It has to be one of the most common questions you will hear uttered in the NICU. What were the cord gases? You have a sick infant in front of you and because we are human and like everything to fit into a nicely packaged box we feel a sense of relief when we are told the cord gases are indeed poor. The congruence fits with our expectation and that makes us feel as if we understand how this baby in front of us looks the way they do.
Take the following case though and think about how you feel after reading it. A term infant is born after fetal distress (late deceleration to as low as 50 BPM) is noted on the fetal monitor. The infant is born flat with no heart rate and after five minutes one is detected. By this point the infant has received chest compressions and epinephrine twice via the endotracheal tube. The cord gases are run as the baby is heading off to the NICU for admission and low and behold you get the following results back; pH 7.21, pCO2 61, HCO3 23, lactate 3.5. You find yourself looking at the infant and scratching your head wondering how the baby in front of you that has left you moist with perspiration looks as bad as they do when the tried and true cord gas seems to be betraying you. To make matters worse at one hour of age you get the following result back; pH 6.99, pCO2 55, HCO3 5, lactate 15. Which do you believe? Is there something wrong with the blood gas analyzer?
How Common Is This Situation
You seem to have an asphyxiated infant but the cord gas isn’t following what you expect as shouldn’t it be low due to the fetal distress that was clearly present? It turns out, a normal or mildly abnormal cord gas may be found in asphyxiated infants just as commonly as what you might expect. In 2012 Yeh P et al looked at this issue in their paper The relationship between umbilical cord arterial pH and serious adverse neonatal outcome: analysis of 51,519 consecutive validated samples. The authors sampled a very large number of babies over a near 20 year period to come up with a sample of 51519 babies and sought to pair the results with what they knew of the outcome for each baby. This is where things get interesting. When looking at the outcome of encephalopathy with seizures and/or death you will note that only 21.71% of the babies with this outcome had a gas under 7.00. If you include those under 7.10 as still being significantly distressed then this percentage rises to 34.21%. In other words almost 66% of babies who have HIE with seizures and/or death have a arterial cord pH above 7.1! The authors did not look at encephalopathy without seizures but these are the worst infants and almost 2/3 have a cord gas that you wouldn’t much as glance at and say “looks fine”
How do we reconcile this?
The answer lies in the fetal circulation. When an fetus is severely stressed, anaerobic metabolism takes over and produces lactic acid and the metabolic acidosis that we come to expect. For the metabolites to get to the umbilcal artery they must leave the fetal tissues and enter the circulation. If the flow of blood through these tissues is quite poor in the setting of compromised myocardial contractility the acids sit in the tissues. The blood that is therefore sitting in the cord at the time of sampling actually represents blood that was sent to the placenta “when times were good”. When the baby is delivered and we do our job of resuscitating the circulation that is restored then drives the lactic acid into the blood stream and consumes the buffering HCO3 leading to the more typical gases we are accustomed to seeing and reestablishing the congruence our brains so desire. This in fact forms the basis for most HIE protocols which includes a requirement of a cord gas OR arterial blood gas in the first hour of life with a pH < 7.00.
Acidosis May Be Good For the Fetus
To bend your mind just a little further, animal evidence suggests that those fetuses who develop acidosis may benefit from the same and be at an advantage over those infants who don’t get acidemia. Laptook AR et al published Effects of lactic acidinfusions and pH on cerebral blood flow and metabolism. In this study of piglets, infusion of lactic acid improved cerebral blood flow. I would suggest improvement in cerebral blood flow of the stressed fetus would be a good thing. Additionally we know that lactate may be used by the fetus as additional metabolic fuel for the brain which under stress would be another benefit. Finally the acidemic fetus is able to offload O2 to the tissues via the Bohr effect. In case you have forgotten this phenomenon, it is the tendency for oxygen to more readily sever its tie to hemoglobin and move into the tissues.
I hope you have found this as interesting as I have in writing it. The next time you see a good cord gas in a depressed infant, pause for a few seconds and ask yourself is this really a good or a bad thing?
