Dr. Amy Brown presented on how the timing of use of systemic corticosteroids may prevent BPD and/or more effectively treat the manifestations of BPD.
Now, it's my pleasure to introduce one of my newer partners to our practice in Phoenix, uh which is Doctor Amy Brown. Um She is our lead at Saint Joe's Hospital, which is our delivery center for our BPD program. Uh She's a clinical assistant professor of the Department of Child Health at the University of Arizona. Uh So we, you know, she's going to take our pharmacologic discussion to, you know, the next large drug class that uh I will say at least for us locally we tend to use. So with that um Doctor Brown. OK, good morning everyone. And thank you Doctor Martin for the introduction. So I will be talking about systemic corticosteroids and, and the timing of their use and prevention of BPD. So all from this quote, the use of postnatal cortical steroids to prevent bronchopulmonary dysplasia is among the most controversial topics in medicine. This is an introductory line from a recent paper by Jensen. All looking at pretreat risk of death or BPD and use of steroids, a paper which we will look into later. But in preparation of this talk, I decided to open with this quote because I don't think I could agree with it anymore as background, bronchopulmonary dysplasia or BPD is a complication of prematurity that affects over 40% of infants with a birth weight. Less than 1500 g. Steroids are among the few medications that have been shown to reduce the risk of developing BPD in randomized controlled trials or RCTS. However, optimal time to initiate a course of steroids in these high per patient population remains unknown. So why is it so hard to give firm recommendations on the use of steroids to prevent BPD? In reviewing the timeline of evidence that has shaped the opinions in neonatology. The evidence itself is controversial. Hence what I call this by the dex methasone dilemma studies in the 19 eighties and nineties provided evidence that dexamethasone improved weaning from respiratory support and reduced the risk of BPD in preterm infants leading to prevalent use of high dose corticosteroids to prevent BP. Then subsequent pub publications showed increase in risk of adverse or developmental effects, especially cerebral palsy or CP with high dose dexamethasone, which then led to widespread recommendations against use of steroids to prevent or treat BPD systemic reviews. Then proposed a more balanced approach by weighing the risks of neurodevelopment impairment due to corticosteroids against the risk of developing DPD which in and of itself is uh is associated with developmental disability meta regression analysis of RCTS by Doyle at all suggested that steroids were associated with decreased rates of death or CP among infants at high risk of developing DPD. So once again, there are revised recommendations to consider. Again, just consider we have no firm rec recommendations for or against the use of low dose corticosteroid therapy for very preterm infants receiving mechanical ventilation after 1 to 2 weeks of age due to their increased risk of EPD. However, most trials that inform these studies use revised guidelines um with current recommendations that have higher than recommended dosages. So this brings us to our current state. If our heads aren't already staying, ideally, the timing of posting austerities should maximize pulmonary benefit without increasing neurodevelopmental risk. Optimal timing is unknown due to safety concerns with early exposure recommendations have been made to limit steroid use to those with evolving chronic lung disease and failure to excavate. After 1 to 2 weeks, average age of her steroid exposure has drifted towards four weeks of life. Although safety and efficacy in this practice is unclear. Further postponement and sterile use may delay extubation and increase cumulative days on mechanical ventilation which is associated with development of BPD and thus neurodevelopmental impairment. So let's now begin with looking at early use of steroids. Um For this talk early is referring to postnatal days. One through seven. This is reviewed by Doyle at all and a recently updated version of this review is, is available in the Cochrane database of systematic reviews for this review. Doctors selected RCTS examine systemic. So, intravenous are oral postnatal steroids and treatment started within the six days after birth and high risk preterm infants. It included studies that both evaluated the use of dexamethasone as well as hydrocortisone even when the latter was used for management of hypotension rather than treatment of lung problems. Majority of studies included use dexamethasone trials within inhaled corticosteroids were not included in this RCT review. Most beneficial and harmful effects are related to early treatment with dexamethasone rather than to early treatment on hydrocortisone. Early treatment with hydrocortisone may prevent mortality. Whereas dexamethasone early treatment does not and looking at the associated risks. Early systemic post natal cortical series treatment resulted in short term benefits which included earlier excavation and decreased risk of BPD and of mortality or BPD at 28 