for review only - american thoracic society€¦ · for review only 7 and ventilation; and the...

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Recombinant Surfactant Protein C Based Surfactant for Patients with

Severe Direct Lung Injury

Roger G. Spragg MD1, Friedemann J. H. Taut MD2, James F. Lewis MD3, Peter

Schenk MD4, Clemens Ruppert PhD5, Nathan Dean MD6, Kenneth Krell MD7,

Andreas Karabinis MD8 , Andreas Günther MD5

1Division of Pulmonary and Critical Care Medicine, University of California San

Diego and San Diego Veterans Affairs Healthcare System, San Diego, CA, USA,

2Nycomed GmbH, Konstanz, Germany; 3St Joseph’s Health Center, University

of Western Ontario, London, Ontario, Canada; 4Department of Internal Medicine

IV, General Hospital Vienna, Vienna, Austria; 5Department of Pulmonary and

Critical Care, Justus-Liebig-University, Giessen, Germany; 6Intermountain

Medical Center and the University of Utah, Salt Lake City, UT, USA; 7Eastern

Idaho Medical Center, Idaho Falls, ID, USA; 8General Hospital of Athens, Athens,

Greece.

Contribution: Drs. Spragg and Taut contributed equally to the study and share

first authorship.

Corresponding author:

Roger G. Spragg, MD Email: [email protected]

VA Medical Center – 151C Tel: +1 858-755-1813

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3350 La Jolla Village Drive Fax: +1 858-642-3081

San Diego, CA, 92161 USA

Reprint requests:

Friedemann Taut, MD

Nycomed GmbH

Byk-Gulden-Str. 2

78467 Konstanz, Germany

Funding: The study in this report was sponsored by Nycomed GmbH, Konstanz,

Germany

Running head: rSP-C Surfactant for Severe Direct Lung Injury

Descriptor: 4.4 - Clinical Trials in Critical Care Medicine

Word count for body of manuscript: 3,227

At a Glance Commentary:

Scientific Knowledge on the Subject: Prior studies have suggested that

treatment with exogenous surfactant of patients with severe direct lung injury

may be beneficial.

What This Study Adds to the Field: As performed in this prospective, blinded,

randomized study of 843 patients, delivery of a recombinant surfactant protein C

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based surfactant provided no benefit to patients with severe direct lung injury.

Shearing of this surfactant may have contributed to impaired clinical

effectiveness.

This article has an online data supplement, which is accessible from this

issue's table of content online at www.atsjournals.org

Authors’ contributions:

Conception and design: RGS, FHT, JFL, AG. Data acquisition: PS, ND, KK, AK,

AG. Analysis and interpretation: RGS, FHT, JFL, CL, AG. Drafting the

manuscript for important intellectual content: RGS, FHT, AG.

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Abstract:

Rationale: Patients with acute lung injury have impaired function of the lung

surfactant system. Prior clinical trials have shown that treatment with exogenous

recombinant SP-C (rSP-C) based surfactant results in improvement in blood

oxygenation and have suggested that treatment of patients with severe direct

lung injury may decrease mortality.

Objectives: Determine the clinical benefit of administering an rSP-C based

synthetic surfactant to patients with severe direct lung injury due to pneumonia or

aspiration.

Methods: A prospective randomized blinded study was performed at 161

centers in 22 countries. Patients were randomly allocated to receive usual care

plus up to 8 doses of rSP-C surfactant administered over 96 hours (n = 419) or

only usual care (n = 424).

Measurements and Main Results: Mortality to 28 days after treatment, the

requirement for mechanical ventilation, and the number of non-pulmonary organ

failure free days were not different between study groups. In contrast to prior

studies, there was no improvement in oxygenation in patients receiving

surfactant compared to the usual care group. Investigation of the possible

reasons underlying the lack of efficacy suggested a partial inactivation of rSP-C

surfactant caused by a step of the resuspension process that was introduced

with this study.

Conclusions: In this study, rSP-C based surfactant was of no clinical benefit to

patients with severe direct lung injury. The unexpected lack of improvement in

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oxygenation, coupled with the results of in vitro tests, suggest that the

administered suspension may have had insufficient surface activity to achieve

clinical benefit.

Abstract word count: 248

Key Words: Respiratory Distress Syndrome, Adult; Acute Lung Injury; Clinical

Trial

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Introduction

Approximately 200,000 patients in the United States develop acute lung injury

(ALI) each year (1), with a mortality in the range of 30-40%. These patients have

a profound loss of functional lung surfactant. As reviewed elsewhere (2), this

loss occurs for a variety of reasons, results in features characteristic of ALI (3),

and thus may contribute to the pathophysiology of that syndrome.

Rationale for treatment of ALI patients with exogenous surfactant includes

supportive observations in animal models, improvement in pulmonary gas

exchange in most clinical trials of surfactant replacement, and decreased

mortality in pediatric patients with ALI treated with exogenous surfactant (2,4).

However, mortality of adults with ALI has been unaffected by treatment with

exogenous surfactant(5), although post-hoc subgroup analysis showed that

adults with severe direct lung injury (from pneumonia or aspiration) might benefit

(6). This benefit could result, in part, through reduction of mechanical stress on

components of the lung parenchyma and reduction of ventilator-induced lung

injury (7).

Improvement in blood oxygenation occurs in almost all trials in which natural

surfactants(4,8-12) or synthetic surfactants(13,14) have been administered. The

exceptions are trials of Exosurf, a non-protein containing formulation (15,16), and

of HL-10 surfactant(17).

The synthetic surfactant containing recombinant surfactant protein C (rSP-C),

phospholipids and palmitic acid (rSP-C surfactant, Nycomed GmbH, Konstanz,

Germany) has excellent surface activity and markedly improves gas exchange in

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animal models of lung injury(18-20). All patient groups receiving rSP-C

surfactant have had had improvement in blood oxygenation(6) . We report here

a phase III prospective, randomized, parallel-group, double-blind, controlled

multinational study to test whether rSP-C surfactant treatment of patients with

severe direct lung injury reduces mortality.

Methods

Study participants and setting

Patients between 12 and 85 years of age with severe impairment of gas

exchange (PaO2/FiO2 ≤ 170 mmHg) due to aspiration of gastric contents or

pneumonia were eligible for study. Patients were not eligible if they had

evidence of a source of infection or sepsis outside the lung. Complete diagnostic

criteria and inclusion and exclusion criteria are listed in the Online Supplement.