A Mother’s arms are full of tenderness and children sleep soundly in them – Victor Hugo
The NICU is a loud and chaotic place, that can be painful to be in at times. Its hard to get a good nights sleep (especially for the nurses!). When you think about how much our infants are handled and disturbed, poked and prodded, all in almost continual daylight, it’s a wonder they get any sleep.
For normal neurodevelopment the infant needs both active and quiet sleep. Sleep in an infant is divided into REM (active sleep) and NON-REM (quiet sleep). During quiet sleep you see very little movement and a regular breathing pattern, whereas active sleep involves movement with an irregular breathing pattern.
The importance of Quiet Sleep:
• Without it, the infant doesn’t get enough active sleep.
• Provides the infant with a break from the busy NICU environment.
• Lessons the release of glucocorticoids (Increased cortisol can cause neuronal cell death).
• Necessary for brain development.
• Increased quiet sleep = decreased risk of SIDS.
The importance of Active Sleep:
• Active sleep promotes brain maturation (US DHHS, 2003; Mirmiran, 1995).
• Most memory consolidation and learning occurs in this state (Smith, 2003).
• Nerve cell connections are restructured (synaptic plasticity) (Marks et al., 1995).
Due to the NICU environment, the infant ends up having slower sleep organization maturation and with increased cortisol they are more apt to have a disturbed and less restful sleep.
A complete cycle of sleep includes moving from active sleep to quiet sleep and back to active sleep. Full term and preterms >32 weeks postconceptional age will need about 60-70 minutes for a cycle. Infants <32 weeks postconceptional age will need about 90 minutes. So when infants come out for KC, we try to plan for at least that amount of time.
You will see when infants are placed in KC, the infant settles and goes into a deep sleep. To accommodate this, you will need comfortable chairs for the parent and good support for their arms. You also want to make sure they have had something to eat or drink, pumped breast milk, used the washroom and had something for pain if needed. Don’t be surprised if your parent falls asleep as well; oxytocin will end up kicking in (the cuddle hormone) and they often find it hard to stay awake. We also provide warmed blankets for our parents to encourage everyone to get comfortable and rest. Snoring is a common side effect of KC in our unit…
While in KC, the infants have a deep sleep with less arousal and better sleep organization than when not in KC (Ludington-Hoe et al., 2006)
In Scher et al.’s study (2009) they found that infants’ brain maturation was accelerated and brain complexity increased with 1.5 hours of KC/day for 4 days/wk from 32-40wks pma. Enhanced development in five sensory areas of the brain was shown with KC that was not seen in infants who did not get KC (both preterm and full term).
With all the evidence pointing to KC being beneficial for a good night’s sleep, I find it difficult to understand why so many are skeptical of it!
Sleep is that golden chain that ties health and our bodies together – Thomas Dekker
One of the first things a student of any discipline caring for newborns is how to calculate the apgar score at birth. Over 60 years ago Virginia Apgar created this score as a means of giving care providers a consistent snapshot of what an infant was like in the first minute then fifth and if needed 10, 15 and so on if resuscitation was ongoing. For sure it has served a useful purpose as an apgar score of 0 and 0 gives one cause for real worry. What about a baby with an apgar of 3 and 7 or 4 and 8? There are certainly infants who have done very well who initially had low apgar scores and conversely those who had higher apgar scores who have had very significant deleterious outcomes including death. I don’t mean to suggest that the apgar scores don’t provide any useful predictive value as they are used as part of the criteria to determine if a baby merits whole body cooling or not. The question is though after 60+ years, has another score been created to provide similar information but enhance the predictive value derived from a score?
