Phototherapy is one of the “bread and butter” treatments in the newborn. For sure it has gone through changes over the years as different light sources have been developed that provide more limited spectrums of blue/green light wavelengths. Gone are the old long white tubes in favour of special blue light emitting banks of lights and with it bilirubin levels are effectively dropping quickly worldwide. There have been a couple concerns raised with phototherapy over the years. One concern has been the risk of DNA damage as shown by Ramy N et al in Jaundice, phototherapy and DNA damage in full-term neonates. It was found in this study that the duration of phototherapy but not it’s intensity were related to the extent of methylation of DNA which is a marker of damage. Shorter durations would therefore be preferable. Repair of damaged DNA is thought in some ways to contribute to risk of cancer so although this has not been demonstrated with phototherapy the concern has been raised before. The other concern pertains to the ELBW infant with very thin skin. In the randomized trial for babies under 1000g entitled Aggressive vs. conservative phototherapy for infants with extremely low birth weight. In this trial a lower threshold for starting phototherapy was used in the “aggressive group”. The findings of this study in a preplanned subgroup analysis was that the babies from 500-750g that had a lower threshold for starting and continuing phototherapy had a trend towards a higher mortality; relative risk, 1.13; 95% CI, 0.96 to 1.34 as the CI just crossed 1. With this information in the literature it stands to reason that the question would come up as to whether continuous phototherapy is needed or whether one could use cycled intermittent phototherapy to give infants “phototherapy breaks”.
Such a study has now been published
This study Cycled Phototherapy Dose-Finding Study for Extremely Low-Birth-Weight Infants A Randomized Clinical Trial enrolled babies with birthweights between 401 – 1000g and Initially randomized using a 1:1:1 ratio to 3 treatment groups: continuous PT (usual care), a PT regimen of 30 minutes or more per hour for each cycle, or a PT regimen of 15 min/h or more. The minutes per hour of PT could be increased for the cycled if TSB values reached specified thresholds. After the first 100 patients a planned analysis was done and the 30 minute group was ended as there was no difference between this group and the 15 minute one. The light sources and spectral irradiance (combination of intensity and distance from the patient) used were all the same and collection times for serum bilirubin levels were standardized as much as possible. Bilirubin levels were collected daily for the first 7 days and anytime infants were on phototherapy. The authors also included a stepwise prolongation of phototherapy for the shorter cycled groups if bilirubin levels were not responding to the provided phototherapy. I have to say they really did a good job of removing as many potential variables to outcome as they could!
The primary outcomes were mean peak TSB levels and mean PT hours through day 14 across all centers and predischarge wave V latency brainstem auditory evoked potential (BAER). In total 305 infants were randomized in the study and the interestingly the study was stopped at that point as a larger study was approved to obtain more precise estimates in the future around mortality and morbidity as a primary outcome. During the trial the authors received approval to do so with this new primary outcome and so we have what we have to analyze.
The authors found that there was no difference in the mean peak bilirubin even among high risk patients when given cycled phototherapy for 15 minutes an hour vs continuous. The total amount of hours of phototherapy was approximately halved. No statistical difference in mortality was observed although as mentioned above this was not the primary endpoint of the study.
Looking at duration of phototherapy in terms of hours per day over the first two weeks is shown below. Although a pre-specified plan was in place to increase time as needed to decrease bilirubin levels the amount of time remained fairly consistent for the cycled group with some increase needed in the early days which would be expected given the typical higher biirbubin tendency in the first week of life.
The BAER tests did not demonsrate any difference between the children who had cycled or continuous phototherapy suggesting that no added neurotoxicity occurred from interrupting phototherapy.
What can we take from this?
All of these infants were ELBW and wth that had very thin skin. Would cycled phototherapy be as effective in more mature infants? As the authors of the study point out, there have already been several trials in more mature infants demonstrating such effects and arguing that continuous phototherapy is not needed. At the very least this paper and the others before it would argue that interrupting phototherapy to allow breastfeeding or some skin to skin time with the mother or father should be acceptable. In the past I can remember many instances of having ordered intensive phototherapy and then questioned whether mom can breastfeed as technically it is supposed to be continuous. With this information I would suggest that continuing to work on oral feeding skills at the breast is reasonable. Clearly this won’t work in the population studied here as they are too small but for the larger infants there would not seem to be harm.