days of life and at 36 weeks, post menstrual age but was associated with significant short term and long term effects. Adverse effects included the shorter term effects of gastrointestinal bleeding, intestinal perforation, hyperglycemia and hypertension as well as long term risks of abnormal neurological examination findings and cerebral palsy. However, the methodological quality of these studies, what is that? And determining long term outcomes was limited in some cases, Children were assessed predominantly before school age and the study was sufficiently and no study was sufficiently powered to detect important adverse outcomes in neurosensory development. But therefore given the risk of potential short term and long term adverse effects. This review supported the curtailment of early systemic corticosteroids for treatment or prevention of BPD. Um I wanna take a moment to highlight the prem lock studies. So this is more specific, it involves early steroid use but applies to infants that are also exposed to chorioamnionitis. In the prem study, infants were exposed to hydrocortisone for a total of 10 days with doses comparable to baseline cortisol levels. Hydrocortisone is initiated prior to 24 hours of age in extremely low birth weight. Infants again with exposure to chio, the primary outcome of this trial was survival without BPD, which is significantly increased by this intervention. As you can see in the last box, 60% of infants treated survived without BPD. Compared to 51% of infants that were not treated, treated with hydrocortisone. There's an odds ratio of developing in BPD of 1.48 in those not treated. The number needed to treat in the study to prevent one diagnosis of BPD was 12. Next we move on to quote unquote late systemic cortical stories which are initiated between days of life eight and 42. Again, this re review was performed by Doyle at all with an updated version again available in the Cochrane Systematic Data database. This review, there were 23 RCTS looking at a total of 1817 infants. 21 of these RCTS involved dexamethasone. One of those also included hydrocortisone and two involve hydrocortisone only overall, there is a reduction in mortality to the latest reported age of 36 months. The latest reported age amongst all the studies though did vary from 12 to 36 months. Late steroids were found to reduce the incidence of BPD at 36 weeks as well as reduce the combined outcome of mortality or BPD at 36 weeks. Post menstrual age reduction of the combined outcome was true for dexamethasone but not so for hydrocortisone. Here you can see that the relative risk with dexamethasone was 0.85. Um whereas oh sorry 0.75 whereas hydrocortisone did not decrease that the relative risk is 0.98. So systemic corticosteroids were found to have little to no effect on developing cerebral palsy. Overall systemic steroids started after seven days of life, reduced the risk of mortality and BPD as well as the combined outcome of mortality and BPD without evidence of increased risk of CP. Longer term. Follow up until late childhood is needed for assessment of outcomes such as cognitive function, executive function, academic performance behavior, mental health, motor function, and longer term lung function similar in this realm. A study by Doctor Heidi Harman, Doctor Eric Jensen and others in 2020 sought to determine the associations between that age at first, postnatal steroid exposure and the risk for neurodevelopment impairment or ND I. This was a retrospective cohort study of respectively, collected data of extremely preterm infants. So those born less than 27 weeks, gestational age who first received postnatal steroids with the specified indication of the prevention or treatment of BPD. And this was between days eight of life and 35 and 67 weeks of post menstrual age. This time period was selected to fall after that whole early period of steroid administration and to correspond to the common practice of starting steroids after the first week of life to treat B PB evolving BPD. But also before the official diagnosis of PPD could be made at 36 weeks. P MA. The infants were compared between steroid exposed groups rather than comparing an unexposed control to steroid exposed infant infant. To allow for comparison specifically based on those um as exposed to steroid, looking at the timing of exposure, primary outcome of interest or severe BPD at 36 weeks and neurodevelopmental impairment or ND I at follow up as well. Composite outcome of severe BPD or death before 36 weeks, P MA and death or ND I at 18 to 26 months corrected age. Pulmonary outcome of severe BPD was selected due to its stronger association with ND I and long term pulmonary sing severe BPD to go back to definition was defined as greater or equal to 30% oxygen use and or positive pressure ventilation at 36 weeks. The IC HDNRN definition of severe ND I was selected for primary developmental outcome to the expected high levels of delay seen in extremely preterm infants with severe respiratory morbidity. So looking at all these spots, you can see they demonstrate a NADER at around four weeks of age and a non linear relationship between age at first a exposure and the probability of each outcome dots are a digestive probability outcome. And the solid lines indicate the boundaries of the seven age categories of steroid initiation again. So looking at severe BPD, there's a NATER at approximately 4 to 5 weeks death prior to 36 weeks, P MA or severe BPD. A NATER again between 4 to 5 weeks, neurodevelopment impairment seems to have a similar inflection point around four weeks of exposure and again, with death prior to follow up our ND I in evaluating secondary outcomes. This study found that 89% of the cohort had moderate or severe BPD and survivors received an average of seven weeks of mechanical ventilation and 63% were discharged on oxygen. However, the group with earlier steroid exposure says steroids started less than 28 days were less likely to be discharged from an oxygen. 