Dr. Anne Hansen - Neonatal Hypothermia in the Low Resource Setting: Context, Scope and Treatment

Good morning. Good morning, how are you? I'm good. Thank you. I'm sorry. I'd love to just get the screen shared thing out and make sure that it all works. And so, of course, let me just promote you to a cohost. And then I believe you'll be sure you're screen. Okay, yeah, I got it. Okay, great. And then, so hold on a second. I have it here. Does that show? Not yet, but sometimes it's a small delay. Do you have more than one screen? I had it as minimized and then I just hear let me let me move this. There we go. Perfect. Okay, and then I'll go like that. But I just want to make it the whole screen. Yes, okay. Now it's the whole screen for me. Perfect. That one looks like a cover slide. Yeah, yeah, exactly. Okay, and I go like that. It goes through. Yes, exactly. Okay. Good. Perfect. That's the hardest part. Yeah. I know it really is actually. It's more nerve-wracking when there's a lot of people watching you. I know why I actually came in because I was so nervous that my internet would freeze at home. Yeah. Because that happens, you know, once a month or something. And I could imagine just talking on for an hour and nobody being in the room. No one, yeah. Okay. Good morning, everyone, and welcome to Grand Rounds. It's my pleasure to introduce Dr. Ann Hanson. She did medical school at Harvard, followed by residency in pediatrics and fellowship in newborn medicine at Boston Children's, as well as an MPH degree from the Harvard School Public Health. She then stayed on as faculty and is the associate chief of the Division of Newborn Medicine and Medical Director of the Neonatal Intensive Care Unit at Boston Children's, associate professor of pediatrics at Harvard Medical School, and an affiliate of the Department of Global Health and Social Medicine at Harvard Medical School. The majority of her academic work now is in the field of Global Health. In collaboration with Lawrence Berkeley National Laboratory Institute for Global Transformative Technologies and Partners in Health, she has spent the last decade developing and pilot testing a low cost, reusable, non-electric infant warmer to complement skin-to-skin care for newborn thermal regulation. This is the first-ever large-scale multi-center randomized controlled clinical trial of a thermal regulatory device specifically designed for the low resource setting across multiple district hospitals in rural Rwanda and eventually globally. She'll be speaking today on neonatal hypothermia in the low resource setting, context, goad and treatment. Dr. Hanson, thank you so much for being here today and for sharing your inspiring work. Thank you so much, Hester, and thank you for all of you for being here this morning to learn about neonatal hypothermia in the low resource setting. Over the next hour, we're going to take everything that you think about when you think of neonatology at Boston Children's Hospital, and we're really going to turn it on at 10, because we're going to talk about taking care of small and sick newborns outside of rich settings like the United States. And you might be wondering, why would I be interested in that? So I thought I'd started the beginning and just take a couple of minutes to tell you why I think it's interesting. To be perfectly honest, when I was a fellow training here at Boston Children's, I didn't think that thermal regulation was interesting at all, because no matter how small the baby, we admitted them into these incubators, and because of the excellent training of our neonatal nurses and cleaning of our environmental services staff and maintenance of our biomedical engineers and our constant supply of electricity backed up by a generator, the babies were always used to their back. So what was interesting about thermal regulation? Then I began to rise in the ranks at Boston Children's, and it really became my job to ensure that every baby admitted to our NICU had the optimal chance of survival with the best outcome. At the same time, I started reading about babies born into low and middle income countries, their morbidity and mortality. And if you think about a traditional math like this, but instead of having the size of the country allocated by land mass, it's allocated by the number of deaths in the first week of life, the math looks like this, whether United States almost disappears, and Africa and India really explode. And then if you take the map and you think about where all the doctors are, the reverse happens. And United States and Europe really explode, and Africa almost disappears. Knowing this kind of information made me really feel differently about coming back to work at Boston Children's Hospital, NICU, being on service where it seemed like all the resources in the world could be brought to there to every patient's bedside. Knowing on the very same day, on the very same planet, there were babies in Africa and India who were dying of 100% preventable conditions, bound into the millions every year. And as a neonatologist, at some point I just felt that this was a problem that I could not ignore any longer. So I accepted an invitation, brought one of our very best nurses, and along with the London Ministry of Health and Partners in Health, we went to a rural hospital in the Wanda for a summer. And to skip over a decade of work in a slide, we basically have helped them to write their national neonatal protocols now out in its third edition. We conducted national training with doctors and nurses from all of the district hospitals throughout the country. And then most recently created an open pediatric scleratial limit we filmed into Gali, featuring Rwanda and pediatricians and nurses teaching every single chapter of the protocols that was just approved and signed off by the Rwanda Ministry of Health last month. But during that entire time, I was really struck by how hard it was to keep babies in thermic. And you may be wondering, I thought you said you were working in steps to hair in Africa, it's so hot there, how could anybody possibly be hypothermic. But it's really important to remember that the smaller and more premature baby, the more they act like vocal reforms and really cool towards the temperature of their environment. And so even though we may be sweating about at 85 degrees, if a baby cools to 85 degrees as a core temperature, that's not a survivable condition. And also, as you can kind of gather from this