Skin to skin care or kangaroo care is all the rage and I am the first one to offer my support for it. Questions persist though as to whether from a physiological standpoint, babies are more stable in an isolette in a quiet environment or out in the open on their mother or father’s chests. Bornhorst et al expressed caution in their study Skin-to-skin (kangaroo) care, respiratory control, and thermoregulation. In a surprising finding, babies with an average gestational age of 29 weeks were monitored for a number of physiological parameters and found to have more frequent apnea and higher heart rates than when in an isolette. The study was small though and while there were statistical differences in these parameters they may not have had much clinical significance (1.5 to 2.8 per hour for apnea, bradycardia or desaturation events). Furthermore, does an increase in such events translate into any changes in cerebral oxygenation that might in turn have implications for later development? Tough to say based on a study of this magnitude but it certainly does raise some eyebrows.
What if we could look at cerebral oxygenation?
As you might have guessed, that is exactly what has been done by Lorenz L et al in their recent paper Cerebral oxygenation during skin-to-skin care in preterm infants not receiving respiratory support.The goal of this study was to look at 40 preterm infants without any respiratory distress and determine whether cerebral oxygenation (rStO2)was better in their isolette or in skin to skin care (SSC). They allowed each infant to serve as their own control by have three 90 minute periods each including the first thirty minutes as a washout period. Each infant started their monitoring in the isolette then went to SSC then back to the isolette. The primary outcome the power calculation was based on was the difference in rStO2 between SSC and in the isolette. Secondary measures looked at such outcomes as HR, O2 sat, active and quiet sleep percentages, bradycardic events as lastly periods of cerebral hypoxia or hyperoxia. Normal cerebral oxygenation was defined as being between 55 to 85%.
Perhaps its the start of a trend but again the results were a bit surprising showing a better rStO2 when in the isolette (−1.3 (−2.2 to −0.4)%, p<0.01). Other results are summarized in the table below:
Mean difference in outcomes
Difference in mean
% time in quiet sleep
No differences were seen in bradycardic events, apnea, cerebral hypoexmia or hyperoxemia. The authors found that SSC periods in fact failed the “non-inferiority” testing indicating that from a rStO2 standpoint, babies were more stable when not doing SSC! Taking a closer look though one could argue that even if this is true does it really matter? What is the impact on a growing preterm infant if their cerebral oxygenation is 1.3 percentage points on average lower during SSC or if their HR is 5 beats per minute faster? I can’t help but think that this is an example of statistical significance without clinical significance. Nonetheless, if there isn’t a superiority of these parameters it does leave one asking “should we keep at it?”
Benefits of skin to skin care
Important outcomes such as reductions in mortality and improved breastfeeding rates cannot be ignored or the positive effects on family bonding that ensue. Some will argue though that the impacts on mortality certainly may be relevant in developing countries where resources are scarce but would we see the same benefits in developed nations. The authors did find a difference though in this study that I think benefits developing preterm infants across the board no matter which country you are in. That benefit is that of Quiet Sleep (QS). As preterm infants develop they tend to spend more time in QS compared to active sleep (AS). From Doussard- Roossevelt J, “Quiet sleep consists of periods of quiescence with regular respiration and heart rate, and synchronous EEG patterns. Active sleep consists of periods of movement with irregular respiration and heart rate, and desynchronous EEG patterns.” In the above table one sees that the percentage of time in QS was significantly increased compared to AS when in SSC. This is important as neurodevelopment is thought to advance during periods of QS as preterm infants age.
There may be little difference favouring less oxygen extraction during isolette times but maybe that isn’t such a good thing? Could it be that the small statistical difference in oxygen extraction is because the brain is more active in laying down tracks and making connections? Totally speculative on my part but all that extra quiet sleep has got to be good for something.
To answer the question of this post in the title I think the answer is a resounding yes for the more stable infant. What we don’t know at the moment except from anecdotal reports of babies doing better in SSC when really sick is whether on average critically ill babies will be better off in SSC. I suspect the answer is that some will and some won’t. While we like to keep things simple and have a one size fits all answer for most of our questions in the NICU, this one may not be so simple. For now I think we keep promoting SSC for even our sick patients but need to be honest with ourselves and when a patient just isn’t ready for the handling admit it and try again when more stable. For the more stable patient though I think giving more time for neurons to find other neurons and make new connections is a good thing to pursue!
