Precision medicine is a growing field in which genetic factors, environment, metabolism and even lifestyle are taken into account when deciding who should receive a treatment or not. When it comes to bronchopulmonary dysplasia I believe anyone who works in Neonatal care can attest it is a mystery why some infants go on to develop BPD while others don’t. We do know that certain treatment strategies may increase risk such as using excessive volumes or pressure to ventilate and in the last 25 years the notion that your level of cortisol in the blood may make a difference as well. I have written about prophylactic hydrocortisone use before in Hydrocortisone after birth may benefit the smallest preemies the most! When looking at the literature thus far and taking into account the results of the individual patient meta-analysis the following table can be generated highlighting a summary of benefits.
A baby’s initial cortisol level may be the answer
The PREMILOC study was a double-blond multicentred trial of 523 infants randomly assigned to either prophylactic hydrocortisone in the first 24 hours of life or placebo. All infants were under 28 weeks at birth and received 1 mg/kg/d of hydrocortisone 1 mg/kg/d for 7 days followed by 3 days of 0.5 mg/kg/d for three days. In a pre-planned study coming out of the PREMILOC study, researchers looked at the role of baseline cortisol in predicting response to treatment or risk of adverse outcomes.
What they found in examining baseline levels for both treatment and placebo groups was that a relationship exists between the baseline level and such outcomes.
From Table 4 they found a relationship between survival without BPD and a higher initial level of cortisol but found no such relationship in the treatment arm. The threshold of what was considered high was 880 nmol/L although the mean cortisol was in the 400-500 nmol/L range. in other words, if having adequate physiologic levels of cortisol is the goal and a baby already has that, giving more non-antiinflammatory dosing of hydrocortisone doesn’t yield benefit.
Similarly, when looking at side effects a positive correlation was found between higher baseline levels of cortisol and risk of grade III/IV IVH and spontaneous intestinal perforation. It would seem therefore that if a baby has the level of cortisol that they would normally have from a physiologic perspective they are no different than a placebo arm patient when given hydrocortisone as you bring them to where they need to be. When you double the dose however that they should have, side effects begin to rear their ugly head.
How can you use this information?
From personal conversations I know that many centres are struggling with what to do about giving hydrocortisone. On the one hand there isn’t much benefit (if at all) for BPD in the 24 and 25 week infants but they do better from a neurodevelopmental standpoint. On the other hand there is a benefit in the 26 and 27 week infants but you may predispose them to side effects as well.
This is where precision medicine comes in. One option for centers unsure of who to provide this to (if at all) could be to use a threshold of 880 nmol/L and if the initial level is above this you would not treat but if below offer treatment. This level while found in the study to be predictive of side effects in particular if high does seem very high to me. I would think most babies would qualify which is not necessarily a bad thing but in our center we have typically used levels above 400 or 500 as an adequate stress response. Regardless of the level picked one would be using physiologic data to determine who to give hydrocortisone to as a way to try and maximize benefit and minimize harm for the individual patient.
Make no mistake. Regardless of whether you decide to try this for your patients I don’t believe this is a magic bullet. The best chances for our patients come from having bundles of evidence based based practices and applying them to the patient population if we hope to reduce BPD and minimize risk from any side effects of our treatments. The question is whether prophylactic hydrocortisone should be part of this bundle.
This could turn into a book one day I suppose but I have become interested in chalenging some of my long held beliefs these days. Recently I had the honour of presenting a webinar on “Dogmas of Neonatology” for the Indian Academy of Pediatrics which examined a few practices that I have called into question (which you can watch in link). Today I turn my attention to a practice that I have been following for at least twenty years. I have to also admit it is something I have never really questioned until now! In our institution and I suspect many others, infants born under 1250g have been fed every two hours while those above every three. The rationale for this has been that a two hour volume is smaller and causes less gastric distention. This in theory would benefit these small infants by helping to not compromise ventilation or lead to reflux. Overwhelming the intestine with large distending boluses would also in theory lead to less necrotizing enterocolitis. All of this of course has been theoretical and I can thank those who preceded me in Neonatology for coming up with these rules!
Study Challenges This Old Belief
Yadav A et al published Two-hourly versus Three-hourly Feeding in Very Low Birthweight Neonates: A Randomized Controlled Trial out of India (well timed given my recent talk!). The authors randomized 175 babies born between 1000-1500g to either be fed q2h vs q3h once they began protocol feeding. The primary outcome was time to full feedings. Curiously, the paper indicates they decided to do a preplanned subgroup analysis of the 1000-1250 and 1251 -1500g groups but in the discussion it sounds like this is going to be done as a separate paper so we don’t have that data here.
