Möller O, Schiffmann JH, Robertson B. Surfactant improves oxygenation in infants and children with pneumonia and acute respiratory distress syndrome. Acta Paediatr. 2002;91(11):1174-1178. [CrossRef] [PubMed]
 
López-Herce J, de Lucas N, Carrillo A, Bustinza A, Moral R. Surfactant treatment for acute respiratory distress syndrome. Arch Dis Child. 1999;80(3):248-252. [CrossRef] [PubMed]
 
Luchetti M, Casiraghi G, Valsecchi R, Galassini E, Marraro G. Porcine-derived surfactant treatment of severe bronchiolitis. Acta Anaesthesiol Scand. 1998;42(7):805-810. [CrossRef] [PubMed]
 
Luchetti M, Ferrero F, Gallini C, et al. Multicenter, randomized, controlled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure. Pediatr Crit Care Med. 2002;3(3):261-268. [CrossRef] [PubMed]
 
Möller JC, Schaible T, Roll C, et al; Surfactant ARDS Study Group. Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study. Intensive Care Med. 2003;29(3):437-446. [PubMed]
 
Willson DF, Jiao JH, Bauman LA, et al. Calf’s lung surfactant extract in acute hypoxemic respiratory failure in children. Crit Care Med. 1996;24(8):1316-1322. [CrossRef] [PubMed]
 
Willson DF, Thomas NJ, Markovitz BP, et al; Pediatric Acute Lung Injury and Sepsis Investigators. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA. 2005;293(4):470-476. [CrossRef] [PubMed]
 
Willson DF, Zaritsky A, Bauman LA, et al; Members of the Mid-Atlantic Pediatric Critical Care Network. Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure. Crit Care Med. 1999;27(1):188-195. [CrossRef] [PubMed]
 
Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics. 1991;87(1):101-107. [PubMed]
 
Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics. 1996;97(1):48-52. [PubMed]
 
Khammash H, Perlman M, Wojtulewicz J, Dunn M. Surfactant therapy in full-term neonates with severe respiratory failure. Pediatrics. 1993;92(1):135-139. [PubMed]
 
Lotze A, Knight GR, Martin GR, et al. Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation. J Pediatr. 1993;122(2):261-268. [CrossRef] [PubMed]
 
Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH; Survanta in Term Infants Study Group. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. J Pediatr. 1998;132(1):40-47. [CrossRef] [PubMed]
 
Clark JC, Wert SE, Bachurski CJ, et al. Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. Proc Natl Acad Sci U S A. 1995;92(17):7794-7798. [CrossRef] [PubMed]
 
Ikegami M, Whitsett JA, Martis PC, Weaver TE. Reversibility of lung inflammation caused by SP-B deficiency. Am J Physiol Lung Cell Mol Physiol. 2005;289(6):L962-L970. [CrossRef] [PubMed]
 
Mizuno K, Ikegami M, Chen CM, Ueda T, Jobe AH. Surfactant protein-B supplementation improves in vivo function of a modified natural surfactant. Pediatr Res. 1995;37(3):271-276. [CrossRef] [PubMed]
 
Oosterlaken-Dijksterhuis MA, van Eijk M, van Golde LM, Haagsman HP. Lipid mixing is mediated by the hydrophobic surfactant protein SP-B but not by SP-C. Biochim Biophys Acta. 1992;1110(1):45-50. [CrossRef] [PubMed]
 
Revak SD, Merritt TA, Degryse E, et al. Use of human surfactant low molecular weight apoproteins in the reconstitution of surfactant biologic activity. J Clin Invest. 1988;81(3):826-833. [CrossRef] [PubMed]
 
Seeger W, Günther A, Thede C. Differential sensitivity to fibrinogen inhibition of SP-C- vs. SP-B-based surfactants. Am J Physiol. 1992;262(3 pt 1):L286-L291. [PubMed]
 
