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 as shown in the table. 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.
We have all been there. After an uneventful pregnancy a mother presents to the labour floor in active labour. The families world is turned upside down and she goes on to deliver an infant at 27 weeks. If the infant is well and receives minimal resuscitation and is on CPAP we provide reassurance and have an optimistic tone. If however their infant is born apneic and bradycardic and goes on to receive chest compressions +/- epinephrine what do we tell them? This infant obviously is much sicker after delivery and when the family asks you “will my baby be ok?” what do you tell them? It is a human tendency to want to reassure and support but if they ask you what the chances are of a good outcome it has always been hard to estimate. What many of us would default to is making an assumption that the need for CPR at a time when the brain is so fragile may lead to bleeding or ischemia would lead to worse outcomes. You would mostly be right. One study by Finer et al entitled Intact survival in extremely low birth weight infants after delivery room resuscitation.demonstrated that survival for infants under 750g was better if they had a history of CPR after delivery. The thought here is that more aggressive resusctiation might be responsible for the better outcome by I would presume establishing adequate circulation sooner even if the neonates did not appear to need it immediately.
The Canadian Neonatal Network
In Canada we are fortunate to have a wonderful network called the Canadian Neonatal Network. So many questions have been answered by examining this rich database of NICUs across the county. Using this database the following paper was just published by Dr. A. Lodha and others; Extensive cardiopulmonary resuscitation of preterm neonates at birth and mortality and developmental outcomes. The paper asked a very specific and answerable question from the database. For infants born at <29 weeks gestational age who require extensive resuscitation (chest compressions, epinephrine or both) what is the likelihood of survival and/or neurodevelopmental impairment (NDI) at 18-24 months of age vs those that did not undergo such resuscitation? For NDI, the authors used a fairly standard definition as “any cerebral palsy (GMFCS1), Bayley-III score <85 on one or more of the cognitive, motor or language composite scores, sensorineural or mixed hearing impairment or unilateral or bilateral visual impairment.” Their secondary outcomes were significant neurodevelopmental impairment (sNDI), mortality, a Bayley-III score of <85 on any one of the components (cognitive, language, motor), sensorineural or mixed hearing loss,or visual impairment.sNDI was defined as the presence of one or more of the following: cerebral palsy with GMFCS 3, Bayley-III cognitive, language or motor composite score <70, hearing impairment requiring hearing aids or cochlear implant, or bilateral visual impairment”
What did they discover?
It is a fortunate thing that the database is so large as when you are looking at something like this the number of infants requiring extensive resuscitation is expected to be small. The authors collected data from January 1, 2010 and September 30, 2011 and had a total number of infants born at less than 29 weeks of 2760. After excluding those with congenital anomalies and those who were born moribund they were left with 2587. From these 80% had follow-up data and when applying the final filter of extensive resuscitation they were left with 190 (9.2%) who received delivery room CPR (DR-CPR) vs 1545 who did not receive this.
Before delving into the actual outcomes it is important to note that neonates who did not receive DR-CPR were more likely to be born to mothers with hypertension and to have received antenatal steroids (89 vs 75%). With these caveats it is pretty clear that as opposed to the earlier study showing better outcomes after DR-CPR this was not the case here.
The results are interesting in that it is pretty clear that receiving DR-CPR is not without consequence (higher rate of seizures, severe neurological injury, BPD). Looking at the longer term outcomes though is where things get a little more interesting. Mortality and mortality or neurodevelopmental impairment are statistically significant with respect to increased risk. When you take out NDI alone however the CI crosses one and is no longer significant. Neither is CP for that matter with the only statistically significant difference being the Bayley-III Motor composite score <85. The fact that only this one finding came out as significant at least to me raises the possibility that this could have been brought about by chance. It would seem that while these infants are at risk of some serious issues their brains in the long run may be benefiting for the neurological plasticity that we know these infants have.
