The Adult Calfactant in Acute Respiratory Distress Syndrome Trial

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The Adult Calfactant in Acute Respiratory Distress Syndrome (CARDS) Trial Douglas F. Willson, MD*; Jonathon D. Truwit, MD, MBA*; Mark R. Conaway, PhD; Christine S. Traul, MD; Edmund E. Egan, MD

*co-first authors

Author Affiliations: Department of Pediatrics, Medical College of Virginia, Virginia Commonwealth University (Dr. Willson); Division of Pulmonary and Critical Care Medicine, Froedtert and Medical College of Wisconsin (Dr. Truwit) and Department of Health Evaluation Sciences (Dr. Conaway), University of Virginia Health Sciences System; Department of Pediatrics, Children’s Hospital Cleveland Clinic (Dr. Traul); Pneuma Pharmaceuticals, Amherst, New York and State University of New York at Buffalo (Dr. Egan)

All authors contributed to the conceptualization and design of the study. Drs. Willson and Truwit were study co-chairs. Dr. Traul coordinated data collection and oversaw study conduct at all study sites. Dr. Conaway was responsible for the statistical design and analysis of study results. Dr. Egan was responsible for overall study coordination and interaction with the clinical research organization. Drs. Willson and Truwit composed the first drafts of the manuscript but all authors participated in the manuscript revisions. Drs. Willson and Truwit take responsibility for the integrity of the work as a whole, from inception to published article.

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This work was supported by Pneuma Pharmaceuticals, Amherst, New York. Dr. Egan is CEO of Pneuma Partners. 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.

Corresponding Author:

Dr. Douglas F. Willson Dept. of Pediatrics Children’s Hospital of Richmond at VCU Old City Hall,1001 E Broad St 2nd Flr, Suite 205A Richmond, VA 23219 Email: [email protected]

Running title:

Calfactant Acute Respiratory Distress Syndrome

Descriptor:

4.4 Clinical Trials in Critical Care Medicine

Word Count:

Manuscript: 3,167 Abstract: 210

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At a glance commentary: Administration of calfactant was not associated with improved oxygenation or longer-term benefits relative to placebo in this randomized, controlled, masked 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.

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balances were collected the first seven days after enrollment in order to determine if calfactant and placebo subjects were managed comparably.

Subjects were followed daily until hospital discharge and all adverse events 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 ventilator free days at 90 days, durations of ICU, hospital stay and oxygen use, and changes in oxygenation after the study intervention. Adverse events 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 alpha (two sided) of 0.05.

An interim analysis for the primary efficacy endpoint was performed at the midpoint of accrual for the first study (n=240 adult subjects) with a planned alpha = 0.005 based on the method of O’Brien and Fleming utilized. If the p-value was less than alpha = 0.005 the trial was to be

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present exogenous surfactant cannot be recommended for routine clinical use in acute respiratory distress syndrome.

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Introduction Acute Respiratory Distress Syndrome 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 ARDS2-13 and early success in pilot studies14-18, five randomized clinical trials of exogenous surfactant in adults with ARDS failed to demonstrate sustained benefit. 19-23 The first trial used an aerosol delivery technique and a synthetic surfactant with no apoprotein activity, Exosurf®, and observed no improvement in oxygenation or longer-term outcomes.19 A second trial used instillation of a semi-synthetic surfactant with sub-threshold levels of surfactant protein B, Survanta® (beractant), and showed transiently improved oxygenation but no change in outcomes.20 Two more recent trials used an instillation of a synthetic surfactant, Venticute®, with a recombinant SP-C protein 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 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.24-32 Surfactant replacement is clearly beneficial in surfactant-deficient preterm infants and studies in term infants with pneumonia and meconium aspiration have consistently shown improved oxygenation, shortened duration of ventilation, and better survival with surfactant administration.33-37 Outside the neonatal period, studies in children have been smaller in scale with more diverse

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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 and colleagues, the survival benefit in that study appeared confined to those subjects with direct lung injury on post-hoc analysis.22

In view of the positive results of our studies in children along with evidence that SP-B containing pharmaceutical surfactants might be more effective38-45, 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 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.

Methods Patient Population Adult subjects were recruited from July 2008 to July 2010 from the intensive care units of 34 medical centers in 6 countries (appendix). The study, registered with clinicaltrials.gov identifier NCT00682500, was performed in accordance with the Declaration of Helsinki (1996) and the rules of 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 and independent ethics committees or institutional review boards at each participating center approved the

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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, 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 hours 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 DSMB to ascertain eligibility. If arterial blood gases were not obtained, oxygen saturation (SpO2) could be substituted for PaO22 in the entry criteria but a SpO22/FiO22 less than 250 (when SpO22 < 97%) was necessary to qualify for study entry. A log of intubated patients with ALI/ARDS was maintained and the primary reason for not enrolling a potentially eligible patient 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.

