Fig 5 - uploaded by Alan R Spitzer
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Cumulative rate curves demonstrating the differences in both the proportion and timing of adverse (A) and favorable (B) ophthalmic outcomes by study arm.
Source publication
Objective:
To determine the efficacy and safety of supplemental therapeutic oxygen for infants with prethreshold retinopathy of prematurity (ROP) to reduce the probability of progression to threshold ROP and the need for peripheral retinal ablation.
Methods:
Premature infants with confirmed prethreshold ROP in at least 1 eye and median pulse oxi...
Contexts in source publication
Context 1
... outcomes occurred soon after randomiza- tion in both groups as shown in Fig 5A, and the elapsed time from study entry to adverse ophthalmic endpoints was slightly longer in the supplemental arm compared with the conventional arm. Mean pro- gression time to threshold disease was 2.4 weeks for eyes in the conventional arm and 2.7 weeks for eyes in the supplemental arm. ...
Context 2
... without plus disease took somewhat longer (mean of 2.3 weeks and 2.7 weeks, respectively; Ta- ble 5). Achieving a favorable outcome took longer (Fig 5B), and the time to full vascularization or zone III vessels on 2 consecutive examinations in eyes To adverse outcome, wk 1.6 1.0 2.2 1.9 1.9 1.6 To favorable outcome, wk 7.5 2.9 7.1 3.3 7.3 3.1 ...
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Background and objective:
Bevacizumab intravitreal injection, a vascular endothelial growth factor inhibitor, is used to treat retinopathy of prematurity (ROP). However, concerns have been raised regarding its systemic absorption and effect on developing tissues including brain. This study compared neurodevelopment at 18 months' corrected age in p...
Citations
... Additional retrospective cohort studies also observed that infants managed with biphasic oxygen saturation targets (85-92% before, 92-97% after 34 weeks corrected gestational age), as opposed to static (91-95% throughout hospital stay) had lower ROP severity [12,13]. To date, only one randomized control trial assessed oxygen supplementation in preventing ROP progression (STOP-ROP) after established ROP [15]. This study did not identify statistically significant benefits or harm of O2 supplementation on ROP. ...
... Currently, the prevention of severe ROP development remains limited. Limiting oxygen exposure by targeting lower oxygen saturations (85-89%) during the vaso-obliterative phase is the only management shown to decrease the rate of severe ROP but is associated with a higher mortality rate in preterm infants [2,12,13,15]. Other therapies during the early postnatal NICU course, such as aggressive parenteral nutrition, use of human milk, and several vitamin supplements, have been shown to decrease the risks of ROP of all stages, but the results on severe ROP needing intervention were mixed [21]. ...
Background
Retinopathy of prematurity (ROP) is a disease that affects preterm infants born younger than 30 weeks of gestation. The pathophysiology of ROP involves an initial vaso-obliterative phase followed by vaso-proliferative phase that leads to disease progression. The use of supplemental oxygen during the vaso-proliferative phase of ROP has been associated with reduced disease progression, but how this impacts the need for ROP treatment is unclear. The goal of this study was to compare the rate of laser or intravitreal bevacizumab after implementation of a new supplemental oxygen therapy protocol in preterm infants with stage 2 ROP.
Methods
This is a retrospective chart review of preterm infants diagnosed with stage 2 ROP at Riley Hospital for Children between 1/2017 and 12/2022. Patients diagnosed between 1/2017 and 6/2020 were classified as Cohort A, preprotocol implementation. Patients diagnosed from 8/2020 to 12/2022 were classified as Cohort B, postprotocol implementation. In Cohort A, oxygen saturation was kept at 91-95% through the entire hospitalization. In Cohort B, oxygen saturation was increased to 97–99% as soon as Stage 2 ROP was diagnosed. Statistical analyses were performed using chi-square and Student’s T test, followed by multivariate analyses to determine the impact of the oxygen protocol on the need for ROP treatment.
Results
A total of 211 patients were diagnosed with stage 2 ROP between 1/2017 and 12/2022. Of those patients, 122 were before protocol implementation therapy (Cohort A), and 89 were after implementation of supplemental oxygen protocol (Cohort B). Gestational age was slightly higher in Cohort B (Cohort A 25.3 ± 1.9, Cohort B 25.8 ± 1.84, p = 0.04). There was no difference in birth weight, NEC, BPD, or survival. Cohort B had lesser need for invasive mechanical ventilation and higher days on CPAP during hospitalization. Notably, Cohort A had 67 (55%) patients treated with laser photocoagulation or intravitreal bevacizumab versus 20 (22%) patients in Cohort B (OR 0.19, 0.08–0.40).