photograph, it's not always hot in southern here in Africa. And much of Rwanda is at quite high elevations and it gets very cold. And in this particular patient, despite doing everything that we could to reduce radiation convection, evaporation and conduction heat loss, this baby was still quite cold. And we had reverted to this old trick of trying to put some hot water bottles around the baby where it's very easy to cause burns. And it was really, really difficult to keep this baby warm. So when I returned, I read everything that I could about the both of problem and potential solutions to hypothermia in low-resource settings. Because at this point, I thought that this was actually extremely interesting. And that brings us to our learning objectives for the remainder of the hour. Where by the end of this hour, I hope that you can describe the incidence of neonatal hypothermia in the low-resource setting and its contribution to mobility and more of warmth mortality. I learned about challenges of current options, the prevention and treatment of neonatal hypothermia, and understand the results of some clinical trials testing the safety, effectiveness, and feasibility of a novel non-electric infant warmer designed for the low-resource setting. And though right now I do have no conflict of interest, I will say that if I'm successful at doing what I'm trying to do, I will, because I am trying to commercialize infant warmer designed specifically for the low-resource setting. So in terms of background, annually, there are about 2.7 million babies who die in their first month of life, and 99% of those deaths are in the low and middle income countries. It estimated that hypothermia contributes to about 40% of this 99% or about a million deaths every year. When we did our national neonatal protocols, we actually had some quality outcomes, and one of them was initial temperature on admission to the NICU or special care nursery ward less than 36 degrees, and whether we were able to warm those babies up within two hours. And even in the hospitals where we had spent a lot of time training the nurses and getting good equipment, we still had about 30% of all comers admitted at less than 36 degrees, and almost more importantly, over 60% of them were still less than 36 degrees after two hours of trying to warm them up. And of course those numbers were slightly higher in the preterm population. Another study published in Pediatrics that was looking at the effect of putting caps on babies who were small. I thought a particularly interesting outcome of this study was that they said, low birth weight infants spend only half of their time in the normal temperature range despite warm rooms and skin-to-skin contact, and conclude that maintaining normal thermia in low birth weight infants remains an unfinished college in the low resource setting. So they're not saying what percentage of kids are cold. They're saying all kids are cold. It's only a question of how often they're cold versus how often they're warm. And interesting as we discussed skin-to-skin care later, the median in here and skin-to-skin was less than 50%. The relationship between hypothermia and mortality is direct. And especially for the preterm population, you can see that once your skin, once your core temperature falls below 36 degrees, there's a very rapid rise in your rate of mortality. When it's not fatal, hypothermia has many morbidities. Most importantly, it increases metabolic demand and inhibits growth, including brain growth, that impairs neurodevelopment and perpetuates the cycle of poverty. And the most heartbreaking part of all of this is morbidity and mortality is 100% preventable. As I said at the beginning, in Boston, babies are never hypothermic or very, very, very, rarely. This problem is a really basic problem. In this article, which I'm going to refer to a couple of times by Joy Lawn and her group that looks at inpatient care of small and sick newborns and bottlenecks to potential solutions, one of the first sentences says inpatient care for small and sick newborns includes, which he has a long list, but the very first thing on that list is the provision of warmth. So this is not something that's new. It's something that's very, very well understood and incredibly basic. The problem is big. Every year, more than 20 million infants are born weighing under 2.5 kilograms. That's the respect for becoming hypothermic. And over 96 of them are born into these developing countries where there's not great solutions to keeping them warm. So in the prevention of hypothermia requires what we call a heat chain to provide external heat to newborns. This heat can be provided by devices such as incubators and warming tables, but these prevent significant challenges, especially in the low resource setting, because they're extremely expensive, which even this one's cost about $5,000. The ones in our NICU right now cost more like $35,000 or $40,000. They're actually quite difficult to use. And if they're used improperly, they can cause hypothermia, but they can also cause hyperthermia. They're difficult to clean, raising a lot of infection control concerns. So multiple babies are often put in the same incubator when there aren't enough of them, raising obviously other infection control concerns. And they're quite difficult to maintain. So usually, once they are broken, they're just discarded, which makes the cost of them even more expensive in terms of numbers of uses that you get out of each machine. There's non-electric methods that are proposed to prevent hypothermia, which are fairly basic. Raise the temperature in the room, avoid drafts, drive a newborn in-map, and then towel immediately to decrease the fat-bootychee's loss, put a hat on the newborn, and provide skin-to-skin contact, which is also called kangaroo mother care. So kangaroo mother care really is the basic and most recommended form of thermoregulation in a low-resource setting. And the WAO-TRA recommends it on a continuous basis for all stable newborns less than two kilos. This is a really effective method of thermoregulation. It has many advantages, including the promotion of maternal child bonding, and lactation, and some interesting evidence about sharing a microbiome, and decreasing infection rates. And overall, it's just an excellent way to go, and absolutely must be supported. It also has many limitations. The first thing is that for the smallest of babies, it sometimes is not providing