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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Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure

Willson DF, Zaritsky A, Bauman LA, et al.

Crit Care Med 1999;27:188-95. [abstract]

Reviewed by Poyyapakkam Srivaths, M.D. and Kathleen Meert, M.D., Children's Hospital of Michigan

Review posted June 10, 1999

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I. What is being studied?:

The study objective:

To study the efficacy of calf lung surfactant in pediatric respiratory failure.

The study design:

Multicenter, prospective, randomized controlled, unblinded study

The patients included had the following characteristics:

1. clinical and radiographic evidence of diffuse, bilateral parenchymal lung injury
2. required mechanical ventilation
3. within 24 hrs of initiation of mechanical ventilation
4. oxygenation index (OI) > 7
5. term infants > 1 day to 18 years of age.

The patients excluded:

1. chronic lung disease
2. status asthmaticus
3. cardiogenic pulmonary edema
4. lethal brain injury
5. congestive heart failure and/or uncorrected congenital heart disease

The interventions compared:

Endotracheal instillation of 80 ml/m2 of Infasurf delivered in 4 equal aliquot portions in rotating positions. The children were hand ventilated during that time with an FiO2 of 1.0 and peak pressures and rates approximating previous ventilator settings. Administration lasted for 10 to 20 minutes. Control patients were hand ventilated in the same positions but surfactant was not instilled.

The outcomes evaluated:

1. Arterial blood gases and ventilator settings just before and at 0.5, 2, 4, 8, 24 and 48 hours after surfactant
2. pulmonary complications of surfactant
3. survival
4. duration of mechanical ventilation
5. pediatric ICU stay
6. hospital stay
7. duration of supplemental oxygen
8. extubated by 72 hours
9. use of nonconventional therapy

The authors originally intended to evaluate mortality (survival) as a primary outcome variable. However, an interim analysis revealed that the expected mortality rate was only a third of the initially anticipated mortality of 40%. The study was stopped at that point since the sample size needed to evaluate mortality would have been larger than initially expected and probably unobtainable in this study. The secondary outcome variables were then analyzed.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, the patients were randomly assigned to receive surfactant or no surfactant. Randomization was performed in blocks of four. Each participating institution received sealed opaque envelopes for sequential patient assignment.

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

Was followup complete?

Yes, all the patients were accounted for. Two of 23 patients randomized to the surfactant group were disqualified. One was discovered to have cyanotic heart disease and one to have chronic lung disease. One of 22 children randomized to the control group was disqualified because his OI was < 7. Although these patients met exclusion criteria for the study, they were eventually included in an intention to treat analysis of the duration of ICU stay.

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

Yes. None of the patients crossed over from one group to the other.

Secondary questions:

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

No. The authors felt that blinding was unreasonable as surfactant is evident in the endotracheal tube after administration and a comparable volume of milky placebo would be unsafe to instill in the control group.

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

Yes. Age, gender and race were similar between the two groups. The surfactant group tended to have higher PRISM scores, OI and ventilation index (VI), however the differences were not statistically or clinically significant. The PaO2/FiO2 ratios were similar between the two groups.

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

The participating institutions agreed to follow a ventilator algorithm designed to minimize barotrauma by allowing mild permissive hypercarbia and moderating peak inspiratory pressure by changing from volume to pressure ventilation. It is not mentioned in the manuscript whether the 2 groups were treated similarly in other aspects of care.

III. What were the results?

1. How large was the treatment effect?

Arterial blood gases and ventilator settings were used to calculate OI and VI. The changes in OI in the first 24 hours after the first dose of surfactant were decreased to 50% of the study entry values. OI remained unchanged from entry value in the control group. The change in VI from entry value was similar in the surfactant and no surfactant groups.

The differences between groups for other continuous variables are shown in Table 1

Table 1 (Data shown are geometric mean)

	Surfactant	No surfactant	p value
Ventilator days	5.3	10.7	0.03
ICU days	8.1	14.4	0.03
Supplemental O2 days	7.6	13.9	0.06
Hospital days	14	20.4	0.12

Since mortality could not be evaluated with the present sample size, the authors have evaluated the frequency of extubation within 72 hours as shown in Table 2.

Table 2

	Extubated by 72 hrs	Not extubatable at 72 hrs (or dead)	Totals
Surfactant	8	13	21
No surfactant	1	20	21

The absolute risk reduction (ARR) for extubation at 72 hours with the use of surfactant is -33%. The negative ARR represents an absolute increased "risk" of being extubated by 72 hours with surfactant. The number needed to treat (NNT) is -3, meaning that 3 patients would have to receive surfactant in order to have one extubated at 72 hours. The relative risk (RR) of extubation at 72 hours with use of surfactant is 800%. This means that treated patients were eight times as likely to be extubated as control patients. Relative risk reduction (RRR) is -700%.

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

The 95% confidence intervals (CI) for the continuous variables are shown in Table 3.

Table 3

	Surfactant	No surfactant
Ventilator days	3.1 - 9.1	7.6 - 15.1
ICU days	5.2 - 12.7	10.9 - 19.1
Supplemental oxygen days	4.3 - 13.4	9.8 - 19.6
Hospital days	9.1 - 21.5	15. 8 - 26.3

The 95% CI for extubation at 72 hours are shown in Table 4.

Table 4

ARR	-56% to -10%
NNT	-10 to -2
RR	100% - 5800%
RRR	-5700 to 0

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

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

The data show that the administration of surfactant for diffuse bilateral parenchymal lung injury, within 24 hours of initiation of mechanical ventilation increases the chance of the patient being extubated by 72 hours. Because of the physical properties of surfactant, the study could not be blinded. Predetermined criteria for extubation were not mentioned in the study. It is possible that there was bias towards extubating surfactant treated patient earlier. An OI of 7 is not extremely high and routine administration of surfactant to all of these patients within 24 hours of mechanical ventilation would be very expensive. Therefore, these results cannot be directly applied to my patient care.

2. Were all clinically important outcomes considered?

No. The sample size was insufficient to assess an effect of surfactant on mortality.

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

The use of surfactant was not associated with any side effects except for one patient who developed bronchospasm which responded to albuterol. As already mentioned, the cost of surfactant prevents its routine use without further controlled trials.

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