Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome.

Spragg RG, Lewis JF, Walmrath HD, et al.

New Engl J Med 2004; 351:884-892. [abstract]

Reviewed by Faraz Norozian MD, Pediatric Intensive Care, Miami Children's Hospital, Miami, Florida

Review posted December 27, 2005

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I. What is being studied?:

The study objective:

To determine the effect of Recombinant Surfactant Protein C-Based Surfactant on number of ventilator free days in adult patients with Acute Respiratory Distress Syndrome (ARDS).

The study design:

Two independent multi-center, randomized, parallel-group, double blind, controlled, prospective trials, (one in 54 sites in North America and the other in 55 sites in Europe and South Africa).

The patients included:

A total of 448 patients were included in two separate studies during the period between October 1999 and September 2000. The inclusion criteria included the diagnosis of ARDS according to the criteria of American-European Consensus Conference on ARDS and a requirement of endotracheal intubation and mechanical ventilation with a positive end-expiratory pressure (PEEP) of at least 5 cm of water.

Patients with a variety of conditions associated with the development of ARDS were enrolled in the study.

The patients excluded:

The author did not mention any preset exclusion criteria. A single patient had a serious adverse event during baseline period and was not treated and was not included in the data analysis.

The interventions compared:

This was a phase 3 randomized control trial of exogenous surfactant in ARDS. The protocol for surfactant therapy used in this study was derived from the preclinical phases.

The control group: Patients received standard therapy for ARDS.

The experimental group: Patients received standard therapy plus up to four intra-tracheal instillations of recombinant surfactant protein C-based surfactant. After the first dose, the subsequent three doses were administered at 4-hour intervals within a period of 24 hours if the PaO2: FiO2 ratio was in the range of 60-240 mmHg and the patient remained intubated and mechanically ventilated with a PEEP of at least 5 cm of water. The investigators were urged not to change ventilator settings during the first 24 hours after treatment unless changes were required for the patient's safety.

The outcomes evaluated:

The primary outcome: the number of ventilator-free days, defined as the number of days the patient was alive and not receiving mechanical ventilation during the 28 days after treatment.

The secondary outcomes:

1. Improvement in oxygenation.
2. The percentage of patients alive on day 28.
3. The percentage of patients weaned from ventilation by day 28.
4. The changes in ventilatory variables (tidal volume, PEEP, FiO2, PaO2: FiO2, end-expiratory plateau pressure, and other ventilation variables).
5. Scores on the Acute Physiology and Chronic Health Evaluation (APACHE II) and the Sequential Organ-Failure Assessment (SOFA); and vital signs.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were randomly assigned in a 1:1 ratio to either experimental or control groups. A good randomization method includes a true random allocation and a procedure of randomization that is tamperproof so that neither intentional nor unintentional biases can influence the allocation process. The exact method of randomization in the study was not mentioned in the manuscript.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. All patients except one were followed for the duration of hospitalization up to 28 days. All the variables included in the study were followed for the duration of the trial. The 28-day outcome may not be sufficient, as patients discharged from the ICU's are known to have increase mortality up to 6 months to one year after discharge.

Were patients analyzed in the groups to which they were randomized?

Yes. All patients were analyzed in the group they were randomized to. All analyses were conducted according to intention-to-treat principal. One patient did not receive treatment because of adverse events during baseline period. This patient was not included in the study.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. Both investigators and patients were blinded to study medication. To maintain blinding, surfactant was delivered from a syringe in the weighted blinding bag. In the control group the blinding bag absorbed the study medication, whereas in the surfactant group, the study medication reached the patient's trachea through the opaque tubing. In addition physicians responsible for weaning patients from the ventilator were absent at the time of study drug administration.

4. Were the groups similar at the start of the trial?

The groups were similar at baseline with respect to age, sex, vital signs, ABG's, ventilatory variables, SOFA scores, and factors predisposing patients to the onset of ARDS. Although, treatment had to be initiated no later than 48 hours after the diagnosis in the North American study and no later than 72 hours in the European and South African study, the mean intervals from the time of diagnosis to enrollment were similar in both groups. Although the mean APACHE II scores were similar in the two groups, number of patients with a score above 23 was significantly higher in the surfactant group than in the control group (P=0.007). This difference might be expected to favor the control group.

5. Aside from the experimental intervention, were the groups treated equally?

Unknown. Authors state that all other aspects of care were similar, although specific data were not provided regarding patient management such as fluid therapy, inotropic support, nutrition, antibiotic therapy, and sedation protocol. Sedation protocol could have a significant impact on the success of weaning from mechanical ventilation. The authors only mentioned that low tidal volume ventilation strategy and an established weaning protocol were followed in the management of patients in both groups. However, there was no mention of the degree of compliance with their protocols.