The study controlled conditions for determining feeding intolerance fairly well. As per the authors:
“Full enteral feed was defined as 150 mL/Kg/day of enteral feeds, hypoglycaemia was defined as blood glucose concentration <45mg/dL . Feed intolerance was defined as abdominal distension (abdominal girth ≥2 cm), with blood or bile stained aspirates or vomiting or pre-feed gastric residual volume more than 50% of feed volume; the latter checked only once feeds reached 5 mL/kg volume . NEC was defined as per the modified Bells staging.”
We don’t use gastric residuals in our unit to guide cessation of feedings anymore but the groups both had residuals treated the same way so that is different but not somethign that I think would invalidate the study. The patients in the study had the baseline characteristics shown below and were comparable.
It will be little surprise to you that the results indicate no difference in time to full feedings as shown in Figure 2 from the paper.
The curves for feeding advancement are essentially superimposed. Feeding every two vs three hours made no difference whatsoever. Looking at secondary outcomes there were no differences as well in rates of NEC or hypoglycemia. Importantly when examining rates of feeding intolerance 7.4% of babies in the 2 hour and 6.9% in the 3 hour groups had this issue with no difference in risk observed.
Taking the results as they are from this study there doens’t seem to be much basis for drawing the line at 1250g although it would still be nice to see the preplanned subgroup analysis to see if there were any concerns in the 1000-1250 group.
Supporting this study though is a large systematic review by Dr. A. Razak (whom I have collaborated with before). In his systematic review Two-hourly versus three-hourly feeding in very low-birth-weight infants: A systematic review and metaanalysis. he concluded there was no difference in time to full feeds but did note a positive benefit of q3h feeding in the 962 pooled infants with infants fed 3-hourly regainin birth weight earlier than infants fed 2-hourly (3 RCTs; 350 participants; mean difference [95% confidence interval] -1.12 [-2.16 to -0.08]; I2 = 0%; p = 0.04). This new study is a large one and will certainly strengthen the evidence from these smaller pooled studies.
The practice of switching to q2h feedings under 1250g is certainly being challenged. The question will be whether the mental barriers to changing this practice can be broken. There are many people that will read this and think “if it’s not broken don’t fix it” or resist change due to change itself. The evidence that is out there though I would submit should cause us all to think about this aspect of our practice. I will!
Private room vs open bay for the NICU. Can always get a quote from a parent saying it is great but….? At what cost? Impact on staff? Is parent time in those NICUs greater now? Other alternatives?
Included in the post was an article discussing the benefits of such a design. Below I will look at the benefits and risks and conclude with an answer to his last question.
The NICUs of the 1970s through late 1990s have been described as “barn like” or “open concept” but in recent years the belief that single patient rooms (SPR) would offer greater benefit to infants led to the adoption of such a unit design across North America. The imagined benefits would be related to improved parent comfort, creating a desire for families to spend more time with their children. As we move to a “family centred” approach to care, a key goal of all units should be to make their families as comfortable and stress free as possible in order to have a positive experience.
Detractors meanwhile, speak of concern regarding isolation of such infants when families do not visit and moreover a risk that such infants deprived of sensory experience will have impaired development. Last year a paper was published that did not help quell such fears; Alterations in Brain Structure and Neurodevelopmental Outcome in Preterm Infants Hospitalized in Different Neonatal Intensive Care Unit Environments (full article in link). This study which compared infants cared for in SPR to an open unit (the hospital in this study had a mixture of both in their NICU) found a worrisome finding at 2 year follow-up in that the infants in SPR had lower scores on language and a trend towards lower motor scores as well. Additionally, partly explaining such findings may have been differences noted at term equivalent age in both the structure and activity of the children’s brains compared to those cared for in an open environment. We were starting construction on a new NICU at the time this paper was published and I can tell you the findings sent shockwaves through our hospital as many wondered whether this was the right decision.
Devil Is in The Details
Looking further into this study, the urban population bore little resemblance to our own. In our hospital all women are taught how to perform skin to skin care and the majority of our mothers spend a great deal of time with their infants. To see how successful have a look at our recent Kangaroo Care drive results! The families in this study however the average hours per week of parent visitation over the length of stay ranged from 1.8-104 hours with a mean of 19+/- 19 hours. The average number of days held per week over the length of stay was 0-6 days with a mean of 2.4 +/-1.5 days. The average number of days held skin-to-skin over the length of stay ranged from 0-4 days, with a mean of 0.7 +/- 0.9 days. In short they were hardly there.
Statistically significant results (all Ps ≤.05) showed that infants in the SPR NICU weighed more at discharge, had a greater rate of weight gain, required fewer medical procedures, had a lower gestational age at full enteral feed and less sepsis, showed better attention, less physiologic stress, less hypertonicity, less lethargy, and less pain.Nurses reported a more positive work environment and attitudes in the SPR NICU.
