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.
A few years ago targeted echocardiography (or functional echo) became all the rage. As trainees in this field have become spread across this country and others it is natural that attention would turn to other deficiencies in Neonatology. The new thing on the block appears to be Neonatal Neurocritical Care with the concept being that building teams devoted to the pursuit of better neuro outcomes for babies is needed. I am not here to say otherwise but to acknowledge that this is a good thing for our field. Building a local expertise for such at risk infants is a wise plan as with anything if we focus and a small area and put lots of hours in you can only get better.
New CPS Statement
This past month the CPS released a new position statement entitled Neuroprotection from acute brain injury in preterm infants . As Chair of the committee and writer of this blog I thought it might be nice to point out the timely release of this statement. One of the authors Dr. Khorshid Mohammad was recently in Winnipeg for our POCUS workshop and spoke about neurocritical care for neonates as part of the meeting. I would encourage you to read through the new statement but wanted to point out a couple interesting recommendations that serve as a departure from practice (or at least my own).
Antenatal steroids should be given to those 34 0 – 34 6/7 weeks.
This is something that comes out of the literature that has looked more broadly at the group from 34 0/7 – 36 6/7 weeks. The recommendation really is an acknowledgement that if there is benefit it is likely coming from those infants just past the 34 week mark. Older infants may benefit but the numbers needed to treat are so high that it calls into question the real need for such treatment.
A new approach to treating hypotension
An approach that moves away from treating numbers is recommended. How many times have you been asked how low a blood pressure should be allowed to drift before starting inotropes? Evidence is mounting that early use of inotropes themselves is linked to IVH. A more nihilistic approach is favoured here by looking at measures of end organ impact before instituting such therapy. What is the urine output, perfusion and lactate should motivate treatment more than just the number itself. If you are fortunate enough to have targeted echocardiography at the ready it is recommended to utilize that modality to help guide your treatment as well.
I won’t go through the whole document as I would love for you to read it yourself and see how it may apply to your own centre. I think the statement is significant though in that it really does marshal in a new era in the field of neuroprotection. I am pleased that the CPS is taking a position on this and if you need any other guidance be sure to visit our webpage at the Fetus and Newborn Committee which can be found at:
To be sure there are fans of both HFNC and CPAP out there. I have often heard from other Neonatologists that they use HFNC and find positive results while other centres refuse to use it in favour of the tried and true CPAP. Turning to the literature you will find some conflicting results with some studies suggesting equity and others more recently favouring CPAP. There has been speculation as to why one would be superior to the other and now we appear to have some answers as to where the differences lie.
A Physiologic Study
Liew et al published Physiological effects of high-flow nasal cannula therapy in preterm infants this month in an elegant study of 40 infants. The study was fairly simple in design either randomizing infants <37 weeks to starting with nCPAP +6 and then transitioning to 8 l/min HFNC followed by stepwise reductions of 1 l/min until 2 l/min was reached or the reverse, starting with 2 l/min and working their way up and then transitioning to nCPAP+6. All infants were on one or the other modality at the start and were all at least 3 days old, they were randomized to one or the other arm regardless of where they started off. Physiologic measurements were taken at each step including the following:
Mv -Minute ventilation
pEEP – nasopharyngeal end-expiratory pressure
pEECO2 -nasopharyngeal end-expiratory CO2
RR – respiratory rate;
SpO2 – oxygen saturation
TCCO2 – transcutaneous CO2
Vt – tidal volume
A Fabian device was used to deliver either HFNC or CPAP at the different flows for all patients.
The authors certainly found some interesting results that I think shed some light on why comparisons of HFNC and CPAP have been so inconsistent.
Table 2 contains the results of the study and I will point out the main findings below.
1. Flow matters – Compared to nCPAP+6 which is fairly consistent flows below 6 l/min deliver pEEP that is below 6 cm H2O.
2. Keep the mouth shut – With CPAP whether the mouth is open or closed the Fabian device delivers +6 cm H2O. As you can see from the table, when the mouth is open transmitted pressures drop off substantially. The infant put on a flow of even 6-8 l/min of HFNC sees pressures less than +6 consistently.
3. As flows increase end expiratory CO2 decreases. HFNC seems to help wash out CO2
4. Low flow rates on HFNC do not seem to help with ventilation as much as higher flow rates. In order to maintain Mv these infants at 2 l/min flow become tachypneic. The low pressures produced likely cause some atelectasis and hence tachypnea.
Size matters! Beware of excessive pressures.
An additional finding of this study was that on “multiple linear regression, flow rate, mouth position, current weight and gestation but not prong-to-nares ratio significantly predicted pEEP and account for a significant amount of its variance (F(4431)=143.768, p<0.0001), R2=0.572, R2=adjusted 0.568).” Essentially, infants under 1000g in particular could see pEEP levels as high as 13 cm H2O with flows of 8 l/min. The variability in transmitted pressures with HFNC is shown nicely in this figure from the study.
As flows increase above 6 l/min the actual pressures delivered become less reliable.
Looking at this data, it becomes evident why HFNC may be failing in its attempt to dethrone nCPAP. In order to achieve higher pressures and provide comparable distending pressure to nCPAP you need higher flows. With higher flows though come the problem of greater variability in delivered pressure. While the average pressure delivered may be equivalent or even higher than a CPAP of +6, in some infants (especially those below 1000g) one may be delivering significantly higher pressures than intended which may help with oxygenation and preventing intubation but others may be seeing far less than needed.
What it comes down to is that nCPAP is better at delivering a consistent amount of pressure. Studies using lower flows of HFNC likely failed to show superiority to CPAP as they just didn’t deliver enough pressure. An example of this was the study by Roberts CT et al Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants, in which flows of 6-8 l/min were used. Other studies using higher pressures could have been problematic due to open mouths, or larger babies not receiving as much benefit.
I am not saying that we should throw out HFNC entirely however. Depending on the unit you practice in you might not be able to use CPAP but HFNC may be allowed. If you had to choose between no support or HFNC I would likely go with the HFNC. For me at least, if I want to delivery reliable pressures in my tertiary care NICU I will be calling for the CPAP.