Patients were recruited during the period November 2003 to March 2008 from

the intensive care units of 161 medical centers in 22 countries. The study,

registered with ClinicalTrials.gov identifier NCT00074906, was performed in

accordance with the declaration of Helsinki (1996), the rules of ICH GCP

Consolidated Guideline E6, CPMP/ICH/135/95 and national legal stipulations. All

patients or their legal representatives provided written informed consent, and the

study protocol was approved by independent ethics committees or institutional

review boards at each center. The study was monitored by an independent Data

and Safety Monitoring Board.

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Patients were pre-screened at each study site; the methods of pre-screening

were not stipulated. Final screening was performed by a Scientific Enrollment

Coordinating Board (SECB), composed of an international panel of trained

intensivists, to which investigators submitted a pre-screened study patient via

internet or telephone (21). A member of the SECB then discussed the patient

with the site investigator and approved or rejected the patient for enrollment

based on compliance with study inclusion and exclusion criteria. Patients could

be approved conditionally, contingent upon meeting study criteria during the

defined protocol enrollment period. Approved patients for whom consent had

been obtained were enrolled in a two hour baseline observation period during

which blood samples and clinical observations were obtained. At the conclusion

of this baseline period, patients who continued to meet inclusion criteria were

randomized to a usual care group or a usual care plus surfactant treatment group

(Figure 1). Although investigators were explicitly advised to use the ARDS

Network lung protective ventilation strategy (7), patients were not required to

have bilateral pulmonary opacities on the chest radiograph, and thus not all

patients fulfilled the criteria for ARDS.

Study intervention

Patients who were approved by the SECB were immediately randomized, using a

computer-based approach (22) on a 1:1 basis to one of the two groups.

Randomization was stratified by center and concealed from the investigators.

After collection of data during a 2 hour baseline period, patients were treated with

1 ml rSP-C surfactant per kg lean body weight (each ml containing 1 mg rSP-C

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and 50 mg phospholipids) exactly as described previously (14). Blinding was

accomplished using a weighted blinding bag as previously described (14).

Patients received a maximum of 7 additional administrations at 6, 12, 24, 36, 48,

72, and 96 hours after the initial treatment provided they remained intubated and

mechanically ventilated with a positive end expiratory pressure ≥ 5 cm H2O, and

with a PaO2/FiO2 value in the range of 60-170 mmHg.

Prior to each administration, the dry rSP-C surfactant powder was reconstituted

with sterile saline, drawn into a syringe, and, in a step not used in prior trials,

passed forcefully six times through a Luer lock adapter with a 3.8 mm internal

diameter orifice to a second syringe so that shear forces generated in the narrow

channel would augment suspension of the surfactant. Non-sheared as well as

sheared rSP-C surfactant had been demonstrated by the manufacturer to have a

surface pressure below 40mN/m measured in vitro at a concentration of 25 mg

phospholipids/ml, a surface age of 0.1 sec, at 37°C in a maximum bubble

pressure tensiometer of the manufacturer’s design. In vivo testing using the

lavaged rat lung (23) showed that non-sheared as well as sheared rSP-C

surfactant, at a concentration of 100 mg phospholipid/kg, restored the PaO2 to

not less than 400 mm Hg 120 min after administration.

Study objectives

The primary study outcome variable was the percentage of patients alive at day

28. Secondary outcome variables of major interest included: ventilator free days

(VFD) at day 28 (assigning 0 VFD to non-survivors); measures of oxygenation

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and ventilation; and the number of non-pulmonary organ failure free days (the

definitions of organ failure are provided in the Online Supplement).

Sample size was calculated based on expected 28 day mortality. A group

sequential design with two interim and one final analysis was planned, and a

one-sided test procedure was chosen with α=0.025 and the power set to 80%.

Based on results of the prior pooled analysis (6), we estimated an overall

mortality difference of 7.6% (25.8% vs. 33.4%). A sample size of 1132 patients

was needed for 80% power based on the chi-squared test. Since a group-

sequential design was chosen, the sample size was slightly higher, and final

plans called for randomization of 1200 patients.

As a result of a first planned interim analysis after enrollment of 400 patients, the

study Data and Safety Monitoring Committee recommended continuation of the

study. Following a second planned interim analysis after enrollment of 800

patients, the Committee recommended termination of the study for futility.

Studies of surfactant activity performed subsequent to the clinical trial

Due to the unexpected observation of complete lack of effect, including lack of

effect on blood oxygenation, further scrutiny was applied to all study related

procedures after termination of the study. To examine the effect of the shearing

maneuver on rSP-C surfactant, surface tension lowering activity was evaluated

using a pulsating bubble surfactometer as reported previously (24). For this

purpose, rSP-C surfactant from a batch used in the clinical trial was resuspended

either by gentle swirling (as in prior clinical studies) or using the protocol

described for this study in which shearing occurred during passage through a

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Luer-Lock adaptor. Because site investigators might introduce small amounts of

air into the syringe when aspirating surfactant from the vial in which it is initially

resuspended, shearing was performed without the introduction of additional air,

or after addition of 0.1, 1, or 2ml of air to the syringe containing surfactant (to

give a final volume in the syringe of 20ml). After incubation of samples for 30min

at room temperature, sheared and non-sheared surfactant was diluted to 0.5 or

1.0 mg phospholipid/ml and tested in a pulsating bubble surfactometer. Three

independent resuspensions were made, and at least 5 samples of each were

tested. In addition, the susceptibility of sheared or non-sheared rSP-C surfactant

to inhibition by fibrinogen was tested. For this purpose, human fibrinogen (kindly

provided by Prof. Heimburger, Behringwerke, Marburg, Germany) was added to

the resuspended surfactant preparations at a final concentration of 0, 0.05, 0.1 or

0.5 mg/ml as described previously (25).

Statistical methods

All data analysis was carried out according to a pre-established analysis plan.

The hypothesis that the odds ratio for mortality of treated patients, compared to

untreated patients, is greater than 1 was evaluated using a group sequential

approach with overall one-sided type I error rate of 0.025. A two-sided 95%

confidence interval was calculated for this value and for mortality rates and the

difference in mortality rates. Comparison of the control group and the treatment

group with regard to the primary efficacy variable was performed using a logistic

regression model with pneumonia, aspiration, age, APACHE II score at baseline,

and region (North America vs Europe and all other countries) as influencing

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baseline variables. Secondary variables were tested by a logistic regression

approach, a one-sided Wilcoxon test, or a one-sided Fisher’s exact test.