Wang Z, Baatz JE, Holm BA, Notter RH. Content-dependent activity of lung surfactant protein B in mixtures with lipids. Am J Physiol Lung Cell Mol Physiol. 2002;283(5):L897-L906. [CrossRef] [PubMed]
 
Wang Z, Gurel O, Baatz JE, Notter RH. Differential activity and lack of synergy of lung surfactant proteins SP-B and SP-C in interactions with phospholipids. J Lipid Res. 1996;37(8):1749-1760. [PubMed]
 
Willson DF, Thomas NJ, Tamburro R, et al; Pediatric Acute Lung and Sepsis Investigators Network. Pediatric calfactant in acute respiratory distress syndrome trial. Pediatr Crit Care Med. 2013;14(7):657-665. [CrossRef] [PubMed]
 
O’Brien PC, Flemming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:153-162.
 
Brower RG, Lanken PN, MacIntyre N, et al; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327-336. [CrossRef] [PubMed]
 
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network;Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307(8):795-803. [CrossRef] [PubMed]
 
Steinberg KP, Hudson LD, Goodman RB, et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671-1684. [CrossRef] [PubMed]
 
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network;Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-2575. [CrossRef] [PubMed]
 
Ferguson ND, Kacmarek RM, Chiche JD, et al. Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial. Intensive Care Med. 2004;30(6):1111-1116. [CrossRef] [PubMed]
 
Villar J, Pérez-Méndez L, López J, et al; HELP Network. An early PEEP/FIO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007;176(8):795-804. [CrossRef] [PubMed]
 
ARDS Definition Task Force;Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-2533. [PubMed]
 
Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010;303(9):865-873. [CrossRef] [PubMed]
 
Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. Circ Arrhythm Electrophysiol. 2013;6(5):843-850. [CrossRef] [PubMed]
 
Lu S, Cai S, Ou C, Zhao H. Establishment and evaluation of a simplified evaluation system of acute respiratory distress syndrome. Yonsei Med J. 2013;54(4):935-941. [CrossRef] [PubMed]
 
Brower RG, Morris A, MacIntyre N, et al; ARDS Clinical Trials Network, National Heart, Lung, and Blood Institute, National Institutes of Health. Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure [published correction appears inCrit Care Med. 2004;32(3):907]. Crit Care Med. 2003;31(11):2592-2597. [CrossRef] [PubMed]
 
Fan E, Wilcox ME, Brower RG, et al. Recruitment maneuvers for acute lung injury: a systematic review. Am J Respir Crit Care Med. 2008;178(11):1156-1163. [CrossRef] [PubMed]
 
Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006;354(17):1775-1786. [CrossRef] [PubMed]
 
Lu Q, Zhang M, Girardi C, Bouhemad B, Kesecioglu J, Rouby JJ. Computed tomography assessment of exogenous surfactant-induced lung reaeration in patients with acute lung injury. Crit Care. 2010;14(4):R135. [CrossRef] [PubMed]
 
Willson DF, Thomas NJ, Tamburro R, et al. The relationship of fluid administration to outcome in the Pediatric Calfactant in Acute Respiratory Distress Syndrome (CARDS) Trial. Pediatr Crit Care Med. 2013;14(7):666-672. [CrossRef] [PubMed]
 
Sibbald WJ, Short AK, Warshawski FJ, Cunningham DG, Cheung H. Thermal dye measurements of extravascular lung water in critically ill patients. Intravascular Starling forces and extravascular lung water in the adult respiratory distress syndrome. Chest. 1985;87(5):585-592. [CrossRef] [PubMed]
 
Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334-1349. [CrossRef] [PubMed]
 
Notter RH. Lung Surfactants: Basic Science and Clinical Applications. New York, NY: Marcel Dekker Inc; 2000.
 
Wang ZHB, Matalon S, Notter RH. Lung Injury: Mechanisms, Pathophysiology, and Therapy. Boca Raton, FL: Taylor Francis Group, Inc; 2005:297-352.
 
Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):1685-1693. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Flowchart for subject entry into the Calfactant in Acute Respiratory Distress Syndrome (CARDS) Trial. ALI = acute lung injury; DNR = do not resuscitate; GCS = Glasgow Coma Scale.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, B, Change in oxygenation after intervention. A, Change in the Pao2 to Fio2 ratio when Pao2 is estimated from SpO2 (using the same formula as in the pediatrics article for SpO2 > 80% and SpO2 < 97%). Time 0: surfactant, n = 135; placebo, n = 147. Time 1 h: surfactant, n = 133; placebo, n = 145. Time 2 h: surfactant, n = 129; placebo, n = 140. Time 4 h: surfactant, n = 134; placebo, n = 142. Time 8 h: surfactant, n = 138; placebo, n = 147. Time 12 h: surfactant, n = 136; placebo, n = 143. B, Change in the ratio of Pao2 to Fio2 when the ratio was available. Time 0: surfactant, n = 82; placebo, n = 88. Time 1 h: surfactant, n = 74; placebo, n = 76. Time 2 h: surfactant, n = 80; placebo, n = 73. Time 4 h: surfactant, n = 87; placebo, n = 76. Time 8 h: surfactant, n = 84; placebo, n = 90. Time 12 h: surfactant, n = 84; placebo, n = 86. SpO2 = oxygen saturation.Grahic Jump Location
Figure Jump LinkFigure 3 –  The relationship of fluid balance and mortality. Day 7 cumulative balance is in units of L/M2. For patients who died before d 7, the cumulative fluid balance was taken as the last recorded cumulative balance (based on 80 deaths and 223 survivors; fluid balance missing in five subjects). The results indicate that each 1,000 mL of cumulative fluid balance is associated with and increased odds of death by a factor of 1.19.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics

Data are given as No. (%) unless otherwise indicated. APACHE = Acute Physiology and Chronic Health Evaluation.

Table Graphic Jump Location
TABLE 2 ]  Study Outcomes

Data are given as No. (%) unless otherwise indicated. Ventilator-free, ICU-free, and hospital-free days are set to 0 for patients who died. P value for categorical outcomes by χ2 test; P values for continuous outcomes by Wilcoxon test.

References

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Günther A, Siebert C, Schmidt R, et al. Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema. Am J Respir Crit Care Med. 1996;153(1):176-184. [CrossRef] [PubMed]
 
Holm BA, Enhorning G, Notter RH. A biophysical mechanism by which plasma proteins inhibit lung surfactant activity. Chem Phys Lipids. 1988;49(1-2):49-55. [CrossRef] [PubMed]
 
Holm BA, Notter RH. Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity. J Appl Physiol (1985). 1987;63(4):1434-1442. [PubMed]
 
Holm BA, Notter RH, Finkelstein JN. Surface property changes from interactions of albumin with natural lung surfactant and extracted lung lipids. Chem Phys Lipids. 1985;38(3):287-298. [CrossRef] [PubMed]
 
Holm BA, Wang Z, Notter RH. Multiple mechanisms of lung surfactant inhibition. Pediatr Res. 1999;46(1):85-93. [CrossRef] [PubMed]
 
Lewis JF, Ikegami M, Jobe AH. Altered surfactant function and metabolism in rabbits with acute lung injury. J Appl Physiol (1985). 1990;69(6):2303-2310. [PubMed]
 
Pison U, Seeger W, Buchhorn R, et al. Surfactant abnormalities in patients with respiratory failure after multiple trauma. Am Rev Respir Dis. 1989;140(4):1033-1039. [CrossRef] [PubMed]
 
Seeger W, Pison U, Buchhorn R, Obertacke U, Joka T. Surfactant abnormalities and adult respiratory failure. Lung. 1990;168(suppl):891-902. [CrossRef] [PubMed]
 
Seeger W, Stöhr G, Wolf HR, Neuhof H. Alteration of surfactant function due to protein leakage: special interaction with fibrin monomer. J Appl Physiol (1985). 1985;58(2):326-338. [PubMed]
 
