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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Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study.

Moller JC, Schaible T, Roll C, et al.

Intensive Care Med. 2003;29(3):437-46. [abstract]

Reviewed by Nilesh Mehta, Children's Hospital, Boston

Review posted September 26, 2003

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I. What is being studied?:

The study objective:

To determine the role of intra-tracheally instilled, exogenous Bovine surfactant in improving oxygenation in children with severe ARDS.

The study design:

The study design involved a single center pilot study (involving 19 pediatric patients) followed by a multicenter (19 PICU's), open, randomized, parallel group comparison.

The patients included:

Patients were randomized (n = 38) if they met the following inclusion criteria; a) ARDS Consensus Conference criteria, b) Lung injury score at least 2, c) duration of mechanical ventilation between 12 - 120 hrs, d) age: 44th post-conceptual week to 14 yrs, e) admission for at least 4 hrs, f) no evidence of left heart failure on echocardiography and g) PaO2:FiO2 ratio < 100

The patients excluded:

Patients were excluded from the study if they met any of the following exclusion criteria; a) any other investigational therapy for ARDS (e.g., nitric oxide, high frequency ventilation, liquid ventilation, prostaglandins, steroids or ECMO), b) chronic lung disease such as BPD or CF, c) participation in other clinical studies (except oncology trials), d) Severe hypoxemia (PaO2 < 50 after 4 hrs of treatment at the referral center).

The interventions compared:

All recruited patients were ventilated according to a standardized ventilation algorithm. Patients randomized to the surfactant group received Alveofact (bovine surfactant) 100 mg/kg administered at the distal tip of the ETT; under continuous PEEP and ventilation; over a max period of 5 min. If PaO2 decreased by 20% or more of the highest achieved level, within the 48 hrs observation period; a second dose (identical) was permitted. Patients in the non-surfactant group continued to be managed according to the ventilation algorithm.

The outcomes evaluated:

The primary outcome in this study was change in the PaO2:FiO2 ratio, 48 hrs after allocation (surfactant / control). Secondary endpoints evaluated were peak inspiratory pressure, positive end-expiratory pressure, mean airway pressure, inspiratory and expiratory times, respiratory rate, FiO2, PaCO2, SaO2, pH, heart rate and blood pressure; 2, 4, 12, 24, 48 and 120 hrs after randomization. Additional parameters recorded were Murray score, PRISM III score at baseline, 48 and 120 hours; clinical status, days on ventilator, days in intensive care, days on supplemental oxygen, mortality and ventilator free days at day 30 after randomization. The necessity for rescue therapy as ECMO, HFOV, NO or rescue surfactant was recorded.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Random allocation was performed centrally by telephone (24 hr coverage) and was designed to achieve 1:1 randomization at each center.

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

Was followup complete?

All patients were followed to day 30 or to the day of discharge / transfer from the referral center and outcome data has been reported.

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

Yes. Of the 38 patients randomized, 3 (2 surfactant and one control) were excluded after randomization as their PaO2/FiO2 ratio improved to above 100 before starting the treatment and are not included in the analysis. For example (table 2) 22 patients were randomized to surfactant and 16 to control. However, only 20 in the surfactant group were treated and 15 in the control. Calculations in table 2 use n = 20 and n = 15 as the denominators, instead of 22 and 16. Mortality of 60% reported in the control group is 9/15 (60%), not 9/16 (56%). 4 control patients did receive surfactant as "rescue therapy" and these 4 were analyzed as part of the control group. (Table 2 is confusing because it combines both baseline characteristics and outcome data). Patients who did not meet all the entry criteria for recruitment but had PaO2/FiO2 less than 100, were followed. The overall mortality rate of these 39 patients was 64%.

Secondary questions:

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

No. Bovine surfactant was instilled intra-tracheally in the experimental group and the controls did not receive any placebo through this route. This was an open study with no attempt at blinding the health workers. Due to the nature of the surfactant and its route of instillation, it would be difficult to mask. A physically similar appearing placebo (inert) solution would be needed for this purpose. Some studies have used controls with saline, air and customized inert solution (1).

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

Yes, Table 2 describes the patient characteristics for the 2 groups prior to the trial. There were no significant differences in these variables between the groups with respect to age, etiology, disease severity (PRISM III), use of ECMO and ventilator free days.

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

Yes. Patients were treated according to a general ventilation algorithm for each group at all the recruiting centers. This algorithm stated guidelines for pressure limited, time-cycled or pressure-controlled ventilation with PIP < 30cm, PEEP < 5cm and rate as tolerated with goals of paCO2 < 65mmHg and pH > 7.2. Patient comfort was achieved with sedation (and possible addition of paralysis). In both treatment and control groups, if PaO2/FiO2 deceased to < 100, PEEP was increased in increments of 1 cm, followed by increase in PIP to 35 cm H2O, followed by increase in I/E ratio if PaO2/FiO2 did not improve. Rate was adjusted to keep pH > 7.15. Arterial BP and CVP monitoring was obligate. Vasopressors and inotropes were to be used as necessary. Echocardiographic and pulmonary artery monitoring were optional. BP was maintained > 50th centile with 90-100% maintenance fluid intake and Hb kept > 12g/dl.