Results

Patients: The SECB screened 1,382 patients. Numbers of patients enrolled,

randomized, treated, and completing treatment are show in Figure 1. Very few

patients did not complete the study; only one discontinued the intervention due to

an adverse event (hypoxemia). Patients were enrolled from 22 countries (Online

Supplement, Table E1). Baseline demographic data are shown in Table 1, and

baseline clinical and physiologic data are shown in Table 2. As illustrated in

these tables, the two treatment groups were well matched. Patients to whom

surfactant was delivered received 5.2 ± 2.4 (mean ± SD) doses, while patients in

the control group were administered (into the blinding bag) 5.4 ± 2.3 doses. The

numbers of doses administered and information on protocol compliance are

detailed in the Online Supplement, Tables E2 and E3. The percentage of

treatment and retreatment surfactant administrations that were compliant with the

protocol, as detailed in the Online Supplement, was above 98% for both groups.

Outcome variables:

Mortality: The study did not meet its primary endpoint of showing significantly

reduced mortality to day 28 for the patients receiving surfactant (22.7% vs.

23.8% for standard care alone, p = 0.26; Figure E1). Subgroup analysis showed

no difference in mortality for groups defined by mechanism of direct lung injury

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(aspiration or pneumonia), presence of ARDS, or geographic location (Table 3).

Additional analyses, including Cox regression analysis, Cochran-Mantel-

Haenszel model analysis, and further logistic regression analysis, failed to show

any 28-day mortality reduction for the group receiving surfactant. The proportion

of patients alive was similar between the groups at 3 months (64.9% for

surfactant plus usual care vs. 65.6% for usual care alone, p = 0.48) and 6 months

(62.5% vs 63.9%, p = 0.57.)

Gas exchange: Both groups had improved oxygenation after randomization; the

administration of surfactant did not result in more pronounced improvement

compared with usual care alone. The mean PaO2/FiO2 ratios for the surfactant

plus usual care group and for the usual care alone group were, respectively,

123.8 and 124.1 mmHg (at baseline), 150.2 and 146.0 mmHg (at 24 hours),

160.7 and 159.9 mmHg (at 48 hours), and 164.8 and 167.0 mmHg (at 96 hours)

(Figure 2). Excess area under the PaO2/FiO2 curve from baseline to 48 hours for

surfactant plus usual care vs. usual care alone was 1026.5 and 840.1 mmHg*h

(median values, p = 0.34), and thus not different between groups.

Requirement for Mechanical ventilation: There was no difference in the median

number of ventilator free days at Day 28 (9.0 d for surfactant plus usual care and

10.0 d for usual care alone). The PEEP values for the surfactant plus usual care

group and for the usual care alone group were, respectively, 11.1 and 11.0 (at

baseline), 10.3 and 10.7 (at 48 hours), and 9.7 and 10.1 (at 96 hours). The

reductions from baseline in PEEP in the surfactant plus usual care group were

significantly greater at 48 hours (p = 0.006) and 96 hours (p = 0.024) than in the

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usual care only group (Figure E2). No other differences in PIP, PPlat, PEEP, or

FiO2 between the two groups were significant. The modified lung injury score

(26) decreased uniformly and without inter-group differences from a median

(range) of 2.67 (1.33, 4.00) at baseline to 2.33 (0.00, 4.00) on day 6.

Non-pulmonary organ failure: The number of patients with non-pulmonary organ

failures decreased steadily during the 28-day observation period. On study day

one, 311 patients (74.2%) in the surfactant plus usual care group and 294

patients (69.3%) in the usual care group had non-pulmonary organ failures. On

study day 28, these values were 139 patients (33.2%) and 146 patients (34.4%),

respectively. There was no difference in non-pulmonary organ failure free days

between the groups (19.0 vs 17.0 d, p = 0.3917).

Adverse events

Serious adverse events were reported for 207 patients (49.4%) who received

surfactant plus usual care and for 198 patients (46.7%) who received only usual

care. Treatment related serious adverse events (predominately hypoxia or

airway obstruction) were reported for 30 patients (7.2%) receiving surfactant plus

usual care and for five patients (1.2%) who received only usual care (p < 0.001,

Chi square test; see the Online Supplement, Table E4).

Studies of surfactant function performed subsequent to the clinical trial

To investigate the apparent absence of a surfactant effect on gas exchange, we

investigated the effect of the shearing step, which had been added to preparation

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of the surfactant suspension subsequent to prior trials, on surface tension

lowering activity. Shearing demulsified the surfactant emulsion (Figure 3),

impaired function both in the presence or absence of added air when the

suspension was diluted to concentrations of < 2 mg PL / ml (Figure 4), and

increased susceptibility to inhibition of surface activity by fibrinogen at the same

low concentrations (Figure 5).

Discussion

The results of this study showed that bolus administration of a recombinant SP-C

based surfactant to patients with severe direct lung injury, as performed in this

study, did not reduce mortality or improve pulmonary gas exchange. The study

was stopped for futility at a planned 800 patient interim analysis, at which time

844 patients had actually been randomized. Overall mortality to day 28 was

23.3%, and did not differ between study groups. This mortality rate is similar to

that reported in recent studies from the NHLBI ARDS Network (27), although

enrollment criteria for ARDS Network studies and for this study differ with respect

to requirements, in the ARDS Network studies, for bilateral opacities on the chest

radiograph and a PaO2/FiO2 value not greater than 300 mmHg.

To our surprise, and in contrast to prior Phase II (13) and Phase III (14) studies

of rSP-C surfactant, no significant improvement in secondary study outcome

variables, including measures of gas exchange and ventilatory parameters, was

observed. Although reduction in baseline PEEP values was significantly greater

at 48 and 96 hours in the surfactant treated group, the actual differences

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between groups were unlikely to be of clinical relevance. Likewise, the incidence

of non-pulmonary organ failures and the number of organ failure free days did

not differ between study groups.

The number of serious adverse events also did not differ between study groups,

and was rather high (48% overall), consistent with the level of critical illness in

the study population. Serious adverse events that were likely or definitely related

to treatment were more frequent in the group treated with surfactant (7.2%) than

in the usual care only group (1.2%), and were due predominately to transient

hypoxemia or airway obstruction associated with bolus administration of

surfactant. In addition, the rate of adverse events is similar to that seen in the

control group of a recently published study of HL-10 surfactant treatment of

patients with acute lung injury (55.2%), but considerably lower than seen in the

treatment arm of that study (76.6%) (17).

Although the results of this study are consistent with prior reports of surfactant

having no overall benefit for patients with severe lung injury (5), they are

surprising in light of prior experience with rSP-C surfactant (6,13,14).

