Skin to skin care (STS) or kangaroo care (KC) has quickly become one of the hot topics in neonatal care these days. The benefits have been spoken of before and as we learn more about the benefits it isn’t surprising to see studies emerge looking at novel groups who might benefit from the same. Dr. Kribs and her team in Cologne, Germany put themselves on the map with studies demonstrating the potential use of and benefits from LISA techniques for surfactant administration. The same unit is at it again but this time asking a different but very important series of questions.
Combatting the challenges the mother-infant dyad face after delivery
Traditionally, our smallest infants are resuscitated and shown to the parents before being taken to the NICU for ongoing care in an isolette. Dr. Kribs and her group wondered about the effect that separation could have on the mother-child interaction (MCI). The groups were comprised of infants born between 25 +0 – 32+ 0 weeks gestation. They postulated in a randomized controlled trial that after stabilization with or without surfactant that there would be a benefit to having these dyads spend 45 minutes in STS vs the traditional 5 minute visual contact with touching allowed of the face but not anywhere on the body since the infant was wrapped in protective thermal wrap. To test the difference in MCI at 6 months the authors shot a 4 minute video of the mother and child together and using blinded reviewers assessed the interaction between the dyad. The interaction involved the mother changing the diaper and playing with their children.
From the study; “Maternal and infant behavior was assessed using the Mannheim Rating System, a well validated standardized observation instrument(16). Videos were analyzed by two trained raters blind to randomization.”
Self reports of other important outcomes such as depression, bonding and more objective study of salivary cortisol were also performed. Salivary cortisol elevations were apparently blunted in another study at 4 months of age in infants who experienced more pain and stress in the NICU.
The studies title is Delivery room skin-to-skin contact for preterm infants – a randomized clinical trial
What did they find?
Like many studies looking at a brief intervention in the life of a child this one had some findings that are worth discussing.
Overall, the rate of positive MCI was higher in the group randomized to STS (86 (±26) vs 71 (±32), p=0.041, OR 0.982, CI [0.7-1]). This difference was due to three particular differences in the MCI studies.
Maternal motoric response, infant vocal response and infant motoric response. What this meant specifically is that infant and maternal physical interactions were deemed positive in terms of facial expressions, physical movement or vocalizations more when delivery room STS was performed than when not. Infants were also more vocal with their mothers when they had experienced this intervention.
Also on the 3rd day of life maternal depressive symptoms were higher in the group randomized to only see their infant for 5 minutes. This was in spite of controlling for factors expected to confound the result. Salivary cortisol did not show a difference at 4 months. While the study was underpowered for the secondary outcomes there was no increase rate of IVH or other adverse outcomes in the study so take that for what its worth.
Lastly, there was less hypothermia in the group randomized to STS care on admission.
Some lessons from this study
As the authors note it is possible that parents prepped themselves for the videos but the number of parents that “put on a show” should roughly be equal between the groups. Not sure given the low number of patients in the study if that would have truly balanced out but the results to me seem plausible. Having a preterm infant for most families who really don’t know what to expect can be a terrifying experience. Such parents may develop the vulnerable child syndrome in which parents hover over their children feeling as if they need to be over protective given the perceived frailty of the child. This constant worry can lead to stress for the family and affect the parent-child interaction. What if you were able to hold your baby though almost from the start for 45 minutes against your chest and see that your infant wasn’t as fragile as you might have thought? Could this lead to a reduction in depressive symptoms by 3 days as found here? Might you spend a lot more time in kangaroo care as the journey of the patient continues in the NICU?
These were not all healthy babies as about 80% in both arms received the LISA procedure for administration of surfactant and then went on to CPAP. To most parents these babies would have indeed appeared fragile but perhaps showing the families that the babies were stronger than they looked and moreover allowing the families to not just be observers but provide direct care indeed had an impact on their mood and that carried over to childhood.
No doubt the naysayers out there will want a larger study that looks at other outcomes in terms of harm such as IVH and sepsis but this study certainly shows the strategy is possible and may just have enough benefit to make it standard of care some day.
Neurally adjusted ventilatory assistance or NAVA is something that has been around for awhile. Available as a mode on the Maquet ventilator it uses an esophageal probe to sense myoelectrical activity in the diaphragm and provide assistance with postive pressure when detected. This is supposed to be better than the more traditional Graseby capsules or sensing based on airflow. Conceptually then if a preterm infant had a typical mixed apneic event with a component of both central and obstructive apnea this technology could sense an attempt to breath and assist the infant with positive pressure when the diaphragm indicates it is time for a breath. Such support should work to maintain functional residual capacity. A better ventilated lung could lead to less systemic oxygen desaturation and bradycardia correct?
