What Can We Learn From STOP-ROP and Earlier Studies?

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COMMENTARIES

Opinions expressed in commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.

What Can We Learn From

STOP-ROP and Earlier Studies?

ABBREVIATION. STOP-ROP, supplemental therapeutic oxygen for prethreshold retinopathy of prematurity.

T

he results of the STOP-ROP study, published elsewhere in this month’s issue,1 _{suggest that} the effect of supplemental oxygen on the con-version rate of prethreshold retinopathy of prematu-rity (ROP) to threshold disease may be less pro-nounced than that found in 2 previous studies, one by Gaynon et al2_{at Stanford and the other by} Seib-erth et al3_{in Germany. For the STOP-ROP group as a} whole, the reduction in the rate of conversion from prethreshold ROP to threshold was from 48.5% for the conventional oxygen group down to 40.9% for the supplemental oxygen group. STOP-ROP did show a trend toward better outcome, which for the group as a whole, did not reach statistical signifi-cance, given the ultimate sample size of 649 infants, down from the initially planned 880 infant enroll-ment.

Results were more dramatically beneficial for those infants without plus disease. Taking this group as a whole, the conversion rate to threshold dropped from 46% for the conventional group to 32% for the supplemental group. This is consistent with the no-tion that plus disease (tortuous and engorged retinal vessels) is a sign of high blood flow through arterio-venous shunting attributable to intraretinal (stage 2⫹) or extraretinal (stage 3⫹) neovascularization. Lack of, or resolution of, plus disease is a favorable sign suggesting that any neovascularization present, as a component of prethreshold ROP, may be resolv-ing.

The time it took for threshold disease to appear was longer for the supplemental group as compared with the conventional group, both for the study as a whole as well as for patient subsets stratified accord-ing to disease severity, suggestaccord-ing a moderataccord-ing ef-fect of supplemental oxygen on disease momentum. At the same time there was evidence that to some extent, chronic lung disease was worse in those in-fants in STOP-ROP given supplemental oxygen (96%–99% oxygen saturation) as compared with those maintained at conventional levels (89%–94%

oxygen saturation), an observation not sought after, but at the same time not observed in the earlier studies. Importantly, no adverse effect on ROP was uncovered as a result of supplemental oxygen at the levels used in this study, which agrees with the earlier studies. Why the difference in outcomes? For that, a closer examination of the differences between STOP-ROP and the 2 earlier studies is in order.

RANDOMIZATION VERSUS HISTORICAL CONTROLS

The most obvious difference to the casual observer is the fact that the earlier studies were unmasked and used historical controls. In the Stanford study (Table 1) an effort was made to determine if there was a level of moderate oxygen saturation that would re-duce the rate of conversion of prethreshold ROP to threshold ROP. To that end, target oxygen satura-tions were increased incrementally between 1985 and 1993 and the rate of progression to threshold was calculated at each level. From 1994 to 1996 we looked at infants excluded from STOP-ROP, who were not assigned to supplemental oxygen.

At the same time, attention was paid to other poten-tial factors that might contribute to worsening of ROP. Beginning in 1991, all prethreshold infants were ex-posed to room lights, thus establishing photopic adap-tation, which has been shown to reduce oxygen con-sumption of the retina, thus helping to reduce retinal ischemia.4,5 _{Retinal ischemia, left unchecked, leads to} extraretinal neovascularization, traction retinal detach-ment, and blindness. Anemia was also corrected if present, if oxygen and light alone did not bring about improvement in the retinopathy. This was done to increase the oxygen carrying capacity of the blood without exposing the lungs to further increases in in-spired oxygen. An effort was also made to minimize desaturations by avoiding noxious stimuli, because de-saturations are associated with more severe ROP.6,7

It was found that an oxygen saturation of 99% to 100% with an arterial oxygen tension preferably no higher than 100 mm Hg, combined with photopic adaptation, was associated with a published reduc-tion in the conversion rate to threshold disease to 7% (4 of 58 infants) between 1990 and 1993. One of these infants was referred in with threshold disease, so the actual conversion rate was 5%, a major reduction from the average rate of 37% (35 of 95 infants) seen at lower levels of target oxygen saturation in the pre-ceding years. Even at 96% target oxygen saturation, 33% of prethreshold infants (8 of 24) reached thresh-old. At the same time, the time to threshold in weeks increased with increasing target oxygen saturation, from 1.6 weeks at 92% saturation to 3.5 weeks at the 99% to 100% target saturation level, suggesting that Received for publication Nov 4, 1999; accepted Nov 4, 1999.

