Keep your eye on the carbon dioxide level in your patient with HIE.  It may matter a lot!

Keep your eye on the carbon dioxide level in your patient with HIE. It may matter a lot!

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.

Newborn Brains After Hypoxia Don’t Like Hyponatremia

Newborn Brains After Hypoxia Don’t Like Hyponatremia

The newborn brain could be described as finicky at best. One of the most difficult things to treat are those things that we can’t see. When a baby is delivered and goes on to develop neurological manifestations, it remains a difficult puzzle to sort out as to what the cause is. Of course, we use all manner of technology to sort this out. The use of EEG, amplitude integrated EEG are helpful in this regard to give us a window into brain excitability but we use all manner of technology to sort this out. When it comes down to it, though we often rely on clinical signs to give us a best guess into whether or not hypoxic injury is at the root of the problem. This, of course, is not always easy as although we have criteria such as those written out by the Canadian paediatric Society to rely on, not all babies fit nicely into the box that provides an easy diagnosis.

For reference, these are the criteria that are recommended by the Canadian paediatric Society for determining who should receive therapeutic hypothermia.

In spite of these criteria, sometimes when babies have Apgar scores or cord blood gases that don’t meet criteria for therapeutic hypothermia, they may still go on to have a seizure. In some of these babies, it is likely that they still experienced a hypoxic injury at some point in time that they have recovered from. In these cases, having a super imposed, metabolic, derangement can tip the scales and cause an already excitable brain to manifest neurological manifestations.

The Brain Does Not Like Low Sodiums

One such abnormality that can tip the scales is a low serum sodium. Babies can develop such derangements from a hypoxic insult that leads to an acute kidney injury. The resultant damage leads to water retention from a poorly functioning, kidney and a dilutional effect on the bloodstream. This usually occurs over time and is not commonly present in the first few hours after birth. When this is seen though with sodium levels below 125 in the first few hours after birth, the likely cause is not renal injury. What is interesting about this phenomenon is that the etiology is most likely related to factors that occurred during labour.

Pregnancy its self has a tendency towards, maternal impairment of water excretion. There is a higher volume status in the pregnant woman and some degree of impairment of excretion of a water load. Maternal hyponatraemia has been described in situations of maternal water, intoxication or provision of excessive dilute fluids to the labouring mother. Add to this, that there is cross-reactivity between oxytocin and ADH receptors in the kidney, and you create a potential problem that a mother can become hyponatraemic simply from frequent administration of oxytocin or Syntocinon. It is possible therefore to have a mother in labour who receives an excessive amount of fluid whether by oral intake or IV and with oxytocin administration develop hyponatremia herself. What follows in terms of the fetus who is an innocent bystander is the eventual development of hyponatremia in utero. As the maternal sodium concentration declines this leads to a difference in maternal and fetal sodium levels. Water flows by osmosis to the fetus and begins to dilute out their blood and bring the sodium levels in line with maternal levels. What comes next can be troublesome to the fetus.

Resultant Seizures

Blake O et al published the paper Therapeutic hypothermia and outcome in hyponatraemic encephalopathy secondary to maternal water intoxication which describes this exact scenario in the setting of maternal water intoxication. The K-series describes three babies all whom developed seizures and had mild The case series describes three babies all whom developed seizures and had mild perinatal asphyxia yet went on to develop seizures. The laboratory results are shown below.

What is most remarkable from the table is the level of serum sodium in the newborns at 1 hour of age. Generally levels of sodium below 125 and certainly 120 can lead to neurological manifestations including seizures and these infants were certainly affected. Much like I explained at the outset of this piece children could be afflicted with a mild form of encephalopathy from hypoxia, and in these cases, each infant by 10 minutes of age had excellent Apgar scores. What I propose, though is that the brain after even a more mild degree of Perinatal asphyxia is more prone to neonatal seizures. I have to say over the years. I have often checked electrolytes after a baby presents with seizures and rarely are they sufficiently abnormal to explain the finding. What I am presenting to you. Here is a special circumstance, in which babies who might not otherwise have seizures, such as those with mild asphyxia go on to have significant convulsions due to the superimposed insult.

The goal of this post was to increase awareness of this phenomenon. Next time you are looking into the events leading up to seizures in a newborn, don’t forget to ask about what fluids a mother received during labour and specifically what her oral intake was like. Don’t forget to have a careful look as well at the amount of oxytocin she received during labour as the combination may be just enough to tip the scales and lied to Neonatal seizures in a baby, who otherwise would not have developed any of those manifestations! While you are at it, take the time to check a maternal sodium and if mother and baby match or at least are both hyponatremic to a similar level you likely have your answer as to what the ethology is.

A bigger question and one that we don’t have the answer to is whether in the presence of hyponatremia and mild asphyxia therapeutic hypothermia offers much benefit. Unfortunately this answer is going to be a tough one to come by as you can’t create an RCT since the numbers are so small but I suspect that most when in doubt will choose to get that temperature down!

Don’t let the cord gas fool you

Don’t let the cord gas fool you

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 acid infusions 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?