that heat, because the baby is getting heat from one side, but the back side of the baby is really very carefully closely to just basic room air temperature. Also it's not feasible if the mother has died or is ill post-partum. She has twins or higher-order multiple babies. It becomes increasingly unfeasible. If the newborn is ill, it's very hard to take care of a newborn in dispositing both for assessment and for treatment. And then it's just hard for the mother to stay in this position 24 hours a day, seven days a week, for the weeks to months that it might take for the baby to no longer need an external heat source. When she needs to attend to some basic tasks such as cooking over a hot stove, or bathing, or being responsible for caring for other family members. So a compliment to some kind of skin to skin is urgently needed, not intended to replace skin to skin, but just to help mothers to be successful at providing skin to skin. So this is a really interesting idea that the Lancet published about something called a Google technology. They say instead of relying on hand-me-down technologies from wealthier countries, which can be costly, inappropriate for local conditions, and even dangerous, the authors urge a renewed effort towards developing what they call Google technologies, which are cost-effective technologies that are developed specifically to cope in local conditions. So I thought that's something I think I could really do. There's nothing out there that's exactly right for the setting where I'm trying to work. I'd love to try to develop a Google technology to address hypothermia in the low resource setting. So along with the groups that I was already working with, which was our self-serif Boston children's, partners in health and the Rwandan Ministry of Health, I started collaborations with some engineers at Lawrence Berkeley Lab. And over about the last, it took about eight years to get what we thought was a good solution. We developed what we call the dream warmer, which is an acronym for a durable, reusable electricity free affordable mattress. And it's specifically designed for babies in the low resource setting. And then explain how it works. It has components that you can see here, a wide-based thermos mattress made of a kind of wax that melts exactly at skin temperature, insulating sleeve to keep it warm for longer and make it easy to wash and clean. And then it needs to be, you need to add a hat and a blanket. And this is just a little thermal gun to take the temperature of the mattress. So as I said, it's not, or I might not have, I'll start by saying it's non-electric. So the heat source is hot water, which hand-be-heated in an electric tea kettle. It's less than two meters of water. So the standard electric tea kettle is enough to heat it. But in places that don't have any electricity, all human societies have figured out how to make hot water. So whether it's like coal or fire, made of wood, it requires a little bit less than two meters of water as a primary heat source. And then there's this mattress, which I described, which is made of a phase-changed material wax that's a food grade quality. And it melts, it's chosen and designed specifically to melt it exactly 37 degrees centigrade. Once it's melted, it stays at that temperature for approximately six hours. It's very simple to prepare, use and clean, and specifically has no attached fabrics or velcro or anything else that would make it hard to clean, just with soap and water. This is important because we're working in settings that really have either diapers or anything approximating a washing machine. It allows EEC access to the baby for medical assessments and interventions. And it's designed to be very durable for multiple uses. Our goal is many hundreds of uses before any part of this would break down. The organization path and also UNICEF developed a list of qualifications for an ideal for a regulatory device. And I won't go through all of these, but I will tell you that we match every single one of these with a sole exception that it does not keep the baby from dropping or falling because it's specifically designed to be able to complement kangaroo leather care. And it really is just a heating pad. It doesn't separate the baby from the mother. So there's no edges by design. And it also does not provide instant heat generation. It requires being seated up in advance. So it does require a little bit of advance planning on the part of the nurses. But otherwise, all of these things that they ask for are well incorporated into the design that we have. It can be used either as a standalone source when the mother is not available. As I said, if she's going to be cooking or bathing, in which case the baby is placed naked on the warmer just for the hat and little booties that they're available and then covered with a blanket that's provided by the nurse or the mom. Or it can be used in addition to skin to skin. So here's a mother who was doing skin to skin. Her baby was not warm enough. And so the in for warmer is placed around the back of the baby and then the from the mother is in the front of the baby. It can be used as an alternative to an electric incubator or warming table. It can be additive to skin to skin if that doesn't provide enough heat. It can be bridge warped when the mother needs to take a break. It can be used during neonatal necessitation, transport or home use for either deliveries in the home setting, which does not occur very often in Rwanda. That's discouraged by the Ministry of Health. Or when low birth rate babies are discharged home when the mother is still needing to do King Room mother care. So we did two pilot studies which I'll combine together in Rwanda. First phase was in the hospital setting in 2016 and then in the health center setting 2017 to 2018. And we wanted to look and see if the dream warmer was a safe and effective and feasible addition to skin to skin to achieve and maintain the thermia when skin to skin was inadequate or unavailable. And it was a prospective interventional study that we conducted into distra hospitals and six health centers in rural Rwanda. Inclusion criteria was any baby who was either at risk of hypothermia by virtual weighing less than 2.5 kilos or hypothermic at the defined as temperature less than 36 degrees. And you may be wondering why we didn't pick 36.5 degrees, which is a more standard definition of hypothermia, but at this point the national protocols