As readers of this blog will know I am a big fan of anything that challenges my practice. It’s something that I think in general is a good practice to live by. For many years now when a preterm infant in particular is hypotensive it has been our practice to draw a serum cortisol level and then determine whether the stress response is adequate before starting hydrocortisone for blood pressure support. Having said that, sometimes we start the hydrocortisone and then use the level afterwards to determine if we need to continue. is this approach right though?
Evidence That Shakes Up Our Approach
It turns out the evidence that preterm infants may not be able to produce a robust cortisol response after birth has been around for sometime. In 1994 Hingre et al published Adrenal steroidogenesis in very low birth weight preterm infants. In this paper they documented the diminished ability of infants born < 30 weeks gestational age to produce cortisol finding preterm newborns had low basal cortisol levels “(mean +/- SEM, 207.4 +/- 23.5 nmol/L), and their levels were similar to basal levels reported for healthy full-term newborns (170.7 +/- 26.8 nmol/L; P = 0.31”. It is worth noting here that commonly held beliefs have been that an adequate adrenal response is in the range of 400 – 450 nmol/L or about 15 microgram/dL and these levels are lower than that. Moreover, when the authors measaured precursors of cortisol and found elevations consistent with a deficiency of decreased activity of 11 beta-hydroxylase (11 beta OH). Knowing this then, the use of a baseline cortisol to determine if an appropriate stress response is present before starting hydrocortisone is questionable. Having said that the practice has been that when it is low we assist with hydrocortisone and when it is high we can ease off the support. A new study that has just come out though I think may turn that thinking on its head!
High Cortisol Levels Are Concerning. Not the Lows!
Absence of relationship between serum cortisol and critical illness in premature infants by Prelipcean I et al was just published and looked at 224 infants at the University of Florida who were born under 30 weeks and had baseline cortisol levels drawn for clinical indications prior to 36 weeks PMA. Like many centres the baseline cortisol was done prior to starting hydrocortisone for hypotension. A baseline level under 15 mcg/dL was considered low which equates to about 413 nmol/L for those using those units (like my own hospital). The Simplified Score for Neonatal Acute Physiology II SNAP-II score , neonatal Sequential Organ Failure Assessment (nSOFA) and Vasoactive-Inotrope Score (VIS) were calculated and used as measures of illness severity against the the cortisol levels obtained in a retrospective fashion. Cortisol levels were taken at a median of 3.8 days with an IQR of 1.2 to 14 days). Hydrocortisone was givne to 71% of patients in the study as well.
What emerged from these results might be counterintuitive. From the figure below it was found that those infants with higher baseline cortisol levels were less likely to survive. This result just reached statistical significance. Thinking about this for a moment, we have traditionally worried about the infants with low cortisol and rushed to supplement them. The babies at real risk though here are the ones with a robust pituitary adrenal axis response. Notably another factor that leads to lower cortisol levels in the first few days of life is provision of antenatal steroids so it may be at least in part that the higher baseline levels might be seen in those without the benefit of antenatal steroids and therefore are at higher risk of adverse outcome. Bottom line though, a robust cortisol level would not necessarily appear to be marker of a good thing.
The second thing to be identified is the scatter of results for these infants across birth weight, day of life and gestational age. The authors discovered using a multivariable model that birth weight was the only statistically significant variable to explain cortisol variation. Interestingly for every 100g increase in birth weight cortisol increased an average of 10%.
Additionally, differences in average cortisol level were affected by chorioamnionitis and antenatal steroids. The presence of chorioamnionitis as a variable is not surprising I suppose given the results from the prophylactic steroid trials for BPD that have consistently found chorio predicts a higher rate of BPD.
Where things get really interesting is in the bottom half of the figure below. While weak linear associations with SNAP-II, nSOFA were found ,no correlation between serum cortisol concentration and concurrent critical illness severity objectively measured by SNAP-II and nSOFA scores at time points beyond the first day of life and prior to 36 weeks PMA in these infants were found. Most intriguing was the complete lack of relationship between the VIS and cortisol levels.
