Here in Winnipeg we don’t use t-piece resuscitators for any resuscitation. I did use them in my past position in Edmonton and I came to appreciate them for their ease of use. For the majority of infants, setting a PIP and a PEEP and then using your finger to occlude and release offers a relatively simple and less difficult approach to ventilation than using a self inflating or jackson-rees bag. I say the majority of infants, as most infants are not born from 22-32 weeks but the lion’s share are born at gestations older than that. The larger more mature infants have lungs that are much more forgiving to excessive ventilation. For the smallest of infants though questions have remained for some time around the volumes delivered to the fragile lung when a fixed pressure is used in the presence of moment to moment changes in compliance.
Measuring Tidal Volume in Intubated At Risk Infants
Vaidya R et al published Tidal volume measurements in the delivery room in preterm infants requiring positive pressure ventilation via endotracheal tube feasibility study in Journal of Perinatology. The prospective observational study looked at 10 infants born at < 32 weeks with a mean GA of 23.9(±1.5) weeks and mean BW 618.5(±155)g. A mean of 17.8 minutes of recordings were examined using the setup below and in total looked at 8175 individual breaths. All patients in the study were intubated with non-cuffed ETT but by only including intubated infants in the delivery room the issue of mask leak was avoided. As in many units the target Vt was 4-6 mL/kg. It wasn’t specified what criteria they use for setting initial pressures but the included patients had a mean PIP of 24.4±5 and PEEP of 5.9 ±2.4. Importantly, those providing ventilation with the t-piece resuscitator were blinded to the data on tidal volume measurements.
How Good Were They At Meeting Their Goal?
It turns out that they weren’t that great (I am not faulting them by the way) as it is a challenge to try and adjust pressures based on chest rise. We are not good at it at all. As shown in the figure below there was a wide range of volumes administered. In fact here is the breakdown. The goal Vt between 4-6 was only 25% of the time. In other words you are dealing with either a risk of atelectotrauma or volutrauma 75% of the time. It is worth noting that the neonatal flow sensor has a dead space of 1 mL. If that is the case and the infants on average were about 600g that is almost 2 mL/kg in non-ventilated space that this volume is going into. It doesn’t change the numbers that much if you factor that in but it does mean that some infants who were getting a measured 3 mL/kg were actually seeing under 2 mL/kg of lung ventilation. On the other hand those getting 7 mL/kg were actually seeing under 6 mL/kg so were in target. Bottom line though is that when using fixed pressure settings in the presence of changing compliance even if one is adjusting pressure in real time it is difficult to maintain stable volumes in target range. The authors also demonstrate in another graph that even in individual patients there is fluctuation as well.
Call to Action
I think this study is actually quite useful in confirming what I imagine many have always suspected. We just aren’t that great at assessing tidal volume when we watch the chest rise. As many have noted, the first 6 breaths at least in an animal model can damage the lungs. Imagine what excessive or low volumes can do to the lung over 18 minutes?!
What this study does is demonstrate especially in the smallest and most vulnerable infants that if ventilation is needed one should put the infant onto a volume guaranteed mode of ventilation ASAP. Ventilators should be in the resuscitation area as we have in our hospital and not have to be brought in should the baby be intubated. Hand bagging even with a t-piece resuscitator should be kept to a minimum. At risk is the development of BPD and knowing that even in experienced hands we just aren’t that good at delivering tidal volumes in a target range we need to strive to minimize the time that we expose our infants to such modalities. Ventilation isn’t always avoidable but when needed my advice is to control volume and allow pressures to fluctuate as resistance and compliance change. Especially after administration of surfactant the pulmonary mechanics are changing constantly and no matter how good you are you just won’t be able to keep pace. Let the ventilator do it!
If you work in Neonatology you no doubt have listened to people talk in rounds or at other educational sessions about the importance of opening the lung. Many units in the past were what you might call “peepaphobic” but over time and with improvements in technology many centers are adopting an attitude that you use enough PEEP to open the lung. There are some caveats to this of course such as there being upper limits to what units are comfortable and not just relying on PEEP but adding in surfactant when necessary to improve pulmonary compliance.