I suspect the larger study to come may change practice if a higher mortality is indeed shown for continuous phototherapy but for now we will need to wait and see. In a few years we will get the chance to review that study here.
Phenobarbital at least where I work has been first line treatment for seizure control for as long as I can recall. We dabbled with using phenytoin and fos-phenytoin in the past but the go to tried and true has been phenobarbital for some time. The use of this drug though has not been without trepidation. Animal studies have linked phenobarbital to increases rates of cerebral apoptosis. Additionally, in a retrospective comparison of outcomes between seizures controlled with phenobarbital vs Levetiracetam, the latter came out ahead in terms of better long term developmental outcomes. This study from 2013 was entitled Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. Purists of course would argue the need for a prospective trial and that is what we have to chat about here.
Levetiracetam vs Phenobarbital
The study in question was a multicenter randomized phase IIb trial (searches for a dose that provides biological activity with the minimal side effect profile) that compared two doses 40 mg/kg and 60 mg/kg of Levetiracetam with standard doses of phenobarbital. The study was done by Sharpe C et al and called Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
In this study patients were randomized to receive levetiracetam or control phenobarbital treatment group in a 60:40 allocation ratio by using a block randomization strategy and stratified by site. The trial design is shown in the diagram below.
The study was designed to not delay institution of the accepted treatement with phenobarbital as usual first line treatment of seizures by more than 1 hour. The strength of this study was that the authors used electrographic seizures confirmed by continuous EEG monitoring. The efficacy of medication effect was blindly interpretted by two independent electrophysiologists. in other words the authors went out of their way to ensure these were real seizures and moreover that any changes to medications were decided upon after interpretation of effect by people remote from the study. The primary outcome though in comparison to the aforementioned retrospective study was a short one. In this study the primary outcome was initialy absense of seizures for 48 hours but then was changed part way through the study to 24 hours. The change was a practical one since it was noted after data collection that in many cases EEG monitoring had been stopped prior to 48 hours.
Honestly it is the results that led me to want to talk about this study. They are the exact opposite of what i thought they would be. Based on my own experience with Levitiracetam seeming like a wonder drug when it comes to seizure control I expected the results to favour it. Not the case.
To say that phenobarbital crushed the competition is an udnerstatement. Having said that the incidence of side effects were higher with phenobarbital as well. Hypotension, respiratory suppression, sedation, and requirement for pressor support, were more common. Nonetheless, this study also included patients with HIE and found even in this subgroup phenobarbital was superior. This is important information as one could speculate that earlier seizure cessation in those with anoxic injury already could be especially beneficial.
What do we do with these results?
As the authors point out this is a study of short term outcomes. In the trial about long term outcome it was clear that treatment with phenobarbital leads to worse outcome than with levitiracetam. Having said that it was a retrospective study so the next step will be to conduct long term outcome studies to see effects. This presents the possibility of an interesting conundrum. What if the newer drug is inferior to tried and true phenobarbital at controlling seizures but leads to better long term outcome? Would you consider allowing seizures to persist longer than you might otherwise want to in the short term but then be able to reassure families that the long term outlook is bettter? The side effect profile of levitiracetam is such that I think neurologists want to use it but the other possibility is that there is another newer anticonvulsant that will need to be tested as wouldn’t it be great not to have to choose either poor acute seizure control but better long term outcome vs better seizure control with concerning long term outcome? As a parent I have no doubt watching a child eize would be terrifying and you would want it to end as soon as possible but the question with phenobarbital is at what cost?
If you are reading this and have a baby in the NICU with respiratory distress syndrome (RDS) otherwise known as hyaline membrane disease you might be surprised to know that it is because of the same condition that modern NICUs exist. The newspaper clipping from above sparked a multibillion dollar expansion of research to find a cure for the condition that took the life of President Kennedy’s preterm infant Patrick Bouvier Kennedy. He died of complications of RDS as there was nothing other than oxygen to treat him with. After his death the President committeed dollars to research to find a treatment and from that came surfactant and modern ventilators to support these little ones.
What is surfactant and what is it’s relationship to RDS?
