Retinopathy of prematurity and oxygen therapy a changing relationship

[Retinopathy of prematurity and oxygen therapy: a changing relationship].

retinopathy of prematurity and oxygen therapy a changing relationship

The relationship between PaO2 and saturation is a "changing" one, as reported many years ago. The relation of prematurity, oxygen and ROP has been studied. Purpose: To compare progression of retinopathy of prematurity (ROP) before and after Infants with stage 2 ROP in cohort B, with oxygen therapy protocol, had . for nonsystematic changes in clinical practice over the 9-year span of this study. . The relationship between patterns of intermittent hypoxia and retinopathy of. Retinopathy of prematurity (ROP) is a potentially blinding disorder, known to be associated with All models included a cubic time trend to reflect the average change management of oxygen treatment for premature newborns. Specific Aims o RQ Is there a relationship between the percentage of time the infants'.

If this is not done, the true rates of ROP in a particular unit will not be accurately known, and could be falsely low and comparisons among different units will not be valid. The issues mentioned above are related to the variability that exists between centers and of course between regions or nations. However, when all steps are followed, there is still significant inter-center variability. This inter-center variability is related to differences in clinical care of oxygen administration and monitoring, and other aspects of care.

retinopathy of prematurity and oxygen therapy a changing relationship

These differences in care also explain, at least in part, within center variability from one epoch to the next. To ensure accurate data, the infants considered at risk should be screened following a detailed protocol so that almost no infant is missed. Additionally, the eye examination should be methodically performed. The infant's pupils must be dilated cyclopentolate 0. If there is poor dilation, cyclopentolate 0. The exam involves the use of a sterile eyelid specula and scleral depressors in order to visualize the peripheral retina with a binocular indirect ophthalmoscope, along with a hand-held lens.

The infants must be carefully monitored for signs of distress caused by the examination. There are also guidelines as to when to repeat follow up exams. If there is no ROP during first exam, the infants need to be examined until retinal vessels had developed.

[Retinopathy of prematurity and oxygen therapy: a changing relationship]. - Semantic Scholar

Zone I ROP needs to be examined every week. Zone II needs to be followed every weeks until full maturity or worsening is found. The significance and impact of ROP is crucial.

A larger percentage has significant visual impairment. If one accepts a gross estimate that each year there are 2, VLBW infants discharged alive from NICU's in the USA who are blind or severely visually impaired and that the life expectancy for those infants is 70 years, one can calculate that each year there arenew years of blinded life entering society. Severe ROP not only leads to blindness but is associated with severe abnormal neurodevelopmental abnormalities.

More than half of the infants with unfavorable vision have severe disability. ROP in these settings is the most common cause of blindness.

The relation between oxygen saturation level and retionopathy of prematurity

The saddest part is that many of these infants are "large" i. Pathophysiology and the Developing Retina The two triggering factors are an incompletely vascularized retina preterm infants and increased PaO2 with relative retinal hyperoxia. These leads to vasoconstriction and decrease in growth factors, among them are insulin like growth factor IGF-1 and vascular-endothelial growth factor VEGF. This leads to arrest of vascularization and capillary obliteration, which leads to decreased perfusion and subsequent retinal ischemia and hypoxia.

If this response is marked and vasogenic factors do not decrease, angiogenesis i. This could finally lead to inflammation, proliferative retinopathy, significant fibrosis and retinal detachment Even though hyperoxia and the formation of radical oxygen species are clearly a predominant part of the pathogenesis, other factors like pro-inflammatory cytokines, cyclooxygenase-2 COX-2neuropeptide Y, Nitric Oxide NO and deficit of trophic factors and anti oxidants have been implicated.

This is why some investigators are exploring COX-2 inhibition to attenuate intra vitreal neovascularization. The neuropeptide Y has 36 amino acids and is upregulated by hyperoxic exposure. Depending on the time a, significant neovascularization can occur Cyclooxygenase-2 COX-2 is involved in neurodegenerative events in the rat retina These findings are leading investigators to study different forms of inhibition in an attempt to attenuate abnormal neovascularization.

Regarding hypercarbia, Holmes reports on carbon dioxide-induced retinopathy in the neonatal rat Furthermore, recent reports in animal model and tissue cultures show that hypercarbia without any hemodynamic effects increases NO synthase NOS isoforms in the retinal vasculature, resulting in cytotoxicity of the vasculature52, When hypercarbia coexists with elevated NO in the retina, the retinal lesions are many fold worse.

In addition it has been clearly demonstrated that hypercarbia induces vascular development and prolongs activation of endothelial NOS52, The clinical information is incomplete and non conclusive55,56, but this is not unexpected due to the multifactorial issues involved in the pathogenesis of ROP. As clinicians we can observe our practices and evaluate if any changes introduced in clinical practice before there is 'enough evidence' of safety and efficacy have any impact on important outcomes.