This study in fact demonstrated greater maternal involvement in a SPR with improvement in outcomes across the board. It would seem then that in a SPR environment, provided there is enough family visitation and involvement this model truly is superior to the open concept. Furthermore despite concerns by some nurses that the loss of line of sight to their patients will make for a more stressful working environment this does not seem to be the case.
What About Families Who Cannot or Simply Aren’t Visiting Frequently?
The reality is that there are many reasons for parents to be absent for long periods during their newborns stay. Having a home outside of the city with other children to care for, work obligations, or loss of custody and abandonment due to apprehension are just some of these reasons. In our hospital, at least 15-20% of all patients admitted are from outside Winnipeg. The evidence as I see it supports the move to a SPR but what do we do for those children who need more visitation? The solution is a cuddler program. In our new hospital we are grateful for the generosity of our Children’s Hospital Foundation who secured a donor to pay for a coordinator of such a program. The veteran parent who is leading this program ensures that no infant goes beyond a set period of time without feeling the touch or hearing the sound of a voice. Such a program is in fact already in place at our other tertiary hospital and was featured in a lovely article attached here. Taking all the information together that is out there I think that if we can provide the necessary stimulation from both touch and auditory stimuli as well we can provide these infants with the developmental needs that each of them requires.
The SPR is the right design in my mind for families with many benefits that spring forth in such an environment. This need not be a win-lose scenario for your hospital. Do not underestimate the power of a cuddler and don’t hesitate to seek support to initiate such a program. It could mean the difference from going from good to great!
In recent years we have moved away from measuring and reporting gastric residuals. Checking volumes and making decisions about whether to continue feeding or not just hasn’t been shown to make any difference to care. If anything it prolongs time to full feeds without any demonstrable benefits in reduction of NEC. This was shown in the last few years by Riskin et al in their paper The Impact of Routine Evaluation of Gastric Residual Volumes on the Time to Achieve Full Enteral Feeding in Preterm Infants. Nonetheless, I doubt there is a unit in the world that has not had the following situation happen. It is 2 AM and the fellow on call is notified that they need to come and see a patient. On arrival the bedside nurse shows them a syringe that contains dark green murky fluid. The fellow is told that NG tube placement was just being checked and this is what was aspirated. The infant is fine in terms of exam but the question is asked “What should I do with this fluid”. The decision is made that the fluid looks “gross” and they discard it and then decide to resume feedings with a fresh batch of milk. Both parties feel good about discarding what looked totally unappealing for anyone to ingest and the night goes on. If this sounds familiar it should as I suspect this happens frequently.
A colleague of mine introduced me to this concept and I think it may apply here. Purdue University’s writing lab defines a Logical Fallacy in this way “Fallacies are common errors in reasoning that will undermine the logic of your argument. Fallacies can be either illegitimate arguments or irrelevant points, and are often identified because they lack evidence that supports their claim.”
I think we may have one here that has pervaded Neonatology across the globe. Imbedded in the fallacy is the notion that because the dark green aspirates look gross and we often see such coloured aspirates in patients with necrotizing enterocolitis or other bowel disease, all green aspirates must be bad for you. The second fallacy is that the darker the aspirate the more seriously you should consider discarding it. This may surprise you but on their own there isn’t much of anything that has been shown to be wrong with them. Looking for evidence to demonstrate increased rates of NEC or other abdominal issues in an otherwise well patient finds pretty much nothing to support discarding.
The main reason for the share of this paper is what is in Table 3.
Although not significantly different the mean estimates for concentration of bile acids in the pale and dark green aspirates came close to being different. Other nutritional content such as fat, protein and carbohydrate were no different. As the bile became darker though the bile acids tended to increase. It is this point that is worthy of discussion.
A Breakdown of the Aspirate
I’m with you. When you look at that murky dark green fluid in the syringe it just seems wrong to put that back into a belly. Would you want to eat that? Absolutely not but when you break it down into what is in there, suddenly it doesn’t seem so bad. We assume that we would not want to refeed such putrid looking material and that is where the logical fallacy exists. What evidence do we have that refeeding that fluid is bad? As I said above not much at all. Looking at the fact that there is actual nutritional calories in that fluid and bile acids as well you come to realize that throwing it away may truly not be in the best interest of the baby. Calories may wind up in the garbage and along with them, bile acids.
Bile acids are quite important in digestion as they help us digest fat and moreover as they enter the ileum they are reabsorbed in large quantities which go to further help digestion. In addition bile acid concentrations are what helps draw fluid into bile and promotes bile flow. By throwing these bile acids out we could see lower bile volumes and possible malabsorption from insufficient emulsification of fat.