This presents a predicament about what to do with these levels. Based on this research the degree of illness and the amount of inotrope one is on (VIS takes into account doses of dopamine, dobutamine, vasopressin, milrinone, epinephrine and norepinephrine) has no relationship to cortisol level. If you are like our centre though you have been considering whether to use hydrocortisone based on the level of cortisol at baseline. Based on this research the message would be that if one wants to know a baseline cortisol it might be useful as a tool to determine how concerned one should be with an infant as risk of mortality is higher if baseline levels are above 413 nmol/L. In terms of determining whether one should support with hydrocortisone though in the face of a sick preterm infant and more specifically a hypotensive one the utility of the baseline measurement I would question. Adding to this the research from 1994 and one has to question if the level is low is that simply because the infant doesn’t have the metabolic machinery yet to produce enough rather than has an abnormal response to stress.
Some qualifiers as with any study like this need to be acknowledged. It is not a study of 1000 patients so the individual numbers of patients at different weight levels will be lower and therefore there could be unusual patients here influencing the results. Having said that, when you combine this information in this study with what is known from before about these preterm infants should we be surprised that there is no relationship between baseline cortisol and illness. If you don’t have the capacity to make it except when exceptionally stressed it would appear that all these baseline cortisols may in fact be good for telling ourselves how stressed we should be about the patient.
Evidence-based Practice for Improving Quality or EPIQ is a collaborative group here in Canada that is producing incredible work to examine the evidence to come up with the best approaches for treating conditions. One such target has been bronchpulmonary dysplasia or BPD. I was sent a document recently summarizing this work and thought it was definitely worth sharing with the masses.
Especially as we are all locked in somewhat with the expansion of COVID-19, a post on a lung disease seemed apropos. Our babies keep being born and with some preterm and at risk of developing BPD, what can you do to try and prevent this condition and moreover if an infant has developed it, what can we do to limit its severity and begin the healing phase?
Choosing to provide postnatal systemic steroids to preterm infants for treatment of evolving BPD has given many to pause before choosing to administer them. Ever since K Barrington published his systematic review The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. and found a 186% increase in risk of CP among those who received these treatments, efforts have been made to minimize risk when these are given. Such efforts have included shortening the exposure from the length 42 day courses and also decreasing the cumulative dose of dexamethasone. Fortunately these efforts have led to findings that these two approaches have not been associated with adverse neurodevelopmental outcomes. Having said that, I doubt there is a Neonatologist that still doesn’t at least think about long term outcome when deciding to give dexamethasone. The systemic application certainly will have effects on the lung but the circulating steroid in the brain is what occupies our thoughts.
All of the included studies used a prophylactic approach of giving between the first 4 hours and the 14th day of postnatal age doses of pulmonary steroids with the goal of preventing death or BPD. The GA of enrolled infants ranged from 26 to 34 weeks, and the birth weight ranged from 801 to 1591 g. Out of 870 possible articles only 12 made the cut and compromised the data for the analysis.
Routes of steroid were by inhalation, liquid instillation though the endotracheal tube or by mixing in surfactant and administering through the ETT.
What Did They Find?
Using 36 weeks corrected age as a time point for BPD or death, the forrest plot demonstrated the following. A reduction in risk of BPD or death of 15% with a range of 24% to only a 4% reduction.
Looking at the method of administration though is where I find things get particularly interesting.
What this demonstrates is that how you give the steroids matters. If you use the inhalational or intratracheal instillation (without a vehicle to distribute the steroids) there is no benefit in reduction of BPD or death. If however you use a vehicle (in both Yeh studies it was surfactant) you find a significant reduction in this outcome. In fact if you just look at the studies by Yeh the reduction is 36% (CI 34 – 47%). In terms of reduction of risk these are big numbers. So big one needs to question if the numbers are real in the long run.
Why might this work though?
In the larger study by Yeh, budesonide was mixed with surfactant and delivered to intubated infants every 8 hours until FiO2 was less than 30%, they were extubated or a maximum of 6 doses were reached. We know that surfactant spreads throughout the lung very nicely so it stands to reason that the budesonide could have been delivered evenly throughout the lung. Compare this with inhalational steroid that most likely winds up on the plastic tubing or proximal airway. The anti-inflammatory nature of steroids should decrease damage in the distal airways offsetting the effects of positive pressure ventilation.
I am excited by these findings (if you couldn’t tell). What we don’t know though is whether the belief that the steroid stays in the lung is true. Are we just making ourselves feel better by believing that the steroid won’t be absorbed and move systemically. This needs to be tested and I believe results of such testing will be along in the near future.