Consistently, in that experience, patients treated with rSP-C surfactant had a

significantly greater improvement in blood oxygenation than occurred in

untreated patients. Thus, it is puzzling that in the study described in this report,

in which the dose and dose volume of rSP-C surfactant were identical to those

used previously in two phase III trials, absolutely no evidence for an improvement

in gas exchange was detected.

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It is unlikely that differences in the study population account for this discrepancy.

In contrast to previous trials employing rSP-C surfactant, the study population

reported here consisted exclusively of patients with severe direct lung injury.

Although the previous rSP-C surfactant studies targeted patients with ARDS

regardless of predisposing event, the subpopulation of patients with severe direct

lung injury who received surfactant had the greatest improvement in blood

oxygenation and the least mortality (6), and was therefore chosen as the target

population for the current study.

Another potential explanation for the absence of improvement in oxygenation

could be systematic errors in surfactant administration, e.g. errors in assignment

of the blinding devices. However, the presence of more treatment-related

adverse events in the surfactant treated group than in the usual care only group

is strong indirect evidence that treatment assignment and administration were

consistent.

To improve dispersion of the rSP-C surfactant during suspension, a shearing

step was added to the surfactant preparation protocol for the current study. This

step, not previously used, may have resulted in administration of surfactant with

impaired surface tension lowering properties. Indeed, testing of sheared and

non-sheared rSP-C surfactant subsequent to termination of the clinical trial

provided indication that such shearing results in demulsification of the surfactant

emulsion and a partial loss of surface activity when the surfactant suspension is

diluted to low concentrations, as may be present in alveoli of an inflamed and

edematous lung. This effect was also evident in the presence of inhibitory

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plasma proteins such as fibrinogen. Based on these data we propose that

shearing-induced loss of surface activity of the rSP-C surfactant may have

contributed to the lack of efficacy observed in our study.

One must ask, however, why shearing appeared to have little adverse effect in

the in vivo rat model yet clearly inhibited in vitro function in the bubble

surfactometer. We consider at least two possibilities. First, the rat lavage model

used for release testing was treated with rSP-C surfactant at a concentration of

100 mg phospholipid/ kg, whereas patients were treated with 50 mg

phospholipid/ kg. In the studies performed after the trial was stopped, it became

apparent that dilution of the surfactant preparation may be important in

uncovering subtle changes in function (as may possibly be produced by

shearing). Secondly, the rat model is an imperfect model of the severe lung

injury present in patients – and it is quite possible that results in the model do not

perfectly predict results in the clinical setting.

In summary, up to eight doses of an rSP-C surfactant suspension administered

as an intratracheal bolus to patients with severe direct lung injury did not reduce

28 day mortality or improve blood oxygenation. No differences in mortality

between patients receiving surfactant plus usual care or only usual care were

detected. Shearing of the surfactant during resuspension may have resulted in

impairment of surface tension lowering function and increased susceptibility to

inhibition by plasma proteins, hence explaining the apparent lack of clinical

efficacy.

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21. Spragg RG, Masys DR, Sergeant D, Lawrie T, Taut FJ. An informatics strategy to

assure enrollment criteria compliance in studies of the critically ill. Contemp Clin

Trials 2010 Aug 4 2010; Epub ahead of print, PMID: 20667511.

22. Fishman GS, Moore LR. A statistical evaluation of multiplicative congruential

random number generators with modulus 231-1. J Am Statist Assoc 1982;77:129-

136.

23. Häfner D, Beume R, Kilian U, Krasznai G, Lachmann B. Dose-response

comparisons of five lung surfactant factor (LSF) preparations in an animal model of

adult respiratory distress syndrome (ARDS). Br J Pharmacol 1995;115:451-458.

24. Markart P, Ruppert C, Wygrecka M, Colaris T, Dahal B, Walmrath D, Harbach H,

Wilhelm J, Seeger W, Schmidt R, Guenther A. Patients with ARDS show

improvement but not normalisation of alveolar surface activity with surfactant

treatment: putative role of neutral lipids. Thorax 2007;62:588-594.

25. Markart P, Ruppert C, Grimminger F, Seeger W, Günther A. Fibrinolysis-inhibitory

capacity of clot-embedded surfactant is enhanced by SP-B and SP-C. Am J Physiol

Lung Cell Mol Physiol 2003;284:L69-L76.

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26. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult

respiratory distress syndrome [published erratum appears in Am Rev Respir Dis

1989 Apr; 139(4):1065]. Am Rev Respir Dis 1988;138:720-723.

27. Spragg RG, Bernard GR, Checkley W, Curtis JR, Gajic O, Guyatt G, Hall J, Israel

E, Jain M, Needham DM, Randolph AG, Rubenfeld GD, Schoenfeld D, Thompson

BT, Ware LB, Young D, Harabin AL. Beyond mortality: future clinical research in

acute lung injury. Am J Respir Crit Care Med 2010;181:1121-1127.

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Table 1: Demographic data*

DEMOGRAPHIC

DATA

Usual Care +

surfactant

(N=419)

Usual Care

(N=424)

Overall

(N=843)

Age [yrs] 57.5 ± 0.8 56.5 ±0.83 57.0 ± 0.58

Body Height [cm] 171.0 ± 0.51 171.4 ± 0.45 171.2 ± 0.34

Body Weight [kg] 80.4 ± 0.92 80.4 ± 0.86 80.4 ± 0.63

Ethnic origin, white

[%] 377 ( 90.0%) 390 ( 92.0%) 767 ( 91.0%)

Sex, female/male [%] 33.9/66.1 32.8/67.2 33.3/66.7

*(Mean ± StdErr)

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Table 2. Clinical and physiologic baseline data*

Surfactant

plus usual

care

(N=419)

Usual Care

(N=424)

Overall

(N=843)

Time from hospital admission

to baseline [hours] 100.9 ± 7.48 107.4 ± 6.88 104.2 ± 5.08

Time from ICU admission to

baseline [hours] 48.9 ± 1.86 48.9 ± 2.01 48.9 ± 1.37

Time from intubation to

baseline [hours] 37.2 ± 0.80 37.3 ± 0.81 37.3 ± 0.57

Aspiration of gastric contents

present 82 ( 19.6%) 92 ( 21.7%) 174 ( 20.6%)

Pneumonia present 359 ( 85.7%) 369 ( 87.0%) 728 ( 86.4%)

Pneumonia - Mode of infection

- Community acquired 292 ( 81.3%) 284 ( 77.0%) 576 ( 79.1%)

- Hospital acquired 67 ( 18.7%) 85 ( 23.0%) 152 ( 20.9%)