Conclusion
The need for laser photocoagulation or intravitreal bevacizumab was significantly decreased in high-risk patients treated with the supplemental oxygen protocol. This result supports the idea that targeted supplemental oxygen therapy to keep saturations between 97 and 99% can reduce disease progression in infants with stage 2 ROP and potentially decrease the burden of additional procedures.
... Although the FiO2 estimated by these formulas has been shown to correlate well with hypopharyngeal FiO2 measurements [3,4], their accuracy critically depends on VT, Ti, and MV values [3,4], which cannot be routinely measured in clinical practice. In the STOP-ROP study [10], a randomized, controlled trial that explored the relationship between oxygen supplementation and ROP in preterm infants, Benaron and Benitz's formula was used to calculate the effective FiO2 assuming a fixed Ti of 300 ms and a fixed VT of 5 mL/kg [11]. The conversion tables of the STOP-ROP study [11], as well as Finner's formula assuming a fixed VT of 5.5 mL/kg [4], are widely used in clinical practice currently [9]. ...
... Their main assumption was that the upper airway (i.e., the space consisting of the nasal cavity, nasopharynx, and oropharynx) is negligible and, thus, does not act as an oxygen reservoir [3]. Since VT and Ti cannot be routinely measured, Benaron and Benitz's formula is used in clinical practice assuming a fixed Ti of 300 ms and a fixed VT of 5 mL/kg [10,11]. In another study, Finer et al. [4] developed an equation to predict hypopharyngeal FiO2 measurements based on cannula flow and infant MV (Figure 1). ...
Background: In infants treated with a low-flow nasal cannula (LFNC), the oxygen concentration delivered to the lungs (i.e., the effective FiO2) is difficult to estimate. The existing mathematical formulas rely on important assumptions regarding the values of respiratory parameters and, thus, may be inaccurate. We aimed to assess oxygen delivery by LFNC to small infants using realistic simulations on a mechanical breathing model. Methods: A mechanical breathing simulator (infant upper-airway replica, single-space breathing compartment, electric motor, microcontroller) was developed. Breathing simulations (n = 1200) were performed at various tidal volume (VT), inspiratory time (Ti), and respiratory rate (RR) combinations and different cannula flows. Results: Minute ventilation (MV) was the most significant predictor of effective FiO2. FiO2 was higher at lower VT and higher Ti values. Benaron and Benitz’s formula underestimated the effective FiO2 at lower MV values, while Finer’s formula significantly overestimated it. A set of predictive FiO2 charts was developed based on cannula flow, infant body weight, and RR. Conclusions: The effective FiO2 delivered by LFNC to small infants critically depends on VT, Ti, and RR. However, since VT and Ti values are not available in clinical practice, the existing mathematical formulas may be inaccurate. Our novel predictive FiO2 charts could assist in optimizing oxygen delivery by LFNC using easy-to-obtain parameters, such as infant body weight and RR.
... There has also been reports on an increased incidence of post cataract endophthalmitis associated with clear corneal temporal incisions in comparison to the superior scleral tunnel incision 33,36,37 . However, review of literature does not convincingly confirm this opinion. ...
... After surgery the IOP should be established at a physiologic level by injection of fluid into the anterior chamber to ensure proper apposition of internal wound. Seidel's testing should be done on all incisions to establish proof of closure 33 . ...
... In the future there might be a role for topical cyclosporine in the treatment of severe allergic conjunctivitis. In several small trials, it has been found to be well tolerated and effective in the therapy of allergic and vernal kerato conjunctivitis [33][34][35] . Currently topical cyclosporine is approved by the US FDA for only increased tear production in dry eye patients. ...
... In the former case, such differences may strengthen our results, but they may become confounders in the latter. The higher use of inhaled and systemic steroids in the HOSG may be related to the higher incidence of BPD following more exposure to oxygen toxicity (33,34). The frequent use of ibuprofen in the LOSG to constrict the ductus arteriosus may indicate a higher spontaneous closure rate in the HOSG (19,35). ...
