Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs
Babies born either prematurely (before 37 weeks) or with a low birthweight
often have breathing problems and need extra oxygen. Accurate oxygen levels
are important as damage to the eyes or lungs can result if levels are wrong.
The decision to stop giving oxygen gradually or abruptly can also affect
the health of the baby. The review of trials found that gradual rather
than abrupt weaning from oxygen supplementation reduces the risk of eye
damage but could not conclude which is the best method of weaning. More
research is needed.
Improvements in technology in the past few decades have led to both the increased survival of preterm and low birth weight infants, and an ability to measure their oxygen levels more accurately. Despite the common use of supplemental oxygen in this population of infants, there is little consensus as to the optimal mode of administration and appropriate levels of oxygen for maximising short or long term growth and development, whilst minimising harmful effects (Poets 1998, McIntosh 2001, Tin 2001).
The issue of whether to abruptly or gradually discontinue supplemental oxygen is a contentious one. In an early controlled trial, Bedrossian et al (1954) reported an increased incidence in retrolental fibroplasia in low birth weight infants who had their oxygen therapy discontinued abruptly compared with those who had a stepwise reduction. More recently, Phelps and Rosenbaum (Phelps 1987) reported no difference in oxygen-induced retinopathy in a kitten model when supplemental oxygen was weaned gradually compared with abrupt discontinuation. However, Chan-Ling et al (Chan-Ling 1995), also using a feline model, have shown that a schedule of managed, gradual oxygen withdrawal can significantly reduce retinal pathology.
A priori sub-group analyses:
- Infants of different gestational age and birth weight subgroups,
as there are differing baseline risks of the outcome measures in these
subgroups.
- Time of discontinuation: early versus late discontinuation (time
in neonatal period when weaning commenced), as this is hypothesised to
influence outcome measures (Gunn 1980).
It was determined a priori that outcome data with attrition rates greater than 20% were not to be included in analyses. The only outcome that was reported in the one eligible trial (Bedrossian 1954) was retrolental fibroplasia. No other outcome measures deemed a priori to be clinically important (as listed above) were reported in the one eligible trial included in this review.
An additional literature search of the MEDLINE (1966-July 2001), and CINAHL (1982-July 2001) databases was conducted using OVID software in order to locate any trials in addition to those provided by the Cochrane Controlled Trials Register (CENTRAL/CCTR). The search strategy involved various combinations of the following keywords, using the search fields of abstract, MeSH subject heading, exploded subject heading, floating subject heading, publication type, registry number word, subject heading word, text word, and title: oxygen, preterm, premature, neonate, newborn, infant, oxygen saturation, hypoxia, retinopathy of prematurity, retrolental fibroplasia, low birth weight, very low birth weight, extremely low birth weight, randomized controlled trial, controlled clinical trial, clinical trial, random allocation, placebo. No further trials, either eligible for inclusion or excluded trials, were identified by the additional literature search.
Participants:
The Bedrossian 1954 trial included infants
with birth weights of 4lb or less. The gestational age range of the participants
is not known. As weaning of oxygen commenced after Day 1 for some infants,
it is assumed that eligible infants were enrolled on admission to the neonatal
unit. The numbers randomized to each group, deaths after randomization,
and losses to followup are unknown. The number of infants who survived
and had outcome assessments were 24 in the experimental (gradual weaning)
group and 25 in the control (abrupt weaning) group.
Intervention:
Infants in the experimental group (gradual weaning) were placed in
50% inspired oxygen and weaned by a step wise reduction. The length of
time at each stage was dependent on birth weight. The control group (abrupt
weaning) were placed in 60% inspired oxygen and remained at this level
for 11-17 days, depending on birth weight, then had supplemental oxygen
withdrawn suddenly. The reasons for choosing different starting FiO2 levels
for each group was not stated.
The study design resulted in both the experimental and control groups receiving the same duration of oxygen therapy (11-17 days based on birth weight). Thus the intervention tested in this trial was, effectively, withdrawal from differing ambient oxygen concentrations, as well as the process of gradual versus abrupt oxygen weaning. It did not test the effect of duration of oxygen therapy on outcome.
Outcomes:
Although eye outcomes were referred to as "retinopathy", the classification
system used was equivalent to that of active retrolental fibroplasia (Kinsey
1956, p536). Thus, stage 1 "retinopathy" as reported in this trial corresponds
approximately with retinopathy of prematurity (ROP) stage 3 plus, using
the International Classification of Retinopathy of Prematurity system (Committee
for the Classification of Retinopathy of Prematurity 1984, 1987) commonly
used today. Ascertainment of RLF in the included trial was by direct ophthalmoscope,
visualising the posterior pole only. The only findings that could be identified
using this method were dilation and tortuosity of the retinal vessels ("plus
disease", using the 1984 and 1987 classifications, as above). The more
common findings in the more anterior retina that today can be visualised
with indirect ophthalmoscopy were unable to be identified. Hence, the eye
outcomes reported in this review equate with what today would be described
as severe ROP.
Although it was stated that patients were referred to an eye clinic for follow-up after discharge, no long term growth, development or visual outcomes were reported.
