Hypoxic ischemic encephalopathy is a very scary condition for both families and health care providers. In my career as a Neonatologist one of the greatest accomplishments has been the recognition that 72 hours of moderate hypothermia can make a big difference to the outcomes of such children. In days gone by our best estimates of outcome relied on Sarnat staging of HIE.
Since the cooling approach was adopted widely however I have relied more on a wait and see approach when advising families on what to expect. On some occasions, is spite of cooling babies go on to develop significant cerebral palsy but in other cases babies who one would have predicted would have dismal outcomes have done quite well. Our best estimates at the moment are that cooling for HIE reduces the risk of death or moderate to severe disability by about 25% with a confidence interval of 17 – 32% around that estimate.
Why would pCO2 matter?
Carbon dioxide has a role to play in outcome and has been the subject of several papers. The theoretical point is that very low carbon dioxide levels lead to vasoconstriction of blood vessels. When it comes to HIE one would be quite worried about vasoconstriction of blood vessels such as the carotids carrying oxygenated blood to an injured brain. Once injured the brain is not going to tolerate further oxygen deprivation and in particular those areas that are teetering on the edge of survival could be tipped the wrong way if further hypoxia is experienced.
Another reason why CO2 matters is due to something called the Bohr effect. For those of you who are scratching your heads and recollecting this term from your training it has to do with the influence of pCO2 on hemoglobin oxygen saturation. The relationship is represented by the following figure.
In the presence of declining pCO2 there is a shift of the oxygen dissociation curve to the left. This means for that as PCO2 declines more of the circulating oxygen will be bound to hemoglobin. In most cases you want your hemoglobin to be great at carrying oxygen but when your tissues are starved of oxygen and injured that is not what you want. You want a selfless hemoglobin molecule that is more than happy to release its oxygen to the tissue. That is not what you get as pCO2 drops.
Why would pCO2 be low at all?
There are a few reasons for this. The first is that many infants born after an asphyxial event have a metabolic acidosis. Our bodies naturally like to maintain a normal pH. In order to do so if your HCO3 in the blood is low you need to blow off CO2 to compensate. The hypocarbia in this case is compensatory but the body in so doing could make matters worse for the brain.
The second reason has to do with both injured tissue and that which is cooled. As metabolic rate decreases the amount of CO2 generated will drop. If you remember the Krebs cycle (shudder) there is a fair bit of CO2 generated from aerobic (oxygen rich) metabolism. If this is reduced so to will the production of CO2. As cooling serves to reduce metabolic rate so the CO2 production would be expected to decrease.
So does it really matter?
The reason for all this preamble is that a “mini-systematic review” has found the CO2 matters to outcome. The review is entitled Hypocarbia is associated with adverse outcomes in hypoxic ischaemic encephalopathy (HIE) and included 9 studies on influence of pCO2 on outcome. Before we look at the results it is important to acknowledge that all of the included studies were retrospective so methodology in each study is not standardized. How one even defines severe hypocarbia varied from <20 mmHg to anything under 35 mm Hg. The other issue is that each study looked at a different period of exposure from the effect of a couple hours to the effect over the first three days of life. The included infants were all cooled so it gives us at least an idea of the effect in a modern cohort of cooled infants.
The summary of the results was that CO2 mattered. As little as a couple hours of very low CO2 levels were found to be associated with adverse outcomes.
The problem of course is the chicken and the egg argument. The most severe hypocarbia might be seen in those with the worst metabolic acidosis. As mentioned above the response to metabolic acidosis is to blow off CO2. Therefore, the worse the metabolic acidosis the greater that respiratory drive.
Strategies to control the pCO2 of course exist. In the presence of a critically low pCO2 one can intubate and control ventilation through sedation and paralysis. This can lead to other issues though as if you normalize the pCO2 in the presence of a significant metabolic acidosis the pH is likely to take a nosedive. The myocardium as it turns out doesn’t like low pH and in fact cardiac output in animal models begins to decrease the closer you get to a pH of 7 and becomes significantly worse as you go beyond that point.
At best then I think one can aim for converting severe hypocarbia to moderate until the HCO3 begins to recover. Based on theoretical issues of oxygen delivery to tissues and cerebral vasoconstriction, notwithstanding the retrospective nature of this review it does make sense to me that there would be a link between severe hypocarbia and outcome. We will likely never see an RCT targeting normalization of pCO2 vs tolerance of hypocarbia in this population so for the purists out there that don’t like this type of retrospective analysis I suspect outside of an animal model this is as good as its going to get.