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!
As someone with an interest in neonatal abstinence (NAS) I am surprised that I missed this study back in May. Anyone who says they aren’t interested in NAS research must be turning a blind eye to the North American epidemic of patients filling neonatal units or postpartum wards in need of treatment for the same. News feeds such as CNN have covered this story many times with concerning articles such as this published “Opioid Crisis Fast Facts” even the Trump White House has officially declared it as an emergency at this point. With NICU resources stretched and care providers fatigue levels wearing thin (these patients are typically very challenging to take care of due to the crying and agitation with neurological excitability that is at the core of the symptoms, something needs to be done. The vast majority of neonatal care providers treat such patients with an approach that promotes first non pharmacologic strategies such as keeping mom and baby together when possible, breast feeding and disturbing these infants as little as possible to name a few points. For those patients though who require pharmacologic support though, the mainstay has been oral morphine. At least in our units though once a patient is admitted and undergoes treatment we are still looking at anywhere from 3-4 weeks on average that they will occupy a hospital bed. If only there was a better way.
Could Buprenorphine do the trick?
While morphine is widely used to treat NAS symptoms unresponsive to other non pharmacologic methods of control, buprenorphine has a similar profile as an opioid but has less risk of respiratory depression as a partial agonist. A small but important trial has been published directly comparing the use of morphine to buprenorphine for treatment of NAS symptoms with the primary outcome being days of treatment and the second important point being length of stay. The trial, Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome.by Kraft WK et al was entitled the BBORN trial for short. This was a single centre trial in which a double blind/double dummy approach was used. By double dummy this meant that after randomization those babies randomized to morphine received morphine plus a buprenorphine placebo and the other arm received a buprenorphine dose and a morphine placebo. In total 33 infants were randomized to buprenorphine and 30 to morphine (hence my comment about this being a small study). Their power calculation had called for 40 infants per arm to detect a 28% difference in the primary end point of duration of treatment but in the end that didn’t matter so much as they found a significant difference exceeding their estimate anyway. A lack of power would have become important mind you had they not found a difference as they wouldn’t have actually had the numbers to do so.
A strength of the study up front was that all care providers scored NAS symptoms the same way (need to take into account there is some subjectivity in scoring altogether though) and escalations and decreases of medication were done following a strict protocol both ways. In both arms, once a maximal dose of 60 mcg/kg of body weight for buprenorphine and 1.2 mg/kg for morphine was reached phenobarbital was added. When comparing the two groups at the outset there were no significant differences in characteristics so two generally similar populations of infants were being treated.
The Results Were Indeed Impressive
Before launching into the table, there were 21 babies in both groups that were bottle fed and 12 in the burprenorphine group and 9 in the morphine group that breastfed.
Median days of treatment
Hospital stay in days
No difference was seen in those who needed phenobarbital. Looking at the table, a couple things really stand out to me. They were looking for a 28% reduction in days of treatment. The results came in far excess of that at a 46% reduction. Curiously, breastfeeding which has classically been associated with a reduction in scores and therefore faster weaning due to less symptoms seemed to have the opposite effect here. Does this imply that breastfeeding slows down both duration of treatment and length of stay as a result? With a study this small it is difficult to say with so few breastfed babies but if I had to guess I would suggest those mothers that worked at breastfeeding may have had longer stays.
Should we all jump on the buprenorphine train?
For now I would give this a big maybe. One of the concerns about burprenorphine is that it comes as a solution of 30% alcohol. Giving multiple doses (3 per day in this study) of such a solution could in part contribute to these results of lower NAS symptoms. Is giving alcohol to reduce symptoms a good idea here? Not sure if there are any long term effects and moreover if the cumulative dose of this medication would be of a concern. Definitely something to check with your local pharmacist before rolling this out. On the other hand if the dose of alcohol provided was truly significant I might have expected the burprenorphine group to be poorer feeders due to intoxication which we certainly did not see.
With increasing volumes of newborns afflicted with symptoms of NAS we do need to find a way to stem the tide. Ideally, primary preventative strategies would be best but until that solution is found could burprenorphine be the next step in tackling this epidemic?