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Investigators were naïve to the randomization scheme. Randomization was performed via the study website in blocks of four. Subjects with an initial PaO2/FiO22 or SpO2/FiO2 < 100 (or an oxygenation index > 30) or who were immune compromised were considered higher risk and were independently randomized in order to assure an even distribution of more severely ill subjects in both groups.

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

Study Intervention The study intervention consisted of direct instillation of up to three doses of calfactant 12 hours apart versus 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. In order to qualify for a

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subsequent dose the subject was required to have at least a 25% improvement in PaO2/FiO2 (or SpO2/FiO2) in the 12 hours following the previous dose with no significant adverse effects. Blood pressure, heart rate, and SpO2 were continuously monitored and recorded every 5 minutes for 30 minutes after the intervention.

Ventilator settings, arterial blood gas results (if performed), and SpO2 and end-tidal CO2 (EtCO2) values were recorded at 1, 2, 4, 8, and 12 hours after each intervention and daily at approximately 0800 hours for the first seven days after study enrollment. Daily fluid balance was collected for the first seven 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 hours 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 (Figures E1 & E2). 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

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balances were collected the first seven days after enrollment in order to determine if calfactant and placebo subjects were managed comparably.

Subjects were followed daily until hospital discharge and all adverse events 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 ventilator free days at 90 days, durations of ICU, hospital stay and oxygen use, and changes in oxygenation after the study intervention. Adverse events 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 alpha (two sided) of 0.05.

An interim analysis for the primary efficacy endpoint was performed at the midpoint of accrual for the first study (n=240 adult subjects) with a planned alpha = 0.005 based on the method of O’Brien and Fleming utilized. If the p-value was less than alpha = 0.005 the trial was to be

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stopped due to efficacy. In addition, conditional power calculations were performed in order to provide a probability for futility. If the conditional power was less than 0.20 the trial was to be terminated due to futility.

For comparing the placebo and surfactant groups, the chi-squared 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, gender, risk strata, immune status, fluid balance, and APACHE score. Repeated measures models were used to compare the groups with respect to oxygenation measures taken 0,1,2,4,8 and 12 hours post-intervention.

Results 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. 317 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 is included in the analysis.

In all 97,135 patients were screened, 34,971 (36%) of whom were intubated and on mechanical ventilation. Of the intubated patients, 17% met definitional criteria for ALI/ARDS and one half of those (2948) were due to direct lung injury (Figure 1). Only 11% of patients with direct lung

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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.

154/308 (50%) of subjects received a second intervention, 76 (47%) placebo and 78 (53%) surfactant subjects. Only 9 subjects (6 placebo, 3 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, gender, diagnostic categories, or the distribution of higher risk subjects.

Outcomes Calfactant therapy did not reduce hospital mortality; calfactant 27.8% versus 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 8 (19%) of whom died.

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 (Table E1). APACHE score and “first subject enrolled at site” did not significantly impact mortality.

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No improvement in oxygenation was observed with calfactant compared to placebo (Figure 2 A&B). As arterial blood gases 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.

Compliance with the ventilator algorithm was not different between surfactant and placebo groups. Peak inspiratory settings > 30 cm H20 were exceeded in 23% and 18% of recorded ventilator parameters in placebo and surfactant subjects (p=0.93), respectively. Tidal volumes exceeded 8 cc/kg predicted body weight (PBW) of recorded ventilator settings in 17.6% of placebo and 12.5% of surfactant subjects (p=0.12).

Seven-day fluid accumulation was not significantly different between surfactant and placebo subjects but, as was seen in the pediatric subjects, there was a strong relationship between fluid accumulation and mortality (Figure 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=0.01). Variation in APACHE score accounted for only 2.3% of the variation in day 7 cumulative fluid balance.

11,051 adverse events were reported. One percent of adverse events were categorized by the site investigator as possibly related (116), probably related, (99), or related (17) to the study intervention. Hypoxia and/or hypotension during the study intervention were the most

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common (Table E2). Most of these AEs were rated as “mild” but there were seven “severe” adverse events felt possibly or probably related to the intervention, 6 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.

