Therapeutic Oxygen For Prethreshold Retinopathy Research Articles

Optimizing Oxygen Saturation Targets in Extremely Preterm Infants

(JAMA. 2018;319(21):2173–2174) While preterm newborns were once routinely exposed to unrestricted oxygen therapy, in the 1950s it was suggested that there may be an association between this practice and development of retinopathy of prematurity. Since then, 2 randomized clinical trials have supported this association [Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) and Benefits of Oxygen Saturation Targeting (BOOST)] and also revealed that higher SpO2 ranges significantly increased the risk of severe pulmonary morbidity.

Influence of prior assignment on refusal rates in a trial of supplemental oxygen for retinopathy of prematurity

Investigators aware of prior treatment assignments may deliberately or subliminally influence rates of subsequent consent in randomised trials, thus introducing the possibility of bias. As a trial of Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) was not masked to health professionals other than ophthalmologists, this possibility was evaluated by comparing the incidence of refusal to participate in relation to the previous assignment. Over 5 years, the STOP-ROP trial enrolled 649 infants, while 394 eligible subjects refused. Enrolled infants were assigned to supplemental oxygen or control groups at 30 centres including 71 hospitals, and stratified into two severity strata of their retinopathy of prematurity. We studied whether the assignment of the previously enrolled infant to either the supplemental arm or the control arm of the study affected the incidence of refusal to participate in the study by the next eligible infant. We also evaluated the possibility that refusal based on the preceding assignment could have influenced either the baseline balance of eye severity and pulmonary status between the two arms of the study or the final outcome of the randomised trial. There was a significantly higher incidence of refusal if the prior enrollee had been assigned to the supplemental oxygen group (44%) as compared with the control group (34%, P = 0.004). This effect from the prior assignment was larger in the later half of the study. Irrespective of the prior enrollee's assignment, refusal was more likely for more mature infants and those with milder baseline disease. Selection bias did not influence the ophthalmic or pulmonary findings at baseline, or the study outcomes. In incompletely masked studies, monitoring the distribution of refusers in relation to the previous assignment can reveal selection bias. Despite evidence of unequal refusal rates, the results of the STOP-ROP trial were not affected.

A Pulmonary Score for Assessing the Severity of Neonatal Chronic Lung Disease

Limited data are available to describe the spectrum of severity of neonatal chronic lung disease. In the multicenter Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity trial, all infants had some degree of pulmonary dysfunction, because eligibility required a median oxygen saturation of < or =94% with room air. Infants randomized to the supplemental oxygen group (oxygen saturation target of 96-99%) had more pulmonary morbidity than did those in the conventional group (oxygen saturation target of 88-94%). This prompted the retrospective development of a pulmonary severity score to compare the baseline status of the 2 groups. To describe a pulmonary score that reflects the severity of neonatal lung disease and to evaluate the association of the score and its components with subsequent pulmonary morbidity through 3 months of corrected age. A pulmonary score was developed empirically by a consensus panel of 3 neonatologists and was defined as the fraction of inspired oxygen (Fio2) x (support) + (medications), where Fio2 is the actual or "effective" (for nasal cannula) Fio2; support is 2.5 for a ventilator, 1.5 for nasal continuous positive airway pressure, or 1.0 for nasal cannula or hood oxygen; and medications is 0.20 for systemic steroids for bronchopulmonary dysplasia, 0.10 each for regular diuretics or inhaled steroids, and 0.05 each for methylxanthines or intermittent diuretics. The scores could range from 0.21 to 2.95. Pulmonary morbidity was defined as any of the following occurring from randomization at a mean of 35.4 weeks' postmenstrual age through 3 months of corrected age: death or rehospitalization with a pulmonary cause; an episode of pneumonia/sepsis/exacerbation of chronic lung disease; or continued hospitalization, supplemental oxygen therapy, diuretic treatment, or systemic steroid therapy at 3 months. Between-group differences were tested with the Kruskal-Wallis or chi2 test. Data through death or the 3-month corrected age examination were available for 588 infants. Enrolled infants represented a wide spectrum of severity of chronic lung disease, with baseline pulmonary scores at randomization ranging from 0.21 to 2.6. The median pulmonary score at enrollment did not differ between the conventional and supplemental groups (0.42 and 0.45, respectively). However, higher baseline pulmonary scores were observed for infants who did versus did not develop subsequent pulmonary morbidity (0.48 vs 0.38). The pulmonary score was associated with subsequent pulmonary morbidity. Regression analyses adjusting for Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity group assignment, gestational age at birth, race, gender, and postmenstrual age at randomization revealed that the score was a significant independent predictor of subsequent pulmonary morbidity (odds ratio: 7.2; 95% confidence interval: 3.6-14.4). The pulmonary score, calculated near term, reflects a wide spectrum of bronchopulmonary dysplasia severity and is associated with subsequent pulmonary morbidity through corrected age of 3 months. This simple score could prove useful in clinical and research settings. Validation of the score requires additional study.