We can always learn and we can always do better. At least that is something that I believe in. In our approach to resuscitating newborns one simple rule is clear. Fluid must be replaced by air after birth and the way to oxygenate and remove CO2 is to establish a functional residual capacity. The functional residual capacity is the volume of air left in the lung after a tidal volume of air is expelled in a spontaneously breathing infant and is shown in the figure. Traditionally, to establish this volume in a newborn who is apneic, you begin PPV or in the spontaneously breathing baby with respiratory distress provide CPAP to help inflate the lungs and establish FRC.
Is there another way?
Something that has been discussed now for some time and was commented on in the most recent version of NRP was the concept of using sustained inflation (SI) to achieve FRC. I have written about this topic previously and came to a conclusion that it wasn’t quite ready for prime time yet in the piece Is It Time To Use Sustained Lung Inflation In NRP?
The conclusion as well in the NRP textbook was the following:
“There are insufficient data regarding short and long-term safety and the most appropriate duration and pressure of inflation to support routine application of sustained inflation of greater than 5 seconds’ duration to the transitioning newborn (Class IIb, LOE B-R). Further studies using carefully designed protocols are needed”
So what now could be causing me to revisit this concept? I will be frank and admit that whenever I see research out of my old unit in Edmonton I feel compelled to read it and this time was no different. The Edmonton group continues to do wonderful work in the area of resuscitation and expand the body of literature in such areas as sustained inflation.
Can you predict how much of a sustained inflation is needed?
This is the crux of a recent study using end tidal CO2 measurement to determine whether the lung has indeed established an FRC or not. Dr. Schmolzer’s group in their paper (Using exhaled CO2 to guide initial respiratory support at birth: a randomised controlled trial) used end tidal CO2 levels above 20 mmHg to indicate that FRC had been established. If you have less CO2 being released the concept would be that the lung is actually not open. There are some important numbers in this study that need to be acknowledged. The first is the population that they looked at which were infants under 32 6/7 weeks and the second is the incidence of BPD (need for O2 or respiratory support at 36 weeks) which in their unit was 49%. This is a BIG number as in comparison for infants under 1500g our own local incidence is about 11%. If you were to add larger infants closer to 33 weeks our number would be lower due to dilution. With such a large number though in Edmonton it allowed them to shoot for a 40% reduction in BPD (50% down to 30%). To accomplish this they needed 93 infants in each group to show a difference this big.
So what did they do?
For this study they divided the groups in two when the infant wouldn’t breathe in the delivery room. The SI group received a PIP of 24 using a T-piece resuscitator for an initial 20 seconds. If the pCO2 as measured by the ETCO2 remained less than 20 they received an additional 10 seconds of SI. In the PPV group after 30 seconds of PPV the infants received an increase of PIP if pCO2 remained below 20 or a decrease in PIP if above 20. In both arms after this phase of the study NRP was then followed as per usual guidelines.
The results though just didn’t come through for the primary outcome although ventilation did show a difference.
Duration of mechanical ventilation (hrs)
The reduction in hours of ventilation was impressive although no difference in BPD was seen. The problem though with all of this is what happened after recruitment into the study. Although they started with many more patients than they needed, by the end they had only 76 in the SI group and 86 in the PPV group. Why is this a problem? If you have less patients than you needed based on the power calculation then you actually didn’t have enough patients enrolled to show a difference. The additional compounding fact here is that of the Hawthorne Effect. Simply put, patients who are in a study tend to do better by being in a study. The observed rate of BPD was 33% during the study. If the observed rate is lower than expected when the power calculation was done it means that the number needed to show a difference was even larger than the amount they originally thought was needed. In the end they just didn’t have the numbers to show a difference so there isn’t much to conclude.
What I do like though
I have a feeling or a hunch that with a larger sample size there could be something here. Using end tidal pCO2 to determine if the lung is open is in and of itself I believe a strategy to consider whether giving PPV or one day SI. We already use colorimetric devices to determine ETT placement but using a quantitative measure to ascertain the extent of open lung seems promising to me. I for one look forward to the continued work of the Neonatal Resuscitation–Stabilization–Triage team (RST team) and congratulate them on the great work that they continue doing.