The Neonatal Resuscitation and Adaptation Score (NRAS)
Back in 2015 Jurdi et al published Evaluation of a Comprehensive Delivery Room Neonatal Resuscitation and Adaptation Score (NRAS) Compared to the Apgar Score. This new score added into a ten point score resuscitative actions taken at the 1 and 5 minute time points to create a more functional score that included interventions. The other thing this new score addressed was more recent data that indicated a blue baby at birth is normal (which is why we have eliminated asking the question “is the baby pink?” in NRP. Knowing that, the colour of the baby in the apgar score may not really be that relevant. Take for example a baby with an apgar score of 3 at one minute who could have a HR over 100 and be limp, blue and with shallow breathing. Such a baby might get a few positive pressure breaths and then within 10 seconds be breathing quite well and crying. Conversely, they might be getting ongoing PPV for several minutes and need oxygen. Were they also getting chest compressions? If I only told you the apgar score you wouldn’t have much to go on. Now look at the NRAS and compare the information gathered using two cardiovascular (C1&2), one neurological test (N1) and two respiratory assessments (R1&2).
The authors in this study performed a pilot study on only on 17 patients really as a proof of concept that the score could be taught and implemented. Providers reported both scores and found “superior interrater reliability (P < .001) and respiratory component reliability (P < .001) for all gestational ages compared to the Apgar score.”
A Bigger Study Was Needed
The same group in 2018 this time led by Witcher published Neonatal Resuscitation and Adaptation Score vs Apgar: newborn assessment and predictive ability. The primary outcome was the ability of a low score to predict mortality with a study design that was a non-inferiority trial. All attended deliveries were meant to have both scores done but due to limited numbers of trained personnel who could appropriately administer both scores just under 90% of the total deliveries were assigned scores for comparison. The authors sought to recruit 450 infants to show that a low NRAS score (0–3) would not be inferior to a similar Apgar at predicting death. Interestingly an interim analysis found the NRAS to be superior to Apgar when 75.5% of the 450 were enrolled, so the study was stopped. What led the apgar score to perform poorly in predicting mortality (there were only 12 deaths though in the cohort) was the fact that 49 patients with a 1 minute apgar score of 0-3 survived compared to only 7 infants with a low NRAS score.
The other interesting finding was the ability of the NRAS to predict the need for respiratory support at 48 hours with a one minute apgar score of 0-3 being found in 39% of those on support compared to 100% of those with a low NRAS. Also at 5 minutes a score of 4-6 for the apgar was found in 48% of those with respiratory support at 48 hours vs 87% of those with a similar range NRAS. These findings were statistically significant while a host of other conditions such as sepsis, hypoglycemia, hypothermia and others were no different in terms of predictive ability of the scores.
An Even Bigger Study is Needed
To be sure, this study is still small and missed just over 90% of all deliveries so it is possible there is some bias that is not being detected here. I do think there is something here though which a bigger study that has an army of people equipped to provide the scoring will add to this ongoing story. Every practitioner who resuscitates an infant is asked at some point in those first minutes to hour “will my baby be ok?”. The truth is that the apgar score has never lived up to the hope that it would help us provide an accurate clairvoyant picture of what lies ahead for an infant. Where this score gives me hope is that a score which would at the very least help me predict whether an infant would likely still be needing respiratory support in 48 hours provides the basic answer to the most common question we get in the unit once admitted; “when can I take my baby home”. Using this score I could respond with some greater confidence in saying “I think your infant will be on support for at least 48 hours”. The bigger question though which thankfully we don’t have to address too often for the sickest babies at birth is “will my baby survive?”. If a larger study demonstrates this score to provide a greater degree of accuracy then the “Tipping Point” might just be that to switching over to the NRAS and leaving the apgar score behind. That will never happen overnight but medicine is always evolving and with time you the reader may find yourself becoming very familiar with this score!
It has been a few months now that I have been serving as Chair of the Fetus and Newborn Committee for the Canadian Pediatric Society. Certain statements that we release resonate strongly with me and the one just released this week is certainly one of them. Guidelines for vitamin K prophylaxis in newborns is an important statement about a condition that thankfully so few people ever experience. To read the statement on the CPS website click here.