The study is remarkable to me in that an infant can have such a difficult start to life yet hope may remain even after dealing with some of the trials and tribulations of the NICU. Parents may need to wade through the troubling times of seizures, long term ventilation and CPAP and then onto a diagosis of BPD but their brains may be ok after all. This is one of the reasons I love what I do!
The metabolic syndrome describes the development as an adult of centripetal obesity, high blood pressure, high triglycerides, elevated blood sugar and low HDL cholesterol. These constellation of problems significantly increase the risk of cardiovascular disease, stroke and diabetes.
The theory here is that conditions in utero in which the fetus is chronically deprived of blood flow and nutrition lead to a tendency towards insulin resistance. The body is essentially trying to use any energy it is receiving to stay alive in an environment in which resources are scarce. Given that situation, resisting the effects of insulin by preventing storage of this needed energy serves a useful purpose but in the long run may be detrimental as the body become programmed to resist the effects of this hormone.
What if this programming could be overcome?
Breast milk certainly has many incredible properties and as we learn more we discover only more applications. My previous post on putting breast milk in the nasal cavity is just one such example (Can intranasal application of breastmilk cure severe IVH?). In 2019 Dr. Hair and Abram’s group looked at this with respect to insulin resistance and with potential extrapolation to the metabolic syndrome in their paper Premature small for gestational age infants fed an exclusive human milk-based diet achieve catch-up growth without metabolic consequences at 2 years of age. Texas Children’s Hospital uses an exclusive human milk diet for premature infants with the following criteria GA of <37 weeks, BW of ≤1250 g, with the diet maintained until approximately 34 weeks PMA. Exclusive human milk is provided through a combination of mother’s own milk and Prolacta instead of a bovine based human milk fortifier. In this study they were able to prospectively track 51 preterm infants of which 33 were AGA and 18 SGA. The first visit (visit 1) was performed at 12–15 months CGA and the second visit (visit 2) was at 18–22 months CGA. The question at hand was whether these children would experience catch up growth at 2 years of age and secondly what their levels of insulin might look like at these times. Higher insulin levels might correlate with levels of insulin resistance with higher levels being needed to maintain euglycemia. As a measure of insuline resistance the authors used the calculation of the Non-fasting homeostatic model of assessment-insulin resistance (HOMA-IR) = (insulin × glucose)/22.5 which has been validated elsewhere. Protein intakes were equal for both groups at about 4 g/kg of human milk protein.
The Results Please
The SGA group had greater weight gain between visit 1 and 2 as evidenced by a significant difference in the change in BMI z-score, AGA −0.21±0.84 vs.SGA 0.25±1.10. I suppose this isn’t too shocking as we know that many babies born SGA experience catch up growth after discharge. What is surprising and once again speaks to the power of breast milk is the impact observed on insulin levels and resistance to the same as measured by the HOMA-IR (AGA babies are the left column and SGA the right).
The adjusted p vlaues for glucose were 0.06 with insulin and HOMA-IR being 0.02. What does this mean? Well, these are not fasting insulin levels which would be ideal but what it does say is that at fairly comparable glucose levels the level of insulin is higher in former AGA babies and the level of insulin resistance lower in the SGA infants! This result is quite the opposite of what previous studies have shown as referenced above. Aren’t these growth restricted infants supposed to have had insulin resistance in utero and been programmed for life to have insulin resistance and as adults develop the metabolic syndrome? This study falls short of making any claims about the latter as these infants are only two years of age. What this study provides though is certainly a raised eyebrow. There will be those of course that look at the size of the study and dismiss it as being too small but at the very least this study will lead to further work in this area. This paper though adds to the mystery around the potential impacts of breast milk and certainly provides strength to the thought that perhaps breastmilk should be the exclusive source of nutrition for preterm infants in the NICU. While I understand that not all women are able to produce enough for their own infants or may choose not to for a variety of reasons, with access to donor milk supply this could become a reality. The cost savings to the health care system by preventing insulin resistance would be many fold greater than the cost of donor milk in the newborn period.