had picked 36 degrees and so we stuck with that. And we measured the temperature of the baby, the warmer and the ambient air for after six hours. Our primary outcome was the correction or prevention of hypothermia. Our secondary outcomes were any adverse events defined as hyperthermia, skin erotary skin such as burns or rashes. And we also looked at feasibility of use of the warmer, including an audit of its preparation, use and cleaning and an duration of the temperature of the mattress at 37 degrees and any evidence of wear and tear. And we also did qualitative interview of the nurses and mothers to assess their end user experience. And just a quick summary slide of the pilot studies, total we used the warmer 204 times, the less than half in hospitals, half in health centers, in 98% of those uses, the infants either attained or maintained a normal temperature, thinking back to that study that was published in pediatric, where they said all babies were cold, it was a question how often they were used to them, we were really pleased with this number. We had absolutely no adverse events except for a 3% instance of mild type or thermia, which we'll get to in a minute. There were zero instances in which the warmer was incorrectly prepared, used or cleaned despite very short trainings. And we have overwhelmingly positive feedback from the mothers and nurses in the qualitative interviews. And this one quote from a romantic mother was very motivating for me. She said, for me, I found that the warmer doesn't cause any problems, it is a very good thing. Maybe you should see how you can supply the warmer to all health facilities and health post just everywhere so the new babies can be warmed up. So just a little bit more data on the pilot study. As I said, we had 3.4% rate of mild type or thermia. Most of those babies were 37.6 degrees and one baby was actually 38.2, which would be really considered that right. We had zero instances as I said, of rashes or burns. We defined warming up from hypothermia in a couple of different ways to try to capture different degrees of hypothermia to start out with and different rates of rise. So as I said, overall, we had three babies who did not warm up out of 120. So that was 97.6%. If we look at that initial quality indicator of reaching use thermia within two hours, which was the Rwandan national standard, 91% achieved that. But some of the babies started out really cold. So this didn't seem like the only good outcome metric. We also just looked at rate of rise at least 0.5 degrees per hour. That's how quickly we warm our babies retrieved with therapeutic hypothermia. So we know that that's a safe and healthy rate of rise. And that was about 77% of kids. The babies who started out euthermic and the mothers just wanted to take a break from KMC. That was 59 patients and all of them who started warm, stayed warm when they were moved from their mother's chest to do, to put directly on the warmer. So just sort of summary of all of that. You can see there was one baby who was just on for 15 minutes. But other than that, all of the babies who started out in the cold range ended up in use thermia range with this one baby who was too hot. And then in terms of the qualitative interview, I thought it'd be kind of interesting to sprinkle some of those responses with some of the concerns that are out there about why it's so hard to take care of hypothermia and the low resource setting. So this is back to this study by Joy Lawn and her group about bottle necks and solutions to care of the small and sick newborn. She says addressing community bottle necks will require a shift in attitude away from the fatalistic assumption that all small newborns will die towards increased awareness and demand for quality in patient care. So this is a comment about from being able to provide quality care and being optimistic about it. Here we have a mother who says, well, what can I say about that blanket is that it really warms up the baby. The baby was really cold and seriously unwell. But once she lay on the blanket, she didn't have any more problems. Additionally, the warm was beneficial to mothers when they grew tired of KMC or her mothers who found KMC to be painful. And a nurse who says it's true that KMC is good because it creates a relationship between mother and baby and love increases. However, this way, meaning KMC can delay to warm the baby slowly in relation to how much the baby is cold. The infant warmer can increase the body's temperature faster than KMC, even if KMC is best. So I felt like this was a nurse who was saying that when she only had KMC, it was difficult to feel optimistic about raising baby's temperatures. But with the addition of the infant warmer, she felt like she could do a better job. Here is another comment about what makes it difficult to take care of babies and low resources in the warm. Country workshop participants underlined that the motivation for neonatal nurses and other professionals to provide high quality care sick babies was low, leading to poor health work attitudes. So this is about low morale taking care of these kids. And here a nurse says, nothing made this difficult for me to learn how to use it. It's something that's easy even for someone without experience. There's nothing difficult with it. And then finally, this is from the same paper. They say it's critical for mothers to spend time with their sick newborns wherever possible. Therefore, local hospital policy guidelines that encourage family-centered care and take into account the local and cultural family structure and vital for mothers to be able to participate in the care of newborns. So again, this is the family-centered care and keeping mother and baby together that we know is so important. And here there's a mother who said, you cannot see the baby when it's on the electric warming table. They placed a baby on it. But with the infant warmer, you line your buy and you breastfeed the baby. And this is actually something that I hadn't really thought of. But this allows the baby and the mother to stay together in the same bed and is really wonderful for optimizing that chance for family-centered care. So given all of this, we decided that we would move on to this prospective cluster randomized step-edge study of the non-electric infant warmer prevention treatment of hypothermia and Rolanda. And this is a very complex study design and I'm not going to have time to describe it in great detail. So