APACHE II Score 18.0 ± 0.33 17.8 ± 0.32 17.9 ± 0.23

# quadrants involved on chest

radiograph 2.81 ± 0.05 2.85 ± 0.05 2.83 ± 0.04

ARDS present at baseline 245 ( 58.5%) 249 ( 58.7%) 494 ( 58.6%)

SIRS present at baseline 373 ( 89.0%) 366 ( 86.3%) 739 ( 87.7%)

Cardiovascular support with 252 ( 60.1%) 244 ( 57.5%) 496 ( 58.8%)

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vasopressors present at

baseline

FiO2 0.64 ± 0.007 0.64 ± 0.007 0.64 ± 0.005

PaO2 76.9 ± 3.8 76.4 ± 3.7 76.7 ± 2.6

PaCO2 46.9 ± 2.3 46.6 ± 2.3 46.7 ± 1.6

PaO2/FiO2 123.8 ± 1.30 124.1 ± 1.32 123.9 ± 0.93

PEEP [cm H2O] 11.1 ± 0.2 11.0 ± 0.1 11.1 ± 0.1

Pplat [cm H2O] 24.2 ± 0.4 24.9 ± 0.4 24.6 ± 0.3

Tidal vol. [ml/kg PBW] 7.4 ± 0.4 7.5 ± 0.4 7.5 ± 0.3

Tidal vol. [ml] 479 ± 5.7 489 ± 5.6 484 ± 4.0

Loge IL-6 5.38 ± 0.66 5.35 ± 0.62 5.36 ± 0.45

* Continuous variables are expressed as mean ± SE; discrete variables are

presented as

N (% of column total). Abbreviations: APACHE Acute Physiology and Chronic

Health Evaluation; ARDS acute respiratory distress syndrome; SIRS systemic

inflammatory response syndrome.

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Table 3: Patients surviving to day 28

Surfactant

plus usual

care*

(N = 419)

Usual care*

(N = 424)

Odds ratio**

(95% CI)

p-value

1-sided

All cases 324 (77.3%) 323 (76.2%) 0.90

(0.64 – 1.25)

0.26

Patients with

aspiration

66 (80.2%) 75 (81.5%) 0.90

(0.41 – 1.99)

0.40

Patients with

pneumonia

276 (76.9%) 280 (75.9%) 0.91

(0.64 – 1.31)

0.31

Patients with ARDS 181 (73.9%) 180 (72.3%) 0.88

(0.58 – 1.34)

0.27

Patients from North

America

73 (79.3%) 70 (81.4%) 1.16

(0.51 – 2.61)

0.64

Patients from

Europe and other

regions

251 (76.8%) 253 (74.9%) 0.86

(0.60 – 1.24)

0.21

* N (%) surviving to day 28

** Odds ratio <1 indicates superiority of surfactant plus usual care over usual

care.

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Figures:

Figure 1: Flow of patients through the VALID trial. In the analysis of patients

receiving at least one study treatment, 419 patients receiving surfactant and 424

patients not receiving surfactant were available for analysis.

Figure 2. PaO2/FiO2 values for patients receiving surfactant plus usual care or

usual care only from the time of randomization to 96 hours. Arrows indicate the

time of possible surfactant administrations. Differences in PaO2/FiO2 values

between groups are not significant.

Figure 3. Shearing in the presence of air demulsifies the surfactant emulsion.

Samples of surfactant were resuspended to a concentration of 50 mg/ml with

saline by gentle swirling. Samples were then: (A) not further treated; (B)

subjected to shearing after careful exclusion of air from the Luer connector; (C)

subjected to shearing without excluding air from the Luer connector; (D)

subjected to shearing after addition of 2 ml of air. Samples were allowed to

stand for 30 min. Surfactant in samples A and B showed minimal sedimentation

of the emulsion, while surfactant in samples C and D showed marked

demulsification.

Figure 4: Shearing impairs surfactant function. Samples of surfactant were

resuspended to a concentration of 50 mg/ml with saline by gentle swirling, and

subsequently sheared in the absence of air, or in the presence of 0.1, 1, or 2 ml

air, or not sheared. Samples were then diluted with saline to concentrations of

0.5 or 1.0 mg/ml phospholipid (PL) and analyzed in a pulsating bubble

surfactometer. Minimum surface tension after 5 min pulsation is shown.

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Samples sheared in the presence of air had significantly impaired surface activity

at both concentrations, and the sample sheared in the absence of air had

significantly impaired surface activity when tested at 0.5 mg/ml PL. The mean ±

SD of 5 measurements is given. Significance vs. unsheared samples (t-test) is

indicated by *(p>0.05), **(p<0.01) and ***(p<0.001).

Figure 5: Shearing increases the susceptibility of surfactant to inhibition of

surface activity by fibrinogen. surfactant prepared as described in Figure 2 was

analyzed in a bubble surfactometer in the presence of various concentrations of

fibrinogen or in the absence of fibrinogen.

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Flow of patients through the VALID trial. In the analysis of patients receiving at least one study treatment, 419 patients receiving surfactant and 424 patients not receiving surfactant were

available for analysis.

190x254mm (96 x 96 DPI)

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PaO2/FiO2 values for patients receiving surfactant plus usual care or usual care only from the time of randomization to 96 hours. Arrows indicate the time of possible surfactant

administrations. Differences in PaO2/FiO2 values between groups are not significant. 254x190mm (96 x 96 DPI)

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Shearing in the presence of air demulsifies the surfactant emulsion. Samples of surfactant were resuspended to a concentration of 50 mg/ml with saline by gentle swirling. Samples were then: (A) not further treated; (B) subjected to shearing after careful exclusion of air from the Luer connector; (C) subjected to shearing without excluding air from the Luer connector; (D) subjected to shearing after addition of 2 ml of air. Samples were allowed to stand for 30 min. Surfactant in samples A and B showed minimal sedimentation of the emulsion, while surfactant in samples C and D showed

marked demulsification. 254x190mm (96 x 96 DPI)

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Shearing impairs surfactant function. Samples of surfactant were resuspended to a concentration of 50 mg/ml with saline by gentle swirling, and subsequently sheared in the absence of air, or in the

presence of 0.1, 1, or 2 ml air, or not sheared. Samples were then diluted with saline to concentrations of 0.5 or 1.0 mg/ml phospholipid (PL) and analyzed in a pulsating bubble

surfactometer. Minimum surface tension after 5 min pulsation is shown. Samples sheared in the presence of air had significantly impaired surface activity at both concentrations, and the sample sheared in the absence of air had significantly impaired surface activity when tested at 0.5 mg/ml PL. The mean ± SD of 5 measurements is given. Significance vs. unsheared samples (t-test) is

indicated by *(p>0.05), **(p<0.01) and ***(p<0.001). 254x190mm (96 x 96 DPI)