Similar story to vaccinations
Prior to the American Academy of Pediatrics in 1961 proclaiming that all newborns should receive IM Vitamin K at birth the incidence of Vitamin K deficient bleeding was 0.25 – 1.7%. Think about that for a moment. A new parent could expect that 1/100 babies roughly might have intestinal bleeding or worse an intracranial hemorrhage due to an insufficient amount of vitamin K levels in the newborn. The types of bleeding could be categorized into three different time epochs. Early onset (occurring in the first 24 hours post-birth), classic (occurring at days 2 to 7) and late onset (at 2 to 12 weeks and up to 6 months of age).
With a rate that high detractors of providing Vitamin K at birth would say “why should we give it; I haven’t heard of any baby getting such bleeding?” Looking at it another way though, why don’t you see congenital rubella or kids with measles much these days? It’s due to vaccination. Thankfully as a Neonatologist, I don’t see Vitamin K deficient bleeding since most parents provide Vitamin K to their babies at birth. If you went back to the era prior to 1961 when widespread supplementation of Vitamin K began in the US, I imagine it would not have been too uncommon to hear about a baby who had bleeding issues after birth. Just because we don’t hear about German Measles much anymore doesn’t mean the virus causing it doesn’t still exist!
How Effective is Vitamin K?
How effective is Vitamin K administration at birth in preventing hemorrhagic disease of the newborn (HDNB)? Studies estimate an incidence of 0.25 per 100000 live births or 1 in 400000 babies vs the 1/100 risk without any vitamin K. That is one effective intervention! At this point I would ask those families that are still concerned about giving Vitamin K to their infants if this is a risk they can accept? If they refuse Vitamin K and there is a significant bleed how will they react?
The Change in this CPS Statement From the Past
In the last statement on Vitamin K, the authors suggested that the oral route was a reasonable option. Instead of giving 1 mg of Vitamin K IM one would dose it as 2 mg orally and then repeat at 2-4 weeks and then 6-8 weeks. In looking at the effectiveness though it is worth noting that while we can assure that families will get the first dose, as with any medication that needs repeat dosing there is the risk of forgetfulness leading to missed dosing down the road. In fact when the authors looked at the risk of late HDNB they found the following “The relative risk for VKDB, when comparing PO versus IM vitamin K administration in these two studies, was 28.75 (95% CI 1.64 to 503.45) and 5.97 (95% CI 0.54 to 65.82), respectively .”
The outcome of course remains rare but the risk based on two studies was almost 30 times higher than if IM dosing was given.
On this basis IM is recommended.
Having said all this I recognize that despite all this information, some families will choose for a number of reasons to still opt for the oral dose. As the statement suggests we need to encourage such use when a family refuses IM vitamin K. The 30 fold risk compared to IM administration is magnitudes lower than the approximate 1/100 risk of giving nothing at all!
In the end I believe that one case of intracranial hemorrhage from inadequate vitamin K is too much. This one vitamin indeed could save a life.
A real change is coming and with this post you will get a glimpse into where the next big thing in Neonatology is likely to be. A catchy title for sure and also an exaggeration as I don’t see us abandoning the endotracheal tube just yet. There has been a lot of talk about less invasive means of giving surfactant and the last few years have seen several papers relating to giving surfactant via a catheter placed in the trachea (MIST or LISA techniques as examples). There may be a new kid on the block so to speak and that is aerosolized surfactant. This has been talked about for some time as well but the challenge had been figuring out how to aerosolize the fluid in such a way that a significant amount of the surfactant would actually enter the trachea. This was really a dream of many Neonatologists and based on a recently published paper the time may be now for this technique to take off.
