The human body truly is a wondrous thing. Molecules made from one organ, tissue or cell can have far reaching effects as the products take their journey throughout the body. As a medical student I remember well the many lectures on the kidney. How one organ could control elimination of waste, regulate salt and water metabolism, blood pressure and RBC counts was truly thought provoking. At the turn of the century (last one and not 1999 – 2000) Medical school was about a year in length and as the pool of knowledge grew was expanded into the three or four year program that now exists. Where will we be in another 100 years as new findings add to the ever growing volume of data that we need to process? A good example of the hidden duties of a molecule is erythropoetin (Epo) the same one responsible from stimulating red blood cell production.
Double Duty Molecule
In saying that I am simplifying it as there are likely many processes this one hormone influences in the body but I would like to focus on its potential role in neuroprotection. In 1999 Bernaudin Et al performed an animal study in mice to test this hypothesis. In this elegant study, strokes were induced in mice and the amount of Epo and Epo receptors measured in injured tissues. Levels of both increased in the following way “endothelial cells (1 day), microglia/macrophage-like cells (3 days), and reactive astrocytes (7 days after occlusion)”. To test the hypothesis that the tissues were trying to protect themselves the authors then administered recombinant human Epo (rhEpo) to mice prior to inducing stroke and the injury was clearly reduced. This established Epo as a potential neuroprotectant. Other animal studies then followed demonstrating similar findings.
A Human Trial
When you think about hypoxic ischemic encephalopathy (HIE) you can’t help but think of whole body cooling. The evidence is pretty clear at this point that cooling in this setting reduces the combined outcome of death or neurodevelopmental disability at 18 months with a number needed to treat of 7. The risk reduction is about 25% compared to not those not cooled so in other words there is room to improve. Roughly 30-40% of infants who are cooled with moderate to severe HIE will still have this outome which leaves room for improvement. This was the motivation behind a trial called High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial. This was a small trial comparing 50 patients (24 treated with rhEpo and cooling to 26 given placebo) who were treated with 1000 U of rEpo on days 1,2,3,5 and 7. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale (AIMS)and Warner Initial Developmental Evaluation. A significant improvement in a subset of mobility on the latter was found and a significant difference in the AIMS overall. An additional finding giving support for a difference was that blinded reviews of MRI scans demonstrated a singificant improvement in brain tissue in those who received rhEPO. One curious finding in this study was that the mean timing of administration of rhEPO was 16.5 hours of life. Knowing that the benefit of cooling is best when done before 6 hours of age one can only wonder what impact earlier administration of a neuroprotective agent might have. This suggests that the addition of rEPO to cooling has additional impact but of course being a small study further research is needed to corroborate these findings.
The Next Step
This past week Malla et al published an interesting paper to add to the pool of knowledge in this area; Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebo-controlled trial. This study was done from the perspective of asking if rhEPO by itself in resource poor settings without access to cooling in and of itself could make a difference in outcome for patients with HIE. This was a larger study with 100 Hundred term neonates (37 weeks or greater) with moderate or severe HIE. Fifty were randomized by random permuted block algorithm to receive either rhEPO 500 U kg− 1 per dose IV on alternate days for a total of five doses with the first dose given by 6 h of age (treatment group) or 2 ml of normal saline (50 neonates) similarly for a total of five doses (placebo group) in a double-blind study. The primary outcome was combined end point of death or moderate or severe disability at mean age of 19 months and the results of this and other important outcomes are shown below.
|Death/disability (mod/severe HIE)
|Death/disability (mod HIE only)
|Seizures treatment at 19 months
To say that these results are impressive is an understatement. The results are on par with those of cooling’s effect on reduction of injury and improvement in outcome. When looking at the primary outcome alone the result in dramatic when put in perspective of looking at number needed to treat which is 4! This is significant and I can’t help but wonder if the impact of this medication is at least in part related to starting the dosing within the same window of effectiveness of therapeutic hypothermia. Importantly there were no adverse effects noted in the study and given that rhEpo has been used to treat anemia of prematurity in many studies and not found to be associated with any significant side effects I would say this is a fairly safe therapy to use in this setting.
I find this puts us in a challenging position. The academic purists out there will call for larger and well designed studies to test the combination of rhEPO and cooling both initiated within 6 hours of age. While it takes years to get these results might we be missing an opportunity to enhance our outcomes with this combination that is right in front of us. The medication in question other than raising your RBC count has little if any side effects especially when given for such a short duration and by itself and possibly with cooling increases the rate of neuroprotection already. I don’t know about you but I at least will be bringing this forward as a question for my team. The fundamental question is “can we afford to wait?”
In the modern day NICU thermoregulation is something that we are concerned with but due to the availability of servo controlled warmers in delivery suites hypothermia is becoming a rarer event. Add to that we have access to polyurethane plastic wraps for our smallest infants and admission into servo controlled environments with additional humidity control and we have all the tools available to prevent hypothermia and it’s consequences. Such adverse effects include hypoglycemia and lethargy the latter being a common cause of septic work-ups leading to increased antibiotic usage. Such interventions are both painful and put the infant at risk of complications related to antibiotic use such as increased resistance, or altered microbiome with puts them at an increased risk of NEC. Just published online today in fact, researchers from the Canadian Neonatal Network have shown a U shaped relationship between admission temperature and outcome (morbidity and mortality including ROP, BPD and NEC etc) from being hypo or hyperthermic on admission. http://bit.ly/1H2384x. Clearly there is harm from being hypothermic so maintaining normothermia must be of prime importance in the care of our patients.