Nowadays many NICU's allow some very ill infants to remain on CPAP early in the infant's life, even if they have high PaCO2 and show significant oxygen fluctuation 'down and up' due to intermittent apneic episodes of variable severity. Interestingly, in addition to GA and BW, it was recently reported that apnea and surfactant therapy are significant independent risk factors for ROP.

Until further evidence is made available, the rates of ROP need to be monitored carefully and accurately if clinical practices are modified. The question today is which among the factors related to hypercarbia, hyperoxia and significant and rapid oxygen fluctuation has a greater or lesser impact on ROP.

They may all modify the expression of some or all of the factors mentioned above, and may be more detrimental in combination when the infant is more immature and the retina significantly underdeveloped. Unfortunately, it seems that there are regions and centers in the industrialized world which are showing an increase in severe ROP, NOT associated with an increased survival of the tiniest infants.

One can only wonder and speculate if the introduction of several new practices has a relation with this. Surfactant came in early 's and can be associated with rapid improvements in oxygenation. Around the same time, SpO2 monitors were introduced. In many centers high SpO2 values were routinely allowed and, therefore, a lack of a fast enough response to the surfactant induced changes in oxygenation could be associated with very high unknown PaO2 levels for varying periods of time early in post natal life.

retinopathy of prematurity and oxygen therapy a changing relationship

This, in addition to the rapidly fluctuating changes in oxygenation associated with the use of SpO2 monitors may explain in part the increase and variability in rates described before.

CPAP with significant hypercarbia and frequent episodes of low and high oxygen levels early in life may also have an impact on ROP. Oxygen Administration, Oxygenation Levels, Rapid Changes and ROP Oxygen was discovered more than years ago see before and it has been administered to more infants in the world than any other neonatal treatment.

However, we still do not fully know how much is wise to give or how much infants actually need in relation to variations in illness and gestational and postnatal age. But we have known for many years that "too much oxygen" damages the retina, Why choosing between the 'extremes" of oxygen dose: This practice of choosing 'one or the other extreme' cannot be a correct practice for many infants since it excludes or limits a more reasonable practice, a practice based on using an 'adequate' dose of oxygen, assessing each infant's needs.

Placing a pulse oximeter, targeting for an "acceptable" SpO2 and using a blender to be able to administer the needed oxygen dose for that target are simple and inexpensive care measures, which are used 'day in and day out' in every NICU in many nations.

Why is this not done routinely from the time of birth in preterm infants treated in many places through out the world? Why is this practice not done consistently during resuscitation, and at any time in the delivery room, in hospital transit or during hand ventilation? Not to do so is not supported by any literature nor by physiological evidence. It is well known that resuscitation without oxygen is effective as described by the references just cited above.

Oxygenation levels and 'bad practices' Currently oxygenation is measured in neonates in one of two ways: The history of oxygen monitoring is also very interesting and has been recently summarized Transcutaneous PO2 electrodes were used in the 's and, as useful as they were in the past, they were replaced by SpO2 in the mid to late 's. SpO2 monitors are currently widely used and this history is still evolving as new technological advances are entered into practice. In a separate review on pulse oximetry in neonatal medicine73, we describe the most important aspects of SpO2 and the significant differences in saturation monitors in the market, and how much we know and do not know about oxygenation.

Additionally, one SpO2 monitor is not the same as another SpO2 monitor. Many SpO2 monitors have high rates of false alarms, are not accurate in eliminating noise, have 'holding periods' and are more sensitive to light and motion artifacts.

In summary, many SpO2 monitors may not function well when clinicians need them the most.

retinopathy of prematurity and oxygen therapy a changing relationship

In addition, some SpO2 monitors measure and display functional O2 saturation and some fractional O2 saturation73, Some monitors read 1. Therefore, this information helps us understand that finding the 'ideal' or best O2 saturation in preterm infants is not easy, and cannot be just one value.

In many places the oxygen dose FiO2 is not measured carefully all of the time when given to premature infants, due to lack of blenders.

In such cases, unless the lungs are severely affected, the PaO2 could be very high i. But this can be done with humility, cognizant of our ignorance of what is "best" and of the caveats regarding monitor's measurement errors and differences between SpO2 monitors But what ever these and other limitations of our current knowledge may be, using a blender and a measurement of oxygenation i.

SpO2 monitor 'increases the evidence'. In such way, the infant would not be exposed to definitely abnormally high oxygenation levels and the FiO2 would be weaned as rapidly as necessary, as tolerated by the infant. Another 'bad practice' is that of manual ventilation in an intubated infant when this is done with gas flowing into a breathing bag directly from the wall O2 flow meter i.