... ROP and BPD occurred much more frequently in the higher target groups of NeOProM, but no differences existed in this study. Similar results had previously been found in the STOP ROP trial regarding BPD (33). Summing up, results from trials could be influenced by one-site patient risks and local health hazards. ...
Background
Randomized controlled trials have indicated reduced mortality rates in very preterm infants assigned to high compared to low oxygen saturation (SpO 2 ) target levels, accompanied by higher rates of retinopathy of prematurity and bronchopulmonary dysplasia. However, the benefit-to-harm ratio may depend on the local background mortality risk. We therefore aimed to quantify the risk–benefit ratios of different SpO 2 target ranges in 10 tertiary newborn intensive care units (NICUs) in East Germany.
Methods
In a retrospective multicenter study, 1,399 infants born between 2008 and 2012 at a gestational age between 24 0/7 and 27 6/7 weeks and with a birthweight below 1,250 g were grouped according to the hospital's target SpO 2 range [high oxygen saturation group (HOSG) above 90%], low oxygen saturation group (LOSG) below 90%] and the compliance of units with their target SpO 2 range. The association between neonatal morbidities, neurodevelopmental outcomes, selected treatment strategies, and target SpO 2 ranges was calculated using chi-squared and Mann Whitney U tests.
Results
Nine of the ten participating NICUs met their SpO 2 target ranges. Five units were considered as HOSG, and five units were considered as LOSG. Necrotizing enterocolitis and intraventricular hemorrhage grade ≥ 2 occurred significantly more frequently in the HOSG than in the LOSG (8.4% vs. 5.1%, p = 0.02; and 26.6% vs. 17.7%, p < 0.001). No significant differences in the mortality rate and the rate of retinopathy of prematurity were found.
Conclusion
In our patient population, a lower SpO 2 target range was not associated with increased safety risks in extremely preterm infants. We cannot be sure that our outcome differences are associated with differences in oxygen saturations due to the retrospective study design and the differences in site practices.
... However, no effective strategy has been found to significantly prevent the progression of ROP before its onset. Limited supplemental oxygen has been evaluated as a potential intervention, but this practice has the counterpart of increasing mortality (9,10). ...
Background
Currently, the treatment of anemia in preterm infants is based on packed red blood cell (RBC) transfusions from adult donors. Oxygen (O2) is mainly transported to the tissues bound to hemoglobin (Hb). In extremely low gestational age neonates (ELGANs), fetal hemoglobin (HbF), which has a higher affinity for O2, represents up to 95% of circulating hemoglobin. During the first month of life, the majority of ELGANs will require an adult-donor RBC transfusion causing HbF levels to rapidly drop. HbA releases 50% more oxygen in peripheral tissues than HbF. Increased release of O2 in the retina is one of the main factors related to the development of retinopathy of prematurity (ROP). Collecting umbilical cord blood and using autologous umbilical cord whole blood (UCB) transfusions would contribute to maintaining physiological HbF concentrations in newborns and avoid oxygen-in-excess derived damage.
Methods
This is a randomized, double-blinded, multicenter clinical trial. ELGANs ≤28 weeks of gestational age will be randomized 1:1 to receive an autologous umbilical cord blood transfusion (intervention arm) or standard transfusion of packed RBC from an adult donor (control arm) to assess ROP development. Assuming a 50% reduction in ROP incidence, 134 patients (67 per group) will be recruited. When blood transfusion is indicated, the Blook Bank will supply UCB or RCB according to the patient's group. The primary endpoint is the incidence of any ROP. Secondary endpoints are assessessment of treatment safety, results of biomarkers related to ROP and its chronology, and urine oxidative stress markers. In addition, the cellular composition of umbilical cord blood and its relationship with prematurity-related pathologies will be analyzed. All patients will be followed-up to 24 months of corrected age to evaluate their neurodevelopment.
Discussion
ROP is a major cause of irreversible blindness in preterm newborns. Transfusions with adult donor blood can lead to complications, including ROP. UCB transfusions offer advantages by maintaining physiological HbF levels and potentially optimizing postnatal development. Moreover, autologous UCB transfusion could reduce risks associated with heterologous blood products, although volume collection remains challenging. UCB contains growth factors and progenitor cells that may impact ROP.