50 55% versus 63%. The early group was also less likely to have moderate or severe BPD with the development of 84 versus 92%. This figure from the same paper depicts the adjusted odds ratios of severe BPDND I and the composites for mortality adjusted odds ratios for developing severe BPD among survivors for 36 weeks were similar among those beginning steroids during weeks, two and three our day of life, 18 to 21 and beginning during weeks, 5 to 7 a day of life, 29 to 49 after birth. However, the adjusted odds ratio for severe BT D was significantly higher among infants with steroids treatment that began after 5 to 7 weeks or sorry, excuse me, after 8 to 9 weeks and after nine weeks, logistic analysis of the composite outcome of BP or death before 36 weeks, post menstrual age demonstrated a more significant U shape pattern with a higher adjusted odds ratio for death or DPD in those receiving steroids both earlier. So during week three and late at week, 10 or later, as compared to those who are exposed to steroids during the fourth week of life. Looking at the bottom figures, you can see that there is a similar inflection point in around four week of life for development of ND I among survivors that were followed to follow up and again, a lower risk of death prior to fall for ND I when steroids were initiated at four weeks of life to summarize the results from this cohort. The percentage of Children with severe BPD was lowest when steroids were initiated at days of life. 22 to 28. While avoiding unnecessary steroid exposure for preterm infants is likely beneficial. There may be a limit around 50 days of life where the anti-inflammatory effects of steroids are less effective after a more prolonged exposure to mechanical ventilation and hydrox for infants at high risk of BPD. Initial postnatal steroids should be considered prior to day of life. 50 for the lowest associated odds of development of severe BPD. Despite multiple risk factors for poor outcomes including postnatal steroid exposure itself, prolonged ventilation and high rates of BPD. 75% of the virus in the current cohort did not have severe Nero developmental impairment at their two year follow up. So to conclude from that paper, contemporary dosing strategies for systemic corticosteroid therapy may be associated with decreased risk of adverse neurodevelopmental outcomes and restricted to preterm infants at moderate to high risk of death or BPD. So I don't like to segue into a deeper look at corticosteroid treatment for BPD prevention and risk of death or disability by the most recent paper by Doctor Jensen and others, which was published in Jamma this past may. So as we've seen from the evidence presented thus far, meta analysis suggests that corticosteroids may be associated with increased survival without cerebral palsy in infants at a high risk of BPD but are associated with adverse neurological outcomes and low risk infants. So, this study aimed to evaluate whether a pretreat risk of death or grade two or three BPD at 36 weeks. Modified the association between postnatal steroid therapy and death or disability at two years. Directed age in extremely preterm infants. Why the deeper look in the beginning of this talk, we reviewed the history of evidence on dexamethasone and the controversy in coming to consensus recommendations. Again, most recent revised recommendations are that clinicians may consider low dose steroid therapy for very preterm infants who are still on mechanical ventilation after 1 to 1 to 2 weeks of age due to the increased risk of developing BPD in this population. However, most trials that informed these guidelines initiated steroids during the first week after birth are used a higher cumulative dose than current recommendations. And thus may not accurately characterize the risks and benefits of postnatal steroid treatment strategies used to prevent BPD in contemporary extremely preterm infants. Here we can see the guidelines from the US Canada as well as Europe. So to briefly go over these in the US high dose dexamethasone in excess of 0.5 megs per kick per day is not recommended early. So less than seven day, low dose hydrocortisone may prevent chronic lung disease or death in infants weighing less than 1000 g who are also exposed to correal late. So exposure of 7 to 28 days low dose sex meth may improve outcomes for preterm infants who remain on significant respiratory support. In Canada guidelines say poly