Discussion There was no immediate or longer-term benefit with calfactant administration. This contrasts with our previous pediatric studies30-32 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.1,47-50 There were no differences between study arms in secondary outcomes; ventilator free days, 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 wellestablished 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.47 Because of the importance of using standardized ventilator setting in judging severity of lung injury51,52, a minimum of 5 cm H2O of PEEP was required for study entry and investigators agreed to follow the ARDSnet 12

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ventilator protocol (including the FiO2/PEEP grid). Our results are consistent with findings in Berlin Consensus Conference and others.47,53-56

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 is limited to the 29 subjects from our first open label trial1-3. The optimal dose and timing of therapeutic surfactant in acute lung injury 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 SpO2/FiO2 (S/F) ratio when PaO2/FiO2 (P/F) ratio when arterial blood gases were not available in deference to the decreasing use of invasive monitoring and arterial blood gases, particularly in pediatric subjects. The relationship of SpO2/FiO2 to PaO2/FiO2 is essentially linear below an SpO2 of 97%4. This potentially allowed earlier study entry in the event arterial catheter placement was delayed, as well as qualification of subjects without such catheters.

Unlike our previous pediatric studies30-32 but consistent with the pediatric arm of this study46, there was no oxygenation benefit with calfactant administration. We chose to forego a

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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.57-59 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 al 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 minutes after instillation.60 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 to 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 14

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because neonatal data suggests that larger volumes of more dilute surfactant distribute more homogeneously5. 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 4 different positions and dividing the administration into 4 rather than 2 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 adverse events 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 intra-thoracic 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 adverse events were more commonly reported for the surfactant group because individuals performing the intervention could not actually be blinded. Immediate adverse events such as hypoxia, hypotension, or increased ventilator requirements are naturally more likely to be directly attributed to the witnessed instillation of surfactant compared to the placebo instillation of air. These observed adverse effects are well described in neonatal surfactant administration6,7. The study by Kesecioglu was stopped early for similar concerns of 15

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hypoxia and hypotension during surfactant administration.21 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.61 On this post hoc analysis it is not possible to ascertain if such fluid accumulation is a cause or consequence of the severity of acute lung injury. 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 non-statistical 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 ccs. Other studies have demonstrated an anti-inflammatory effect of exogenous surfactants8,9 so this in unlikely to relate to a pro-inflammatory effect of surfactant. Nonetheless, it is clear that the lung inflammation in acute lung injury is associated with capillary leak and, in the presence of pulmonary endothelial injury, lung water increases in direct proportion to venous pressure.62,63 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.50 Whether more aggressive fluid management

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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.50

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.30-32,64,65 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 intubated patients met criteria for ALI/ARDS, somewhat lower than Rubenfeld’s 26% from the Kings County study.66 Similar to the Kings County population, about half of the patients suffered from “direct” causes of ALI/ARDS.

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Many of these could not be recruited because of the coexistence of pre-existing lung disease (17%), significant other organ dysfunction (13%), or limitations of care/do not resuscitate orders (10%).

Conclusions 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.

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Hospital St Justine Riley Children’s Cincinnati Children’s Rosemount Hospital Royal Perth Royal Adelaide Westmeade Children’s Royal Children’s University of Florida Rabin Hospital University of British Columbia University of Virginia West Suburban Asan University of Tennessee – Memphis University of Iowa Medical College of Wisconsin Innova Surrey University of Texas San Antonio Laval Nation Wide Children’s University of Cincinnati Jackson Memorial Darwin Freemantle Haemek New York Hospital Princess Margaret Hospital Ohio State Women & Children’s Baylor University Royal Columbia Starship Children’s Pennsylvania State Creighton Dartmouth Queen’s University University of Illinois-Peoria Samsung Methodist University of Nebraska Oregon Clinic Florida Hospital Kingston General

Location Quebec Indiana Ohio Quebec Australia Australia Australia Australia Florida Israel British Columbia Virginia Illinois Korea Tennessee Iowa Wisconsin Virginia British Columbia Texas Quebec Ohio Ohio Florida Australia Australia Israel New York Australia Ohio Australia Texas British Columbia New Zealand Pennsylvania Nebraska New Hampshire Ontario Illinois Korea Indiana Nebraska Oregon Florida Ontario

IRB# & Org1 #2789 #0802-16 #2008-0473 #2789 (St. Justine) #2009/017 #081120 #08/CHW/96 28141 A 110788 Western IRB #5321 H08-01599 R112307 1099571 Western IRB 2008-0245 10-00837-FB 1105143 Western IRB PR00008773 #08.069 2009-006 Fraser Health REB #HSC20090167H 20348 IRB08-00105 #08-05-21-01 20071227 (U. Miami) 08155 09/2 EMC 0006-09 0806009859 (Cornell University) 1542/EP 2008H 0107 REC 2073 H-22548 2009-006 NTX/08/07/068 27879 08-14922 21231 2008676-01H 109593-12 2008-05-036 08-014 (University of Indiana) #571-0408 08-0408 FH 08.02.09 (Queen’s University) DMED 1186-09

1

All sites had approval from their own institutional Institutional Review Boards (IRBs) or Ethics Committess unless another Committee is identified.