Secondly, we need a bigger study or at least another to add to the body of research being done. Such a study will also need long term follow-up to determine if this strategy does at least have equal neurodevelopmental outcomes to the children who don’t receive steroid. The meta-analysis above does show in a handful of studies that long term outcome was no different but given the history of steroids here I suspect we will need exceptionally strong evidence to see this practice go mainstream.
What I do believe is whether you choose to use steroids prophylactically using hydrocortisone or using intratracheal surfactant delivered budesonide, we will see one or both of these strategies eventually utilized in NICUs before long.
I feel like this has been a story in the making for some time. Next to caffeine, the story of prophylactic hydrocortisone must be one of my more popular topics and has been covered more than once before as in A Shocking Change in Position. Postnatal steroids for ALL microprems or Early Hydrocortisone: Short term gain without long term pain. and the last post Hydrocortisone after birth may benefit the smallest preemies the most! After reporting on this topic about once a year, a recent paper may wrap it all up in a bow for the holidays and present to us the conclusion after all this work on the topic. I was extremely interested in this topic not just because I believe this therapy may have a future in the standard approach to neonatal care for VLBWs but because I have served on the CPS Fetus and Newborn committee with two of the authors of the paper. Dr. Lacaze and Dr. Watterberg have an exceptional understanding of this topic and so when they band together with other experts in the field I take notice.
An Individual Patient Data Meta-Analysis
If you have read my previous posts then you know the story of why hydrocortisone given over the first 10-12 days of life might help those born before 30 weeks or < 1250g. In essence the concept is that it has been shown previously that many infants with relative adrenal insufficiency may go on to develop BPD. If you treat all such infants at risk you could theoretically reduce BPD. Typically after a few studies examining a similar topic come out, one can combine them in a meta-analysis using aggregate data (averages of effect sizes for the individual studies) and see what the larger sample shows. Another way to do it though is to go back to the original data and examine the infants at a more granular level allowing a greater identification and control of variables that might influence outcomes. This is what the authors led my Michele Shaffer did here in the paper Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis. There were a total of 5 studies on this topic but one study of 40 patients no longer had individual data so was excluded from analysis leaving 4 to look at. The details of the four studies are shown below. You can see that the inclusion criteria differed slightly but in general these were all infants up to 27 – 29 completed weeks and 500 – 1250g maximum who were treated with regimens as shown in the table.
What were the results?
Treatment with early low-dose hydrocortisone was associated with greater odds of survival without BPD at 36 weeks PMA after adjustment for sex, gestational age, and antenatal steroid use (aOR, 1.45; 95% CI, 1.11-1.90; I 2 = 0%). Also found were lower individual odds of BPD (aOR, 0.73; 95% CI, 0.54-0.98; I 2 = 0%), but not with a significant decrease in death before 36 weeks PMA (aOR, 0.76; 95% CI, 0.54-1.07; I 2 = 0%). Importantly although death by 36 weeks was not different, a decrease in death before discharge (aOR, 0.70; 95% CI, 0.51-0.97; I 2 = 0%) was found. Also noted and important was a reduction in medical treatment for PDA OR 0.72 (0.56-0.93)
All of these outcomes sound important but in a subgroup analysis other interesting findings emerged.
When dividing the patients into those less then 26 weeks and those at or greater than that gestational age, the benefits appear to be limited to those in the latter group. Levels of significance are high once you reach that GA suggesting that issues affecting those at younger gestational ages are less amenable to treatment. On the other hand one could say that the benefits seen at 26 – 29 weeks GA are relatively strong using a glass is half full approach. An important outcome worth noting is that while spontaneous intestinal perforation is noted to be a risk with prophylactic hydrocortisone, when you remove indomethacin from the equation the risk disappears. For those units using prophylactic hydrocortisone one would likely need to choose between the two but if you are like our unit where we don’t have that option this may be one strategy to consider.
In terms of risk to giving such therapy the big one noted in the paper was an increase in risk for late onset sepsis. Interestingly, this was limited though to the group under 26 weeks GA. In essence then the messaging would appear to be that under 26 weeks there may be less benefit to such treatment and therefore the increased risk of late onset sepsis without such benefits on BPD would suggest not using it in this GA group.