Sadly such technology does not exist everywhere and in developing nations the common alternatives may be non-servo controlled warmers, warmed blankets, cribs or Kangaroo Care (Skin to Skin). There is no question that Skin to Skin (STS) care provides excellent thermoregulation and bonding for the parent and child but what do you do when the mother or father is unavailable (ill after delivery) or unwilling? The benefits of STS to prevent hypothermia and infant mortality are striking and were first described in 1978 by Drs Rey and Martinez. A brief history of the practice following their description can be found here http://bit.ly/1CgDm9t.
This month Bhat SR et al published the following article (http://1.usa.gov/1HRRZoo) Keeping babies warm: a non-inferiority trial of a conductive thermal mattress. Arch Dis Child Fetal Neonatal Ed. 2015 Mar 19
This study compared the above mentioned modes of warming infants with a warming mattress over a four hour period in a non-inferiority trial of temperature regulation. The concept here is that the authors were simply trying to show that the use of the mattress as a thermoregulation device was just as good as the other means of controlling temperature. For a video demonstrating this technology please look at http://embraceglobal.org/. Briefly the system involved a containment device that has a paraffin based material that when preheated with an inexpensive electric heater absorbs the heat and then when placed in a pouch provides constant temperature regulation for a 4-6 hour period. The pouch was subsequently placed in a mattress with wrap as shown in the video to yield the desired temperature regulation. The authors of this study looked at a total of 160 infants with a birthweight between 1500 – 2499g in four centres located in India and observed infant temperatures hourly over a four hour period. Temperatures were compared in each case between those randomized to the standard temperature regulation strategies in each centre versus the warming mattress. The findings were in agreement with the hypothesis of the study in that the mattress was equivalent to the other methods of regulating temperature.
Specifically the temperature of the infants during the 4 hour trial period was 0.11 +/1 0.03 degrees higher than the other methods. None of the infants developed hypothermia during the trial and while 5 of the infants randomized to the mattress were withdrawn from the study it was due to the temperature of the infants being in the upper range of an acceptable level between 37.5 – 37.9 degrees.
My first reaction when I read this paper was that it was interesting but did it really apply to our population? As the authors suggest it was not a blinded intervention and over time, temperature regulation improved so could the Hawthorne effect be at play? The infants in this study were larger (1500 – 2499g) than the infants that we would typically put at highest risk. Also how useful is an intervention that only lasts 4-6 hours when we need to care for these kids for weeks? Lastly, I live in North America and work in an intensive care unit with access to state of the art equipment for thermoregulation and also have a team that proudly promotes STS care so is this really needed? Despite all of these concerns the conclusion I have come to is that the technology provides reasonable thermoregulation for a 4-6 hour period. Can this be applied to our patients in the end? I think there may be a role.
I would see the role being in managing newly born infants in remote communities prior to the arrival of a Neonatal Transport Team. In our own centre about 75% of our patients or about 230 patients are transferred from outside of the city borders. On occasion, a premature infant will be born in such places and hypothermia on arrival of the team is not an uncommon occurrence. In Manitoba and many parts of Canada there are communities that are quite isolated from tertiary care centres. These centres have limited equipment and even then it can often be quite outdated if functioning properly at all. Given that the average time to arrival for such infants is less than the 4-6 hours that the mattress provides warmth for, this would seem to be a very beneficial tool to have in such communities. It appears to be the ideal product as the website indicates the following
- Special phase change material in WarmPak maintains a temperature of ~37 °C for at least 4 hours
- Does not require a constant supply of electricity Portable for in-clinic or transport usage
- Reusable and easy to sanitize and reuse
- Enables mother-to-child bonding
As I write this I wonder how many other centres not just in Canada but also in the USA would benefit from looking into such technology. Providing servo controlled infant warmers for each centre that delivers infants is certainly the gold standard and in fact is recommended for all neonates undergoing resuscitation at 10 minutes of age. While ideal we need to acknowledge that some centres do not have such resources so this could very well serve a useful purpose particularly in the Northern US and Canada. According to the Embrace website the concept for this came out of a student project at Stanford University with the goal of designing an infant warmer with a cost of <1% of a traditional infant warmer (about $20000). If the cost is then $200 for the warmer for a completely reusable warming mattress I think they have hit the mark.
Finally, it must be pointed out again that the smallest infants treated in this way have been 1500g. We do not know if smaller infants would remain normothermic or become hypothermic if the same paraffin sized material was utilized. It will be interesting to see if Embrace releases a smaller unit for infants under 1500g. If proven to be successful in maintaining normothermia in this population I believe the use of this device will become widespread. Such a simple concept to treat a big problem in Neonatal Transport!