The other unmeasured factors in this fluid are the local hormones produced in the bowel such as motilin which helps with small bowel contractility. Loss of this hormone might lead to impairment of peristalsis which can lead to other problems such as bacterial overgrowth and malabsorption.
Now all of this is speculative I will admit and to throw out one dark green aspirate is not going to lead to much harm I would think. What if this was systematic though over 24 or 48 hours that such aspirates were being found and discarded. Might be something there, What I do think the finding of such aspirates should trigger however is a thorough examination of the patient as dark green aspirates can be found in serious conditions such as NEC or bowel perforation. In the presence of a normal examination with or without laboratory investigations what I take from this study is that we should question are tendency to find and discard. Maybe the time has come to replace such fear with a practice of closing our eyes and putting that dark green aspirate right back where it came from.
Sometime between a week to two weeks you will hear that an ultrasound of your baby’s brain has been ordered. What the team is looking for here is bleeding eithre within the fluid filled chambers of the ventricles (appear black in the picture below with blood that shows up as white). This early ultrasound is meant to pick up this type of injury while one done a few weeks later attempts to pick something else up.
Bleeding occurs due to the fragile naure of the brain tissue when born preterm. The more preterm an infant is the greater the risk of a signficant amount of bleeding. Bleeding tends to occur from an area of the brain just under the lining of the fluid filled ventricles that has a very rich blood supply. Anything that causes fluctuations in blood flow to this area of the brain can lead to injury and bleeding from this site. Blood in the ventricles of the brain is referred to as an Intraventricular hemorrhage or IVH for short.
Classically you will hear the team discuss the results of your baby’s head ultrasounds as having one of five possible categories.
Grade 1 IVH – blood just under the lining of the ventricle
Grade 2 IVH – blood has gotten into the ventricle but is not causing it to get signiicantly enlarged
Grade 3 IVH – blood has entered the ventricle and is causing the chamber to grow as fluid that normally drains out is getting blocked by blood from leaving. As fluid (cerebral spinal fluid) continues to be produced, if it has trouble draining out it is like a kitchen sink with the tap turned on and something blocking the drain)
Grade 4 IVH – this is actually a bit different and is blood within the tissues of the brain outside of the ventricles. This is caused by blood flow in the veins of the brain being too slow and then causing vessels to rupture from lack of flow and oxygen.
A grade 3 IVH is shown below with the chambers swelling (black).
What can happen if the bleeding is significant?
It is the Grade 3 and 4 bleeds that we really worry about. The grade 1 bleeds tend to resolve on their own. When we see a bleed you can expect to see a new ultrasound be done in 1-2 weeks to folllow up and make sure it doesn’t get worse. If a grade 3 bleed continues to cause the ventricles to increase in size we worry with time that this may put pressure on the brain and affect the amount of blood flow the brain receives. If this is happening you may hear that we are asking Neurosurgery to see your infant. They will work with us to determine whether your baby needs a drain put into the ventricle to help get rid of the excess fluid. Many times the ventricles as we watch them with additional ultrasounds get smaller with time but some do not and will need this plastic drain put in to allow the brain to have this pressure relieved.
With the Grade 4 bleeds with time the body will absorb this damaged tissue and your baby may be left with a hole in the brain where the injured tissue was. While this sounds frightening the ability of our ultrasounds to predict eventual outcome is not great. Such infants though will generally be followed in a high risk follow up clinic and carefully monitored for their development. If they are found to have any deficits, depending on your location a variety of services may be offered to help optimize the best chance for a good outcome. Such services might include involvement of an occupational therapist or physiotherapist.
Sometime between about 4-6 weeks after birth or in some cases near discharge another ultrasound will be done. This time the team is looking for something different. The risk of fresh bleeding has passed but now we are looking for evidene of a lack of blood supply at some point from the arteries that provide blood supply to the brain. Many weeks after being born if there has been a period of significant impairment of blood flow to the brain we may see evidence of this. The brain has both white and gray matter (tissue). The gray matter is all along the surface of the brain. Underneath though and right next to the ventricles is the white mattter. This white matter is where the injury we are looking for may have occurrred. We call this injury periventricular leukomalacia. This means injury to the white matter. The white matter is where our neurological tissue for motor function travels so in these infants with such injury there can be problems with normal movement in the legs usually, moreso than the arms. Assessments in babies with such injury may find increases in the muscle tone in the NICU. In such cases, referral to a physiotherapist early to teach families how to do stretching exercises as an example will be done. Similarly, positioning devices from an occupational therapist may also be recommended.