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Shearing increases the susceptibility of surfactant to inhibition of surface activity by fibrinogen. surfactant prepared as described in Figure 2 was analyzed in a bubble surfactometer in the

presence of various concentrations of fibrinogen or in the absence of fibrinogen. 254x190mm (96 x 96 DPI)

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Recombinant Surfactant Protein C Based Surfactant for Patients with

Severe Direct Lung Injury

Roger G. Spragg MD1, Friedemann J. H. Taut MD2, James F. Lewis MD3, Peter

Schenk MD4, Clemens Ruppert PhD5, Nathan Dean MD6, Kenneth Krell MD7,

Andreas Karabinis MD8 , Andreas Günther MD5

Online Data Supplement

1. Inclusion / exclusion criteria and diagnostic criteria for pneumonia and

aspiration:

Inclusion Criteria at start of baseline: For enrollment into the study, to enter

the baseline period the patient was to have met all the following inclusion criteria:

• Intubation due to one of the following primary pulmonary insults:

1) Aspiration of gastric contents

• witnessed, or proven by visualization of food particles in the tracheobronchial

tree during bronchoscopy; and

• presence of a new radiographic pulmonary infiltrate (either on chest radiograph

or on CT scan).

2) Pneumonia. Diagnosed according to

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i) criteria modified from Fine et al. (E1) and Leroy et al. (E2): presence of a new

radiographic pulmonary infiltrate and acute onset of at least one major clinical

finding (cough/sputum production/fever) and acute onset of at least two minor

clinical findings: dyspnea/pleuritic chest pain/altered mental status/pulmonary

consolidation by physical examination/total leukocyte count >12000/µL;

OR

ii) presence of a new radiographic pulmonary infiltrate and microbiologic proof of

pulmonary infection.

Intubation was not to have been predominantly due to conditions like congestive

heart failure, pleural effusion, pulmonary embolism, surgery, serious central

nervous system injury (eg elevated intracranial pressure, GCS [Glasgow Coma

Scale] score ≤9), neuromuscular disorder, polytrauma, COPD (chronic

obstructive pulmonary disease), asthma (however, a history of COPD or asthma

was not exclusionary) or pneumothorax. In addition, patients who had

undergone elective surgery and remained intubated due to pneumonia or

aspiration as defined above could be eligible for the study. These represent

patients who normally would have been extubated no later than 6 h after

completion of surgery. Patients remaining intubated for surgical reasons were

not eligible (eg high blood loss with circulatory instability). Patients after thoracic

surgery were not eligible.

• intubation and mechanical ventilation for at least 18 h but less than 72 h (ie the

baseline period must have started within 18 to 72 h after intubation);

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• severely impaired oxygenation, ie PaO2/FiO2 (inspired oxygen fraction) ≤170

mmHg. An arterial catheter was required for blood gas analyses;

• able to tolerate deep sedation and/or neuromuscular blockade (paralysis)

during study drug administration.

• ≥12 years and ≤85 years of age.

• physical examination, including vital signs, completed within 24 h prior to start

of baseline and recorded in the patient chart;

• meeting the requirements of the local IRB/IEC. Written informed consent was

obtained from the patient or from the patient's legally authorized representative

according to the respective local/national legal regulations;

• approval from the SECB to include the patient after reviewing basic patient

data.

Inclusion Criteria at randomization

At the end of the two hour baseline period, patients had to satisfy the following

criteria to be eligible to enter the treatment period:

• 60 mmHg ≤ PaO2/FiO2 ≤170 mmHg;

• mechanically ventilated with a PEEP (positive end expiratory pressure) ≥5 cm

H2O;

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• hemodynamically stable (mean arterial blood pressure ≥60 mmHg).

Patients failing to satisfy these criteria were not randomized and did not continue

to participate in the study.

Exclusion Criteria

Patients with any of the following exclusion criteria and conditions present during

the screening period could not be enrolled into the study:

a) Diseases and health status

• principal source of infection or sepsis outside the lung;

• severe pre-existing lung disease, eg lung fibrosis or COPD requiring

supplemental oxygen, prior pneumonectomy, or lung cancer;

• cancer metastatic to the lung or any end stage malignancy (eg metastases to

more than one organ, patient not eligible for further anti cancer treatment, poorly

controlled neoplasms, eg of pancreas);

• history of lung, liver, pancreas, small bowel, or bone marrow/stem cell

transplantation;

• morbidly obese patients (BMI [body mass index] ≥45) BMI = body weight

[kilograms]/(height [meters])2 or BMI = 703.1 * body weight [pounds]/(height

[inches]);

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• diagnosis of acute necrotizing pancreatitis; an acute exacerbation of malaria;

near drowning; burns of >15% of body surface area.

b) The patient was excluded if one or more of the following signs of

extrapulmonary organ failure were present:

• Cardiovascular system:

i) myocardial infarction within 1 month prior to the start of baseline or has chronic

heart failure (NYHA [New York Heart Association] IV) documented any time prior

to the start of baseline;

ii) cardiopulmonary resuscitation and had early signs of hypoxic brain damage

(eg neurological symptoms on clinical investigation, elevated neuron specific

enolase, typical findings on cranial CT [computed tomography] scan);

iii) hemodynamic instability: the patient could not be stabilized (eg with volume,

vasopressors, or inotropics) to have a mean arterial blood pressure of at least 60

mmHg at start of baseline.

• Liver: Severe chronic liver disease or symptoms of liver failure (eg ascites,

hepatic encephalopathy, signs of portal hypertension) or had diagnosis of acute

liver failure (eg serum total bilirubin >5 mg/dL [85 _mol/L]) within 24 h prior to

enrollment.

• Immune System:

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i) immunocompromised according to the criteria from the NNIS (National

Nosocomial Infections Surveillance) system of the CDC (Centers for Disease

Control and Prevention): neutropenia (absolute neutrophil count <500/µL at any

time within 24 h preceding start of baseline at B0 h), leukemia, lymphoma, HIV

(human immunodeficiency virus) with CD4 count <200/µL, or splenectomy;

patients who were on cytotoxic chemotherapy or on high dose steroids (eg >40

mg of prednisone or its equivalent daily for >2 weeks);

ii) if no differential white blood count was available the total WBC (white blood

cell count) must not have been ≤2000/µL at any time within 24 h preceding start

of baseline;

iii) AIDS (Acquired immunodeficiency syndrome); concerning manifestation of

AIDS the CDC criteria was used.