Unfortunately, no data were reported on any other outcome measures that were deemed a priori as clinically important, such as mortality (either in the early or late neonatal period), apnoea of prematurity, or chronic lung disease.
Allocation concealment was inadequate in this trial. It is not known what proportion of eligible infants were randomised, or if any were excluded prior to randomization. There was no blinding of the intervention. Eye outcome assessments were done blinded to treatment allocation. However, if RLF progressed, assessors were unblinded to treatment allocation and infants were returned to the same oxygen concentration from which they had been removed (n=7). The number of deaths or losses following randomisation is unknown. No power calculations were reported.
In a sub group of infants weighing less than 3 lb at birth, gradual weaning resulted in reductions in vascular RLF (any) and vascular RLF (severe), but these did not reach statistical significance.
No other outcome measures specified a priori as clinically meaningful were reported in enough detail or with satisfactory follow-up rates to include in the analysis (mortality, chronic lung disease, long term growth, development, lung or visual function).
As there was only one eligible trial (Bedrossian 1954), an evaluation of heterogeneity and sensitivity analyses were inappropriate.
The single trial included in this review (Bedrossian 1954) was conducted during an early era of neonatal care, and had only a small number of infants with very low birth weights, who today are the infants who contribute most to the significant mortality and morbidity (e.g. ROP) seen in preterm/LBW infants. Blood oxygen levels were not measured in this trial. Criteria for the weaning of oxygen were day of life, birth weight or other clinical signs such as respiratory distress. Such methods of assessing oxygen requirements would not be appropriate in modern neonatal intensive care settings where continuous, non-invasive oxygen monitoring is now the norm.
Although there was quasi-random patient allocation and blinding of outcome measures in this trial, its overall methodological quality was poor with unclear allocation concealment, unknown numbers lost to followup, no blinding of intervention, and no short (e.g. mortality) or long term (e.g. growth and development) outcomes reported. As such, the results of this analysis should be regarded with caution.
Thus, the results of this systematic review do not provide strong evidence for either the benefits or harms of gradual versus abrupt oxygen weaning in preterm/LBW infants.
Whilst historically important, the results of this systematic review have few implications for current oxygen weaning practices as the unmeasured, unrestricted method of oxygen administration used in this trial is no longer considered appropriate. Also, improvements in oxygen delivery systems has meant that gradual titration of oxygen concentration is now much more refined than was possible in the 1950s. It would now be uncommon for preterm/LBW infants removed from ambient concentrations as high as 30% to be considered as "gradually" weaned, as was the case in the Bedrossian trial. The results do, however, provide additional evidence linking routine exposure to high ambient oxygen in the early neonatal period to the development of ROP .
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Bedrossian 1954 | Quasi-random alternate patient assignment. There was no blinding of the intervention. Eye outcome assessments were done blinded to treatment allocation. However, if RLF progressed, assessors were unblinded to treatment allocation and infants were returned to the same oxygen concentration from which they had been removed (n=7). No power calculations were reported. | Low birth weight infants less than or equal to 4 lb birth weight were included. No exclusion criteria were stated. The numbers of infants potentially eligible or excluded before randomization is not stated. The numbers randomized to each group, deaths after randomization, and losses to followup are unknown. The number of infants who survived and had outcome assessments were 24 in the experimental (gradual weaning) group and 25 in the control (abrupt weaning) group. | Experimental group (gradual weaning): commenced in 50% inspired oxygen
and weaned by step wise reduction. The length of time at each stage was
dependent on birth weight. BW <3lb: 50% for 7 days; 40% for 5 days;
30% for 5 days. BW 3-4lb: 50% for 1 day; 40% for 5 days; 30% for 5 days.
Control group (abrupt weaning): commenced on 60% inspired oxygen and remained at this level for 17 days if BW <3lb or 11 days if BW 3-4lb, then sudden withdrawal of supplemental oxygen. |
RLF (vascular, any stage)
RLF (vascular, severe stages) Outcomes reported in the two birth weight strata. Two infants (1 in experimental and 1 in control group) were reported as post randomization exclusions as they were returned to oxygen as treatment for respiratory disease. They are both reported as having RLF (although not specific stage) so are included in the analyses of this review according to the groups they were originally assigned (intention-to-treat analysis). Seven infants were reported as having been returned to oxygen as treatment for progressive RLF. It is not clear whether these were post randomization exclusions, or whether they are an additional seven infants to the 51 infants whose outcomes are reported in this paper. |
Both experimental and control groups received same duration of oxygen therapy (11-17 days based on birth weight). Thus the intervention tested in this trial was withdrawal from differing ambient oxygen concentrations, rather than duration of supplemental oxygen. | C |
Bedrossian RH, Carmichael P, Ritter J. Retinopathy of prematurity (retrolental fibroplasia) and oxygen. Am J Ophthalmol 1954;37:78-86.
* indicates the primary reference for the study
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Chan-Ling T, Gock B, Stone J. Supplemental oxygen therapy. Basis for noninvasive treatment of retinopathy of prematurity. Investigative Ophthalmology and Visual Science 1995;36:1215-1230.
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02 Gradual versus abrupt oxygen weaning (BW < 3lb)
02.01 RLF vascular (any)
02.02 RLF vascular (severe)