I'll just ask you if you have questions. But essentially, we took 10 hospitals. Everybody started with a two-week period of observation in which we collected pre-data on every baby admitted to a special care nursery. And then every two weeks, the warmer was brought to another setting. And then it was then collected at the very end for four weeks and the entire study duration was 26 weeks. Our study aim was to assess the effect of introducing the warmer on rates of uthermia in rural Rolanda hospitals. So 10 just-of-costals were selected by the Rolanda Ministry of Health and they picked them based on high admission rates with a variety of regional temperatures. And then the hospitals were ordered by a random number generator. To ensure that no patient would be denied the warmer if needed, we felt that we needed to collect data on every single patient admitted to the union award and not just the low birth weight babies because sometimes term babies also need the warmer. And we did we're going to collect this on all babies both before and after the warmer was introduced. The same criteria for using the warmer was hypothermia or being at risk for hypothermia. So the same inclusion criteria as for the pilot studies. And the exclusion criteria were also similar except that we added phototherapy because we realized we really hadn't tested the interaction between the photos therapy lamp and the warmer and any skin condition just to avoid any confusion. Oh, sorry, that the warmer itself might contribute to the skin condition. If there was a contraindication to KMC such as medical instability or if the baby's admission temperature was less than 35 degrees and there was electric shooting source available, we felt that that should be provided first. And then the study was completed for that patient when the mother wanted to resume KMC or the infant warmer itself had dropped its temperature to less than 37 degrees, which you could tell when the wax becomes hard. So in the pre phase, we conducted the temperature, daily weight, length of hospital stay and mortality for all infants and mids of the neonatal ward and then ambient air temperature every three hours. Then our intervention was the provision of the dream warmer. And as I said before, it could be easier used with KMC or as a standalone heat source. And here's my study manager showing how the infant warmer looks. These things on the bottom are a little thermo indicators showing that it's cool to be safe enough to use. In the post phase, we collected the same data as we had on the pre phase for all infants and mids of the neon ward. And then in addition for the babies who received the warmer, we'll collect a very similar data on effectiveness, safety, and peaceability. So the degree that the temperature that you survey was achieved and maintained or that the rate of warming was rated in 0.5 degrees per hour, whether the warmer was used with KMC or as a standalone device, whether the baby had a blanket, had a diaper or any other clothing, whether the baby developed hyperthermia, again, any skin irritations, abrasions, rashes of burns, and whether the warmer was correctly prepared, used and cleaned. And again, the same functionality data about how long the infant warmer stayed at gold temperature and wear and tear. So we had a total of 12,000 plus encounters. I should tell you that the whole study, as you might imagine, was shut down for COVID for two months. And then we were very happy that it was picked among the very first projects to resume, which really showed how important this was for the Rwanda Ministry of Health to see this project through its conclusion. What we didn't realize was that because the hospitals that they chose were so busy, the nurses, the setting nurses had to spend an enormous amount of time just getting that pre-data on all of the babies. And so a lot of babies who would have been eligible for use of the warmer did not get to use the warmer because the nurses were too busy getting all of the background data, which ended up being a pretty significant problem with the study. So in the pre-intervention period, we had about 5,000 patients and the post-intervention period, about 7,000 patients, 2,000, the warmer wasn't needed. And in almost 5,000, the warmer wouldn't have been needed. Of those, about 2 plus,000 was because the babies were actually cold. Sorry, 2 plus,000 because the babies were actually cold. And another 2 plus,000 because the babies were at risk for hypothermia and the mother wanted to stop doing cancer. Unfortunately, about 1,000 plus the warmer could not be provided. And here with this at-risk group, almost all of them, the warmer could not be provided because the way that study was designed, the nurses were busy getting data on patients not using the warmer. And because of COVID, there was no way to get back over there and tweak that. So in the end, though, we still had 892 times when the warmer was used. And so we ended up having a lot more data about background temperatures, but still a significant amount of data about how the warmer was used. In terms of encounters with the warmer, a lot of the babies used it just more once, but some of them used it after 21 times. So here's the efficacy data slide. So we were just looking among all takers how many babies became usurvec before and after the warmer was introduced. I was really worried that because the rate of use of the warmer was so low, we were not going to see an effect. But in fact, you can see that before the intervention, 51% of babies were usurvec. And after the intervention, 67% were usurvec with a p-value of less than 0.001. If you look specifically at when the warmer was used and not used, not just the whole population, but the use that data becomes much stronger, 59% were usurvec without using the warmer, and 79% with using the warmer. And you can see that 78% of them used the warmer because they were actual usurvec, and 75% were in that at risk group. And then the hypothermia is basically the mirror opposite of this. One thing that I thought was really fascinating is that there was a quite high rate of hyperthermia across the board. So 12% of all babies had a temperature higher than 37.5 degrees. In fact, of babies who used the warmer, it was more like 10%, and babies who didn't use the warmer, it was more like 12%. So if anything, the warmer health babies to avoid hyperthermia, as well as hypothermia. And again, this is the across the room chart. So