When we think about giving nitric oxide the importance of opening the lung can’t be stressed enough. I have heard it said many times when a baby has been found to be a “non responder” to inhaled nitric oxide that they may have been so because the lung wasn’t open. What we mean by this is that the distal alveoli are open. One can administer all the iNO in the world but if the majority of alveoli are collapsed the drug can’t get to the pulmonary vasculature and cause the pulmonary vasodilation that is so sorely needed in the presence of hypoxemic respiratory failure. Surfactant and inhaled nitric oxide in the presence of hypoxemic respiratory failure could be a great combo as one would help open the alveoli and then the iNO could address any pulmonary vasoconstriction which might be exacerbating the hypoxemic state.
Study Tests This Theory
Researchers in Chile led by Gonzalez A published Early use of combined exogenous surfactant and inhaled nitric oxide reduces treatment failure in persistent pulmonary hypertension of the newborn: a randomized controlled trial in the Journal of Perinatology. The concept of this study was to compare in a double blind RCT for 100 patients (based on a power calculation looking for a 25% reduction in treatment failure) whether provision of surfactant as up to 2 doses and iNO would be better than just iNO alone. Included infants needed an oxygenation index (OI = MAPXFiO2/pO2) of 20 or more to qualify and treatment failure was an OI of 40 or more. The patients recruited were similar in common characteristics including types of conditions that would benefit from iNO. RDS, meconium aspiration syndrome and pneumonia certainly have been shown to benefit from surfactant before while in the PPHN category that is questionable. In order to ensure that it was not just the primary disease but pulmonary hypertension that was present as well, all patients required confirmation of pulmonary hypertension prior to enrollment via ECHO with either a TR jet indicating a pulmonary pressure at least 2/3 of systemic or right to left shunting at the ductal or atrial level.
The results of the study demonstrated a clear difference in the primary outcome.
Patients receiving the combination of surfactant prior to starting iNO showed a faster reduction in OI than those receiving iNO alone. In fact the reduction in primary outcome of treatment failure was over 50% different while the power calculation had been based on only a 25% difference. That’s ok as this means there were more than enough patients to demonstrate a difference. As a secondary outcome the rate of ECMO or death was also different between the groups favouring use of surfactant.
It works so now what?
Who doesn’t like seeing a study that confirms what you have long believed. I feel that this study validates the teaching I received throughout the years about ensuring the lung is open before giving iNO. There are some caveats to this however. About 90% of the patients studied had conditions present (RDS, MAS, pneumonia) for which surfactant would have been indicated anyway. If this study had been done let’s say in patients with asphyxia induced pulmonary hypertension and clear lungs the surfactant may have made no difference as the lungs were already open. I mention this as I don’t think readers of this analysis need to jump to the conclusion that every time there is a patient with PPHN that you MUST give surfactant. What I think this illustrates though is the importance of first asking the question if iNO is being considered “Have I opened the lungs?”. The next time you encounter such a patient consider whether you are using enough PEEP and whether surfactant is indicated. The bottom line is if the lung isn’t open then all the iNO in the world isn’t going to make much difference!
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.
IVH in the high VT group was diagnosed in 63 (51%) infants compared with 5 (13%) infants in the normal VT group (P=0.008).Severe IVH (grade III or IV) developed in 33/124 (27%) infants in the high VT group and 2/41 (6%) in the normal VT group (P=0.01)
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.
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.
As a Neonatologist, there is no question that I am supportive of breast milk for preterm infants. When I first meet a family I ask the question “are you planning on breastfeeding” and know that other members of our team do the same. Before I get into the rest of this post, I realize that while breast milk may be optimal for these infants there are mother’s who can’t or won’t for a variety of reasons produce enough breast milk for their infants. Fortunately in Manitoba and many other places in the world breast milk banks have been developed to provide donor milk for supporting these families. Avoidance of formula in the early days to weeks of a ELBWs life carries benefits such as a reduction in NEC which is something we all want to see.