Reprint requests to (D.K.S.) Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5119. E-mail: dstevenson@ stanford.edu

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the disease process was slowed, even in those infants who eventually reached threshold. This meant that disease momentum was less, suggesting that out-comes after laser or cryotherapy were more likely to be good. Birth weights and gestational ages were similar over time, and in fact the group with the best outcomes had the lowest average birth weight.

As a counterbalance to the issue of historical con-trols, the infants excluded from STOP-ROP at Stan-ford between 1994 and 1996, who were not assigned to any particular level of oxygen saturation to main-tain equipoise for the study, were examined for out-come. At most centers, two-thirds of prethreshold infants were excluded from the study for various reasons, and this was true at Stanford as well. Ten of the 26 STOP-ROP excluded prethreshold infants reached threshold for a conversion rate of 38%, and time to threshold dropped to 1.6 weeks, arguing against the notion that improvements in care ac-counted for the beneficial trend observed earlier with higher levels of target oxygen saturation. This is despite the fact that this group had a larger birth weight than the group with the best outcomes be-tween 1990 and 1993 (868 g vs 814 g).

The Seiberth study (Table 2) showed a similar benefit, comparing a control group of prethreshold infants with variable levels of oxygen saturation be-tween 1991 and 1993 to a group bebe-tween 1994 and 1996 in which the target oxygen saturation was 98% or above (Table 2). Birth weights and gestational ages were similar for both periods. Conversion rate from prethreshold to threshold dropped from 43.4% in the variable saturation group to 14.1% in the supplemen-tal group. What else distinguishes STOP-ROP from the previous studies that might explain the differ-ences in outcome?

STUDY POPULATION

In both the Stanford and Seiberth studies, all pre-threshold infants encountered during the specific time periods were studied. In STOP-ROP, infants were excluded if they had a recorded oxygen satu-ration on room air at or above 94% at any time before enrollment. This produced a group with substan-tially lower birth weights and gestational ages than the population of prethreshold infants at the study

centers as a whole, as well as compared with the previous 2 studies. An indication of this is the fact that the excluded prethreshold infants at Stanford had an average birth weight of 868 g as compared with an average of 726 g for the 649 infants enrolled in STOP-ROP.

As a result, these were likely to be the sickest infants, more likely to desaturate (a risk factor for threshold ROP), and more likely to be adversely affected from a pulmonary standpoint by supple-mental oxygen, because higher levels of oxygen were likely required for them to reach target oxygen sat-urations. One third of prethreshold infants were ex-cluded because their lungs were too healthy, pre-cisely the group most likely to respond beneficially to supplemental oxygen. The enrolled group was more likely to desaturate frequently, which likely damages the growing retinal vessels because of re-peated toxic hyperoxic insults occurring with each effort at resuscitation. Once retinal vessels are suffi-ciently damaged, they will not mature, leading in many cases to eventual threshold disease, no matter at what level their subsequent target oxygen satura-tion is set. Another third of the prethreshold infants was eliminated because of parent or neonatologist refusal, for a variety of reasons, meaning that only one third of prethreshold infants at the sickest end of the spectrum entered the study.

FREQUENCY OF SCREENING EXAMINATIONS

In the Stanford study all infants were screened weekly from age 6 weeks on, whereas in STOP-ROP infants were screened every 2 weeks before the de-velopment of prethreshold disease. If pretheshold disease was found, supplemental oxygen was begun immediately at Stanford, whereas there was often up to a 48-hour delay for the supplemental group in STOP-ROP. In a disease that often moves very quickly, the time lost in making the diagnosis and implementing the treatment may be critical.

