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

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

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Multicenter randomized, controlled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure

Luchetti M, Ferrero F, Gallini C et al.

Pediatr Crit Care Med 2002; 3:261-268. [abstract; full-text on Medscape]

Reviewed by Michael Wilhelm MD , Pediatric Critical Care Medicine, Columbia College of Physicians and Surgeons

Review posted October 1, 2002

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I. What is being studied?:

The study objective:

To determine surfactant's effect on children less than 2 years old with RSV-induced respiratory failure not improving on mechanical ventilation.

The study design:

This is a phase 3, multicenter, randomized, controlled trial. No placebo was given to controls.

The patients included:

Patients aged 1 week to 2 years were included if:

1. They had both chest x-ray findings consistent with air-trapping and positive immunofluoresence for RSV
2. PaO2/FIO2 ratio < 150 and PaCO2 > 40 mm Hg on PICU admission
3. Peak Inspiratory Pressure > 35 cm H2O with no PEEP while ventilated
4. After 12 hours of ventilation, their PaO2 had not increased by 30% on the same FIO2

The patients excluded:

1. Head injury with a GCS < 8
2. Brain death, imminent risk of death or a terminal disease
   The authors did not comment whether this included imminent risk of death from the patients' RSV.
3. Preexisting airway disease that might prolong intubation
   This did NOT include reactive airways disease/asthma.
4. Congenital heart disease
5. Neuromuscular disease

The interventions compared:

50 mg/kg of porcine-derived, natural surfactant was administered in 2 aliquots over 5 minutes to the treatment group. Although not stated by the authors, the use of a natural surfactant was presumably chosen because of previous studies showing increased efficacy of natural surfactants when compared to synthetic varieties (1,2). The rationale for the amount given is not stated. Controls underwent the other parts of the procedure without instillation of a placebo. Both groups were sedated and paralyzed and received hand ventilation with 100% O2. They also received chest percussion and postural drainage for approximately 10 minutes. Following these procedures, suctioning was not permitted for 1 hour.

The outcomes evaluated:

Primary Outcomes:

1. Duration of mechanical ventilation
   If reintubated within 24 hours, it was counted as no interruption in mechanical ventilation.
2. Length of ICU stay

Secondary Outcomes:

The first four were all assessed at 1, 3, 6, 12, 24 and 48 hours of the study

1. PaO2/FIO2 ratio
2. PaCO2
3. Static compliance
4. Peak inspiratory pressure
5. Complications
   Desaturation, hemodynamic deterioration, air-leak syndromes, bronchospasm requiring additional therapy
6. Mortality

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Sealed envelopes were used to randomize 20 patients to each group.

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

Was followup complete?

Yes. All randomized patients completed the study and were managed according to the study protocol.

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

Yes, this was an intention-to-treat analysis.

Secondary questions:

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

Patients were not blinded, but this likely isn't a concern as the appropriate study personnel were blinded. Specifically, the administrator of the therapy, who clearly could not be blinded, was not part of the patient care team. The data collector was blinded to treatment group, though they weren't responsible for any interventions. Although not explicitly stated, it appeared that the patient care team recorded data on a standardized form that the 'data collector' then compiled for the study.

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

Very likely. The authors evaluated potential predisposing factors as well as several indicators of disease severity in the two groups. None of these parameters were statistically significant. Unfortunately, to assess the degree of respiratory failure, the authors used only the PaO2/FIO2 ratio. Unlike an oxygenation index, which is frequently used in pediatric ARDS studies, this does not account for the degree of respiratory support. The authors did, however, ensure that the initial PEEP setting was similar between the two groups (mean of 5.6 in the treatment group and 5.8 in the control group with a non-significant P value). Interestingly, the entry criteria "a PIP >35 with a PEEP of 0" might also ensure a similar degree of alteration in respiratory compliance. However, it is unclear whether the authors actually placed patients on a PEEP of 0 to make this measurement. Furthermore, the tidal volume for this measurement was not standardized, creating further confusion.

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

Although the two groups received essentially the same care, chest percussion was uninterrupted for 10 minutes in the control group and followed each surfactant aliquot in the treatment group. Also, the description of the procedure in the article emphasizes the careful monitoring of ventilator settings following surfactant administration and does not comment on that following control interventions. Thus, it is possible that the patient care team, which made the treatment decisions, might have been able to decipher to which group a patient belonged. This could result in more frequent assessment of ventilator settings and blood gasses. Otherwise, the groups were treated identically.

However, there are several areas where the authors could have given more information. They do not describe what therapies the patients were receiving prior to enrollment. Therapies such as beta agonists, steroids and theophylline were discontinued during the study period but differences between the groups prior to the study period might have influenced the results. Also, the authors do not describe how far into their illness patients were at the time of intubation. Evidence that time may be very important in this process is typified by the five patients who were treated over 24 hours after meeting criteria. Three of these patients (60%) "needed" an additional dose of surfactant, a much lower success rate than those treated within 24 hours. Furthermore, the control group did not have a rescue therapy if their PaO2/FIO2 ratio stayed below 200, which may provide a source of bias between the groups.

Finally, the weaning strategy was only vaguely described. Given that duration of mechanical ventilation was an outcome variable, more description of the weaning process and reassurance of lack of bias between the two groups would be useful. The hope is that, since the patient care team was blinded to the treatment, that weaning decisions were made uniformly in the two groups.