Another intriguing question will be whether use of an exclusive human milk diet with use of only mother’s own milk will have similar effects or even greater impact on glucose homestasis later in life. I think the authors are to be commended for their dedication to work in this field and I certainly look forward to the next publication from this group.
Recently the practice of keeping ELBW infants with a midline head position for the first three days of life has been recommended to reduce IVH as part of a bundle in many units. The evidence that this helps to reduce IVH has been somewhat circumstantial thus far. Studies finding that decreased sagittal sinus blood flow, increased cerebral blood volume with increased intracranial pressure all occur after head turns would theoretically increase the risk of IVH. Raising the head of the bed would help in theory with drainage of the venous blood from the head and in fact systemic oxygenation has been shown to improve with such positioning. This presumably is related to increased cardiac output from better systemic venous return.
Bringing it to the bedside
Interestingly, some of the above studies are from over thirty years ago. We now have some evidence to look at involving this practice. Kochan M et al published Elevated midline head positioning of extremely low birth weight infants: effects on cardiopulmonary function and the incidence of
periventricular-intraventricular. The study involved maintaining ELBW infants in an elevated midline head position (ELEV- supine, head of bed elevated 30 degrees, head kept in midline) versus standard head positioning (FLAT–flat supine, head turned 180 degrees every 4 h) during the first 4 days of life to see if this would decrease in the incidence of IVH. Ninety infants were randomized into both arms of the study. In terms of baseline characteristics, BW of 725g in the FLAT vs 739 in ELEV were comparable as well as GA both at 25 weeks. Two differences on the maternal side existed of 40% ELEV vs 24.4% FLAT of mothers having preeclampsia and 23.3% FLAT vs 10% ELEV having prolonged rupture of membranes both of which were statistically significant.
What did they find?
Ultrasounds were performed at entry into the study and then daily for days 1-4 and then on day 7 with abnormal scans repeated weekly. In terms of IVH the authors noted no overall difference in rate of IVH. What they did find however was a statistically significant reduction in the rate of Grade IV IVH. The p value for the finding of lower rates of Grade IV IVH was 0.036 so not strikingly significant but different nonetheless. Given that the venous drainage of the head is also dependent on the resistance to flow from the pressure in the thorax one can’t infer that the intervention alone is responsible for this without ensuring that that respiratory findings are similar as well. Similarly without knowing inflow of blood into the head as measured by blood pressure it is difficult to say that the reduction in IVH isn’t related to differences in blood pressure.
The authors helpfully looked at both of these things. For those infants on high frequency ventilation the mean airway pressure was higher on day one being 11.5 cm H2O (FLAT) vs 9.9 cm H2O (ELEV) neither of which are high although different. The rest of the three days were no different. For those on conventional ventilation the only difference was on day 4 where the MAP was higher for ELEV at 8 vs 7.4 cm H2O which again is fairly mild. Interestingly, as was found in other studies that oxygenation was improved with elevation of the head, the maximum FiO2 for the two groups was different on day 1 being 46% in the FLAT vs 37.5% in the ELEV.
Looking at the hemodynamic side of things there were differences in the lowest mean BP recorded on day 1 and 3 but otherwise the groups were similar. It would have been nice to see mean results during this time rather than lowest but this is what we have.
In terms of complications of preterm birth there were no differences found in rates of sepsis (important given the increase rate of prolonged rupture in the FLAT group), NEC or ROP.
Although length of stay was no different 92 vs 109 days ELEV (NS), survival to discharge was at 88% vs 76% (p=0.033) which also may explain the longer length of stay.
What Can We Learn From This
Don’t worry. I am not about to throw the results out. There are a couple observations though that need to be addressed. The first is the increased rate of preecampsia in the ELEV group. This finding could have impacted the results. We know that fetuses exposed to this condition are stressed and are often born with better lungs than their non-exposed counterparts. The endogenous increase in steroids due to this stress is attributable and may explain the better oxygenation and lower mean airway pressures needed in the ELEV group rather than improvements in flow alone from positioning. The second issue is adherence to the protocol as there were some infants in the ELEV group who were placed flat for the final 1-2 days of the study. Having said that, this would serve to dilute the effect rather than strengthen it so perhaps it makes the results more believable.
