5-page Summary:

TRIP Study of Early and Prophylactic Surfactant Therapy in Preterm
Infants

Laura C. Leviton, Ph.D. and Gautham Suresh, MD

August 9, 2005

**Background.** Surfactant is a highly effective therapy to prevent
disease and death from Respiratory Distress Syndrome (RDS) in preterm
infants.[^1] However, benefit is greatest when infants receive
surfactant early, before symptoms of RDS develop.[^2] 1998 Vermont
Oxford Network data indicated that of infants getting surfactant only
19% received it within 15 minutes of birth and 27% received it over 2
hours after birth.[^3]

**Objectives.** To evaluate a multifaceted, coordinated intervention
designed to close a gap between research and practice in the use of
early surfactant therapy.[^4]

**Intervention.** The theory underlying intervention came from the
Network's long-standing experience with collaborative quality
improvement, modeled upon the Institute for Healthcare Improvement (IHI)
Breakthrough Series. The Network stresses 4 key habits of clinical
improvement: the habit of change, the habit of evidence-based practice,
the habit of systems thinking, and the habit of collaborative learning.
The focus on "habit" is essential to understand the effect of the trial
and its generalizability (see below).

Intervention was multifaceted and consisted of ta careful sequence
of: 1) providing confidential, individualized feedback to member
hospitals on surfactant use (group level audit and feedback); 2) at a
workshop, presentation of the evidence on early and prophylactic
surfactant use, indicating to them that there was a gap between their
practice and the evidence; 3) teaching, at the same workshop, the
methods of rapid cycle improvement to the participants. 4) rapid cycle
PDSA work within small teams from each hospital, both at the initial
workshop and at individual NICUs. Certain of the study investigators
facilitated conference calls and an email discussion list (listserv).
The investigators who participated in implementation at this level were
by general agreement, divorced from the analysis of outcome data.

The phone calls and listserv provided ongoing motivation as well as
forums to share suggestions to overcome logistical barriers. Specific
technical suggestions were outlined in detail for speedier
administration of surfactant and for the use of data to identify and
overcome additional barriers and to assess progress.

**Intervention "targets."** Neonatal intensive care units belonging to
the Network. Secondary targets were hospitals referring outborn infants
to the NICU (if any).

**Where did the QI take place?** 57 member hospitals in the United
States and Canada.

**Outcome measures.** As a part of their normal data submissions to the
Network, hospitals provided information on the timing of surfactant
therapy and whether it was provided in the delivery room (DR). The
primary patient-level outcomes were mortality and pneumothorax (air
leaking into the chest cavity).

**Study design.** 114 member hospitals were randomly assigned to
intervention or control. Outcome measures were obtained in the year
prior to the workshop and in the year subsequent to the workshop. No
methods adaptations were needed in this cluster-randomized trial.
Because the unit of assignment was the hospital, contamination was not a
problem, and data collection was a by-product of member hospitals' usual
provision of data to the Network.

**Control group.** Member hospitals were randomized to the control
group; NICUs were eligible if they were not participating in other
quality improvement collaboratives or other studies of surfactant. Of
the 300 member hospitals in North America in 2000, 178 were eligible for
the trial and 114 agreed to participate. There was no sample attrition.

**Analytic approach.** Intent to treat, with the analyst masked as to
group assignments. The hypothesis of differences between intervention
and control hospitals on timing of surfactant and DR administration was
tested via logistic regression, using treatment condition as a
covariate. The statistical methods accounted for both the cluster data
(using SAS PROC: GENMOD) and intrahospital correlation.[^5] No analysis
was conducted concerning disparities in care.

**Results.** A significantly greater proportion of infants in the
intervention hospitals received surfactant in the DR than in the control
hospitals. The adjusted odds ratio, of 5.38, translates into a 37%
increase in early surfactant use. By way of comparison, a systematic
review of 8 other multifaceted QI interventions obtained effect sizes
ranging from 2.6 to 9.0%.[^6] A significantly smaller proportion of
infants in the intervention hospitals received the first dose more than
2 hours after birth, and the median time until the first dose was
received was 21 minutes in intervention hospitals, compared to 78
minutes in control hospitals. For infants born at the referring
hospitals and then transferred, these results are also statistically
significant, but effect sizes are smaller. The patient-level outcomes of
mortality and pneumothorax were not statistically different between
treatment and control hospitals.