Maybe avoiding anything with the word severe attached to it though is sensible when it comes to this population.
Over the last number of years clinicians have sought more and more to limit the experience of babies to painful stimuli. In the area of surfactant administration this has focused on “less invasive” strategies such as use of small catheters while on CPAP (LISA or MIST) and surfactant via LMA or Surfactant Administration Through Laryngeal or Supraglottic Airways (SALSA) as it is sometimes known. Intubation Surfactant Extubation (INSURE) while not generally included in the less invasive approach is to a degree fitting since it involves at least intubating for a very brief period after surfactant is administered. SALSA has been growing in popularity due to its “extreme” non-invasiveness since babies are receiving surfactant without instrumentation of the airway at all. It should come as no surprise then that head to head comparisons will be done to determine which should be reigned king!
The Contenders
A group out of Albany, NY has looked at SALSA vs INSURE before in which they used morphine for premedication prior to the procedure. You might ask why any premedication is needed at all but I would suggest that covering one’s airway and dripping liquid into it might cause some irritation so why not keep them calm. The authors in their paper Randomized trial of laryngeal mask airway versus endotracheal intubation for surfactant delivery found a high rate of failure in the intubation arm which more than likely was attributable to the respiratory depressive effect of the same.
This time around in the current paper Randomized Trial of Surfactant Therapy via Laryngeal Mask Airway Versus Brief Tracheal Intubation in Neonates Born Preterm they switched to remifentanil for its brief duration of action. Babies in the SALSA arm received that drug while those in the ETT group received atropine as well. The authors included infants born from 27 weeks to 36 weeks gestation who were larger than 800g at birth. This was a non-inferiority trial with the primary outcome being Our primary outcome was failure of surfactant therapy to prevent the need for invasive mechanical ventilation or its surrogate indicators, namely, more than 2 doses of surfactant therapy, sustained need for FiO2 >0.60 to maintain target O2 saturations, or a second dose of surfactant within 8 hours of the first dose.
Surfactant redosing criteria were the same for both groups: FiO2 >0.60 or FiO2 >0.30 with clinical signs of worsening RDS. If surfactant needed to be given a second time it was via intubation. The decision to ultimately intubate though was in the hands of the practitioners.
Unfortunately, the trial was stopped after only 51 patients were enrolled into the LMA and 42 into the INSURE groups respectively. Randomization was by block design and the authors were looking for 130 patients per group so they fell far short of that. The reasons for falling short were interesting as they demonstrate one of the challenges of research and changing beliefs. At the start of the trial there was equipoise among practitioners with respect to the two modes of surfactant delivery but part way through people preferred SALSA. The authors changed the randomization to try and deal with that to a 2:1 favoring SALSA but with the combination of that and COVID they had to stop. They did manage to get enough though to determine the primary outcome in spite of this.
What did they find in the end?
Well first of all it is worth noting that there were no differences in baseline characteristics between the two groups. As it turns out, while the numbers were small it didn’t seem to lead to an unbalancing of groups.
With respect to inferiority the finding was that it was in fact not inferior as per the figure below.
In table 2 some interesting findings emerge
Early failure of surfactant which was defined as within 1 hour of surfactant administration was found to be significantly increased in the intubation group. Late failure through at 5 days of age was not any different. An early failure is suggestive of the procedure not working to deliver the surfactant. When you look at the bottom half of table 2 the answer may be there. As part of the planned procedure the authors aspirated a gastric tube after surfactant administration to ensure that it went to the right place. There was no difference in surfactant volume aspirated via this route. There was however 9.7% of infants in the ETT group that experienced reflux in the ETT vs zero with observed reflux in the SALSA group (in the mouth perhaps?). Is surfactant without PPV better tolerated maybe?
There was a trend overall to more failures in the ETT arm although this was not found to be significant either in the intention to treat or per protocol analysis.
Where do we go from here?
First off it is important to look at who was chosen for this strategy. You may have noticed that there were no micropreemies in this trial. The reason for this is likely two-fold. The first is that prior trials on SALSA have found it doesn’t work as well to prevent intubations in babies below 27 weeks. This is very similar to the findings of studies using aerosolized surfactant. It may well be that there just isn’t enough of the total dose getting to the alveoli. If you can get some of the dose in deep into the lung for those with less severe RDS it may work ok for those babies. The second reason likely has to do with using LMAs in those in that weight range as they generally are designed for larger preemies although I understand smaller ones are becoming more readily available.