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10 Seeger W, Pison U, Buchhorn R, et al. Surfactant abnormalities and adult respiratory failure. Lung 1990; 168 Suppl:891-902 11 Seeger W, Stohr G, Wolf HR, et al. Alteration of surfactant function due to protein leakage: special interaction with fibrin monomer. J Appl Physiol (1985) 1985; 58:326-338 12 Veldhuizen RA, McCaig LA, Akino T, et al. Pulmonary surfactant subfractions in patients with the acute respiratory distress syndrome. Am J Respir Crit Care Med 1995; 152:1867-1871 13 Seeger W, Grube C, Gunther A, et al. Surfactant inhibition by plasma proteins: differential sensitivity of various surfactant preparations. Eur Respir J 1993; 6:971-977 14 Gunther 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; 19:797-804 15 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; 105:195-202 16 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; 19:805-810 17 Walmrath D, Gunther 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; 154:57-62 18 Wiswell TE, Smith RM, Katz LB, et al. Bronchopulmonary segmental lavage with Surfaxin (KL(4)-surfactant) for acute respiratory distress syndrome. American journal of respiratory and critical care medicine 1999; 160:1188-1195

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19 Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsisinduced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. The New England journal of medicine 1996; 334:14171421 20 Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. American journal of respiratory and critical care medicine 1997; 155:1309-1315 21 Kesecioglu J, Beale R, Stewart TE, et al. Exogenous natural surfactant for treatment of acute lung injury and the acute respiratory distress syndrome. American journal of respiratory and critical care medicine 2009; 180:989-994 22 Spragg RG, Lewis JF, Walmrath H-D, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. The New England journal of medicine 2004; 351:884-892 23 Spragg RG, Taut FJH, Lewis JF, et al. Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury. American journal of respiratory and critical care medicine 2011; 183:1055-1061 24 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; 17:247-251 25 Herting E, Möller O, Schiffmann JH, et al. Surfactant improves oxygenation in infants and children with pneumonia and acute respiratory distress syndrome. Acta paediatrica 2002; 91:1174-1178 26 Lopez-Herce J, de Lucas N, Carrillo A, et al. Surfactant treatment for acute respiratory distress syndrome. Arch Dis Child 1999; 80:248-252

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27 Luchetti M, Casiraghi G, Valsecchi R, et al. Porcine-derived surfactant treatment of severe bronchiolitis. Acta anaesthesiologica Scandinavica 1998; 42:805-810 28 Luchetti M, Ferrero F, Gallini C, et al. Multicenter, randomized, controlled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2002; 3:261-268 29 Moller JC, Schaible T, Roll C. Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study. Inten Care Med 2003; 29:437-446 30 Willson DF, Jiao JH, Bauman LA, et al. Calf's lung surfactant extract in acute hypoxemic respiratory failure in children. Critical care medicine 1996; 24:1316-1322 31 Willson DF, Thomas NJ, Markovitz BP, et al. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA : the journal of the American Medical Association 2005; 293:470-476 32 Willson DF, Zaritsky A, Bauman LA, et al. Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure. Members of the Mid-Atlantic Pediatric Critical Care Network. Critical care medicine 1999; 27:188-195 33 Auten RL, Notter RH, Kendig JW, et al. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics 1991; 87:101-107 34 Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics 1996; 97:48-52 35 Khammash H, Perlman M, Wojtulewicz J, et al. Surfactant therapy in full-term neonates with severe respiratory failure. Pediatrics 1993; 92:135-139

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36 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. The Journal of pediatrics 1993; 122:261-268 37 Lotze A, Mitchell BR, Bulas DI, et al. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. The Journal of pediatrics 1998; 132:40-47 38 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. Proceedings of the National Academy of Sciences of the United States of America 1995; 92:77947798 39 Ikegami M, Whitsett JA, Martis PC, et al. Reversibility of lung inflammation caused by SP-B deficiency. American journal of physiology. Lung cellular and molecular physiology 2005; 289:L962-970 40 Mizuno K, Ikegami M, Chen CM, et al. Surfactant protein-B supplementation improves in vivo function of a modified natural surfactant. Pediatric research 1995; 37:271-276 41 Oosterlaken-Dijksterhuis MA, van Eijk M, van Golde LM, et al. Lipid mixing is mediated by the hydrophobic surfactant protein SP-B but not by SP-C. Biochimica et biophysica acta 1992; 1110:45-50 42 Revak SD, Merritt TA, Degryse E, et al. Use of human surfactant low molecular weight apoproteins in the reconstitution of surfactant biologic activity. The Journal of clinical investigation 1988; 81:826-833 43 Seeger W, Gunther A, Thede C. Differential sensitivity to fibrinogen inhibition of SP-C- vs. SP-B-based surfactants. Am J Physiol 1992; 262:L286-291