III. What were the results?

1. How large was the treatment effect?

1. No significant treatment effect with surfactant was noted for the number of ventilator-free days for the pooled data (for 2 sites of clinical trials). European and South African studies report 0 median days for both groups. North American study shows a decrease from median 6 ventilator free days for the control group to median 3.5 ventilator free days for the surfactant group with a similar 68% range (0 to 26). The RR of additional mechanical ventilation (not precisely defined) was 0.94, 95% CI 0.78, 1.13, indicating no treatment effect.
2. In the pooled data, oxygenation improved as evidenced by increasing in the area under the PaO2: FiO2 time curve from baseline to 24 hours in surfactant group (674 ±1229 vs. 369± 900; P=0.003; univariate analysis). The mean difference in the area under curve from baseline to 24 hours between control and surfactant groups was 331 mmHg in multivariate analysis (95 percent confidence interval, 137 to 525 mmHg)
3. The average PaO2: FiO2 values in pooled data were significantly higher in surfactant group during 4-24 hours after the first treatment but not significantly different at 48 hours.
4. The survival rate at the end of 28 days also did not differ between the groups (68 percent in control vs. 64 percent in surfactant group).
5. Using logistic-regression model, the study site (North American vs. European and South African: P=0.001; odds ratio for death, 0.48; 95 percent CI, 0.31 to 0.74), APACHE II scores (P=0.001; odds ratio, 1.06; 95 percent CI, 1.02 to 1.10), age (P<0.001;odds ratio, 1.04; 95 percent CI, 1.02 to 1.05), and the baseline PaO2: FiO2 value (P=0.07; odds ratio, 0.995; 95 percent CI, 0.989 to 1.001), were shown to effect survival rate at 28 days. This may indicate that severe lung disease and older patients were more likely to die than less ill and younger patients. The results also suggest lower mortality in the North American study group that in the European and South African study group.
6. During the first 24 hours after the initial treatment, 51 of the 224 patient receiving surfactant (23 percent) and 11 of the 224 patients receiving standard therapy (5 percent) had adverse events that were probably or definitely related to treatment (P<0.001).

Post Hoc Analysis of Direct versus Indirect ARDS:

1. In patients with ARDS due to direct lung injury (pneumonia and gastric aspiration), surfactant decreased mortality (p=0.05; odds ratio for death in the surfactant group compared with the control group, 0.49; 95 percent CI, 0.24 to 1.00; Backward-selection logistic model) Other factors significant in this analysis include, APACHE score (P=0.002; odds ratio, 1.09; 95 percent confidence interval, 1.03 to 1.15), age (p<0.001; odds ratio, 1.05; 95 percent confidence interval, 1.03 to 1.07), and presence or absence of pneumonia as a predisposing event (P=0.003; odds ratio, 0.05; 95 percent confidence interval, 0.01 to 0.37).
2. In patients with ARDS due to indirect lung injury, the mortality was 41 percent in surfactant group and 28 percent in control group (p=0.04 by the chi-square test). The interaction between treatment and cause of ARDS (direct versus indirect) was significant (P=0.002) for mortality and not for ventilator free days. However, exact model used for this analysis was not mentioned in the manuscript. Using the data presented in the manuscript, the calculated relative risk of death with surfactant treatment in patients with ARDS due to indirect causes is 1.48 with relative and absolute risk increase of 48% and 13% respectively.
3. The results of post hoc analysis may reveal some associations just by chance alone as so many analyses were done. They should be viewed cautiously.

2. How precise was the estimate of the treatment effect?

A sample size of 110 patients per group was chosen in each of the two studies to provide each study with a statistical power of 80 percent to detect a mean (±SD) difference between groups of 4 ± 10 ventilator-free days. The authors enrolled 221 patient in the North American study and 227 patients in the European and South African study. For the primary outcome, the ventilator-free days surfactant did not have any significant effect with a RR 0.94 (95 percent CI, 0.78 to 1.13; P=0.51). The treatment effect is reasonably precise due to a narrow confidence interval and we can be 95% confident that the true RR of additional mechanical ventilation from treatment could be as low as 0.78 or as high as 1.13.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

All patients included in the study are adults and one needs to be careful in extrapolating these results to pediatric population. There is no evidence in this study to support the use of surfactant for all children with ARDS. However, the study shows transient improvement in oxygenation. The use of surfactant beyond first 24 hours is worth investigating. Post hoc analysis revealed improved mortality with surfactant in ARDS patients due to direct lung injury and worsened mortality in ARDS patients due to indirect lung injury.

Recently, Wilson et al (1) showed that surfactant acutely improved oxygenation and significantly decreased mortality in infants, children, and adolescents with ALI although no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was observed. Pediatric ARDS studies stratifying direct and indirect lung injury must be done before any firm conclusion about surfactant use in ARDS in children can be made.

2. Were all clinically important outcomes considered?

Authors have included several clinically important outcomes in the study but failed to include some commonly measured outcomes such as length of ICU and hospital stay.

3. Are the likely treatment benefits worth the potential harms and costs?

No. Except improvement in oxygenation surfactant has not shown any benefit in the treatment of all ARDS patients. Transient improvement in oxygenation has not proven to improve, thus far, the mortality or any other relevant clinical benefits. There were significant adverse effects in the form of hypoxemia and hypotension with surfactant therapy (23% versus 5%). Absolute risk increase of adverse events due to surfactant therapy is 18% with number need to harm is 5.5.

There appears to be increased mortality with surfactant in subgroup of patients with ARDS due to indirect lung injury. Surfactant may be beneficial in ARDS patients with direct lung injury. The study was not intended to study cost effectiveness of the therapy and cost of the therapy was not reported.

References:

1. Willson DF, Thomas NJ, Markovitz BP et al. Effect of Exogenous Surfactant (Calfactant) in Pediatric Acute Lung Injury: A Randomized Controlled Trial. JAMA 2005;293 470-476 [abstract]; PedsCCM EB Journal Club Review, by A Shieh Czaja

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