PHOTOPIC ADAPTATION

The recent article by Cringle et al5_shows convinc-ingly that it is possible to improve oxygenation of all layers of the retina with a combination of supple-mental oxygen and photopic adaptation, the latter

TABLE 1. Stanford Study: Oxygen Saturation Versus Threshold ROP

Years 1985–1987 1988 1989 1990–1993 1994–1996

Prethreshold 55 16 24 58 26

Threshold 24 3 8 4 10

% Threshold 44% 19% 33% 7% 38%

Weeks to threshold 1.6 2.3 2.9 3.5 1.6

Birth weight (g) 932 986 886 814 868

Gestational age (wk) 27 26 26 27 26

Oxygen saturation 92% 95% 96% 99%–100% Variable

TABLE 2. Seiberth Study2

Years Preterm

Infants

Birth Weight (All Preterm)

Gestational Age (All Preterm)

Target Oxygen

Stage 3 Infants

Threshold (%)

1991–1993 545 1281 29.8 —Variable 53 23 (43.4%)

1994–1996 510 1297 29.5 ⱖ98% 64 9 (14.1%)

COMMENTARIES 421

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aimed at reducing oxygen consumption by reducing retinal metabolism. Photopic adaptation is a no cost adjunct to supplemental oxygen, achieved by remov-ing the cover over the incubator and exposremov-ing the infant to room lights, similar to walking out of a movie theater into daylight. No spotlights are used. Concerns about light toxicity with regard to ROP were allayed recently by the LIGHT-ROP study, which showed no deleterious effect of exposure to average levels of room light.8 _{Photopic adaptation} probably has a lesser effect on raising oxygen tension in the retina as compared with supplemental oxygen, but the results are additive and potentially beneficial, given the basic science evidence. Photopic adapta-tion was not used in STOP-ROP.

OXYGEN SUPPLEMENTATION LEVELS

STOP-ROP defined supplemental oxygen therapy as a range from 96% to 99% saturation, using a pulse oximeter that typically reads 1.6% lower than those from other manufacturers. Even allowing for this dif-ference in instrumentation, the supplemental oxygen levels in STOP-ROP were lower than that found to be effective in the previous 2 studies. At Stanford, many infants hovered around 100% saturation with periodic dips that helped to ensure that the arterial oxygen tensions were not too high. Table 4 of the STOP-ROP paper1 _{shows that the vast majority of supplemental} infants were maintained at median pulse oximetry lev-els of 96% (23.5% of supplemental infants) to 97% (56.5% of infants). Only 3 infants (0.9%) had a median pulse oximetry of 99% to 100%. At Stanford, the rate of conversion to threshold did not drop to low levels until target pulse oximetry reached 99% to 100%.

ANEMIA

At Stanford, severe anemia was sometimes corrected with a transfusion if supplemental oxygen and pho-topic adaptation did not lead to a reduction in ROP severity. This sometimes led to improvement in the retinopathy. Anemia is not addressed in STOP-ROP.

AVOIDING DESATURATIONS

At Stanford, a concerted effort was made to limit to the extent possible repeated desaturations throughout the period of hospitalization, in an effort to avoid fur-ther worsening of ROP attributable to hyperoxic insults resulting from resuscitation. This is not addressed in STOP-ROP before enrollment, although monitoring after enrollment did serve to accomplish this end there-after.

CONCLUSION

For all of the above reasons, the results of STOP-ROP do not argue convincingly that moderate oxygen sup-plementation is not valuable for infants with prethesh-old ROP. Prethreshprethesh-old ROP, like many other diseases, has a spectrum of severity. As a parallel, unstable an-gina may be treated medically at one end of the spec-trum with a␤-blocker, whereas at the other end of the spectrum bypass surgery is required. ROP, too, may more often be treatable in the less severely diseased infant with medical means, whereas the sickest infants, as studied in STOP-ROP, may more often go on to need

surgical intervention in the form of laser or cryother-apy, both of which may fail and have significant asso-ciated complications.9_{The failure rate for ablative} treat-ment of threshold disease in the STOP-ROP trial (combined retinal detachment, retinal folds or obstruc-tion of the visual axis, excluding macular ectopia) was substantial at 9.2% for the conventional group and 13.2% for the supplemental group at 3 to 6 months. This suggests that it would be valuable from the stand-point of preserving vision to avoid reaching threshold disease by any potentially beneficial medical means.