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44 Wang Z, Baatz JE, Holm BA, et al. Content-dependent activity of lung surfactant protein B in mixtures with lipids. American journal of physiology. Lung cellular and molecular physiology 2002; 283:L897-906 45 Wang Z, Gurel O, Baatz JE, et al. Differential activity and lack of synergy of lung surfactant proteins SP-B and SP-C in interactions with phospholipids. Journal of lipid research 1996; 37:1749-1760 46 Willson DF, Thomas NJ, Tamburro R, et al. The Pediatric Calfactant in Acute Respiratory Distress Syndrome (CARDS) Trial. Pediatr Crit Care Med 14. 2013:657-665 47 Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. The New England journal of medicine 2004; 351:327-336 48 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; 307:795-803 49 Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. The New England journal of medicine 2006; 354:1671-1684 50 Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of Two Fluid-Management Strategies in Acute Lung Injury. 2006; 354:2564-2575 51 Ferguson ND, Kacmarek RM, Chiche J-D, et al. Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial. Intensive care medicine 2004; 30:1111-1116

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52 Villar J, Pérez-Méndez L, López J, et al. An early PEEP/FIO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome. American journal of respiratory and critical care medicine 2007; 176:795-804 53 Ards. The Task Force. Acute Respiratory Distress Syndrome The Berlin Definition JAMA 2012; 307:2526-2533 54 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 : the journal of the American Medical Association 2010; 303:865-873 55 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. Circulation. Arrhythmia and electrophysiology 2013; 6:843-850 56 Lu S, Cai S, Ou C, et al. Establishment and evaluation of a simplified evaluation system of acute respiratory distress syndrome. Yonsei medical journal 2013; 54:935-941 57 Brower RG, Morris A, MacIntyre N, et al. Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure. Crit Care Med 2003; 31:2592-2597 58 Fan E, Wilcox ME, Brower RG, et al. Recruitment maneuvers for acute lung injury: a systematic review. American journal of respiratory and critical care medicine 2008; 178:1156-1163 59 Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. The New England journal of medicine 2006; 354:17751786

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60 Lu Q, Zhang M, Girardi C, et al. Computed tomography assessment of exogenous surfactantinduced lung reaeration in patients with acute lung injury. Critical care 2010; 14:R135 61 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 14. 2013 SRC - GoogleScholar:666-672 62 Sibbald WJ, Short AK, Warshawski FJ, et al. 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; 87:585-592 63 Ware LB, Matthay MA. The acute respiratory distress syndrome. The New England journal of medicine 2000; 342:1334-1349 64 Notter RH. Lung surfactants: Basic science and clinical applications. New York Marcel Dekker Inc 2000 65 Wang Z HB, Matalon S, Notter RH. . Lung injury: Mechanisms, pathophysiology, and therapy. . Boca Raton: Taylor Francis Group, Inc., 2005; 297-352 66 Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. The New England journal of medicine 2005; 353:1685-1693

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Table 1. Baseline Characteristics Demographic Data Age, years; mean (SD) Male, N (%) Primary diagnosis, N (%) Viral pneumonia Bacterial Pneumonia Aspiration Pneumonia Other APACHE Scores, Mean (SD) High Risk, N (%) Immune Compromised, N (%) Influenza A, N (%) N1N1 Strain, N (%)

Placebo (n = 157) Surfactant (n = 151) 54 (16) 55 (15) 85 (54%) 80 (53%) 41 (26%) 55 (35%) 44 (28%) 17 (11%) 60 (28) 81 (52%) 42 (27%) 28 (18%) 23 (15%)

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41 (27%) 60 (40%) 38 (25%) 12 (8%) 63 (31) 72 (48%) 33 (22%) 20 (13%) 18 (12%)

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Table 2. Study outcomes. Outcomes Placebo (n = 157) Surfactant (n = 151) P In-hospital Mortality (all) 40 (25.5%) 42 (27.8%) 0.64 90-day mortality 41 (26.1%) 42 (27.8%) 0.74 Ventilator-free days at day 28 13.0 (9.8) 12.5 (9.9) 0.64 ICU-free days at day 28 8.5 (8.7) 7.8 (8.5) 0.69 Hospital-free days at day 28 4.6 (6.7) 4.5 (6.7) 0.77 Discharge outcomes 0.78 Discharged on no oxygen 83 (53%) 80 (53%) Discharged on oxygen only 25 (16%) 20 (13%) Discharged on ventilator 8 (5%) 9 (6%) Died 41 (26%) 42 (28%) Tracheostomy 38 (24%) 37 (25%) 0.95 Day 7 Cumulative Fluid balance 1190 2363 0.60 (med) Ventilator-free, ICU-free and hospital-free days are set to 0 for patient who died. P-value for categorical outcomes by chi-squared test; p-values for continuous outcomes by Wilcoxon test.