The second point is that this was not a blinded study. This could have become an issue as the authors acknowledge that there was a growing institutional preference for SALSA as the study went on. If the Neonatologist subconsciously believes it is better, might that have influenced some of the decisions to intubate again since one of the criteria was “clinical signs of worsening RDS”. It is quite possible this could have led to a few more intubations in the INSURE group for repeat doses. We can’t prove that but it is a weakness of the study.
At the very least it can be argued that the use of SALSA works as a small percentage overall failed the procedure. The largest groups of infants though were above 29 weeks so we also might not expect a high rate of failure after one dose though. It works but how well is tough to say.
Where I think this study is really important though is what it tells us for centers in particular who don’t intubate as often. Intubation is a skill that is declining in opportunity, both because of a turn to more use of non-invasive support as a primary mode of treatment. It also has become scarcer at an individual level due to there being more practitioners who can perform the skill. Having an option to use SALSA for those who aren’t as comfortable with intubation will no doubt be of much interest to many in this situation.
What is no doubt going to come next is the LISA/MIST vs SALSA trials. I hope that in the future pain scores are included in these sorts of analyses to really determine if in being less invasive we are also ensuring that we are also not undertreating discomfort. I suppose the lesson being learned from all of this is that less very well may be more.
Anyone who has watch the delivery of a baby knows that in some cases things go very smoothly and in others every care provider in the room would likely have tachycardia themselves. In some cases where labour is quite prolonged and some degree of cephalopelvic disproportion exists, the fetal head can become quite wedged in the pelvis. When this occurs it is not uncommon to hear of an ob/gyn having to dislodge the entrapped head from below and then perform a c-section to get the baby out safely.
In some of these cases though on the newborn exam a depression of the skull is found such as with the figure on the right. As our brains like to link things together we may jump to the conclusion that the pressure exerted on the head from below led to a fracture. This fracture in turn may lead to injury to the underlying brain. At least that is what our brains want us to think but what if the reason for the fracture has nothing to do with the maneuver as described?
Spontaneous Skull Fractures
This exact situation has been described in two cases and with a review of the literature in a paper entitled Spontaneous Intrauterine Depressed Skull Fractures: Report of 2 Cases Requiring Neurosurgical Intervention and Literature Review. In this report they describe two cases, the first of which was a term infant born via SVD without instrumentation and was described as atraumatic. The figure above was from this infant and thankfully the underlying brain was free of hemorrhage. The second case was also term and again there was no need for forceps or vacuum. In this case there was significant parietal fracture with a small amount of subdural blood collection. This infant unlike the other one due to significant depression required neurosurgical intervention to correct the skull deformity and lift the bone off the brain. As the authors go on to describe there have been 39 other such patients described in the literature with the features as shown in the table from the paper. While there are 4 more in the paper they had vacuum extractions so I wouldn’t count them.
Why Does This Happen?
The short answer in most cases is a tight fit! In the 1960s this was postulated that in the right occiput posterior and and right occiput transverse positions the fetal head becomes compressed between the sacral promontory and pubic bones. Other implicating factors have been maternal fibroids leading to chronic pressure on the developing skull along with oligohydramnios that may lead to fetal compression as well.
When you look at the above table though what stands out is failure to progress as an ethology. One can imagine the contracting uterus attempting to propel the fetus forward and if impacted in the pelvis the pressure on the skull may well lead to fracture.
The other thing of note is the overwhelming involvement of the parietal bone in these cases. A presentation in another bone might lead one to think of a different etiology.
As far as treatment, many of these as you can see are simply observed but in the presence of significant bleeding neurosurgical intervention is needed. At the outset it is sensible to consult neurosurgery as one never knows which ones need intervention and which ones do not.
As you can see, the presence of a fracture and a history of forceful pushing from below MAY be related to a fracture but on the other hand these may occur simply with protracted labours themselves. In these situations while it may be tempting to blame the ob/gyn we also need to ask ourselves what the alternative they had was. Should they have let the mother continue to push with the potential risk of asphyxia or potentially even uterine rupture? At some point the delivering physician needs to get the baby out and if that is what needs to be done to extract the baby then that is what they will need to do. At the end of the day one thing is for sure that we don’t know for sure what caused the fracture and as tempting as it may be to blame the ob/gyn or GP delivering a baby it just might have been spontaneous!
This is one of the most difficult things to determine. Families being given a diagnosis of asphyxia in their baby often ask the question when did this happen? For sure this is not an exact science and in my opinion it is often difficult to answer the question with certainty. There are of course situations in which we can offer an educated guess such as if there is a witnessed acute cord compression such as with a cord presentation. In many other instances though it is more difficult to ascertain.