Statistical issues related to early closure of STOP-ROP, a group-sequential trial

The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity trial used the group-sequential alpha-spending approach with asymmetrical tails to investigate whether supplemental oxygen therapy would reduce the proportion of infants progressing from prethreshold retinopathy of prematurity (ROP) to threshold ROP from 30% to 20%. Three years of enrollment were predicted. After 4 years, the data and safety monitoring committee (DSMC), faced with a projected delay of 2–3 more years, opted to terminate the trial after 1 further year of enrollment despite a continually borderline test statistic. We discuss factors relating to the DSMC decision and its effect upon the conclusions that may be drawn from the trial.

Retinopathy of prematurity outcome in infants with prethreshold retinopathy of prematurity and oxygen saturation >94% in room air: the high oxygen percentage in retinopathy of prematurity study.

To determine the rate of progression from prethreshold to threshold retinopathy of prematurity (ROP) in infants excluded from Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) because their median arterial oxygen saturation by pulse oximetry (SpO2) values were >94% in room air at the time of prethreshold diagnosis and to compare them with infants who were enrolled in STOP-ROP and had median SpO2 < or =94% in room air. Fifteen of the 30 centers that participated in STOP-ROP elected to participate in the High Oxygen Percentage in Retinopathy of Prematurity study (HOPE-ROP) from January 1996 to March 1999. Infants were followed prospectively from the time prethreshold ROP was diagnosed until ROP either progressed to threshold in at least 1 study eye (adverse outcome) or resolved (favorable outcome). A total of 136 HOPE-ROP infants were compared with 229 STOP-ROP infants enrolled during the same time period from the same 15 hospitals. HOPE-ROP infants were of greater gestational age at birth (26.2 +/- 1.8 vs 25.2 +/- 1.4 weeks) and greater postmenstrual age at the time of prethreshold ROP diagnosis (36.7 +/- 2.5 vs 35.4 +/- 2.5 weeks). HOPE-ROP infants progressed to threshold ROP 25% of the time compared with 46% of STOP-ROP infants. After gestational age, race, postmenstrual age at prethreshold diagnosis, zone 1 disease, and plus disease at prethreshold diagnosis were controlled for, logistic regression analysis showed that HOPE-ROP infants progressed from prethreshold to threshold ROP less often than STOP-ROP infants (odds ratio: 0.607; 95% confidence interval: 0.359-1.026). The mechanisms that result in better ROP outcome for HOPE-ROP versus STOP-ROP are not fully understood. It seems that an infant's SpO2 value at the time of prethreshold diagnosis is a prognostic indicator for which infants may progress to severe ROP. When other known prognostic indicators are factored in, the SpO2 is of borderline significance.

Supplemental oxygen did not reduce progression of pre-threshold retinopathy of prematurity in infants

The STOP-ROP Multicenter Study Group. Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics2000 Feb; 105 : 295 –310 [OpenUrl][1][Abstract/FREE Full Text][2]...