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Figure Legends Figure 1: Flow Chart for Subject Entry into CARDS Trial Figure 2a and 2b: Change in Oxygenation after Intervention (A) Change in PaO2/FIO2 ratio when PaO2 is estimated from SpO2. (using same formula as in pediatrics paper for SpO2 > 80% and SpO2 < 97%). Time 0: Surfactant N = 135, placebo N=147; Time 1 hour: Surfactant N=133, Placebo N=145; Time 2 hours: Surfactant N=129, Placebo N=140; Time 4 hours: Surfactant N= 134, Placebo N=142; Time 8 hours: Surfactant N=138, Placebo N=147; Time 12 hours: Surfactant N=136, Placebo N=143 (B) Change in PaO2/FIO2 ratio when the ratio was available. Time 0: Surfactant N=82, Placebo N=88; Time 1 hour: Surfactant N=74, Placebo N=76; Time 2 hours: Surfactant N=80, Placebo N=73; Time 4 hours: Surfactant N=87, Placebo N=76; Time 8 hours: Surfactant N=84, Placebo N=90; Time 12 hours: Surfactant N=84, Placebo N=86. Figure 3: The Relationship of Fluid Balance and Mortality. Day 7 cumulative balance is in units of L per M2. For patients who died before day 7, the cumulative fluid balance was taken as the last recorded cumulative balance (based on 80 deaths and 223 survivors; fluid balance missing in 5 subjects). The results indicate that each 1000 ml of cumulative fluid balance is associated with and increased odds of death by a factor of 1.19.

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Collaborating Institutions in Order of Subjects Enrolled Institution Florida Hospital Ottawa Hospital Northwestern

Location Orlando, FL Ontario, Ca Chicago, IL

Asan Medical Center

Seoul, S. Korea

Samsung Medical Center Rabin Medical Center Oregon Health Center Inova Fairfax University of Florida Vancouver Hospital Dartmouth-Hitchcock Methodist Hospital UT Health Center University of Iowa West Suburban Hospital

Seoul, S. Korea Petah Tikva, Israel Portland, Oregon Fairfax, VA Gainsville, FL Vancouver, Br.Columbia Hanover, NH Indianapolis, IN San Antonio, TX Iowa City, Iowa Chicago, IL

Creighton University Illinois Lung Institute Medical College of Wisconsin Ohio State Royal Adelaide Auckland City Penn State Medical Center Royal Columbian Rosemount Royal Darwin University of Virginia VA Medical Center Kingston General London Health Center

Omaha, Nebraska Peoria, IL Milwaukee, WI Columbus, Ohio Adelaide, Australia Auckland, NZ Hershey, PA Vancouver, CA Quebec, CA Darwin, Australia Charlottesville, VA San Antonio, Tx Kingston, Ontario London, Ontario

Fremantle Hospital Laval Hospital Nebraska Medical Center Royal Perth Hospital University of Cincinnati

Perth, Australia Quebec, CA Omaha, Nebraska Perth, Australia Cincinnati, Ohio

Site Primary Investigators Michael Rodricks, MD Gwynne Jones, MD Sarice Bassin, MD and Rich Wunderrink, Chae-Man Lim, MD Younsuck Koh, MD Geeyoung Suh, MD Pierre Singer, MD Rhett Cummings, MD James Lamberti, MD Eloise Harman, MD Juan Ronco, MD Harold L. Manning, MD Christopher Naum, MD Antonio Anzueto, MD Gregory Schmidt, MD Tony Marinelli, MD Benjamin Margolis, MD Lee Morrow, MD William P. Tillis, MD Rahul Nanchal, MD James O’Brien, MD Marianne Chapman, MD Colin McArthur, MD Sandy Blosser, MD Steven Reynolds, MD Brian Laufer, MD Diane Stephens, MD Jonathon Truwit, MD Virginia Doyal, MD John Muscedere, MD Claudio Martin, MD Alik Kornecki, MD David Blythe, MD Francois Lellouche, MD Ed Truemper, MD Geoff Dobb, MD Richard Branson, MD

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142x154mm (72 x 72 DPI)

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112x85mm (72 x 72 DPI)

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112x85mm (72 x 72 DPI)

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The Relationship of Fluid Balance and Mortality. Day 7 cumulative balance is in units of L per M2. For patients who died before day 7, the cumulative fluid balance was taken as the last recorded cumulative balance (based on 80 deaths and 223 survivors; fluid balance missing in 5 subjects). The results indicate that each 1000 ml of cumulative fluid balance is associated with and increased odds of death by a factor of 1.19. 151x115mm (72 x 72 DPI)