Where do we land then?
It would be easy to cast this aside I suppose as the group you are most worried about (22-25 weeks) doesn’t seem to really benefit but has a risk of late onset sepsis. That leaves us though with the group from 26-29 weeks. They do seem to benefit and may do so to a significant degree. They do develop BPD and to be honest we don’t have much outside of trying our best to use gentle ventilation to ameliorate their course in hospital. It is worth noting that the one group that does seem to show the greatest benefit are those exposed to chorioamnionitis. It is this group in particular that may be the best target for this intervention and I gather this has been discussed at a recent EPIQ meeting.
If one says no to trying this approach then the question that needs to be asked is whether doing nothing for this group is better than supporting them with hydrocortisone? If your centre’s rates of BPD are top notch then maybe you don’t want to add something in. If not though maybe it is time to rock the boat and try something different.
This must be one of my favourite topics as I have been following the story of early hydrocortisone to reduce BPD for quite some time. It becomes even more enticing when I have met the authors of the studies previously and can see how passionate they are about the possibilities. The PREMILOC study was covered on my site twice now, with the first post being A Shocking Change in Position. Postnatal steroids for ALL microprems? and the second reviewing the 22 month outcome afterwards /2017/05/07/early-hydrocortisone-short-term-gain-without-long-term-pain/.
The intervention here was that within 24 hours of birth babies born between 24-27 weeks gestational age were randomized to receive placebo or hydrocortisone 1 mg/kg/d divided q12h for one week followed by 0.5 mg/kg/d for three days. The primary outcome was rate of survival without BPD at 36 weeks PMA. The finding was a positive one with a 9% reduction in this outcome with the use of this strategy. Following these results were the two year follow-up which reported no evidence of harm but the planned analysis by gestational age groupings of 24-25 and 26-27 weeks was not reported at that time but it has just been released this month.
Is there a benefit?
Of the original cohort the authors are to be commended here as they were able to follow-up 93% of all infants studied at a mean age of 22 months. The methods of assessing their neurological status have been discussed previously but essentially comprised standardized questionnaires for parents, assessment tools and physical examinations.
Let’s start off with what they didn’t find. There was no difference between those who received placebo vs hydrocortisone in the 26-27 week group but where it perhaps matters most there was. The infants born at 24-25 weeks are certainly some of our highest risk infants in the NICU. It is in this group that the use of hydrocortisone translated into a statistically significant reduction in the rate of neurodevelopmental impairment. The Global Neurological Assessement scores demonstrated a significant improvement in the hydrocortisone group with a p value of 0.02. Specifically moderate to severe disability was noted in 18% compared to 2% in the group receiving hydrocortisone.They did not find a difference in the neurological exam but that may reflect the lack of physical abnormalities with cognitive deficit remaining. It could also be explained perhaps by the physical examination not being sensitive enough to capture subtle differences.
Why might this be?
Adding an anti-inflammatory agent into the early phase of a preemies life might spare the brain from white matter damage. Inflammation is well known to inflict injury upon the developing brain and other organs (think BPD, ROP) so dampening these factors in the first ten days of life could bring about such results via a mechanism such as that. When you look at the original findings of the study though, a couple other factors also pop up that likely contribute to these findings as well. Infants in the hydrocortisone group had a statistical reduction in the rate of BPD and PDA ligations. Both of these outcomes have been independently linked to adverse neurodevelopmental outcome so it stands to reason that reducing each of these outcomes in the most vulnerable infants could have a benefit.
In fact when you add everything up, is there much reason not to try this approach? Ten days of hydrocortisone has now been shown to reduce BPD, decrease PDA ligations and importantly in the most vulnerable of our infants improve their developmental outcome. I think with this information at our fingertips it becomes increasingly difficult to ignore this approach. Do I think this will become adopted widely? I suspect there will be those who take the Cochrane approach to this and will ask for more well designed RCTs to be done in order to replicate these results or at least confirm a direction of effect which can then be studied as part of a systematic review. There will be those early adopters though who may well take this on. It will be interesting to see as these centres in turn report their before and after comparisons in the literature what the real world impact of this approach might be.
Stay tuned as I am sure this is not the last we will hear on this topic!