you can see that overall the babies who had low temperatures, some of them quite, quite low, essentially all of them warmed up, except for a few here, pretty similar numbers to our pilot study. And overall, it was quite effective. I did not expect to see any of effect on the mortality rate because the overall use of the warmer was so low. But in fact, we did see that of the babies who used the warmer, the rate of mortality fell from 2.8% to 0.9%. So across all of the uses, all of the data points across the whole study, there was not a change with 2.8 before the intervention and 2.3 after because the rate of use was so low. But looking at the babies who actually used the warmer, the rate of death fell by p-value of 0.1. So we were really pleased to see that. And I was thrilled that the paper was just accepted for one of the Lancet family journals in clinical medicine and was published about a week ago. So putting all three of these trials together, you can see that we've now treated over a thousand patients and that was an initial goal of ours and something that people said with medical devices is important to treat, to have it used over a thousand times in a research setting. Of all of those uses, 826 of them were because babies were actually hypothermic and of those 89% of them came into a normal temperature. And 248 were used because they're the same at risk group. So less than 2.5 kilos with KMC not available and of those 99% state warm. So it definitely seems like if you take a warm baby and instead of putting them on a bed, you put them on this infant warmer, they will stay warm. And so then if you take absolute, we all come across, our rate of use thermia is 92%. And again, this is just an interesting thing that if you take all of the babies who are hyperthermic with using the warmer, it's about 9%. But as we learned in our step to edge study, it's 12% of babies not using the warmer. And I've been doing some additional reading to try to understand why so many babies are in this hyperthermic range. And it turns out that the we take 37.5 as a cutoff and then we say 38 degrees is a fever. And at 37.5 to 38 degrees, there are a lot of babies who hang out in that temperature range. Seven of them obviously might be have a low grade fever and have an infection. And I think also they just don't have quite a tight thermostat as older kids. So in terms of the next steps, there's some really exciting things that I'm doing at this point. The first thing is that I'm collaborating with partners in health. That's a big, wonderful healthcare organization that works across the healthcare and healthcare and hating. Probably a lot of you have heard of them. And we're developing a new African, some here in African novel neonatology collaborative. They are working in five different countries that are extremely high risk. Malawi, Lisoito, Liberia, Sierra Leone, and Rwanda. And we are going to commit to a decade of collaboration to try to achieve the 2030 sustainable development goals, which is for newborns less than 12 deaths per thousand by births together. So we'll be taking the open pediatrics curriculum and starting with education, developing an essential list of medicines, medical devices, and human resources and educational needs, and all working together to be able to try to get these sites to have adequate neonatal care to achieve that sustainable development goal. And bringing the infant warmer to all of these sites will be a great way to scale it, working with an organization that has a very strong collaboration with ministries of health, and really wonderful track record of providing excellent training and staff development in countries. We'll also be in Haiti, where they have a very strong footprint and in Chiapas, Mexico. And the other thing that I've been doing is collaborating with a really wonderful organization called NEST360. They're out of Rice University and the London School of Hygiene and Tropical Medicine. And their big push is for health care, this Google technology. So health care devices designed for the neonatal setting out in the low and middle income countries. And so what they've done is they're trying to get specific medical devices that are designed for the low, really the low resource setting, and then they test them for high altitude, low altitude, lots of dust, all the different things that make these devices not work. And I visited both the Rice University and London School of Hygiene and Tropical Medicine on invitation and described the infant warmer. And they agreed that they think that this is an ideal solution to thermal regulation for places that really can't have intimators. I have agreed that once it can be FDA approved and it's available commercially, they would like to include it in their quote unquote NEST of options to equip neonatal ward in the low resource setting. And so then the next question that came up is sort of where to go from here because it's a little bit beyond the book of business for Boston Children's Hospital to be manufacturing and distributing medical devices. And so about two years ago I decided that if this was going to not just sit in a museum as an academic medical prototype, we needed to take the next step and start figuring out how to manufacture and distribute it globally. So we were able to get a 501-C3 whenever the right term is agreement, I'm sorry, not sure there were, we became a 501-C3 for an organization called Global New One Solutions. And our goal is to start with hypothermia and the dream warmer as our first device, but then to move on to other places where it would be wonderful to have a Google technology for newborns and where it can really be designed by somebody like myself as a neonatologist working within country, ministries of health and medical providers so that it's really designed to work in the setting where it's needed. We have our website, we are just finalizing licenses of several patents on the technology, we've got our trademarking done and now we're really at the manufacturing and distribution phase, the warmer that we have now is made of a plastic that's not quite strong enough to repeal both exposure to this phase change wax as well as multiple exposures to boiled water and so we're trying to find a stronger plastic and then we're also trying to find a manufacturer that's willing to work making relatively small volumes of a watcher that has been actually slightly complicated device. And I always like to end on this