All rescue therapies felt necessary by the principal investigator were allowed if PaO2 decreased below 50mmHg for at least 1 hour.

III. What were the results?

1. How large was the treatment effect?

Patients in this study were randomized either to receive surfactant therapy or controls. Of the 22 patients randomized to surfactant group, 20 were treated with this therapy. Following randomization of 16 patients to the control group, 15 were treated as controls. The surfactant group had a mortality of 8 (44%) as compared to the mortality of 9 (64.3%) in the control group. Ventilator-free survival for more than 20 days was seen in 4 (21.1%) patients in the surfactant group as compared to 2 (14.3%) in the control group. Both mortality and ventilator-free days were not primary endpoints and the sample size did not allow any statistical significance. This study was not powered to show differences in these outcome parameters, which are clinically more relevant in comparison to the physiological parameters used as the primary endpoints by the authors.

The primary outcome parameter for this study was the change in PaO2/FiO2 ratio at 48 hours after the first administration of surfactant or randomization to the control group. The study showed a significant improvement in the ratio at 2 hrs in the surfactant group as compared to the control group. At 48 hrs, although the trend toward a benefit in the surfactant group continued, the effect did not reach statistical significance.

	Surfactant group	Control group
Change in PaO2/FiO2 ratio @ 2 hrs	54	9
Change in PaO2/FiO2 ratio @ 48 hrs	38	22

Using the Hallman oxygenation index [(FiO2 x mean airway pressure)/PaO2] as outcome variable a significant decrease was noted at 2 hrs but was not sustained at 48hrs in the surfactant group.

	Surfactant group	Control group
Change in OI @ 2 hrs	-10	-2
Change in OI @ 48 hrs	-9	-5

A reduction in mean airway pressures was noted in the surfactant group at 2hrs (p < 0.005) and 24hrs (p = 0.007). There was no significant benefit for any of the other outcome parameters for the surfactant group in this study.

11 patients received the 2nd surfactant dose (100mg/kg) but without any significant benefit for any of the outcome variables. The study reported no lasting adverse effects associated with the surfactant administration. Three surfactant treated patients experienced intermittent obstruction of the endotracheal tube with short periods of deterioration in oxygenation.

The authors conducted a post hoc analysis of the change in PaO2/FiO2 ratio from baseline at 2 and 48 hrs considering various patient characteristics as additional information. No significant differences were shown for most of these parameters. Patients with PaO2/FiO2 ratio >65 at baseline had a significant difference in the ratio change as compared to those with PaO2/FiO2 ratio < 65.

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

The primary outcome of this study (PaO2/FiO2 ratio) was reported as median values with 25th and 75th percentiles. The authors report some of the outcome data with mean and SD values. However, for the primary outcome it is not possible to calculate the 95% Confidence Intervals. Thus, the precision of the point estimate for the PaO2/FiO2 ratio could not be ascertained.

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

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

The population addressed in this review is comparable to intensive care patients in other PICU's. The results of this study are relevant to our patient group, comprised of children with ARDS. The results are similar to a previous study, which also showed transient oxygenation benefit in surfactant group (2). There were no side effects reported for the intervention in this study. Until studies show a convincing long-term benefit or an effect on mortality, surfactant therapy will continue to be used sporadically and is unlikely to be recommended generally. In the future, studies evaluating its use in selective groups of patients may be relevant, although recruitment of required number of cases will be challenging (as in this study) as the incidence of pediatric ARDS has recently declined.

2. Were all clinically important outcomes considered?

This study addresses clinical outcomes such as the change in PaO2/FiO2 ratio and OI and follows these parameters over a period of time. However, these are physiologic parameters, which are not clinically relevant as primary endpoints. Studies are needed which examine durable clinical outcomes. This study looks at secondary outcome parameters such as days on ventilator, days in intensive care, days on supplemental oxygen, mortality and ventilator free days at day 30 after randomization. Need for rescue therapy such as ECMO, HFOV and NO has also been recorded. In the future, studies powered to detect significant differences in these parameters would be desirable.

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

The results of the study show a transient improvement in the surfactant group. At 48 hrs, the difference in PaO2/FiO2 ratio or the OI is not significant. The authors did not have any lasting adverse effects associated with the administration of surfactant. Although a cost analysis was not performed, the authors state that surfactant therapy is very expensive. Without proven long-term benefit, the added cost is not justified.

Transient oxygenation benefits may impact on ventilation parameters and may affect outcome. Overall, although the administration of surfactant was safe in this study, the primary outcome showed a very transient benefit, and unlikely to merit generalized recommendations.

References

1. Tibby SM, Hatherill M, Wright SM, Wilson P, Postle AD, Murdoch IA. Exogenous surfactant supplementation in infants with respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1251-6. [abstract]; PedsCCM EB Journal Club Review
2. Willson DF, Zaritsky A, Bauman LA et al. Instillation of calf lung surfactant extract is beneficial in pediatric acute hypoxemic respiratory failure. Critical Care Med 1999;27:188-195. [abstract]; PedsCCM EB Journal Club Review

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