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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Surfactant treatment for acute respiratory distress syndrome

López-Herce J, de Lucas N, Carrillo A, Bustinza A, Moral R.

Arch Dis Child 1999;80:248-252. [abstract]

Reviewed by Joel Barron, MD and Andrianik Madikians, MD, UCLA, Los Angeles, CA

Review posted May 30, 2001

I. What is being studied?:

The study objective:

To determine prospectively the effectiveness of surfactant in acute respiratory distress syndrome (ARDS).

The study design:

Prospective, non-randomized, uncontrolled, unblinded clinical trial. The authors do not identify the study as prospective, nor do they state that it was retrospective

The patients included:

Twenty patients (13 boys and 7 girls) aged 1 month to 16 years diagnosed with severe ARDS, defined as "an acute pulmonary disease, non-cardiogenic in origin, with diffuse bilateral infiltrates on the chest x-ray, and hypoxemia with a PaO2/FiO2 lower than 200 mm Hg."

Patients were divided into two study groups: 13 patients with ARDS secondary to pulmonary or systemic disease and 7 patients with pulmonary pathology (ARDS) in the postoperative period of cardiovascular surgery not believed to be the result of cardiac pathology. The assessment of ARDS in the postoperative cardiac patients was supported by clinical history, chest x-ray, and echocardiography, although pulmonary artery pressure data was not universally available.

The patients excluded:

No specific data was offered regarding patients excluded from the study.

The interventions compared:

Patients were also divided into treatment groups. Fourteen patients received one to six doses of porcine surfactant given at 50 mg/kg at intervals of between six and 24 hours. The remaining six patients were given surfactant at doses of 200 mg/kg, in nine doses. The authors did not explain how patients were assigned to treatment groups.

The outcomes evaluated:

The primary outcome evaluated was an increase in PaO2/FiO2 ratio in the first four hours after surfactant administration, without modification of respiratory support. An increase in PaO2/FiO2 > 20% was considered a positive effect. Other outcomes evaluated include oxygenation index (OI; mean airway pressure x FiO2 x 100/PaO2), change in PaCO2, and mortality.

II. Are the results of the study valid?

1. Is there a strong, independent, consistent association between the surrogate end point and the clinical end point?

The oxygenation index or "pressure cost of oxygenation" in adults has been significantly correlated with mortality in ARDS, and has proven to confer predictive value for survival(1). An improvement in the OI could therefore conceivably improve outcome.

2. Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently led to improvement in the target outcome?

Inhaled nitric oxide (iNO) has been studied in patients with ARDS. Several studies demonstrate the efficacy of iNO in increasing the PaO2/FiO2 ratio, but these do not report improved rates of mortality. Therapeutic trials with several other drugs and modalities have been unsuccessful and thus fail to show that improvement in oxygenation leads to a decrease in mortality (2).

Lung protective strategies of mechanical ventilation (PEEP above lower inflection point on pressure-volume curve, permissive hypercapnia, tidal volumes < 6cm/kg, and peak airway pressures < 40 cm H2O) have demonstrated improved over all survival rates than patients managed with conventional ventilation strategies. In one such trial, Amato et al documented improvement in oxygenation and 28 day survival rate using this method of ventilation (3). This group did not, however demonstrate a significantly higher rate of survival to hospital discharge.

The most recent multicenter NIH trial evaluating lower tidal volumes showed a significant mortality reduction in the treatment group; however the PaO2/FiO2 ratios were lower in the treatment group early in their treatment course (4). This calls into question the predictive ability of the PaO2/FiO2 ratio in the setting of at least this particular therapeutic regimen.

3. Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently led to improvement in the target outcome?

Willson et al demonstrated improvement in oxygenation and earlier extubation in pediatric patients with acute hypoxemic respiratory failure treated with intratracheal calf lung surfactant (5). This group, however, did not find a significant decrease in mortality or length of hospitalization. A large, prospective, multicenter, double blind, randomized, placebo-controlled study of aerosolized surfactant replacement in patients with ARDS and sepsis demonstrated no benefit in terms of improvement in oxygenation or survival (6).

In a randomized, controlled, open-label trial, Gregory et al found improvement in oxygenation as well as survival in a group that received 100 mg phospholipid/kg surfactant (p = 0.075) (7). Surfactant administration in ARDS appears to improve oxygenation, as is shown in multiple studies. Improved survival, however, has yet to be firmly linked to this surrogate outcome.

IIa. Validity Questions for Therapy Articles:

Primary questions:

1. Was the assignment of patients to treatments randomized?

Patients were not randomized to treatment groups. There was no control group.

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

Was followup complete? and were patients analyzed in the groups to which they were randomized?

All patients who entered the trial were accounted for and attributed at its conclusion. Followup data was complete for all patients. Patients were not randomized into study or treatment groups.

Secondary questions:

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

The authors do not report "blinding" of personnel to aspects of treatment.

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

As there was no control group in this study, one cannot compare control to treatment group. There were, however, two arms of the study group, patients in the postoperative period of cardiovascular surgery and those who were not. The postoperative cardiac surgical patients were as a group younger and consisted of only male patients, as compared to the patients with pulmonary or systemic disease. The two groups were similar with respect to acute lung injury score.

Oxygenation index (OI) was calculated for both groups. The mean OI for patients with pulmonary or systemic disease was 36.9, standard deviation 16.6. The mean OI for patients with cardiac disease was 32.1, standard deviation 13.9.