When you take a breath (all of us including you reading this) oxygen travels down your windpipe (trachea) down into your lung and goes left and right down what are called your mainstem bronchi and then travels to the deep parts of the lung eventually finding its way to your tiny air sacs called alveoli (there are millions of them). Each alveolus has a substance in it called surfactant which helps to reduce the surface tension in the sac allowing it to open to receive oxygen and then shrink to get rid of carbon dioxide that the blood stream brings to these sacs to eliminate. Preterm infants don’t have enough surfactant and therefore the tension is high and the sacs are hard to open and easily collapse. Think of surface tension like blowing up those latex balloons as a child. Very hard to get them started but once those little balloons open a little it is much easier! The x-ray above shows you what the lungs of a newborn with RDS look like. They are described as having a “ground glass” appearance which if you recall is the white glass that you write on using a grease pencil when you are using a microscope slide. Remember that?
Before your infant was born you may have received two needles in your buttocks. These needles contain steroid that helps your unborn baby make surfactant so that when they are born they have a better chance of breathing on their own.
Things we can do after birth
Even with steroids the lungs may be “sticky” after birth and difficult to open. The way this will look to you is that when your baby takes a breath since it is so difficult the skin in between the ribs may seem to suck in. That is because the lungs are working so hard to take breath in that the negative pressure is seen on the chest. If your baby is doing that we can start them on something called CPAP which is a machine that uses a mask covering the nose and blows air into the chest. This air is under pressure and helps get oxygen into the lungs and gives them the assist they need to overcome the resistance to opening.
Some babies need more than this though and will need surfactant put into the lungs. The way this is done is typically by one of two ways. One option is to put a plastic tube in between the vocal cords and then squirt in surfactant (we get it from cow’s or pigs) and then typically the tube is withdrawn (you may hear people call it the INSURE technique – INtubate, SURfactant, Extubate). For some babies who still need oxygen after the tube is put in they may need to remain on the ventilator to help them breathe for awhile. The other technique is the LISA (Less Invasive Surfactant Administration). This is a newer way of giving surfactant and typically involves putting a baby on CPAP and then looking at the vocal cords and putting a thin catheter in between them. Surfactant is then squirted into the trachea and the catheter taken out. The difference between the two methods is that in the LISA method your baby is breathing on their own throughout the procedure while receiving CPAP.
Even if no surfactant is given the good news is that while RDS typically worsens over the first 2-3 days, by day 3-4 your baby will start to make their own surfactant. When that happens they will start to feel better and breathe easier. Come to think of it you will too.
I knew it was a matter of time before a study looking at this strategy came out. Whether you intubate using INSURE or a LISA/MIST technique (passing a semi-rigid catheter through the vocal cords to give surfactant while a baby is on CPAP) there would have to be those that argue the placement of the laryngoscope blade in the mouth and passage of the catheter through the trachea must be uncomfortable. Given such concerns, why wouldn’t you want to provide some sedation to the patient? The main concern would be suppression of respiratory drive and need for intubation or PPV. LISA/MIST usage has been found in systematic reviews to lead to less risk of BPD but what if sedation leads to more PPV especially with uncontrolled tidal volumes on these fragile lungs? Will the benefits remain?
Propofol Before MIST
Dekker et al published Sedation during minimal invasive surfactant therapy: a randomised controlled trial in which they looked at infants receiving surfactant administration by MIST in infants born at 26 – 36 weeks with stratification of results into two groups (26–31+6 and 32–36+6 weeks). The intervention was to give a relatively small dose of propofol 1 mg/kg compared to the typical dose of 2.5 mg/kg prior to using MIST. Physicians were unblinded to the intervention but nurses were asked (they were blinded) to determine the COMFORTneo score as a measure of discomfort or pain. The primary outcome was the percentage of infants with a score <14 during the procedure. A power calculation to determine numbers needed for the study indicated 39 per arm and was based on a previous study (not using propofol though). While it does not appear that a sham was used for a placebo arm, sucrose was utilized for additional comfort in both arms.
The Results Please
Sedation seemed to work even at this lower dose of propofol as the group who received it had a higher percentage with a score <14 (32/42 (76%) vs 8/36 (22%), p<0.001). Moreover, the overall mean scores were also lower (12±3 vs 17±4; p<0.001). When looking at rates of complications though some interesting but perhaps not surprising findings emerge. A greater risk of desaturation events existed in the group receiving even a low dose of propofol.