When meconium is passed in utero it is attributed to a hypoxic insult leading to internal anal sphincter relaxation. Depending on the length of exposure to this green amniotic fluid we also know that some babies may have a green or yellow hue to them from exposure of tissues to the pigments in meconium. What do we know about exposure of tissue to meconium? It turns out not too much but I will share with you a couple of interesting papers that help to give us a clue with a window into the past to provide a best estimate of how many hours have passed since a baby passed meconium. By knowing that we can then get a better guess as to when a hypoxic event may have happened.
Going way back in time
It was almost 70 years ago that Desmond MM et al published a paper trying to establish the answer to this question. The paper published in 1956 was called Meconium Staining of Newborn Infants. This paper out of Houston Texas did something that while on the surface seems disturbing was actually a creative way of determining how long exposure to meconium really takes. The authors took meconium stained fluid from 6 babies and put the fluid into sterile gloves. They then placed the feet of babies who had not been exposed to meconium into the meconium filled gloves to determine how long it took for nails to discolor and secondarily for vernix (the cheesy coating on the skin of newborns) to change color as well. The authors also created meconium slurries in normal saline of various percentages of 1 and 5% to get an idea in an artificial way with simulated meconium how long staining took. In order to determine timing of staining, at regular intervals the authors washed the baby’s feet under running water, removed the moisture with with absorbent paper, and the nails were checked for yellow staining under natural light.
As you can see from Table 1 of the paper surprisingly for natural meconium stained amniotic fluid the time it takes to stain the nails of a baby yellow ranged from 4-6 hours. This occurred faster with meconium in normal saline but for run of the mill meconium you are looking at least 4-6 hours of exposure time.
Curiously for vernix in one case it took 10 hours to turn it yellow and 12 hours in another infant.
What About Umbilical Cords and Placenta
To answer this question we need to look at another study By Miller PW et al from 1985 entitled Dating the Time Interval From Meconium Passage to Birth. in this study meconium was collected from pregnancies experiencing passage before birth and similar to the 1950s study a slurry was created in normal saline. The placenta and umbilical cord were collected from pregnancies without meconium and exposed to the slurry while being incubated at 37 degrees Celsius.
The authors in this case demonstrated that over a period of 1-3 hours the tissues subjected to the meconium slurry became stained. One might come to the conclusion that this means at least 1-3 hours is needed to stain the tissues but in all likelihood it is probably longer. We know from the previous study that an artificial slurry in normal saline seems to stain faster than meconium in amniotic fluid so it would not surprise me if the authors were to have done the study using the meconium filled glove technique the tissues might need 4-6 hours as we saw in the last study. Regardless however the point is that it takes time.
What might this mean for timing a hypoxic episode
In the absence of any meconium staining it would suggest that a baby born with meconium likely had some distress that is less than 4 hours in duration. A baby who has a stained umbilical cord, yellow nails and discolored skin has likely been exposed to meconium for greater than 4 hours. To be sure this is not an exact science but let’s say there was a labor in which 8 hours prior to delivery there were some late decelerations and practitioners were questioning could there have been a significant hypoxic injury at that time. If the infant was born with meconium staining one might argue that indeed those decelerations may have contributed to the passage of meconium. If however a baby was born through meconium and there was no staining of the tissues it might lead one to conclude that if there were a significant hypoxic event it may have occurred after that time points since there should have been staining present.
I continue to say that in these cases one cannot determine exactly when a hypoxic event occurred most of the time but the degree of meconium staining and the information provided in this piece just might help give you some added information to try and make that educated guess a little more sophisticated.
Hypoxic Ischemic Encephalopathy or HIE is a condition in which a baby presents with cord blood gases, a gas at one hour of age, low apgar scores and neurological findings which point to an event occurring that has interrupted blood flow to the brain. The Canadian Pediatric Society further defines this by looking at who may benefit from whole body cooling to mitigate the risk of an abnormal outcome for these patients. The criteria are shown below from the CPS Guideline
Invariably when HIE has occurred and there is neurological injury, two predominant patterns appear on MRI. The first is of a subacute hypoxic injury that typically involves multiple areas of the brain such as the frontal, parietal and occipital lobes but in particular the cortex. When a sentinel event has occurred, which is defined as a sudden interruption of blood supply to the fetus, the pattern is decidedly different. This may occur in such situations as an acute abruption, or umbilical cord compression as with cord presentation. When this occurs, the pattern is more typically white matter injury along with involvement of deep brain structures such as the thalami and basal ganglia (putamen and globus pallidus as examples).