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Hospital St Justine Riley Children’s Cincinnati Children’s Rosemount Hospital Royal Perth Royal Adelaide Westmeade Children’s Royal Children’s University of Florida Rabin Hospital University of British Columbia University of Virginia West Suburban Asan University of Tennessee – Memphis University of Iowa Medical College of Wisconsin Innova Surrey University of Texas San Antonio Laval Nation Wide Children’s University of Cincinnati Jackson Memorial Darwin Freemantle Haemek New York Hospital Princess Margaret Hospital Ohio State Women & Children’s Baylor University Royal Columbia Starship Children’s Pennsylvania State Creighton Dartmouth Queen’s University University of Illinois-Peoria Samsung Methodist University of Nebraska Oregon Clinic Florida Hospital Kingston General

Location Quebec Indiana Ohio Quebec Australia Australia Australia Australia Florida Israel British Columbia Virginia Illinois Korea Tennessee Iowa Wisconsin Virginia British Columbia Texas Quebec Ohio Ohio Florida Australia Australia Israel New York Australia Ohio Australia Texas British Columbia New Zealand Pennsylvania Nebraska New Hampshire Ontario Illinois Korea Indiana Nebraska Oregon Florida Ontario

IRB# & Org1 #2789 #0802-16 #2008-0473 #2789 (St. Justine) #2009/017 #081120 #08/CHW/96 28141 A 110788 Western IRB #5321 H08-01599 R112307 1099571 Western IRB 2008-0245 10-00837-FB 1105143 Western IRB PR00008773 #08.069 2009-006 Fraser Health REB #HSC20090167H 20348 IRB08-00105 #08-05-21-01 20071227 (U. Miami) 08155 09/2 EMC 0006-09 0806009859 (Cornell University) 1542/EP 2008H 0107 REC 2073 H-22548 2009-006 NTX/08/07/068 27879 08-14922 21231 2008676-01H 109593-12 2008-05-036 08-014 (University of Indiana) #571-0408 08-0408 FH 08.02.09 (Queen’s University) DMED 1186-09

1

All sites had approval from their own institutional Institutional Review Boards (IRBs) or Ethics Committess unless another Committee is identified.

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On line supplement for The Adult Calfactant in Acute Respiratory Distress Syndrome (CARDS) Trial Douglas F. Willson, MD*; Jonathon D. Truwit, MD, MBA*; Mark R. Conaway, PhD; Christine S. Traul, MD; Edmund E. Egan, MD

*co-first authors

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Detailed Explanation for Stopping the Trial The study was stopped at a point where 41 deaths were observed out of 157 patients in the placebo group and 42 deaths were observed out of 151 patients in the surfactant group. Methods based on stochastic curtailment or conditional power can be used to estimate the probability, under different assumptions about the true probabilities of 90day mortality in each group, that the null hypothesis will be rejected after accruing the remaining 383 (540 - 157) patients to the placebo group and 389 patients to the surfactant group. Assuming that the rates under the alternative hypothesis hold (25% in the placebo group and 18% in the surfactant group), there is a 38% chance that the null hypothesis will be rejected at the end of the study (1080 patients). We note that a 95% confidence interval for the difference in the proportion of deaths by 90 days has, as its upper limit, a 7.5% decrease in mortality with surfactant, meaning that, given the results observed at the time the study was stopped, the 7 percentage point difference stated in the alternative hypothesis was an optimistic estimate of the effect of surfactant. If we assume surfactant decreases 90-day mortality by 5 percentage points, the probability of rejecting the null hypothesis after accruing 540 per group is only 18%. If the true rates were equal to the observed rates at the time the study was stopped, the probability of rejecting the null hypothesis in favor of surfactant was less than 1%.

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Table E1: Factors Associated with Mortality Odds Ratio Estimates Effect

Point Estimate

95% Wald Confidence Limits

P

Age

1.025

1.005

1.046

0.0138

Apache Score

1.006

0.996

1.017

0.2384

Initial PaO2/FiO2 ratio

0.992

0.985

0.998

0.0077

First patient at Site

0.787

0.373

1.662

0.5302

High Risk*

1.198

0.544

2.636

0.6535

Immune Compromised

4.070

1.870

8.861

0.0004

Calfactant 1.241 0.700 2.201 0.4592 * High-risk subjects were immune compromised or had an initial PaO2/FiO2 or SpO2/FiO2 < 100 or an oxygenation index > 30.