Retrospective review in Virginia
Tabacaru CR et al just published NAVA—synchronized compared to nonsynchronized noninvasive ventilation for apnea, bradycardia, and desaturation events in VLBW infants. This is a retrospective study and non randomized looking at a single centres experience in 108 VLBW infants in which the attending providers were free to choose the type of respiratory support infants received after extubation. The authors from this group examined 61 epochs of time on niNAVA compared to 103 for the non invasive positive pressue ventilation nIPPV group. niNAVA patients received an initial level (the factor by which the electric diaphragmatic signal intensity (edi) is multiplied) of 1.0 and a PEEP of 5 to 6 cm H2O. NIPPV was initiated at a positive inspiratory prrssure (PI)P of 14 to 16 cm H2O, PEEP of 5 to 6 cm H2O and a rate of 20 breaths per minute. Adjustments were dictated by oxygenation and blood gases and were not described as protocolized but rather left up to clinicians. All events were recorded manually by nursing.
What impact did niNAVA have on apnea and bradycardia?
There were no significant differences noted between the two study groups including such important parameters as birthweight, day of life of extubation, sepsis or whether they needed to be reintubated. All of these could be markers of worse lungs in one group or the other so at least them seem pretty much the same.
What about the effect on apnea and bradycardia? The bold numbers in the table indicate that only the number of bradycardias per day differed between the groups. Whether patients desaturation events or not was not affected. Also not effected was whether or not patients had apnea.
Why might these results make sense?
First off since the study was not randomized and is small there is always the possibility that these results are not real and occurred just by chance. There could be variables for example that we are not taking into account to explain why some patients were chosen for one modality or the other than affect the outcomes here. Having said that let’s look at the three outcomes.
Apnea – why would this be different at all? Both modalities provide support when needed. If the infant decides to stop breathing I would see the lack of neural output not being affected by either modality so perhaps if the primary issue is lack of respiratory drive for most we wouldn’t expect a difference.
Desaturation – if pulmonary reserve is kept about the same with both approaches it seems reasonable that we might not see a difference here either.
Bradycardia – here there was a difference. Can this be explained as something plausible. I think there might be something here. Use of NAVA just might have a faster and more accurate response time than nIPPV that relies on airflow. Due to leaks around the prongs or mask it is possible that while background pressures are relatively maintained, not all needed positive pressure helping breaths are received in as timely a fashion as when they are detected via electrical activity. The ability of niNAVA to help the infant overcome the obstructive component of breathing might be reason why bradycardia is reduced. The interruption of ventilation is briefer with less reflexive bradycardia.
What is needed of course next is a randomized prospective controlled trial. Who knows when that will come but for the infants that we see with seeminly methylxanthine resistant apnea might niNAVA be the path to avoiding reintubations? Time will tell
Glucose metabolism in the newborn can be a tricky thing to manage. Neonates can have significant fluctuation in their serum glucose in the first few days of life which can lead heels to look like pin cushions. How many times have you been asked as a physician if there is anything we can do to reduce the number of pokes? That something may have arrived at least in a feasibility study that could pave the way for this becoming the standard approach to hypo/hyperglycemia in the newborn. This is an important area to improve tightness of control as hyperglycemia has been associated in VLBW infants with such adverse outcomes as IVH, ROP and NEC.
Continuous glucose monitoring (CGM) with closed loop insulin delivery
The study was a pilot of 20 patients randomized to have an automated system to regulate glucose based on CGM data from 48-72 hours of age vs a paper based algorithm to manage dextrose or insulin infusion rates during the same period. The sample size was one of convenience to test the concept and the period was chosen to allow for time to recruit patients. The sensor used was an Enlite attached to a laptop with software capable of delivering infusion rates to two alaris pumps (one with 20% dextrose and the other with insulin). Target serum glucose levels were set to be between 4-8 mmol/L. The babies included were all under 1200g and had mean weights of 962g in the closed loop and 823g in the control arm.