slide because this I think is really motivating. So these are the very first two babies that were ever put on the dream warmer for the first pilot study and when this mother had her babies on here, she looked at them and she said to me that she felt that this was the first time that she had ever seen her babies look comfortable since they had been born. And then this is a picture of those same babies at 15 months of age and actually this is funny because I had thought initially that this was a baby girl just based on the pink hat but the Rwanda that color of pink and blue is not assigned by gender so I was a little surprised to realize that these have been two baby boys the whole time and you can see how well they're doing and how happy the mother is and I think that there's just an idea that when you see these tiny babies that they're just not going to survive and that we should all as it said in an earlier slide just almost expect that many of them won't survive but in fact with just a small amount of help they can really do great and they cannot only survive but they can thrive and have great outcomes. And so I feel like the dream warmer is a really great way to help babies not suffer from the 100% preventable conditions of hypothermia to cause both yet and not an optimal outcome. So with that I'd like to say thank you to our two engineers at Lawrence Berkeley Lab, Professor Scott Gillen, Matt. Our all of the work has been done with folks on the ground in Rwanda for every position that we have here in the United States so where I was the PI from here in Boston, we had Dr. Mazenpaka who was our local PI who's a physician working with partners in health, our study manager Joe Say who was Rwandan and didn't absolutely fantastic job not realizing that I would never be back after the initial orientation because of COVID. We have a fantastic biostatistician, Al Fons who did the vast majority of the biostatistics even though the study design was so complex. We were working in very close collaboration with the Rwandan Ministry of Health and they've been offered on all of our papers and also been with us every step of the way of the design of the warmer and then here at Boston Children's on Henry Feldman has been the biostatistician working with Al Fons and then of course I'd like to thank Stella, my division chief. And here this is a little picture that I took during that same very first baby we were taking the temperature and this little baby's actually holding her own, well now turns out to be a boy. His own thermometer which says 36.9 degrees which is perfect and I would just say at this point in 2021 no baby should ever die from getting cold. So thank you and I hope I left some time for questions. Well and wow, you know all of us trained in this incredibly high tech, high resource environment and our job and our goal is to make a different furry baby. And all of us realized that we make a very small difference in the care of children over all. In fact, the surgeons, you know most of us only take care when patient at a time. We may say the life but it's only one at a time. And you were maps at the beginning to sort of demonstrate that small, small, small scale that we work on and I think a lot of people on this screen didn't know how much time you had voted your career to magnifying your impact in a place that we'll never have. Anyone who has any other resources that we have, we're, we complain about seven North. You and I have commis ready for decades and you are getting into NICU. Really. And but to compare what we have in seven North to what you see in South Carolina Africa is literally different continents. And so each of us, you know, drives gratification from the impact we make and the patients will never see. We do it through our training, knowing that the people that have had experience here go on to do good things elsewhere. But this is a, you know, couple orders of magnitude greater potential impact through what you say is simple, just warming. But obviously you've demonstrated this kind of complicated to get to the stage of easy implementation and life pretty utilization, which I am totally confident you will do. You have been selfless in this. You don't advertise that you do this. You have enrolled and empowered the locals instead of taking all the credit yourself. They're the authors of your protocols. They are, you know, authors open feeds. They have prominent roles in all the manuscripts. And you're often a little off on these papers. You have been totally selfless in this. And although you say you may have a conflict of interest and only if you're going to get very rich, I'm doing this because you're going to do these possible costs. And you're company in which your CEO is a nonprofit. So so wow. I know there's not so many questions, but I just want to also comment that I mean, you and I started together. You taught me to take care of your babies. And you were kind of at the surgery, right? Of all that new technologists in the world who has been so committed to surgical newborns. And seven North is in, you know, proportionally of a very, very surgical unit. And you've always been pleased and proud of that. And you have been very committed to training people to take care of surgical babies. And we have some of the most complex surgical babies. You're into, I don't know, how many additions of the ear manual that you're written with Mark for care of the surgical newborn. And I, this is something you don't know. A while back, Chris Weldon did an anonymous survey of the last decade or so surgical critical care fellows, which he hasn't seen results of. But I have. And all the people who made comments by name, you were the single most named individual. And 100% of those comments were positive. And that is, that is really, really, and so thank you for all you've done for us and for our patients and for our faculty and our fellows. Wow. I'm jealous. Well, thank you so much. I would just turn to the ground around sooner if I knew this was going to be so nice. Thank you. Thank you. Thank you. And lots of questions. Or maybe not. And someday, a great job. Great to hear about you getting nearer to the end of your project here. I know we spoke about a long time ago. And it's great to see how far you've come. It's curious about the regulatory issues that you face both internationally and in the US. And can you just tell us about how what the regulatory pathway for this has been? Because it sounds like