I know how to bag a baby. At least I think I do. Providing PPV with a bag-valve mask is something that you are taught in NRP and is likely one of the first skills you learned in the NICU. We are told to squeeze the bag at a rate of 40-60 breaths a minute. According to the Laerdal website, the volume of the preterm silicone bag that we typically use is 240 mL. Imagine then that you are wanting to ventilate a baby who is 1 kg. How much should you compress the bag if you wish to delivery 5 mL/kg. Five ml out of a 240 mL bag is not a lot of squeeze is it? Think about that the next time you find yourself squeezing one. You might then say but what about a t-piece resuscitator? A good choice option as well but how much volume are you delivering if you set the initial pressures at 20/5 for example? That would depend on the compliance of the lung of course. The greater the compliance the more volume would go in. Would it be 5 mL, 10 ml or even 2.5 mL based on the initial setting? Hard to say as it really depends on your seal and the compliance of the lung at the pressure you have chosen. If only we had a device that could deliver a preset volume just like on a ventilator with a volume guarantee setting!
Why is this holy grail so important?
It has been over 30 years since the importance of volutrauma was demonstrated in a rabbit model. Hernandez LA et al published Chest wall restriction limits high airway pressure-induced lung injury in young rabbits. The study used three models to demonstrate the impact of volume as opposed to pressure on injuring the lung of preterm rabbits. Group 1 were rabbit ventilated at pressures of 15/30/45 cm H2O for one hour, group 2 rabbits with a cast around their thorax to limit volume expansion and group 3 sets of excised lungs with no restriction to distension based on the applied pressures. As you might expect, limitation of over distension by the plaster cast led the greatest reduction in injury (measured as microvascular permeability) with the excised lungs being the worst. In doing this study the authors demonstrated the importance of over distension and made the case for controlling volume more than pressure when delivering breaths to avoid excessive tidal volume and resultant lung injury.
The “Next Step” Volume Ventilator BVM
Perhaps I am becoming a fan of the Edmonton group. In 2015 they published A Novel Prototype Neonatal Resuscitator That Controls Tidal Volume and Ventilation Rate: A Comparative Study of Mask Ventilation in a Newborn Manikin. The device is tablet based and as described, rather than setting a PIP to deliver a Vt, a rate is set along with a volume to be delivered with a peep in this case set at +5. This study compared 5 different methods of delivering PPV to a 1 kg preterm manikin. The first was a standard self inflating bag, the next three different t-piece resuscitators and then the Next Step. For the first four the goal was to deliver a pressure of 20/5 at a rate of 40-60 breaths per minute. A test lung was connected to the manikin such that each device was used for a one minute period at three different levels of compliance (0.5 ml/cmH2O, 1.0 ml/cmH2O and then 2.0 ml/cm H2O representing increasing compliance. The goal of the study was to compare the methods in terms of delivering a volume of 5 mL to this 1 kg model lung. The order in which the devices were used was randomized for the 25 participants in the study who were all certified in NRP and included some Neonatologists.
Some Concerning Findings
As I said at the beginning, we all like to think we know how to ventilate a newborn with BVM. The results though suggest that as compliance increases our ability to control how much volume we deliver to a lung based on a best guess for pressures needed is lacking. One caveat here is that the pressures set on the t-piece resucitators were unchanged during the 1 minute trials but then again how often during one minute would we change settings from a starting point of 20/5?
Without putting in all the confidence intervals I can tell you that the Next Step was the tightest. What you notice immediately (or at least I did) was that no matter what the compliance, the self inflating bag delivers quite an excessive volume even in experienced hands regardless of compliance. At low compliance the t-piece resuscitators do an admirable job as 5-6 ml/kg of delivered Vt is reasonable but as compliance improves the volumes increase substantially. It is worth pointing out that at low compliance the Next Step was unable to deliver the prescribed Vt but knowing that if you had a baby who wasn’t responding to ventilation I would imagine you would then try a setting of 6 ml/kg to compensate much like you would increase the pressure on a typical device. How might these devices do in a 29 week infant for example with better compliance than say a 24 week infant? You can’t help but wonder how many babies are given minutes of excessive Vt after birth during PPV with the traditional pressure limited BVM setup and then down the road how many have BPD in part because of that exposure.