The Results were fairly dramatic in my mind at least. A remarkable 91% of the infants in the closed loop system had glucose levels in the target range vs 26% in the control arm. Nutritional intakes and mean insulin dosing were not any different between groups. No harm in addition was noted from use of the CGMs. You don’t escape pokes all together though as the device does require q6h checks to calibrate and ensure it is reading properly. Every 6 hours is better though than every three for those with brittle control!
Tightly regulating blood glucose and avoiding both lows and highs has benefits on the low end to neurological preservation. On the high end some complications such as IVH, NEC and ROP may be avoided by better control. The challenge with the system as is at the moment is that it is not widely available. I am eager for a company out there to create software for mass distribution that would enable us to try this out. While the calibration is still required I can’t help but think this is an improvement over what we have at the moment. Stay tuned as I think this one is for real and will appear in NICUs sooner than you think!
The story around cord management after birth continues to be an evolving one. I have certainly posted my own thoughts on this before with my most recent post being Delayed cord clamping may get replaced. Time for physiological based cord clamping. While this piece demonstrated that there are benefits to longer times till clamping is done, it also showed that if you go too long hypothermia becomes a real risk and with it possible complications. At least in our centre the standard that we have tried to reach is DCC for one minute for our infants. As you will no doubt know from the literature reviewed here before, this is likely not long enough!
Inclusion criteria were such that these were all low risk vaginal deliveries with fetal heart rate (FHR) ≥100 ≤ 160 bpm and all infants were ≥33 weeks. Although 1510 were randomized (power calculation for sample size found there should be 566 per group based on an expected loss of 25% per arm. In the end there were 670 in the ECC and 594 in the DCC groups that adhered to the protocol. In the ECC group the mean duration of time till clamping occurred was 31.2 s (+/-14.4) vs 198.5s (+/-16.9).
The goal after delivery is to increase blood flow to the lungs as PVR drops. In order to do so this requires adequate ventilation but it also requires adequate perfusion of the myocardium. If you clamp too early and pulmonary blood flow has not yet increased you run the risk of having a sudden drop in coronary blood flow with oxygenated blood from the placenta and with that bradycardia. A longer time on “heart lung bypass” from the placenta should allow for a smoother transition. That is what was seen here. At 1, 5 and 10 minutes infants randomized to the DCC had better oxygen saturations. Heart rates interestingly were lower in the DCC group but that could also be related to better oxygenation leading to less compensatory tachycardia. In other studies in which the cord was clamped immediately bradycardia was more common. This difference here may reflect timing of the clamp on heart rate. Lastly, time to first breath was much faster in the group randomized to DCC. Might this be an effect of better oxygenation?
What they didn’t measure?
There was no comment on risk of hypothermia or other markers of illness such as rates of admission to NICU, hypoglycemia, lethargy or other markers of an infant who became cold. If this is to become standard practice measures need to be in place to prevent these concerns from becoming reality. It is also worth noting the population studied. These are healthy late preterm and term pregnancies. More work is needed on younger infants and those with risk factors in pregnancy. How would mothers with poor tracings, diabetes or hypertension fare as well as those who have growth restricted infants?
This field is growing and I will continue to follow this evolving story and share information as it becomes available. One thing in my mind is fairly certain though and that is that clamping right after delivery for routine births should be a thing of the past.
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. Not surprisingly with a greater risk of oxygen desaturation there was a need for more nasal intermittent mechanical ventilation (93% vs 47%). Finally, while the numbers are small the incidence of grade 3 or 4 IVH was 0 in the group that received no sedation and 5% in the group that did. While non significant it is worth pointing out that as with all of the listed complications, this study was underpowered for any meaningful secondary outcome conclusions. Given what we know about the interaction of positive pressure ventilation and risks of IVH it is just something to raise an eyebrow at for now.
What is the biggest problem with the study?
As I see it the absence of the placebo group such that the Neonatologists knew who received propofol and who did not makes it difficult to know if there really was a true need for PPV. In the sedation group the percentage of babies that received nasal IMV almost matches perfectly those that experienced desaturation events (93 and 91%) but in the non-sedated group it was 47% and 69%. Were Neonatologists more apt to let the desaturations sit without PPV if they knew the infant did not get propofol and conversely assume they needed PPV if they received a sedative? It seems to me that the study would have been improved with the use of the sham procedure. The scoring by the nurses who were blinded shows that even with a lower dose of propofol than normal though it still provides some sedation.
I would stay tuned in this area as I am sure this will not be the last we hear of this but for now I would suggest that sedation for MIST/LISA should not be routinely done, at least based on this study.