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

The authors relate standard practices of mechanical ventilation in their patients with ARDS: I:E ratio of 1:2 to 3:1, PEEP and FiO2 adjusted to maintain oxygen saturation of 85%-90% and PaO2 greater than 50-60 mm Hg, permissive hypercapnia up to PaCO2 85-90 mm Hg, and maintenance of pH higher than 7.15-7.20. Changes in ventilator parameters were made according to arterial blood gas measurements, whenever possible.

Postoperative cardiac surgical patients were treated differently with regard to mechanical ventilation if they were found to have pulmonary hypertension. Target pH was maintained between 7.45 and 7.50, and other agents used include prostaglandin infusion and inhaled nitric oxide (iNO). Eight patients outside the postoperative cardiac group received iNO at a dose concentration between 3 and 25 ppm, but there is no discussion of how these patients were selected for treatment.

III. What were the results?

1. How large, precise, and lasting was the treatment effect? (Effect should be large, precise, and lasting to consider a surrogate trial as possible basis for offering patients the intervention.)

The study compares two outcome variables, OI and PaO2/FiO2, before and after treatment with surfactant. Tables 5 and 6 in the paper illustrate the results. In the group with pulmonary or systemic pathology, the mean (SD) PaO2/FiO2 increased from 68 (18.4) to 111.2 (64.7) (p < 0.01), after the first dose of surfactant. The PaO2/FiO2 improved greater than 20% in 10 patients. There was no significant change in the PaCO2. When each of the 33 surfactant doses was analyzed separately, the mean (SD) PaO2/FiO2 increased from 73.2 (19.7) to 100.8 (49.7) (p <0 .01). The mean (SD) OI diminished from 34.4 (14) to 28.6 (13.7) (p < 0.05), and the mean (SD) PaCO2 from 59.9 (16.7) mmHg to 56.8 (23.5) (not significant).

In the cardiac group, there were no significant changes in PaO2/FiO2, OI, or PaCO2 after the first dose of surfactant. When each of the surfactant administrations was analyzed separately, the mean (SD) PaO2/FiO2 increased from 65.3 (24.7) to 70.6 (22); the PaO2/FiO2 increased > 20% in only 3 of the 13 administrations. The mean (SD) OI diminished from 36.9 (17.4) to 35 (13.6) and the mean (SD) PaCO2 increased from 34.2 (8.1) to 36.2 (9.1) (not statistically significant).

With regard to the two dosages evaluated, the mean (SD) PaO2/FiO2 increased from 73.4 (20.8) to 115.2 (77.8) after administration of 200 mg/kg of surfactant, and after 50 mg/kg it increased from 70.4 (21.6) to 86.7 (32.9). The difference between the two doses was not significant. In six of the nine surfactant administrations of 200 mg/kg there was an increase in PaO2/FiO2 of > 20%, whereas this occurred in only 14 of the 37 administrations of 50 mg/kg.

An evaluation of patients who survived and patients who died was performed. Improvement in the oxygenation of the patients who survived was greater than that of the patients who died. The PaO2/FiO2 increased 51 points, and the OI decreased 10 points in the survivors; whereas the PaO2/FiO2 increased by 8 and the OI did not decrease in the non-survivors. The differences between these two groups were significant (p < 0.05).

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

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

While the results of this study are encouraging for the possible role of surfactant replacement in ARDS, I would use this information with caution when applying it to the care of my patients. This study is very limited in both its sample size and study design (i.e., lack of study controls). It does reveal interesting avenues for study. Comparing outcomes in the two patient groups suggests that multiple pathologic entities causing ARDS may have variable response to surfactant replacement. Perhaps the cardiac group really did not have pulmonary edema from a permeability alteration as in the "true" ARDS patients, or their hypoxemia was at least in part unrelated to pulmonary disease. With respect to survival outcome data, those patients who survived their disease apparently responded well to treatment. Of course without controls it is impossible to know if the survivors were going to improve on their own without surfactant. I believe that this trial (as well as other work in this area) does not merit institution of standard use of surfactant administration in ARDS.

2. Were all clinically important outcomes considered?

Measures of functional lung impairment, PaO2/FiO2 ratio, OI, PaCO2, were addressed by the study, as was survival. Duration of ICU stay, mechanical ventilation, and hospital length of stay were not reported.

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

It is difficult to say with certainty whether the cost-benefit ratio is satisfactory, as the likely treatment benefits cannot be quantified. The potential harms are noted Ð hypoxemia, bradycardia, hypotension, airway obstruction, pneumothorax Ð but are difficult to quantify without controls. The cost of Survanta^TM, a brand of pulmonary surfactant is $550/200 mg. At the doses deemed efficacious by this trial, the cost would be approximately $550/kg/dose.

References

1. Monchi M, Bellenfant F, Cariou A, et al. Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis. Am J Respir Crit Care Med. 1998;158(4):1076-81. [abstract]
2. McIntyre RC, Pulido EJ, Bensard DD, Shames BD, Abraham E. Thirty years of clinical trials in acute respiratory distress syndrome. Crit Care Med. 2000;28(9):3314-31. [abstract]
3. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347-54. [abstract]
4. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18):1301-8. [abstract]
5. 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. Crit Care Med. 1999;27(1):188-95. [abstract]
6. Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. N Engl J Med. 1996;334(22):1417-21. [abstract]
7. Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155(4):1309-15. [abstract]

 

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