I wanted to share this piece as I think volume resuscitation will be the future. This is just a prototype or at least back then it was. Interestingly in terms of satisfaction of use, the Next Step was rated by the participants in the study as being the easiest and most comfortable to use of all the devices studied. Adding this finding to the accuracy of the delivered volume and I think we could have a winner.
I would consider myself fairly open minded when it comes to care in the NICU. I wouldn’t call myself a maverick or careless but I certainly am open to new techniques or technologies that may offer a better level of care for the babies in our unit. When it comes to “non-Western” concepts though such as therapeutic touch, chiropractic manipulations of infants and acupuncture (needle or otherwise) I have generally been a skeptic. I have written about such topics before with the most popular post being Laser acupuncture for neonatal abstinence syndrome. My conclusion there was that I was not a fan of the strategy but perhaps I could be more open to non traditional therapies.
This would appear to be the newest and perhaps strangest (to me at least) approach to pain relief that I have seen. I do love name of this study; the MAGNIFIC trial consisted of a pilot study on the use of auricular magnetic acupuncture to alleviate pain in the NICU from heel lances. The study was published in Acta Paediatrica this month; Magnetic Non-Invasive Acupuncture for Infant Comfort (MAGNIFIC) – A single-blinded randomized controlled pilot trial. The goal here was to measure pain scores using the PIPP scoring system for pain in the neonate before during and after a painful experience (heel lance) in the NICU. Being a pilot study it was small with only 20 needed per arm based on the power calculation to detect a 20% difference in scores. The intervention used small magnets placed at specific locations on the ear of the infant at least two hours before the heel lance was to occur. Before I get into the results, the authors of the study provide references to explain how the therapy works. Looking at the references I have to admit I was not able to obtain complete papers but the evidence is generally it would appear from adult patients. The explanation has to do with the magnetic field increasing blood flow to the area the magnet is applied to and in addition another reference suggests that there are affects the orbitofrontal and limbic regions which then impacts neurohormonal responses as seen in functional MRI. The evidence to support this is I would have thought would be pretty sparse but I was surprised to find a literature review on the subject that looked at 42 studies on the topic. The finding was that 88% of the studies reported a therapeutic effect. The conclusion though of the review was that the quality of the included studies was a bit sketchy for the most part so was not able to find that this should be a recommended therapy.
So what were the results?
Despite my clear skepticism what this study did well was that aside from the magnets, the intervention was the same. Twenty one babies received the magnetic treatments vs 19 placebo. There was a difference in the gestational ages of the babies with the magnet treated infants being about two weeks older (35 vs 33 weeks). What difference that might in and of itself have on the PIPPs scoring I am not sure. The stickers were applied to the ears with and without magnets in a randomized fashion and the nurses instructed to score them using the PIPP scoring system. Interestingly, as per their unit policy all babies received sucrose as well before the intervention of a heel lance so I suppose the information gleaned here would be the use of magnets as an adjunctive treatment. No difference was noted in the two groups before and after the heel lance but during the procedure the magnet treated infants had a difference in means (SD): 5.9 (3.7) v 8.3 (4.7), p=0.04). No differences were found in secondary measures such as HR or saturation and no adverse effects were noted. The authors conclusions were that it was feasible and appears safe and as with most pilot studies warrants further larger studies to verify the results.
Should we run out and buy it?
One of the issues I have with the study is that in the introduction they mention that this treatment might be useful where kangaroo care (KC) is not such as a critically ill infant. Having placed infants who are quite sick in KC and watched wonderful stability arise I am not sure if the unit in question under utilizes this important modality for comfort.
The second and perhaps biggest issue I have here is that although the primary outcome was reached it does seem that there was some fishing going on here. By that I mean there were three PIPP scores examined (before, during and after) and one barely reached statistical significance. My hunch is that indeed this was reached by chance rather than it being a real difference.
The last concern is that while the intervention was done in a blinded and randomized fashion, the evidence supporting the use of this in the first place is not strong. Taking this into account and adding the previous concern in as well and I have strong doubts that this is indeed “for real”. I doubt this will be the last we will hear about it and while my skepticism continues I have to admit if a larger study is produced I will be willing and interested to read it.