III. What were the results?

1. How large was the treatment effect?

Primary outcomes:

• Mean ICU stay decreased from 8.2 +/- 1.1 days to 6.8 +/- 0.9 days, a 22% reduction.
• Mean duration of mechanical ventilation decreased from 5.8 +/- 0.7 days to 4.6 +/- 0.8 days, a 14% reduction.

Secondary outcomes (measured at 48 hours after treatment):

• The PaO2/FIO2 ratio nearly tripled in the treatment group while remaining unchanged in controls.
• The PaCO2 dropped by 15 mm Hg vs. 2 mm Hg in the controls.
• The peak inspiratory pressure dropped by 12 cm H2O vs. 7 cm H2O in controls
• Static compliance increased by 0.42 vs. 0.15 in the controls

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

The 95% confidence intervals of the difference between the means for length of ICU stay were 1.2 and 2.4 days. Using the same formula, the 95% confidence limits for the difference in mean duration of mechanical ventilation between the two groups were 0.7 and 1.7 days.

The precision of the secondary outcomes can only be inferred grossly from their P values. The vast majority of the time points showed differences with p values of 0.001. Thus there seems to be a reasonably large difference between the groups.

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

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

The data seems applicable to many patients, as even some premature infants were included in each group. However, the study did not include patients with congenital heart disease or, at least not obviously, patients with severe BPD. Since these patients are predisposed to severe RSV infection, it is not clear that the data can be generalized to those situations. Having said this, these patients may receive even more noticeable benefits from surfactant therapy. Further study needs to be done to clarify this issue.

Also, as mentioned above, measurement of the oxygenation index would have helped further define the patient population at study entry. Furthermore, change of the oxygenation index in the two groups would have been a useful secondary outcome measure.

Unfortunately, the authors do not state how many ventilated patients there were with RSV who were not included in the study for various reasons; some of the entry criteria are easily manipulated and not true independent patient factors. Thus, it is not clear if this group is truly representative of all intubated RSV patients.

2. Were all clinically important outcomes considered?

Yes. However, the study did not have much power to detect less common, severe complications such as death or air leak syndromes. Furthermore, there is no specific comment about desaturation during surfactant administration or pulmonary hemorrhage in the results section. However, in the methods, the authors claim to have analyzed desaturations less than 80% for more than 60 sec despite hand ventilation with 100% O2. Furthermore, they looked for any "other" significant complications within one hour of the intervention.

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

Since there were no complications, this seems quite likely. In addition, the authors present a simple cost/benefit analysis at the end of the discussion. Using their estimates, considering the reduction in ICU stay, surfactant therapy in this setting could save 3,000 Euro per patient. Using the worst possible results based on the 95% confidence limits, this would still be 1,700 Euro per patient. Even without a reduction in morbidity or mortality the financial results would make this therapy worthwhile. Furthermore, less time ventilated or in the ICU reduces patientsÕ risk of nosocomial infections and iatrogenic disease. Although the magnitude of this reduction is not clear from this study, the apparent lack of negative consequences of surfactant therapy make it quite attractive.

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References:

1. Jobe AH, Which surfactant for the treatment of respiratory-distress syndrome, 2000;355(9213):1380-1. [citation]
2. Ainsworth SB, et al, Pumactant and poractant alfa for treatment of respiratory distress syndrome in neonates born at 25-29 weeks' gestation: a randomised trial. Lancet. 2000;355(9213):1387-92. [abstract]

Comments

May 1, 1997

With respect to the two reviews on papers investigating post-extubation stridor: The review did not address the issue of assessing for ETT leak prior to inclusion in the randomization group. While neither showed tremendous benefit from the use of decadron, it appears to me that the study group was inappropriate. I would be more interested in seeing whether dex. relieves post-extubation stridor in patients whom you are reasonably sure will have it--ie, those who do not have a ETT leak at less than 20 cm H20. I am concerned that these two trials will lead to the assumption that dexamethasone is not useful in treating those those for whom it may actually be a benefit.

Laura Ibsen, MD (LIBSEN@chmca.org)
Children's Hospital Medical Center of Akron
Akron, Ohio

May 2, 1997

Some problems with the review:
RR values are EXTREMELY low, and indicate a marked preference for the better outcome. Were they calculated correctly?

Why were the patients with hypertension excluded from the analysis? What was the justification for excluding the patient with GI bleeding? The rationales were unclear in the abstract and the review.

Again, as with my previous critique, a more useful way of analyzing the data may be 1) logistic regression, using a dichotomous outcome (e.g. racemic epi yes/no, reintubation yes/no) or a polytomous outcome (e.g. croup score). In this way, one could calculate odds ratios and CI's for the odds ratios as well as adjusting for other independent variables. 2) Survival analysis as a means of determining if differences exist between the two groups say, in the rate of increase in croup score, or time to first racemic epi.

Finally, I've found the use of formal decision analytic techniques VERY helpful in eliciting the relative clinical values of different therapies, and certainly more useful than straight statistics in answering the question about usefulness in practice. The problem of the use of dexamethasone is a perfect one to which decision analysis can be applied.

Jay R. Shayevitz, MD (jayshay@umich.edu)
Providence Hospital and Medical Centers
Southfield, MI

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