**Study strengths, limitations and lessons.**

[Strengths]{.underline}: This study makes a cogent case for the value of
cluster randomized trials in quality improvement. Most quality
improvement investigation has occurred at the level of the individual
practitioner. Yet, we know that many practice improvements are dependent
on actions at higher levels of aggregation, as with care teams,
organizations, and regional markets. Having a sample of 114 permits
further analysis of these organizational unitsl: for example, of
hospital characteristics that may have promoted or hindered the
improvements.

Also noteworthy is the fact that this study was conducted for about a
million dollars, yet it includes substantially more organizations than
is the case for most published QI studies. By way of contrast, an AHRQ
funded study of corticosteroid administration in perinatal medicine
accrued 27 hospitals for roughly the same cost as the surfactant
trial.[^7] The scale of the surfactant trial was made possible by the
fact that member NICUs were accustomed to providing data to the Network
as a part of their general orientation to quality improvement. In the
corticosteroid trial by contrast, data collection was by far the largest
component of the study cost. The preexisting relationship between the
Network and member hospitals may also have contributed to the quality of
the data in the study. Quality of the Network data is generally high,
probably because of longstanding protocols to which the member hospitals
were accustomed. [^8] However, the quality is also likely to be high
because member hospitals value and use the information that they receive
back from the Network.

A sample this large provides some information about generalizability. On
the one hand, the sheer number of NICUs in the study and the Network,
assists in generalizing to the larger class or category of NICUs. On the
other hand, it may be that Vermont Oxford Network members are somewhat
more interested in quality improvement to begin with, more accepting of
feedback from the Network, and more open to changes suggested by the
Network and their peers. The Network's focus on the 4 QI habits
described above, makes it plausible that they are more amenable to QI
interventions than are other neonatologists, or other physicians
generally.

[Lessons]{.underline}. It is important to emphasize that the
participating teams were not given a specific guideline or package of
interventions to implement. Participant hospitals were exposed to the
evidence summary (A Cochrane systematic review), provided with their own
data and then requested to set their own aims based on their assessment
of what was most appropriate for their center. This allowed centers to
have a degree of autonomy regarding the implementation of the evidence
in practice and may have contributed to the uptake of the evidence.

Because the effect size is large, it is important to understand the
potential differences between this trial and other trials of
multifaceted QI intervention. Some literature reviews have concluded
that multifaceted intervention is more effective than using a single
strategy by itself, yet a recent systematic review concluded that the
average effect sizes of multifaceted interventions are no greater than
those seen in single-intervention studies.^6^ The apparent discrepancy
may perhaps be accounted for by reference to the theory of change
underlying this trial. It is our impression that most multi-faceted
studies of QI represented an agglomeration of strategies that had been
found effective previously, but might be unrelated logically to each
other. In the surfactant QI trial, by contrast, the different components
of intervention built logically one upon the other. Future studies
should employ, and reviews should assess, the logic model or theory of
change underlying the study interventions.

[Limitations]{.underline}. The lack of significant differences in
mortality and pneumothorax is subject to many possible explanations.
Most reasonable, perhaps, is that perinatal and neonatal medicine have
advanced considerably since the time that the original studies of
surfactant were conducted. Improvements in care would plausibly have led
to a lower background rate of mortality and pneumothorax.

The most important "road not taken" in this study had to do with
studying implementation of QI. With 114 institutions, it was simply not
possible to conduct qualitative investigation at a level where new
insights might be gained. A limited set of quantitative variables that
may be related to institutional changes are undergoing active study at
this time. However, for the cost of the study a great deal of
information was obtained in a fairly unobtrusive way. Specifically we
have an opportunity through the conference call transcripts and
listserv, to characterize and classify PDSA cycles. It is likely that in
this specific case, the majority of such cycles concerned logistics of
storing surfactant in the delivery room and assuring that trained staff
were available in the delivery room to intubate the babies. Next in
order might be solving logistics in the NICUs, and third in order might
be a variety of ways to deal with surfactant provision at the referring
hospitals. This is important information for other institutions
undertaking a similar quality improvement effort, and the results should
be shared. This information is available from taped conference calls;
however, it is not likely to be a complete or comprehensive set of PDSA
cycles.