Veldhuizen RA, McCaig LA, Akino T, Lewis JF. Pulmonary surfactant subfractions in patients with the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995;152(6 pt 1):1867-1871. [CrossRef] [PubMed]
 
Seeger W, Grube C, Günther A, Schmidt R. Surfactant inhibition by plasma proteins: differential sensitivity of various surfactant preparations. Eur Respir J. 1993;6(7):971-977. [PubMed]
 
Günther A, Schmidt R, Harodt J, et al. Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on biophysical and biochemical surfactant properties. Eur Respir J. 2002;19(5):797-804. [CrossRef] [PubMed]
 
Spragg RG, Gilliard N, Richman P, et al. Acute effects of a single dose of porcine surfactant on patients with the adult respiratory distress syndrome. Chest. 1994;105(1):195-202. [CrossRef] [PubMed]
 
Walmrath D, Grimminger F, Pappert D, et al. Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on gas exchange and haemodynamics. Eur Respir J. 2002;19(5):805-810. [CrossRef] [PubMed]
 
Walmrath D, Günther A, Ghofrani HA, et al. Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis. Am J Respir Crit Care Med. 1996;154(1):57-62. [CrossRef] [PubMed]
 
Wiswell TE, Smith RM, Katz LB, et al. Bronchopulmonary segmental lavage with Surfaxin (KL(4)-surfactant) for acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;160(4):1188-1195. [CrossRef] [PubMed]
 
Anzueto A, Baughman RP, Guntupalli KK, et al; Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med. 1996;334(22):1417-1421. [CrossRef] [PubMed]
 
Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155(4):1309-1315. [CrossRef] [PubMed]
 
Kesecioglu J, Beale R, Stewart TE, et al. Exogenous natural surfactant for treatment of acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2009;180(10):989-994. [CrossRef] [PubMed]
 
Spragg RG, Lewis JF, Walmrath H-D, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med. 2004;351(9):884-892. [CrossRef] [PubMed]
 
Spragg RG, Taut FJH, Lewis JF, et al. Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury. Am J Respir Crit Care Med. 2011;183(8):1055-1061. [CrossRef] [PubMed]
 
Hermon MM, Golej J, Burda G, et al. Surfactant therapy in infants and children: three years experience in a pediatric intensive care unit. Shock. 2002;17(4):247-251. [CrossRef] [PubMed]
 
Herting E, Möller O, Schiffmann JH, Robertson B. Surfactant improves oxygenation in infants and children with pneumonia and acute respiratory distress syndrome. Acta Paediatr. 2002;91(11):1174-1178. [CrossRef] [PubMed]
 
López-Herce J, de Lucas N, Carrillo A, Bustinza A, Moral R. Surfactant treatment for acute respiratory distress syndrome. Arch Dis Child. 1999;80(3):248-252. [CrossRef] [PubMed]
 
Luchetti M, Casiraghi G, Valsecchi R, Galassini E, Marraro G. Porcine-derived surfactant treatment of severe bronchiolitis. Acta Anaesthesiol Scand. 1998;42(7):805-810. [CrossRef] [PubMed]
 
Luchetti M, Ferrero F, Gallini C, et al. Multicenter, randomized, controlled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure. Pediatr Crit Care Med. 2002;3(3):261-268. [CrossRef] [PubMed]
 
Möller JC, Schaible T, Roll C, et al; Surfactant ARDS Study Group. Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study. Intensive Care Med. 2003;29(3):437-446. [PubMed]
 
Willson DF, Jiao JH, Bauman LA, et al. Calf’s lung surfactant extract in acute hypoxemic respiratory failure in children. Crit Care Med. 1996;24(8):1316-1322. [CrossRef] [PubMed]
 
Willson DF, Thomas NJ, Markovitz BP, et al; Pediatric Acute Lung Injury and Sepsis Investigators. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA. 2005;293(4):470-476. [CrossRef] [PubMed]
 