Oxygen did no harm to the eyes of these pre-threshold infants, and showed a trend toward im-provement. The earlier studies examining the full range of prethreshold infants showed a strong beneficial ef-fect for moderate oxygen supplementation, often com-bined with photopic adaptation and other supportive measures. The issue of chronic lung disease deserves attention, but blindness from ROP is often total and devastating lifelong for the affected individual. The issue of costs associated with delay in discharge from the nursery brought about by supplemental oxygen therapy ignores the fact that successful treatment of ROP by any means including extension of hospitaliza-tion is by far more cost-effective in terms of years of vision saved than any other medical or surgical treat-ment currently in use for any other eye disease. Be-cause no study to date has shown harm to eyes with prethreshold ROP from moderate supplemental oxy-gen, and because there may be a benefit, we would argue in favor of giving medical therapy a chance.

Michael W. Gaynon, MD

Palo Alto Medical Foundation Palo Alto, CA 94301

David K. Stevenson, MD

Stanford University School of Medicine Stanford, CA 94305-5119

REFERENCES

1. The STOP-ROP Multicenter Study Group. Supplemental therapeutic oxy-gen for prethreshold retinopathy of prematurity (STOP-ROP), a random-ized, controlled trial. I. Primary outcomes.Pediatrics.2000;105:295–310 2. Gaynon MW, Stevenson DK, Sunshine P, Fleisher BE, Landers MB.

Sup-plemental oxygen may decrease progression of prethreshold disease to threshold retinopathy of prematurity.J Perinatol.1997;17:434–438 3. Seiberth V, Linderkamp O, Akkoyun-Vardarli I, Jendritza W, Voegele

C. Oxygen therapy in acute retinopathy of prematurity stage 3.Invest Ophthalmol Vis Sci.1998;39:S820

4. Braun RD, Linsenmeier RA, Goldstick TK. Oxygen consumption in the inner and outer retina of the cat.Invest Ophthalmol Vis Sci.1995;36:542–554 5. Cringle SJ, Yu DY, Alder V, Su EN. Light and choroidal PO2modulation of intraretinal oxygen levels in an avascular retina.Invest Ophthalmol Vis Sci.1999;40:2307–2313

6. Saito Y, Omoto T, Cho Y, Hatsukawa Y, Fujimura M, Takeuchi, T. The progression of retinopathy of prematurity and fluctuation in blood gas tension.Graefes Arch Clin Exp Ophthalmol.1993;231:151–156

7. Penn JS, Henry MM, Wall PT, Tolman BL. The range of PaO2variation determines the severity of oxygen-induced retinopathy in newborn rats.

Invest Ophthalmol Vis Sci.1995;36:2063–2070

8. Reynolds JD, Hardy RJ, Kennedy KA, Spencer R, van Heuven WAJ, Fielder AR. Lack of efficacy of light reduction in preventing retinopathy of prematurity.N Engl J Med.1998;338:1572–1576

9. Gaynon, MW, Trautman M, Stevenson DK, Sunshine, P. Complications of cryotherapy for threshold stage 3⫹retinopathy of prematurity. Oph-thalmology.1991;98:(suppl)168. (Presented at the American Academy of Ophthalmology annual meeting; October 13–17, 1991; Anaheim, CA)

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DOI: 10.1542/peds.105.2.420

2000;105;420

Pediatrics

Michael W. Gaynon and David K. Stevenson

What Can We Learn From STOP-ROP and Earlier Studies?

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DOI: 10.1542/peds.105.2.420

2000;105;420

Pediatrics

Michael W. Gaynon and David K. Stevenson

What Can We Learn From STOP-ROP and Earlier Studies?

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