[What might one do with a less ideal study situation]{.underline}? Data
collection would cost more and data quality might not be as good.
However, these methods are surely applicable to collaborative
improvement more generally. The cluster randomized design is a key
advantage and actually makes the studies easier to conduct under most
circumstances, than randomly assigning individuals within institutions.
This is because contamination is kept to a minimum and the logistics of
intervention are simplified.

Very important is the multi-level statistical analysis, because it
provides information about organization level behavior, which may differ
from the behavior of specific individuals nested within the larger unit.
This kind of design can be rigorous even where large numbers of
organizations are not available. Generally, between 7 and 15
organizations or units per arm are required for conventional levels of
statistical power and significance, depending on the size of the
intraclass correlation.[^9] However a smaller sample of organizations
can hinder the potential to explore organization-level factors affecting
the outcome. In the particular case of the TRIP study, sample size
calculations were geared to detect a significant difference in infant
mortality.

This type of study can be done rigorously even without a randomized
design. Several quasi-experimental designs can be adapted to the
purpose.[^10] Most promising is the interrupted time series design, in
which an intervention is associated temporally with a change in the
quality improvement indicator (or outcomes). Time series analysis is
highly compatible with the use of medical records and other data that
must be kept over the course of months or years by a medical care
organization. For example, a hospital might decide to take steps to
reduce the number of code incidents. These need to be tracked and
maintained, thus providing an archival record for use in statistical
analysis. Interrupted multiple time series, in which intervention is
sequenced over several organizations, will be even more persuasive about
the causal relationship between QI and outcomes, by ruling out
additional alternative explanations.

**Funding source.** AHRQ and the member hospitals of the Vermont-Oxford
Network (by subscription).

**This evaluation was subject to both peer review and IRB approval.**

[^1]: Soll RF, McQueen MC. Respiratory distress syndrome. In: Sinclair
    JC, Bracken MB, eds. *Effective Care of the Newborn Infant.* Oxford,
    UK: Oxford University Press; 1992

[^2]: Soll RF, Morley CJ. Prophylactic surfactant vs treatment with
    surfactant. (Cochrane Review) In: The Cochrane Library, Issue 2.
    Oxford, England: Update Software; 1998. Updated quarterly

[^3]: Horbar, JA, Carpenter, J.H, Buzas, J., Soll, RF, Suresh, G,
    Bracken, MB, Leviton, LC, Plsek, PE, and Sinclair, JC. for the
    Vermont Oxford Network. 2004. Timing of initial surfactant treatment
    for infants 23 to 29 weeks gestation: Is routine practice
    evidence-eased? Pediatrics 113: 1593-1602.

[^4]: Horbar, JA, Carpenter, J.h, Buzas, J., Soll, RF, Suresh, G,
    Bracken, MB, Leviton, LC, Plsek, PE, and Sinclair, JC. 2004. A
    cluster randomized trial of a multifaceted intervention for
    promoting evidence-based surfactant therapy. British Medical Journal
    329: 1004-1100.

[^5]: Donner A. and Klar, NS. 2000. Design and Analysis of Cluster
    Randomisation Trials in Health Research. London. Hodder Arnold.
    2000.

[^6]: Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L,
    et al. 2004. Effectiveness and efficiency of guideline dissemination
    and implementation strategies. Health Technology Assessment 2004;8:
    iii-iv, 1-72.

[^7]: Leviton et al., 1999. Leviton, L.C., Goldenberg, R.L., Baker,
    C.S., Freda, M., et al. 1999. Randomized controlled trial of methods
    to encourage the use of antenatal corticosteroid therapy for fetal
    maturation. Journal of the American Medical Association 281: 46-52.

[^8]: Horbar JD and Leahy K, for the Invesigators of the Vermont-Oxford
    Trials Network. 1995. An assessment of data quality in the
    Vermont-Oxford Trials Network Database. Controlled Clinical Trials
    16: 51-61

[^9]: Murray, D. 1998. *Design and analysis of group-randomized trials.*
    New York: Oxford University Press.

[^10]: Shadish WR, Cook TD and Campbell DT. *Experimental and
    Quasi-Experimental Designs for Generalized Causal Inference.* New
    York: Houghton Mifflin Company, 2001.