Willson DF, Zaritsky A, Bauman LA, et al; Members of the Mid-Atlantic Pediatric Critical Care Network. Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure. Crit Care Med. 1999;27(1):188-195. [CrossRef] [PubMed]
 
Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics. 1991;87(1):101-107. [PubMed]
 
Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics. 1996;97(1):48-52. [PubMed]
 
Khammash H, Perlman M, Wojtulewicz J, Dunn M. Surfactant therapy in full-term neonates with severe respiratory failure. Pediatrics. 1993;92(1):135-139. [PubMed]
 
Lotze A, Knight GR, Martin GR, et al. Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation. J Pediatr. 1993;122(2):261-268. [CrossRef] [PubMed]
 
Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH; Survanta in Term Infants Study Group. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. J Pediatr. 1998;132(1):40-47. [CrossRef] [PubMed]
 
Clark JC, Wert SE, Bachurski CJ, et al. Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. Proc Natl Acad Sci U S A. 1995;92(17):7794-7798. [CrossRef] [PubMed]
 
Ikegami M, Whitsett JA, Martis PC, Weaver TE. Reversibility of lung inflammation caused by SP-B deficiency. Am J Physiol Lung Cell Mol Physiol. 2005;289(6):L962-L970. [CrossRef] [PubMed]
 
Mizuno K, Ikegami M, Chen CM, Ueda T, Jobe AH. Surfactant protein-B supplementation improves in vivo function of a modified natural surfactant. Pediatr Res. 1995;37(3):271-276. [CrossRef] [PubMed]
 
Oosterlaken-Dijksterhuis MA, van Eijk M, van Golde LM, Haagsman HP. Lipid mixing is mediated by the hydrophobic surfactant protein SP-B but not by SP-C. Biochim Biophys Acta. 1992;1110(1):45-50. [CrossRef] [PubMed]
 
Revak SD, Merritt TA, Degryse E, et al. Use of human surfactant low molecular weight apoproteins in the reconstitution of surfactant biologic activity. J Clin Invest. 1988;81(3):826-833. [CrossRef] [PubMed]
 
Seeger W, Günther A, Thede C. Differential sensitivity to fibrinogen inhibition of SP-C- vs. SP-B-based surfactants. Am J Physiol. 1992;262(3 pt 1):L286-L291. [PubMed]
 
Wang Z, Baatz JE, Holm BA, Notter RH. Content-dependent activity of lung surfactant protein B in mixtures with lipids. Am J Physiol Lung Cell Mol Physiol. 2002;283(5):L897-L906. [CrossRef] [PubMed]
 
Wang Z, Gurel O, Baatz JE, Notter RH. Differential activity and lack of synergy of lung surfactant proteins SP-B and SP-C in interactions with phospholipids. J Lipid Res. 1996;37(8):1749-1760. [PubMed]
 
Willson DF, Thomas NJ, Tamburro R, et al; Pediatric Acute Lung and Sepsis Investigators Network. Pediatric calfactant in acute respiratory distress syndrome trial. Pediatr Crit Care Med. 2013;14(7):657-665. [CrossRef] [PubMed]
 
O’Brien PC, Flemming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:153-162.
 
Brower RG, Lanken PN, MacIntyre N, et al; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327-336. [CrossRef] [PubMed]
 
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network;Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307(8):795-803. [CrossRef] [PubMed]
 
Steinberg KP, Hudson LD, Goodman RB, et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671-1684. [CrossRef] [PubMed]
 
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network;Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-2575. [CrossRef] [PubMed]
 
Ferguson ND, Kacmarek RM, Chiche JD, et al. Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial. Intensive Care Med. 2004;30(6):1111-1116. [CrossRef] [PubMed]
 
Villar J, Pérez-Méndez L, López J, et al; HELP Network. An early PEEP/FIO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007;176(8):795-804. [CrossRef] [PubMed]
 
ARDS Definition Task Force;Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-2533. [PubMed]
 
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