Cycled vs Continuous Phototherapy. Are breaks ok?

Cycled vs Continuous Phototherapy. Are breaks ok?

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 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 Results

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.

What is Respiratory Distress Syndrome & How Do We Treat It?

What is Respiratory Distress Syndrome & How Do We Treat It?

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.

Posts related to RDS

Sedation before LISA/MIST? Is it safe?

Sedation before LISA/MIST? Is it safe?

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!

Cycled vs Continuous Phototherapy. Are breaks ok?

SAIL away. The death of sustained inflations for resuscitation.

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,

 

High tidal volume during PPV for infants

High tidal volume during PPV for infants <29 weeks GA linked to IVH

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.

The Edmonton group led by Dr. Schmolzer has had several papers examined in these blogs and on this occasion I am reviewing an important paper that really is a follow-up study to a previous one looking at the impact of high tidal volume delivery after birth.  I have written on this previous paper before in It’s possibile! Resuscitation with volume ventilation after delivery.  On this occasion the authors have published the following paper; Impact of delivered tidal volume on the occurrence of intraventricular haemorrhage in preterm infants during positive pressure ventilation in the delivery room.This observational study had a simple enough premise.  Will the use of Vt > 6 mL/kg in infants given PPV for at least two minutes lead to worse rates of IVH?  All infants were < 29 weeks and if they had chest compressions or epinephrine were excluded.  All infants were treated equally in terms of delayed cord clamping and antenatal steroid provision.  Ventilation was done with a t-piece resuscitator and Vt measured with an NM3 monitor connected to the face mask.  First ultrasounds were done for all at 3 days of age.

What did the authors find?

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.  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.