postnatal steroid use within the first seven days of life to prevent chronic lung disease is also not recommended. Ta brain high dose dexamethasone again with 0.5 makes per ta per day or greater to prevent or treat chronic lung disease is not recommended hydrocortisone and inhaled corticosteroids are not recommended to prevent or treat chronic lung disease. For Canadian guidelines and the benefits of late low dose dexamethasone are unclear but they recommend to discuss low dose. So 0.15 meg per cake per day to two to 0.2 meg per cake per day with parents and taper. That course over 7 to 10 days. Europe is a little more straightforward in their guidelines. They recommend a short tapering course of low dose or very low dose dexamethasone that should be considered to facilitate excavation in babies who remain on mechanical ventilation. After 1 to 2 weeks, the European guidelines did also mention the minix trial saying that there's anecdotal evidence that starting doses of dexamethasone as low as 0.05 makes per kick per day might be effective. But this minix RCT failed to recruit enough participants to confirm this. So neither the American or Canadian guidelines felt there was enough evidence from the minix trial to make these recommendations for the very low dose dexamethasone. So going back to the study by Jensen, this cohort study analyzed data on 482 matched pairs of infants from 45 hospitals participating in the NR A generic database. Infants were included if they were born less than 27 weeks, survived the first seven postnatal days and had two year death or developmental follow up data collected exclusion Tricia for infants who were enrolled in the NRN hydrocortisone for BPD trial, treated with systemic steroids less than day of life. Eight or greater than day of life. 42 after birth had severe congenital disease or had missing data for key variables. Infants in this cohort had exposure of systemic corticosteroid therapy specific for BPD prevention that was started between day of life. Eight and 42. Information is available on the steroid type and date of initiation but not the dose treatment duration or presence of subsequent treatment courses. This figure further outlines the inclusion and exclusion criteria. Furthermore, from the mass, we can see that again. Dexamethasone is the primary steroid used. The exposure of cohort again with systemic steroids initiated between days of life. Eight and 42 with the intention of BPD prevention. Primary outcome was death or moderate to severe neurodevelopment impairment at two years, corrupted age. Again, definitions for this paper in terms of BPD, they specifically looked at grade two or three BPD, which was defined as treatment with mechanical ventilation, noninvasive positive airway pressure or nasal cannula delivering greater than 2 L per minute. And grade two or three BPD was assessed as a composite with death at 36 weeks. P MA in terms of moderate to severe ND I that was defined with the Bailey three cognitive or motor composite score less than 85 the gross motor functional classification system level of two or higher, moderate to severe CP and or severe visual or hearing impairment. This table reports the steady outcomes in the full mash cohort. There were no differences in the adjusted odds of death or moderate to severe neurodevelopment on impairment or death or moderate to severe CP at two years. Corrected age that were associated with corticosteroid therapy, adjusted odds of developing death or grade two or three BPT at 36 weeks. P MA were not significantly different between the groups. But interestingly, there is an inverse association between the pretreat probability of death or grade two or 3d PD at 36 weeks. P MA. The risk differences for death or disability associated with, with corticosteroid therapy for each 10% increase in the probability of death or grade two or three BPD. The risk difference for death or moderate severe neurodevelopment impair impairment associated with steroid use decreased by 2.7%. So in this top figure, the line crosses the X axis at a probability of death or grade two or three BPD at 53%. These values quantified the pretreat probability of death or grade two or three BPD where the risk of death or moderate to severe neurodevelopment impairment associated with steroids transition from estimated net harm on the left side to net benefit. The corresponding analysis for um death or moderate to severe CP also found in inverse association for each 10% increase in the pretreat probability of death or grade two or three BPD. The risk difference for death or CP associated with steroids decreased by 3.6%. And this line process act a access at a pretreat probability of grade two or three BPD of 40%. The post hoc analysis demonstrated similar inverse associations between probability of death or grade two or three BPD and risk of death or severe disability associated with steroids. So, when averaged over the full mesh cohort postnatal steroids in the study were not associated with a significant increase or decrease in the risk of death or moderate severe neurodevelopment impairment or death or moderate to severe CP. However, pretreat probability of death or grade two or three BPD at 36 