• Coagulation: Diagnosis of DIC (disseminated intravascular coagulation) or other

severe coagulation disorders eg platelet count ≤50/nL at any time within 24 h

preceding start of baseline (B0 h);

c) General criteria:

• participation in a clinical study with an investigational product within the past 30

d;

• use of other experimental therapies (eg NO [nitric oxide]), even those not

involving drugs (eg ECMO [extracorporeal membrane oxygenation]), at any time

during the hospitalization;

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• commitment for aggressive treatment had not been obtained: the patient was

moribund (ie death was perceived to be imminent or inevitable during the next

month);

• the investigator anticipated difficulty in locating the patient and/or family

member during the 6 month follow-up period; or, the patient or family member

was unwilling or unable to cooperate during the 6 month follow-up period.

2. Definitions of organ failure:

Non-pulmonary organ failure was assessed daily until Day 8 and on even study

days thereafter (Days 10, 12, 14 etc until Day 28) based on the following:

• circulatory failure (systolic blood pressure of 90 mmHg or less or the need for

treatment with any vasopressor);

• coagulation failure (platelet count of 80,000 per mm3 or less);

• hepatic failure: (serum bilirubin concentration of at least 2 mg per deciliter

(34 µmol/L);

• renal failure: serum creatinine concentration of at least 2 mg per deciliter

(177 µmol/L).

For assessment of nonpulmonary organ failure, the most abnormal data from the

respective study day was utilized.

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3. Patient eligibility for surfactant treatment.

Initial treatment: Patients were eligible for the initial surfactant treatment at the

end of the baseline period if:

• 60 mmHg ≤ PaO2/FiO2 ≤170 mmHg;

• mechanically ventilated with a PEEP (positive end expiratory pressure)

≥5 cm H2O;

• hemodynamically stable (mean arterial blood pressure ≥60 mmHg).

Retreatment: Within the 96 h treatment period, a maximum of 7 additional

administrations, in addition to the initial administration, were allowed at study

times T6 h (± 30 min), T12 h (± 1 h), T24 h (± 1 h), T36 h (± 4 h), T48 h (± 4 h),

T72 h (± 4 h), and T96 h (± 4 h), provided the patient met the following

retreatment criteria:

• intubation and mechanical ventilation with a PEEP ≥5 cm H2O;

• 60 mmHg ≤ PaO2/FiO2 ≤170 mmHg

• mean blood pressure ≥60 mmHg;

• patient’s preparation for study drug administration completed

4. Method of surfactant administration:

As reported previously (manuscript reference #14), surfactant was administered

as follows; “Before treatment, patients transiently received 100 percent oxygen

and were sedated or sedated and paralyzed. Next, 1 ml of recombinant

surfactant protein C–based surfactant (containing 1 mg of recombinant surfactant

protein C and 50 mg of phospholipids) per kilogram of lean body weight was

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administered in a continuous stream through a weighted blinding bag, which

concealed the medication,and an opaque catheter inserted into the endotracheal

tube, with the distal end approximately 1 cm above the carina. The first half of the

dose was administered during a pause in mechanical ventilation in which PEEP

was maintained and the patient was in the left or right lateral decubitus position,

and the second half was administered similarly several minutes later, with the

patient in the opposite lateral decubitus position.” Investigators were advised to

avoid ventilator changes or suctioning the patient for one hour after treatment

unless there were clear clinical indications.

5. Severe adverse events: See Table E4.

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Reference List

E1. Fine MJ, Orloff JJ, Rihs JD, Vickers RM, Kominos S, Kapoor WN, Arena

VC, Yu VL. Evaluation of housestaff physicians' preparation and interpretation of

sputum Gram stains for community-acquired pneumonia. J Gen Intern Med

1991;6:189-198.

E2. Leroy O, Santre C, Beuscart C, Georges H, Guery B, Jacquier JM,

Beaucaire G. A five-year study of severe community-acquired pneumonia with

emphasis on prognosis in patients admitted to an intensive care unit. Intensive

Care Med 1995;21:24-31.

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Table E1. Countries contributing patients, and the number of centers and

patients from each country.

Country No. of centers No. of patients

USA 29 165

Austria 5 91

Hungary 10 80

Germany 13 74

Spain 9 64

Australia 12 61

Canada 10 56

Finland 8 56

Greece 6 42

United Kingdom 6 37

Russia 6 36

Israel 5 36

New Zealand 3 34

Switzerland 5 33

Belgium 7 26

Denmark 3 25

Argentina 7 21

Estonia 3 18

Brazil 6 14

South Africa 2 6

Netherlands 2 5

Sweden 4 5

Overall 161 985

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Table E2. Number of treatments received by patients in each treatment group

Number (%) of patients Number of treatments received

Surfactant + usual care

(n=419)

Usual care only (n=424)

1 41 (9.8) 32 (7.5%)

2 35 (8.4) 38 (9.0%)

3 48 (11.5) 41 (9.7%)

4 38 (9.1) 37 (8.7%)

5 40 (9.5) 52 (12.3%)

6 49 (11.7) 48 (11.3%)

7 65 (15.5) 63 (14.9%)

8 103 (24.6) 113 (26.7%)

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Table E3.

Number (%) of patients eligible for (re-)treatment at

each time point

Number (%) of patients with discrepancies in

eligibility or administration at each time point

Study

time point


(n=419)

Usual care only

(n=424)


Usual care only

T0 h 413 (98.6) 417 (98.3) 7 (1.7) 7 (1.7)

T6 h 325 (77.6) 332 (78.3) 6 (1.4) 4 (1.0)

T12 h 289 (69.0) 320 (75.5) 1 (0.2) 2 (0.5)

T24 h 274 (65.4) 297 (70.0) 4 (0.9) 0 (0.0)

T36 h 229 (54.7) 266 (62.7) 1 (0.2) 2 (0.5)

T48 h 239 (57.0) 237 (55.9) 1 (0.2) 1 (0.2)

T72 h 215 (51.3) 203 (47.9) 3 (0.7) 4 (1.0)

T96 h 184 (43.9) 175 (41.3) 2 (0.5) 0 (0.0)

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Table E4: Treatment-Associated Serious Adverse Events. Causality

implied

(all events) and any causality reported for ≥ 0.2% in any

treatment group.