For many reasons, like intubation in the delivery room, "deterioration" in NICU, change of ET tube, and others, manual ventilation may be necessary. However, we must remind ourselves that the gas "from the wall" is 'pure oxygen' and is cold and dry. These last two issues will change flow dynamics and affect the lung and the airways. Yet another bad practice occurs in many places when the dose of oxygen FiO2 is changed significantly without written orders or documentation.

Even today, in many places and during many NICU shifts, the FiO2 is modified significantly during some periods of time by care providers caring for preterm infants. For the most part, these modifications go undocumented in the clinical records. This delivery of clinical care with risk for "abnormally high" FiO2 and oxygenation levels is described in the following circumstances.

Many infants are left like this, without accurate documentation. And many monitors' alarms are turned off. Most infants, if not all, do not have an ABG measured during the period just described, when the FiO2 has been changed significantly.

Additionally, the infant may be subject to wide fluctuations in oxygenation. A similar situation is observed with the use of nasal cannulas.

An infant is with 0. The FiO2 is increased to 0. The saturation "recovers" and reads higher. The infant is left "in good condition" with such treatment.

How high is the PaO2 level?

4.3.3 Weaning, Approach to Oxygen Weaning in Children with ILD Q&A - Youtube_480P

This is of particular significance since the pulse oximeters do not give enough information about the blood oxygen tension PaO2which could be very high i.

Oxygen saturation monitors were entered into practice in the s not only without randomized trials but also, and probably more importantly, without education of bedside care providers around the world i. The optimal or ideal SpO2 for preterm infants is not known. Therefore evidence based clinical practice is impossible. However, since so many babies receive O2 and are monitored with SpO2 monitors, we should make an effort to identify and try to eradicate 'bad practices' like the ones described here.

What is the evidence that high PaO2 and SpO2 levels and widely fluctuating levels are 'bad practices? There were surviving infants, but the policy regarding SpO2 was found out retrospectively and 4 different types of monitors with different techniques were used. Several surveys reveal similar situations. Marlow, commenting on future clinical trials mentioned that SpO2 climbing too high should be avoided and probably not accepted by ethical committees Avoiding high oxygen saturation and the possibility of hyperoxia high P O2 is clearly supported in all current studies.

Additionally, oxidative stress influences apoptosis and cell growth This may have some relation to white matter injury and to long term consequences in growth and development and even in carcinogenesis. In this regard it has been reported that oxygen at birth increased the risk of childhood lymphatic leukemia OR 2. In relation to fluctuating oxygen levels and ROP, several animal and humans studies lend support to the relation between fluctuation and retinal damage The severity was of 5 clock hours in the first group of animals vs 2.

Saito88 found that the larger the coefficient of variation of PaO2 the worse was the retinopathy; Cunningham studied the variability of TcPO2 31 vs 38 infants and found worse retinopathy when the variability was larger Finally, York analyzed arterial blood gases in infants between and On average the blood gases were measured every 2.

Very recently, McColm has shown the effects of hyperoxic fluctuation in a rat model In summary, in the past few years, a number of studies have suggested that the "physiologically normal" O2 saturation of healthy infants breathing room air, long-accepted by many as targets for SpO2 in NICU, may be too high for the premature infant, and that allowing significant fluctuation is detrimental.

Unfortunately, aiming for "high" O2 saturation i. A "comfort zone" exists, and within this, it is assumed that if the O2 saturation is "high" the preterm baby is doing well. This needs to change, but the values and ranges of "lower" SpO2 saturations reported in recent cohort studies cannot be the basis for routine treatment for all premature infants of all gestational and post natal ages.

No range should become established practice before questions regarding short and long-term risks and benefits are resolved and until if ever the same SpO2 last generation monitor technology is used universally. However, this is not the same as saying "we'll continue to deliver care as always because that is the way we have done it". Eradicating some bad practices is not the same as implementing routinely unproven practices in a rigid way. Increased awareness and education of known and proven facts must be disseminated, since the gap between knowledge and practice is associated with morbidity and can sometimes be lethal.

The practice change occurred from the time of birth, with implementation of blenders and SpO2 monitoring in the delivery room, and the acceptance of "lower than usual" SpO2 values until the retina became mature. This included survivors and examined infants who had a birth weight of to 1, grams8. In addition, the rate of BPD decreased significantly also figure 2. In order to accomplish these changes in practice, it was necessary to "change culture". For this, we studied about the fascinating topic of culture change in health care.

We learned that it is important to understand the meaning of organizational culture in NICU, since each facility has its own unique character that strongly influences the quality of care and overall environment. When managing culture change one can try to lead reform or transformation.

We learned that coming to grips with culture in NICU facilities is a serious and necessary undertaking if real transformation is to occur. To implement transformation, every member of the leadership team, including medical directors, must be prepared for the hard work and time needed to shift organizational culture.