weeks, modified the association between steroid therapy and risk of death or disability, steroids were associated with a reduced risk of death or disability among infants who were at moderate to high risk of death or grade two or three BPD, but were also associated with the possible increased risk of death or disability among infants who are at low risk of grade two or three BPD. So overall from the study, it's estimated that potential benefit exceeds net harm at a pretreat probability of death or grade two or three BPD of 40%. So I thought I spoke a bit about pre treatment of probability and on this slide, I pulled this from the NRN website. They do have a useful tool for estimating, develop the risk of developing BPD as well as the likelihood of severity of BPD. So predictions with this model improved with advancing postnatal age. One limitation of using this tool is that the postnatal age you're pretty stuck on which days you can put in. So you can use days 137, 1421 or 28. So it has to be one of those six days. But as we've seen previously, days, 14 to 28 do seem to be the most likely window for steroid initiation on postnatal days. One and three, the gestational age using this calculator best improves prediction of developing BPD. Whereas at the later four days that you can put in the type of respiratory support that the infants on leads to better prediction of whether or not they develop severe BPD. So, aside from the neurodevelopment effects, considering er use, there are a variety of additional effects. So the use of steroids can suppress the immune system. And there's evidence from a variety of RCTS and one in particular that showed very low birth weight infants exposed to a two week course dexamethasone were more likely. So 48 versus 30% to have at least one positive blood culture. That, that when compared to infants exposed to placebo growth is another concern in steroid use growth velocity occurs as steroid treated infants showed a decrease when compared to non steroid, treated premature infants. In this particular figure, you can see a decrease in the standard deviation of infants treated with dexamethasone, which is the blue line and those treated with hydrocortisone which is a red line compared to the black line of infants that were not treated with corticosteroids for BPD prevention growth velocity curves are also shifted to the right. Again, the figure DEX treatment is in blue hydrocortisone treatment is red and no treatment is in black. So the data from this paper and others show that treatment steroids acutely slows down growth velocities. But data on the effect of longer term growth, especially past hospital discharge is more scarce adrenal suppression is another side effect to consider the cumin of doses. Depending on the dosing regimen, used can be very high, particularly if infants are exposed to more than one regimen. And they are at risk for secondary adrenal insufficiency if they've been given super physiological glucocorticoid doses in excess of 14 days. Exogenous steroids cause adrenal insufficiency through myriad effects on the H VA A access. They may be at risk for an adrenal crisis following the steroid therapy. So, tapering doses after 14 days are likely beneficial but again, would contribute to more prolonged exposure to steroids. Pharmacological doses for BPD prevention of either dexamethasone or hydrocortisone can range from slightly above physiological dosing to greater than recommended than stress dosing at such doses. The exogenous steroids may induce the mineral corticoid effect which can cause hypertension or they may induce a Glucocorticoid effect which would lead to hyperglycemia. So, hypertension hyperglycemia being two of the shorter term effects that we deal with when initiation of steroids. So overall take white pains from this talk. Unfortunately, I still can't tell you when to start staring for BPD prevention. But evidence does suggest that starting between days of life, 7 to 28 has the most impact on BPD prevention. While also mitigating adverse outcomes. When steroids are initiated past the fourth week of life, the risk of developing BPD neurodevelopment, impairment and mortality may start to increase and the initiation of steroids past day of life. 50 carries a higher risk of harm with potentially minimal ben benefit in BPD prevention. When considering initiation of steroids for prevention of chronic lung disease risk, calculators like the one demonstrated from the NRN could be variable could be helpful in um weighing in our decisions. So premature infants who are likely to have at least a 40% risk of developing moderate to severe BPD stand to benefit the most from steroid use. If they're at a relatively low risk of developing BPD, then steroids are unlikely to alter their course enough enough for the net benefit of these steroids to outweigh the risk of net harm. Aside from assessing the risk of neurodevelopment impairment and counseling families on such, there are variety of effects such as decreased growth velocity in the short term hypertension, hyperglycemia, impaired immunity and potential adrenal suppression to consider and monitor for. So this wraps up my talk with the references. I think you will.