Can Bloodwork Give Us Clues As To When The Injury Occurred?
One of the questions that I am often asked is to determine when such injury occurred. Is this an injury that was sustained a day or two before birth or during labor minutes or hours prior to delivery. The timing of such injury is often difficult to determine. It is said that about 90% of such injuries do not occur during labor but that of course leaves 10% that do. Alternatively, the number might be greater than 10% but it is simply difficult to really determine timing but 10% is a best guess.
I had often relied on what I felt was a logical conclusion that in the presence of an acute and profound interruption of blood supply sufficient enough to cause neurological injury that there would be similar perturbations of blood work in the newborn. The absence of renal, hepatic or coagulation disturbance would mean one of two things. Either the injury was remote and while profound, the fetus had recovered and these disturbances resolved or absence indicated to look for another etiology.
Recently the following paper has led me to a different conclusion. Broni et al published Blood Biomarkers for Neonatal Hypoxic-Ischemic Encephalopathy in the Presence and Absence of Sentinel Events. The authors performed a retrospective analysis of all neonates with HIE admitted to their NICU with sentinel events in the first three days of life and compared them to those without. All infants met the criteria for whole body cooling and were cooled for three days. The goal was to see how those infants with a sentinel event compared to those without in terms of patterns of bloodwork. Presumably those with sentinel events since they were so severe might show a different pattern of bloodwork after birth.
What Did They Find?
The authors had 277 babies with HIE treated with whole body hypothermia. The blood used to look for biomarkers was discarded blood not used for regular sampling and in all there were 68.6% of babies that had such blood for analysis. Of the babies tested 40.5% had a sentinel event and 59.6% did not.
In terms of baseline characteristics, the groups were similar with the exception (not surprisingly) that there were 32 women with abruptions in the sentinel event group and none in the no sentinel event group. Also, meconium was present at delivery about 2.5 times as common with the subacute patients than the sentinel event group.
The goal of the study was to look at biomarkers.
The authors examined a wide range of them but the only two that showed a significant difference in babies with and without sentinel events were vascular endothelial growth factor (VEGF) and IL-10. VEGF levels increase in the presence of hypoxia related to placental secretion of the factor. IL-10 levels increase during hypoxia and is protective since it inhibits secretion of IL-1β, IL-8 and TNF-α. This interrupts the production of leukocyte aggregation, and reduces inflammatory responses in the brain. Looking at the first figure you can see that VEGF levels were higher in those with sentinel events on day 2 and 3 while IL-10 levels were lower on days 1-3 in those with sentinel events. In other words, in the presence of a sentinel event there higher VEGF levels are present after hypoxia and protective IL-10 levels are lower.
Looking at Figure 2, other than initial glucose being lower in those with sentinel events (but not clinically relevant as still above normal) one cannot discern any differences between those with and without a sentinel event.
Possibly even more surprising is that my long held belief that those with a sentinel event should have significant multiorgan system involvement doesn’t appear to be true. Such things as platelet counts, white blood cell counts and initial blood gases show no difference between groups.
Putting it all together
The authors here have shown that two biomarkers display different patterns in babies born after a sentinel event than those with a subacute hypoxic course. It is possible that had they been able to test blood from all babies instead of 68.6% the results may have been different but there is biological plausibility to a more acute and severe event having this pattern of greater hypoxic injury since these babies are also at risk for significant neurological impairment later on. These tests are not routinely done but, in the future, might there be a role for drawing IL-10 and VEGF levels when trying to determine etiology?
What was also surprising was the fact that not all babies with sentinel events show a clear pattern of that demonstrates they fall into that group. The clinical appearance alone does not differ between the two groups of patients with HIE. While liver, renal and coagulation systems were not individually reported here, the lack of difference at one hour in terms of blood gases, lactates and platelet counts suggests that it would be unlikely to see a difference in those end organs. If measures of perfusion are no different as measured by gases and lactates then why would organ injury be different?
At least for me my conclusion is that laboratory measures are not able to discern whether a sentinel event occurred or not. Additionally, those who believe that the absence of laboratory markers indicate that an injury occurred remotely and the baby recovered should be careful in making such conclusions solely based on laboratory data. It will be interesting to see if anyone begins testing IL-10 and VEGF levels routinely in such patients but I guess time will tell.