Number (%) * of patients

rSP-C surf. plus

Standard Care Standard Care

n = 419 n = 424

All

causality Related

All

Causality Related

Medicinal Dictionary for

Regulatory

Activities Preferred Term

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At least one SAE 207 (49.4) 30 (7.2) 198 (46.7) 5† (1.2)

Respiratory failure 26 (6.2) 2 (0.5) 34 (8.0) 1 (0.2)

Septic shock 30 (7.2) 0 0.0 25 (5.9) 0 0.0

Pneumothorax 19 (4.5) 2 (0.5) 15 (3.5) 1 (0.2)

Pneumonia 22 (5.3) 0 0.0 11 (2.6) 0 0.0

Hypoxia 19 (4.5) 13 (3.1) 8 (1.9) 0 0.0

Multi-organ failure 25 (6.0) 0 0.0 22 (5.2) 0 0.0

Cardiac arrest 10 (2.4) 1 (0.2) 12 (2.8) 0 0.0

Renal failure acute 10 (2.4) 0 0.0 11 (2.6) 0 0.0

Shock 9 (2.1) 0 0.0 12 (2.8) 0 0.0

Renal failue 8 (1.9) 0 0.0 8 (1.9) 0 0.0

ARDS 6 (1.4) 0 0.0 9 (2.1) 0 0.0

Hypotension 9 (2.1) 2 (0.5) 5 (1.2) 0 0.0

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Sepsis 8 (1.9) 0 0.0 6 (1.4) 0 0.0

Atrial fibrillation 6 (1.4) 0 0.0 3 (0.7) 0 0.0

Obstructive airways

disorder 8 (1.9) 7 (1.7) 1 (0.2) 0 0.0

Polyneuropathy 5 (1.2) 0 0.0 3 (0.7) 0 0.0

Pulmonary embolism 3 (0.7) 0 0.0 5 (1.2) 0 0.0

Gastrointestinal

haemorrhage 1 (0.2) 0 0.0 5 (1.2) 0 0.0

Hepatic failure 2 (0.5) 0 0.0 4 (0.9) 0 0.0

Lung abcess 1 (0.2) 0 0.0 5 (1.2) 0 0.0

Oxygen saturation

decreased 4 (1.0) 1 (0.2) 2 (0.5) 0 0.0

Cardiac failure 3 (0.7) 0 0.0 2 (0.5) 0 0.0

Agitation 1 (0.2) 0 0.0 3 (0.7) 0 0.0

Atelectasis 2 (0.5) 1 (0.2) 2 (0.5) 1 (0.2)

Bacteraemia 1 (0.2) 0 0.0 3 (0.7) 0 0.0

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Bradycardia 4 (1.0) 0 0.0 0 0.0 0 0.0

Gastrointestinal necrosis 1 (0.2) 0 0.0 3 (0.7) 0 0.0

Pneumonia herpes viral 2 (0.5) 1 (0.2) 1 (0.2) 0 0.0

Acute hepatic failure 2 (0.5) 0 0.0 1 (0.2) 0 0.0

Acute respiratory failure 0 0.0 0 0.0 3 (0.7) 0 0.0

Aspiration 3 (0.7) 0 0.0 0 0.0 0 0.0

Cerebral infarction 3 (0.7) 0 0.0 0 0.0 0 0.0

Deep vein thrombosis 2 (0.5) 0 0.0 1 (0.2) 0 0.0

Empyema 3 (0.7) 0 0.0 0 0.0 0 0.0

Intestinal perforation 2 (0.5) 0 0.0 1 (0.2) 0 0.0

Lung injury 1 (0.2) 0 0.0 2 (0.5) 0 0.0

Myocardial infarction 2 (0.5) 0 0.0 1 (0.2) 0 0.0

Peripheral ischemia 0 0.0 0 0.0 3 (0.7) 0 0.0

Peritonitis 2 (0.5) 0 0.0 1 (0.2) 0 0.0

Pulmonary edema 0 0.0 0 0.0 3 (0.7) 0 0.0

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Respiratory distress 2 (0.5) 0 0.0 1 (0.2) 0 0.0

Staphylococcal infection 2 (0.5) 0 0.0 1 (0.2) 0 0.0

Thrombocytopenia 1 (0.2) 0 0.0 2 (0.5) 0 0.0

Acinetobacter bacteraemia 2 (0.5) 0 0.0 0 0.0 0 0.0

Acute pulmonary edema 0 0.0 0 0.0 2 (0.5) 0 0.0

Arterial injury 2 (0.5) 0 0.0 0 0.0 0 0.0

Bronchospasm 2 (0.5) 2 (0.5) 0 0.0 0 0.0

Cerebrovascular accident 0 0.0 0 0.0 2 (0.5) 0 0.0

Coma 0 0.0 0 0.0 2 (0.5) 0 0.0

Convulsion 2 (0.5) 0 0.0 0 0.0 0 0.0

Death 2 (0.5) 0 0.0 0 0.0 0 0.0

Hypercapnia 1 (0.2) 1 (0.2) 1 (0.2) 0 0.0

Hypoglycaemia 2 (0.5) 0 0.0 0 0.0 0 0.0

Myopathy 0 0.0 0 0.0 2 (0.5) 0 0.0

Pneumonia klebsiella 2 (0.5) 0 0.0 0 0.0 0 0.0

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Subarachnoid

haemorrhage 2 (0.5) 0 0.0 0 0.0 0 0.0

Airway complication of

anesthesia 0 0.0 0 0.0 1 (0.2) 1 (0.2)

Ventricular asystole 0 0.0 0 0.0 1 (0.2) 1 (0.2)

* Percentages are based on the total number of patients in a

treatment group

† p<0.001, chi square test

Table E4

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Figure Legends:

E1. Kaplan-Meyer curve showing survival to day 28 of patients receiving rSP-C

surfactant plus usual care (n = 419, solid line) or usual care only (n = 424,

dashed line).

E2. PEEP values from baseline to 96 hours after initial treatment for patients

receiving rSP-C surfactant + usual care (squares) or usual care only (circles).

There is no significant difference between the two groups.

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Kaplan-Meyer curve showing survival to day 28 of patients receiving rSP-C surfactant plus usual care (n = 419, solid line) or usual care only (n = 424, dashed line).

254x190mm (96 x 96 DPI)

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PEEP values from baseline to 96 hours after initial treatment for patients receiving rSP-C surfactant + usual care (squares) or usual care only (circles). There is no significant difference between the

two groups. 254x190mm (96 x 96 DPI)

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for review only - american thoracic society€¦ · for review only 7 and ventilation; and the...

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