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Table E2: Adverse Events Judged Possibly or Probably Related to the Study Intervention Event Respiratory Hypoxia/desaturation Hypercarbia/acidosis Increased ventilator requirements Bronchospasm/atelectasis/secretions Air leaks Pulmonary hemorrhage Hemodynamic Hypotension Bradycardia Hypertension Tachycardia Cardiac arrest Atrial fibrillation Premature ventricular contractions Miscellaneous Leukocytosis/leukopenia Electrolyte disturbance Hyperglycemia Fever/hypothermia Other (renal failure; DVT*, anemia, increased secretions, + respiratory culture, increased LFTs**) * Deep venous thrombosis ** Liver function tests

Surfactant

Placebo

20 3 3 7 2 1

15 4 2 2 0 0

15 1 2 3 1 1 1

2 0 0 0 0 0 0

9 10 2 1 6

0 1 1 3 0

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Figure Legends Figure E1 Simplified FACT Algorithm for Fluid Management(50) Figure E2: Ventilator Guidelines adapted from ARDSnet guidelines(1)

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Figure E1

Clinical Shock or Mean Arterial Pressure (MAP) < 60 mmHg: Fluid resuscitation and/or inotropes as per clinician discretion MAP > 60 mmHg and no vasopressors

CVP > 8 mmHg Urine output (UO) .< 0.5 cc/Kg/hr

Furosemide & reassess in 1 hr

CVP 4-8 mmHg U.O.< 0.5 cc/Kg/hr

Fluid & reassess in 1 hr

CVP 4-8 mmHg U.O.> 0.5 cc/Kg/hr

Furosemide & reassess in 4 hrs

CVP < 4mmHg U.O.> 0.5 cc/Kg /hr

Observe & reassess in 4 hrs

CVP < 4mmHg U.O.< 0.5 cc/Kg/hr

Fluid & reassess in 1 hr

Notes: 1. Fluid bolus = 15 ml/Kg isotonic crystalloid or 10 ml/Kg PRBCs (one unit in adults) or 0.5 gm/Kg albumin 2. Furosemide dosing = begin with 0.3 mg/Kg or 0.1 mg/Kg/hr infusion or last known effective dose. Double each subsequent dose until goal achieved (oliguria reversal or intravascular pressure target) or maximal infusion rate of 0.3 mg/Kg/hr or bolus dose of 2 mg/Kg (adult doses maximum of 24 mg/hr or 160 mg bolus). Do not exceed 12 mg/Kg/day. Hold furosemide if creatinine > 3 mg/dl, acute tubular necrosis present, or continuous renal replacement to be provided. 3. Consider inotrope treatment for patients with evidence of cardiac failure. 4. Daily total fluid input and output should be recorded on study database for first 7 days.

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Figure E2

Oxygenation

Ventilation

PaO2 50-80 mmHg &/or O2 Sats 85-92%

pH 7.25-7.45

PaO2 < 50 mmHg and/or sat < 85%

PaO2 > 80 mmHg and/or O2 sats > 92%

In tandem, increase PEEP/FiO 2 by chart

In tandem, decrease PEEP/FiO 2 by chart

FiO2 .30 PEEP 5

.40 6

.40 8

.50 10

.60 10

.70 10

FiO2 .70 PEEP 12

.80 14

.90 14

.90 14

1.0 16

1.0 18

If PaO2/FiO2 < 150 and decreasing consider HFOV

1.0 20

Volume Recruitment Maneuver with suctioning or disconnects: Sustained inflation (30-40 secs) At higher pressure (30-40 cmH2O)

pH < 7.25

Increase ventilator rate by 2-4 bpm until pH > 7.25

pH > 7.45

Decrease ventilator rate by 2 -4 bpm to a minimal bpm while maintaining respiratory rate goal.

Respiratory Rate Goal < 6 mos: 20-60 bpm 6 mos – 2 years: 15 - 45 2-5 yrs: 15 – 40 5-13 yrs: 10 - 35 > 13 yrs: 10-25

Accept lower pH range Or if HCO3 < 32 may Give NaHCO3 to buffer pH > 7.25 or may increase Vt to 8ml/kg if Vd/Vt > 0.7

Switch to straight PS (Minimal PS + 2 cmH2O) t o maintain Vt at 6 ml/Kg

An FiO2 of 1.0 may be used briefly (< 10 mins) to manage transient desaturation

Additional Notes 1. Weaning should be considered as soon as the patient is improving as evidenced by decreasing FiO2 requirements and decreasing ventilator pressures. Keys to weaning include daily evaluation to decrease pressure and/or FiO2 as well as assessment of sedation level. 2. In light of the fact that many patients are ready to extubate by the time they are evaluated for weaning, consider a daily “drug holiday” to allow sedation to lighten and a daily “spontaneous breathing trial” to evaluate suitability for weaning and/or extubation when and if appropriate. 3. Successful weaning and extubation requires 48 hours off positive pressure ventilatory support. CPAP alone does not constitute ventilatory support but cycled non-invasive positive pressure does (e.g., BIPAP)

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