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,
Just about all of our preterm infants born at <29 weeks start life out the same in terms of neurological injury. There are of course some infants who may have suffered ischemic injury in utero or an IVH but most are born with their story yet to be told. I think intuitively we have known for some time that the way we resuscitate matters. Establishing an FRC by inflating the lungs of these infants after delivery is a must but as the saying goes the devil is in the details.
One hundred and sixty five infants comprised this cohort. Overall, 124 (75%) infants were in the high volume group compared to 41 (25%) with a mean VT<6 mL/kg. Median Vt were 5.3 (4.6-5.7) ml/kg for the low group and 8.7
(7.3-10.6) mL/kg which were significantly different.
When looking at the rates of IVH and the severity of those affected the results are striking.
IVH in the high VT group was diagnosed in 63 (51%) infants compared with 5 (13%) infants in the normal VT group (P=0.008).Severe IVH (grade III or IV) developed in 33/124 (27%) infants in the high VT group and 2/41 (6%) in the normal VT group (P=0.01)
Hydrocephalus, following IVH developed in 7/49 (14%) and 2/16 (13%) in the >6 mL/kg and <6 mL/kg VT groups. Looking at other factors that could affect the outcome of interest the authors noted the following physiologic findings. Oxygen saturations were lower in the low volume group at 6, 13 and 14 min after birth while tissue oxygenation as measured by NIRS was similarly lower at 7,8 and 25 min after birth (P<0.001). Conversely, heart rate was significantly lower in the VT>6 mL/kg group at 5, 20 and 25 min after birth (P<0.001). Fraction of inspired oxygen was similar in both groups within the first 30 min. Systolic, diastolic and mean blood pressure was similar between the groups. What these results say to me is that despite having lower oxygen saturations and cerebral oxygen saturation at various time points in the first 25 minutes of life the infants seem to be better off given that HR was lower in those given higher volumes despite similar FiO2. Rates of volume support after admission were slightly higher in the high volume group but inotrope usage appears to be not significantly different. Prophylactic indomethacin was used equally in the two cohorts.
Thoughts for the future
Once a preterm infant is admitted to the NICU we start volume targeted ventilation from the start. In the delivery room we may think that we do the same by putting such infants on a volume guarantee mode after intubation but the period prior to that is generally done with a bag and mask. Whether you use a t-piece resuscitator or an anesthesia bag or even a self inflating bag, you are using a pressure and hoping not to overdistend the alveoli. What I think this study demonstrates similar to the previous work by this group is that there is another way. If we are so concerned about volutrauma in the NICU then why should we feel any differently about the first few minutes of life. Impairment of venous return from the head is likely to account for a higher risk of IVH and while a larger study may be wished for, the results here are fairly dramatic. Turning the question around, one could ask if there is harm in using a volume targeted strategy in the delivery room? I think we would be hard pressed to say that keeping the volumes under 6 mL/kg is a bad idea. The challenge as I see it now is whether we rig up devices to accomplish this or do the large medical equipment providers develop an all in one system to accomplish this? I think the time has come to do so and will be first in line to try it out if there is a possibility to do a trial.