... Between 1994 and 2014, large, multi-centre randomised control trials (RCTs)-STOP-ROP [40], SUPPORT [41], BOOST II [42], and COT [43]-have been conducted across developed countries. Table 2 compares these studies (Table 2). ...
Introduction
Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the premature retina with the potential to progress to extraretinal neovascularisation. This review serves as an introduction to retinopathy of prematurity (ROP), outlining key parts of ROP pathophysiology, diagnosis and treatment. ROP is traditionally diagnosed by indirect ophthalmoscopy and classified using anatomical zones, stages of disease, and the presence or absence of “plus disease” (dilation and tortuosity of the major retinal arterioles and venules). ROP has a bi-phasic pathophysiology: initial hyperoxia causes reduced retinal vascularisation, followed by pathological vaso-proliferation resulting from subsequent hypoxia and driven by vascular endothelial growth factor (VEGF).
Advancements in management
This review summarises previous trials to establish optimum oxygen exposure levels in newborns and more recently the development of anti-VEGF agents locally delivered to block pathological neovascularisation, which is technically easier to administer and less destructive than laser treatment.
Future directions
There remains an ongoing concern regarding the potential unwanted systemic effects of intravitreally administered anti-VEGF on the overall development of the premature baby. Ongoing dosing studies may lessen these fears by identifying the minimally effective dose required to block extraretinal neovascularisation.
... An effective FiO 2 was calculated for infants on oxygen nasal cannula using the equations from the STOP-ROP trial. 15 Chorioamnionitis was defined by clinical diagnosis and/or placental pathology. Severe intraventricular hemorrhage (IVH) was made by radiologic diagnosis of a Grade 3 or 4 IVH by head ultrasound during hospitalization. ...
Background:
Intermittent hypoxemia (IH) events are common in preterm neonates and are associated with adverse outcomes. Animal IH models can induce oxidative stress. We hypothesized that an association exists between IH and elevated peroxidation products in preterm neonates.
Methods:
Time in hypoxemia, frequency of IH, and duration of IH events were assessed from a prospective cohort of 170 neonates (<31 weeks gestation). Urine was collected at 1 week and 1 month. Samples were analyzed for lipid, protein, and DNA oxidation biomarkers.
Results:
At 1 week, adjusted multiple quantile regression showed positive associations between several hypoxemia parameters with various individual quantiles of isofurans, neurofurans, dihomo-isoprostanes, dihomo-isofurans, and ortho-tyrosine and a negative correlation with dihomo-isoprostanes and meta-tyrosine. At 1 month, positive associations were found between several hypoxemia parameters with quantiles of isoprostanes, dihomo-isoprostanes and dihomo-isofurans and a negative correlation with isoprostanes, isofurans, neuroprostanes, and meta-tyrosine.
Conclusions:
Preterm neonates experience oxidative damage to lipids, proteins, and DNA that can be analyzed from urine samples. Our single-center data suggest that specific markers of oxidative stress may be related to IH exposure. Future studies are needed to better understand mechanisms and relationships to morbidities of prematurity.
Impact:
Hypoxemia events are frequent in preterm infants and are associated with poor outcomes. The mechanisms by which hypoxemia events result in adverse neural and respiratory outcomes may include oxidative stress to lipids, proteins, and DNA. This study begins to explore associations between hypoxemia parameters and products of oxidative stress in preterm infants. Oxidative stress biomarkers may assist in identifying high-risk neonates.
... The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial found that there was no difference in the development of threshold ROP between preterm infants with prethreshold ROP in at least one eye when they were maintained at either conventional oxygen levels (89-94% SaO 2 ) or supplemental oxygen levels (96-99%) [40]. Results from the STOP-ROP trial also revealed that maintaining supplemental oxygen levels in infants without plus disease was protective against the progression to threshold ROP, compared to conventional oxygen levels [40]. ...
... The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial found that there was no difference in the development of threshold ROP between preterm infants with prethreshold ROP in at least one eye when they were maintained at either conventional oxygen levels (89-94% SaO 2 ) or supplemental oxygen levels (96-99%) [40]. Results from the STOP-ROP trial also revealed that maintaining supplemental oxygen levels in infants without plus disease was protective against the progression to threshold ROP, compared to conventional oxygen levels [40]. However, infants maintained at supplemental oxygen levels were more likely to develop pneumonia and exacerbations of chronic lung disease, as well as to require oxygen, diuretics, or hospitalization at three months of age [40]. ...