So where does this leave us? This study demonstrates improved survival and a reduction in Grade IV IVH without an overall reduction in IVH. There was nothing found to suggest that the intervention is harmful. Given the background studies demonstrating improved systemic oxygenation, reductions in ICP and cerebral blood volume the finding of reduced severe IVH seems plausible to me. This could be a practice changing study for some units who have perhaps only adopted midline positioning in the first few days of life. It will be interesting to see if this takes off but is certainly worth a good look at.
Choosing to provide postnatal systemic steroids to preterm infants for treatment of evolving BPD has given many to pause before choosing to administer them. Ever since K Barrington published his systematic review The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. and found a 186% increase in risk of CP among those who received these treatments, efforts have been made to minimize risk when these are given. Such efforts have included shortening the exposure from the length 42 day courses and also decreasing the cumulative dose of dexamethasone. Fortunately these efforts have led to findings that these two approaches have not been associated with adverse neurodevelopmental outcomes. Having said that, I doubt there is a Neonatologist that still doesn’t at least think about long term outcome when deciding to give dexamethasone. The systemic application certainly will have effects on the lung but the circulating steroid in the brain is what occupies our thoughts.
All of the included studies used a prophylactic approach of giving between the first 4 hours and the 14th day of postnatal age doses of pulmonary steroids with the goal of preventing death or BPD. The GA of enrolled infants ranged from 26 to 34 weeks, and the birth weight ranged from 801 to 1591 g. Out of 870 possible articles only 12 made the cut and compromised the data for the analysis.
Routes of steroid were by inhalation, liquid instillation though the endotracheal tube or by mixing in surfactant and administering through the ETT.
What Did They Find?
Using 36 weeks corrected age as a time point for BPD or death, the forrest plot demonstrated the following. A reduction in risk of BPD or death of 15% with a range of 24% to only a 4% reduction.
Looking at the method of administration though is where I find things get particularly interesting.
What this demonstrates is that how you give the steroids matters. If you use the inhalational or intratracheal instillation (without a vehicle to distribute the steroids) there is no benefit in reduction of BPD or death. If however you use a vehicle (in both Yeh studies it was surfactant) you find a significant reduction in this outcome. In fact if you just look at the studies by Yeh the reduction is 36% (CI 34 – 47%). In terms of reduction of risk these are big numbers. So big one needs to question if the numbers are real in the long run.
Why might this work though?
In the larger study by Yeh, budesonide was mixed with surfactant and delivered to intubated infants every 8 hours until FiO2 was less than 30%, they were extubated or a maximum of 6 doses were reached. We know that surfactant spreads throughout the lung very nicely so it stands to reason that the budesonide could have been delivered evenly throughout the lung. Compare this with inhalational steroid that most likely winds up on the plastic tubing or proximal airway. The anti-inflammatory nature of steroids should decrease damage in the distal airways offsetting the effects of positive pressure ventilation.
I am excited by these findings (if you couldn’t tell). What we don’t know though is whether the belief that the steroid stays in the lung is true. Are we just making ourselves feel better by believing that the steroid won’t be absorbed and move systemically. This needs to be tested and I believe results of such testing will be along in the near future.
Secondly, we need a bigger study or at least another to add to the body of research being done. Such a study will also need long term follow-up to determine if this strategy does at least have equal neurodevelopmental outcomes to the children who don’t receive steroid. The meta-analysis above does show in a handful of studies that long term outcome was no different but given the history of steroids here I suspect we will need exceptionally strong evidence to see this practice go mainstream.
What I do believe is whether you choose to use steroids prophylactically using hydrocortisone or using intratracheal surfactant delivered budesonide, we will see one or both of these strategies eventually utilized in NICUs before long.