A Randomized Trial of Aerosolized Surfacant
Minocchieri et al as part of the CureNeb study team published Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. This trial set out to obtain a sample size of 70 patients between 29 0/7 to 33 6/7 weeks to demonstrate a difference in need for intubation from 30% down to 5% in patients treated with CPAP (30% was based on the historical average). The authors recognizing that the babies in this GA bracket might behave differently, further stratified the randomization into two groups being 29 0/7 – 31 6/7 weeks and 32 0/7 to 33 6/7 weeks. Those babies who were on CPAP and met the following criteria for intubation were either intubated in the control group and given surfactant (curosurf) using the same protocol as those nebulized or had surfactant delivered via nebulisation (200 mg/kg: poractant alfa) using a customised vibrating membrane nebuliser (eFlow neonatal). Surfactant nebulisation(100 mg/kg) was repeated after 12 hours if oxygen was still required. The primary dichotomous outcome was the need for intubation within 72 hours of life, and the primary continuous outcome was the mean duration of mechanical ventilation at 72 hours of age.
Criteria for intubation
1. FiO2 >0.35 over more than 30 min OR FiO2 >0.45 at
2. More than four apnea/hour OR two apnea requiring BVM
3. Two cap gases with pH <7.2 and PaCO2 >65 mm Hg (or) >60 mm Hg if arterial blood gas sample).
4. Intubation deemed necessary by the attending physician.
Did It Work?
Eureka! It seemed to work as 11 of 32 infants were intubated in the surfactant nebulisation group within 72 hours of birth vs.22 out of 32 infants receiving CPAP alone (RR (95% CI)=0.526 (0.292 to 0.950)). The reduction though was accounted for by the bigger babies in the 32 0/7 to 33 6/7 weeks group as only 1 of 11 was intubated when given nebulized surfactant compared to 10 of 13 managed with CPAP. The duration of ventilation in the first 72 hours was not different between the groups: the median (range) 0 (0–62) hour for the nebulization group and 9 (0–64) hours for the control group (p=0.220). It is important in seeing these results that the clinicians deciding whether infants should be intubated for surfactant administration were blind to the arm the infants were in. All administration of curosurf via nebulization or sham procedures were done behind a screen.
The total number of infants randomized were 66 so they did fall shy of the necessary recruitment but since they did find a difference the results seem valid. Importantly, there were no differences in complications although I can’t be totally confident there really is no risk as this study was grossly underpowered to look at rarer outcomes.
Breaking down the results
This study has me excited as what it shows is that “it kind of works“. Why would larger babies be the ones to benefit the most? My guess is that some but not a lot of surfactant administered via nebulization reaches the alveoli. Infants with lesser degrees of surfactant deficiency (32 0/7 to 33 6/7) weeks might get just enough to manage without an endotracheal tube. Those infants (in particular less than 32 0/7 weeks) who have more significant surfactant deficiency don’t get enough and therefore are intubated. Supporting this notion is the overall delay in time to intubation in those who were intubated despite nebulization (11.6 hours in the nebulization group vs 4.9 hours in the control arm). They likely received some deposition in the distal alveoli but not enough to completely stave off an endotracheal tube.
One concerning point from the study though had to do with the group of infants who were intubated despite nebulization of surfactant. When you look at total duration of ventilation (hours) it was 14.6 (9.0–24.8) in the control arm vs 25.4 (14.6–42.2) p= 0.029*. In other words infants who were intubated in the end spent about twice as long intubated as those who were intubated straight away. Not a huge concern if you are born at 32 weeks or more but those additional thousands of positive pressure breaths are more worrisome as a risk for CLD down the road.
As it stands, if you had an infant who was 33 weeks and grunting with an FiO2 of 35% might you try this if you could get your hands on the nebulizer? It appears to work so the only question is whether you are confident enough that the risk of such things as pneumothorax or IVH isn’t higher if intubation is delayed. It will be interesting to see if this gets adopted at this point.
The future no doubt will see a refinement of the nebulizer and an attempt to see how well this technique works in infants below 29 weeks. It is in this group though that prolonging time intubated would be more worrisome. I don’t want to dismiss this outright as I see this as a pilot study that will lead the way for future work that will refine this technique. If we get this right this would be really transformative to Neonatology and just might be the next big leap.