Digesting this information it would seem that giving propofol prior to MIST may defeat the purpose of avoiding positive pressure ventilation as nearly all patients given propofol required nasal intermittent mandatory ventilation. As this is a small study we have to take the secondary outcomes with a grain of salt as the study would not have been powered to detect all these important outcomes such as IVH and pulmonary hemmorhage. Moreover the real question here would be whether BPD would be different between the groups but again not reported and even if it had been the numbers would be a little low to see a real difference.
The next steps I think will be to look at this question using medications such as atropine and fentanyl which I understand in other centres are in use. To do so though will require some pretty big numbers for enrolment. in the meantime what are we to do? Putting a catheter into the trachea I would think would be uncomfortable if not painful. Something should be given prior to the procedure but it is now on the research community to determine what that is and a what dose!
This post has the potential to be polarizing as sustained inflations while common as an approach after delivery in Europe has not been widely adopted in Canada and the United States. Some time ago I wrote about sustained inflations and a reader commented that I should wait for the results of the The Sustained Aeration for Infant Lungs (SAIL) trial before forming a final opinion on whether this is a good strategy or not. The previous blog post on this topic was Is It Time To Use Sustained Lung Inflation in NRP? and was followed by Is expired CO2 the key to making sustained inflation a standard in resuscitation? The first post concluded that there was a concerning trend towards more IVH in those who received sustained inflations (SI) while the second showed both a reduction in BPD and duration of mechanical ventilation with this approach. I suggested that maybe we were really onto something here and then I was asked to wait before coming to a conclusion until the SAIL trial was done. Well that day has come.
The SAIL trial
This trial led by Dr. H. Kirpalani and involving 18 NICUs in 9 countries was a big endeavour. The paper was just published and is entitled Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants The SAIL Randomized Clinical Trial. The trial compared SI of 15 seconds at a peak pressure of 20 cmH2O, followed if needed by a second SI of 15 seconds
at a peak of 25 cmH2O to traditional PPV for infants who after initial 30 seconds of CPAP required further intervention to establish breathing. These were provided via facemask or nasopharyngeal tune attached to a t-piece resuscitator. In both groups after the initial intervention standard resuscitation steps were carried out. The primary outcome was death or BPD at 36 weeks PMA. A data safety monitoring board (DSMB) was formed as well and it is this group that became very important to the conclusions of the study and led to its early termination. All infants were 23 weeks 0 days’ to 26 weeks 6 days’ GA. Before the study was terminated the final totals were 215 patients in the SI arm and 211 in the traditional PPV group.
The trial was stopped after the DSMB identified an excessive number of early deaths within 48 hours in the SI group. The findings were “11 of 16 early deaths in the sustained inflation group vs 1 of 3 in the standard
resuscitation group were considered possibly related to allocation group”. A number of these deaths occurred in the highest risk group of those born at 23-24 weeks but it was enough to stop recruitment.
With respect to the primary outcome the results showed no difference between the two approaches. In saying this however, if the study did not recruit enough patients as planned to demonstrate a difference one has to question whether the study had enough power to find a benefit.
To answer this question the authors performed a Bayesian Analysis to determine the probability that adding more patients would have led to a different conclusion. That is to determine if they would have found a difference favouring SI. In the end they found that their conclusions would not have changed. Sustained inflations in infants from 23 weeks 0 days’ to 26 weeks 6 days’ GA do not confer a benefit and may be associated with a higher likelihood of death within 48 hours of birth.
What do we do with these results?
I think this is it. I can’t see a research ethics board allowing another study at this point. This by neonatal standards was a big study given the relative scarcity of infants at these gestational ages. The fact that no difference was found in rates of death or survival with BPD for those at highest risk of these outcomes suggests to me that looking at older GA at birth will not produce different results. Sustained inflation to establish FRC and initiate respiration was a good concept backed by animal research. Moreover, clinical work out of Edmonton in recent years suggested potential benefits but with the publication of this study I suspect we will need as a neonatal community to look at other strategies to decrease rates of BPD. Concerns over increased risk of death in my opinion mean this ship has SAILed,