... Results from the STOP-ROP trial also revealed that maintaining supplemental oxygen levels in infants without plus disease was protective against the progression to threshold ROP, compared to conventional oxygen levels [40]. However, infants maintained at supplemental oxygen levels were more likely to develop pneumonia and exacerbations of chronic lung disease, as well as to require oxygen, diuretics, or hospitalization at three months of age [40]. Overall, the optimal oxygen saturation levels to minimize severe ROP risk, as well as mortality, have yet to be determined. ...
Severe ROP is characterized by the development of retinal fibrovascular proliferation that may progress to retinal detachment. The purpose of this report is to review five of the most common and well-studied perinatal and neonatal modifiable risk factors for the development of severe ROP. Hyperoxemia, hypoxia, and associated prolonged respiratory support are linked to the development of severe ROP. While there is a well-established association between clinical maternal chorioamnionitis and severe ROP, there is greater variability between histologic chorioamnionitis and severe ROP. Neonatal sepsis, including both bacterial and fungal subtypes, are independent predictors of severe ROP in preterm infants. Although there is limited evidence related to platelet transfusions, the risk of severe ROP increases with the number and volume of red blood cell transfusions. Poor postnatal weight gain within the first six weeks of life is also strongly tied to the development of severe ROP. We also discuss preventative strategies that may reduce the risk of severe ROP. Limited evidence-based studies exist regarding the protective effects of caffeine, human milk, and vitamins A and E.
... This study randomized preterm infants with pre-threshold ROP at 35 weeks of gestational age to either 89-94% or 96-99% SpO2. STOP-ROP demonstrated that supplemental oxygen to keep saturations in the 96-99% range did not prevent the progression of pre-threshold disease but increased the risk of adverse pulmonary events including pneumonia, chronic lung disease, the need of diuretics, and hospitalization at 3 months of corrected age [87]. ...
Oxygen supplementation is widely used in neonatal care, however, it can also cause toxic effects if not used properly. Therefore, it appears crucial to find a balance in oxygen administration to avoid damage as a consequence of its insufficient or excessive use. Oxygen toxicity is mainly due to the production of oxygen radicals, molecules normally produced in humans and involved in a myriad of physiological reactions. In the neonatal period, an imbalance between oxidants and antioxidant defenses, the so-called oxidative stress, might occur, causing severe pathological consequences. In this review, we focus on the mechanisms of the production of oxygen radicals and their physiological functions in determining a set of diseases grouped together as “free radical diseases in the neonate”. In addition, we describe the evolution of the oxygenation target recommendations during neonatal resuscitation and post-stabilization phases with the aim to define the best oxygen administration according to the newest evidence.
... Two studies investigated the possibility that higher oxygen saturation thresholds (96-99% and 95-98%) in newborns with ROP who still required supplemental oxygen at 32 weeks of gestation would be advantageous [33,34]. A greater oxygen saturation goal was related with poorer respiratory outcomes in both investigations, and neither study found any substantial advantage from setting a higher target. ...
(1) Background: Retinopathy of prematurity (ROP) can cause severe visual impairment or even blindness. We aimed to assess the hematological risk factors that are associated with different stages of ROP in a cohort of preterm newborns, and to compare the clinical characteristics and therapeutic interventions between groups. (2) Methods: This retrospective study included 149 preterm newborns from a tertiary maternity hospital in Romania between January 2018 and December 2018, who were segregated into: Group 1 (with ROP, n = 59 patients), and Group 2 (without ROP, n = 90 patients). The patients that were affected by ROP were subsequently divided into the following subgroups: Subgroup 1 (Stage 1, n = 21), Subgroup 2 (Stage 2, n = 35), and Subgroup 3 (Stage 3, n = 25). The associations were analyzed using multivariate logistic regression and sensitivity analysis. (3) Results: Platelet mass indexes (PMI) that were determined in the first, seventh, and tenth days of life were significantly associated with Stage 1 ROP. PMI determined in the first day of life was also significantly associated with Stage 2 ROP. The sensitivity and specificity of these parameters were modest, ranging from 44 to 57%, and 59 to 63%. (4) Conclusions: PMI has a modest ability to predict the development of ROP.