Mother’s own milk though is known to have additional benefits compared to donor milk which requires processing and in so doing removes some important qualities. Mother’s own milk contains more immunologic properties than donor including increased amounts of lactoferrin and contains bioactive cells. Growth on donor human milk is also reduced compared to mothers’ own milk and lastly since donor milk is obtained from mothers producing term milk there will be properties that differ from that of mothers producing fresh breast milk in the preterm period. I have no doubt there are many more detailed differences but for basic differences are these and form the basis for what is to come.
The Dose Response Effect of Mother’s Own Milk
Breast milk is a powerful thing. Previous studies on the impact of mother’s own milk (MOM) have shown that with every increment of 10 mL/kg/d of average intake, the risk of such outcomes as BPD and adverse developmental outcomes are decreased. In the case of BPD the effect is considerable with a 9.5% reduction in the odds of BPD for every 10% increase in MOM dose. With respect to developmental outcome ach 10 mL/kg/day increase in MOM was associated with a 0.35 increase in cognitive index score.
The same group just published another paper on this cohort looking at a different angle. NICU human milk dose and health care use after NICU discharge in very low birth weight infants. This study is as described and again looked at the impact of every 10 mL/kg increase in MOM at two time points; the first 14 and the first 28 days of life. Although the data for the LOVE MOM trial was collected prospectively it is important to recognize how the data for this study was procured. At the first visit after NICU discharge the caregiver was asked about hospitalizations, ED visits and specialized therapies and specialist appointments. These were all tracked at 4 and 8 months of corrected age were added to yield health care utilization in the first year, and the number of visits or provider types at 4, 8, and 20 months of corrected age provided health care utilization through 2 years.
What were the results?
“Each 10 mL/kg/day increase in HM in the first 14 days of life was associated with 0.26 fewer hospitalizations (p =
0.04) at 1 year and 0.21 fewer pediatric subspecialist types (p = 0.04) and 0.20 fewer specialized therapy types (p = 0.04) at 2 years.” The results at 28 days were not statistically significant. The authors reported both unadjusted and adjusted results controlling for many factors such as gestational age, completion of appointments and maternal education to name a few which may have influenced the results. The message therefore is that the more of MOM a VLBW is provided in the first 14 days of life, the better off they are in the first two years of life with respect to health care utilization.
That even makes some sense to me. The highest acuity typically for such infants is the first couple of weeks when they are dealing with RDS, PDA, higher oxygen requirements etc. Could the protective effects of MOM have the greatest bang for your buck during this time. By the time you reach 28 days is the effect less pronounced as you have selected out a different group of infants at that time point?
What is the weakness here though? The biggest risk I see in a study like this is recall bias. Many VLBW infants who leave the NICU have multiple issues requiring many different care providers and services. Some families might keep rigorous records of all appointments in a book while others might document some and not others. The big risk here in this study is that it is possible that some parents overstated the utilization rates and others under-reported. Not intentionally but if you have had 20 appointments in the first eight months could the number really by 18 or 22?
Another possibility is that infants receiving higher doses of MOM were healthier at the outset. Maternal stress may decrease milk production so might mothers who had healthier infants have been able to produce more milk? Are healthier infants in the first 14 days of life less likely to require more health care needs in the long term?
How do we use this information?
In spite of the caveats that I mentioned above there are multiple papers now showing the same thing. With each increment of 10 mL/kg of MOM benefits will be seen. It is not a binary effect meaning breastfed vs not. Rather much like the medications we use to treat a myriad of conditions there appears to be a dose response. It is not enough to ask the question “Are you intending to breastfeed?”. Rather it is incumbent on all of us to ask the follow-up question when a mother says yes; “How can we help you increase your production?” if that is what the family wants>