A 'First Order Change' implies doing what you do better; by quantitative reproduction and repetition i. The 'Second Order Change', on the other hand, is qualitative growth, something different. This is said to be necessary when an existing culture has begun to stagnate. They also proposed that the exposure of preterm neonates to hyperoxia could negatively affect the retinal vascular endothelial growth factor VEGF and damage normal retinal vascular migration which leads to vaso-obliteration.

In contrast, based on different protocols, application of higher oxygen saturation at later postmenstrual ages is proposed to be effective in reducing the progression and occurrence of ROP 13, In this systematic review, we aim to compare the efficacy of higher or lower oxygen saturations on the development of severe retinopathy of prematurity which is a major cause of blindness in preterm neonates.

Methods Relevant articles were retrieved through a comprehensive literature search in PubMed. All English language articles were identified with no time limitation based on the following search terms: All the human randomized controlled clinical trials RCTs published in English studied the efficacy of supplemental low and high SpO2 in premature infants, measured by pulse oximetry were eligible to be included.

The incidence of ROP at different stag es was also regarded as the outcome in all the included studies. Exclusion criteria were all the case reports, reviews, and the studies with no certain oxygen saturation level. Study selection Abstract and title of the articles obtained at primary search were studied. The results of those that discussed the effect of oxygen on the incidence of ROP were extracted.

Reference lists of the retrieved articles were also studied to prevent the possibility of missing any relevant article. Quality assessment of the included studies is detailed in Table 1. Result At the initial search, articles were obtained from which articles were excluded based on the exclusion criteria by screening the title and abstracts. Therefore, 20 articles were selected for further evaluation of the full text.

Overall, five articles that were the most relevant studies were included. Included studies were published between and A total of infants were evaluated in included studies, infants were in groups treated with low oxygen supplementation and the same number in groups with high oxygen saturation. The mean gestational age was almost 26 weeks. Discussion In this review, we aimed to study the incidence rate and progression of severe ROP in premature infants under the oxygen-saturation procedure measured by pulse oximetry.

It has been proposed that the first phase of the ROP consists of hyperoxia and following by vaso-obliterative phase during 30 to 32 weeks of postmesentural age; supplemental oxygen could arrest VEGF, interrupt normal vessel growth, and deteriorate the existing vessels. During the second phase of the disease after the 32 weeks of gestationthe presence of hypoxia increases VEGF expression and the subsequent pathologic neovascularization. Therefore, administration of appropriate level of therapeutic oxygen-saturation at each phase of the disease could adjust VEGF expression and pathologic neovascularization due to the ROP.

In this regard, there is a positive relation between postmenstrual age and the development of ROP. Previous laboratory and experimental examinations have proven the contribution of elevated VEGF in pathological retinal vasculature of animal models, transgenic mouse models, and nonhuman primates Although the appropriate level of oxygen saturation is not clearly revealed, pulse oximetry is nowadays routinely used for the monitoring of oxygen-fluctuation in preterm infants.

This relation has been demonstrated in 5 large clinical trials including three Boost trials, COT, and Support study groups Based on the study of Askie et al. Nevertheless, this trial did not have appropriate statistical strength to reveal the significant differences in secondary eye-related outcomes by applying higher levels of oxygen saturation, and further large trials are suggested to confirm the efficacy of different oxygen saturation ranges on the incidence rate of ROP.

Similar result was also reported in another study performed inwhich suggested a no significant decreased risk of ROP progression following higher oxygen-saturation levels applied at almost 2. Some limitations were associated with the study of STOP-ROP multicenter group, including the application of high saturation oxygen at a mean of 2. Because of the possibility of the enrolled infants to be at phase 1 or 2 of the ROP posmesentural age ranged from 30 to 48 weeksthe protective effect of oxygen-saturation therapy could not be determined exactly.

In contract with the two mentioned studies, results obtained through three large clinical randomized trials COT, three BOOST studies, and Support showed that application of high oxygen saturation compared with low concentration, within the initial time after the birth could increase the mortality rate and also develop severe ROP In all these five trials, supplemental oxygen saturation was applied soon after birth, and they confirmed that lower target ranges of oxygenation reduced the incidence of severe retinopathy.

Strategies of targeting levels of oxygen saturation in low or high range should be performed cautiously and careful attention should be devoted to the postmesentural age at the time of starting the procedures in preterm infants. Conclusion Based on included articles, it can be suggested that both the concentration of the applied oxygen and the timing of the oxygen application are important factors in severe ROP risk reduction.

Conflict of Interest The authors declare no conflict of interest. Risk factors and rate of progression for zone I versus zone II type 1 retinopathy of prematurity. Oxygen studies in retrolental fibroplasia.