you're getting FDA approval at some point. Yeah. Is that necessary to conduct these clinical trials in Africa? Great question. So it's not been necessary to conduct the files, but it will be necessary, especially to work with Nest 360. Kudos to them. They insisted everything either be United States FDA approved or something called CE approval, which is the European equivalent. We are so we decided to find for the United States FDA process. And as you can imagine, the FDA has been kind of busy this year dealing with COVID vaccines and it's been a very, very slow process. But we had our application in for over a year. And we're just waiting to hear back from them about what class of device will be and what will be required. And we have hired a consultant to help us with that process. We're unbelievably complex and expensive. And I just feel like it's really a problem for people like myself who have a very simple device that should have some more straightforward process, but there doesn't seem to be any way to simplify it. And then we also have a pride for the London FDA approval. That process was really simple when we started eight years ago and it would have been a shoe in if we had just thrown it in then. But they also have really evolved very much in terms of just their entire medical complexity. And so that process now also is highly complex. But that I hope will finish first. So both of those applications have been in for over six months and it's a little bit of a race between the real London United States. But yes, you want to get FDA approval by the United States because UNICEF and NESC and 60 and most NGOs will not be willing to endorse or distribute a medical device that's not approved by some regulatory agency. And how about the intellectual property issues? Sounds like you worked with other people at other institutions. How did that work? Looking at this typical, the intellectual property goes to the engineers. So Lawrence Berkeley lab holds a patent on both the design and on using 40 degree phase change material as the thermo indicator that shows when it's safe to use. And we are licensing both of those patents to be able to use exclusively by global new point solutions. And that again is an unbelievably long complex and expensive process. I should say that I have gotten pro bono help from Wilmer Hale Law Office that has done the 501-C3 process. All of the patenting work hundreds of hours of pro bono work which would otherwise have been completely impossible for me to do. So there's been so many people who hear about this problem. They never in the world knew that there were babies who were dying because they were cold. As soon as they hear about it, they want to jump on board and help. And that's been just absolutely critical to my success because as you can imagine, and now especially with COVID, it's really difficult to raise funds for this kind of a very niche and small business. And so all of the pro bono donated work has been amazing. And Lawrence Berkeley lab, those engineers have been academic collaborators. They have never charged for their time. So it's been a lot of good hearts doing the right thing for free. And as she said, I obviously never intend to get rich doing this. We want to keep this at under $100, which will mean really going for Uber affordability. And so the point would be that basically, you know, we do as much wallet sharing as we possibly can to the cost as well as we possibly can. Great. Thanks and congratulations. It's an amazing work. Thank you. Thanks, and thanks. Thank you. Thanks, and thanks. Other questions or comments? What's your next project? Well, the next thing I would actually love to do is think about a frugal technology for perinatalisticia. That's the other huge problem in the low resource setting. Unfortunately, where we provide therapeutic hypothermia in rich countries, there's been a recent study that showed that actually babies have a higher rate of mortality when they're exposed to therapeutic hypothermia in a low resource setting. And so that's known a big wrench in my plans. The problem is that babies in the United States generally have perinatalisticia because there's some acute sentient event during birth, like a potential adoption, for example, whereas in the low resource setting, it's a lot more of a kind of a chronic, a special situation with small placenta, poor nutrition, chronic infection, things where it's not just something where that six-hour window providing hypothermia is effective. And also, as you might have seen if you're up in the NICU, it's actually quite difficult to provide therapeutic hypothermia safely. And babies can have very low part rates and become quite illopathic and have all kinds of responses to the cold. But I have found somebody who has a really cool device, which is a nasal. It provides cooling through evaporative losses through the nasal mucusa, and it actually cools just the brain and not the whole body. And it's very, very inexpensive and very safe and servo-controlled. And it was designed for migraine headaches and adults. But I think it would be amazing to look at in the low resource setting where there is a real sentinel event because those babies who have perinatal esphyxia not only is it tragic, as it always would be, but there's very few resources to take care of those kids and there's also not a culture of really accepting children who have severe cerebral palsy, quite the way that we have in the United States. And so actually through this collaborative that I talked about with Partners in Health, one of the things that we'd be interested in doing is setting up a research network just like I have in Rolanda because people who love participating in research and don't always have a chance to. And so we could find the right population and assure the safety of this for neonates. I would be incredibly interested in tackling that whole piece, which is again about a third of the reasons for preventable deaths in the low resource setting. And I guess I should just add also this neonatal consortium is going to have a maternal piece as well because obviously you can't take care of newborns if you haven't taken good care of mothers. And so maybe by combining those two things and having this nasal cannula evaporative approach to just brain pooling, we could start to get a little bit of a handle on that neonatal dysphyxia. So cool them down and we'll warm up. All about thermal regulation. I started doing some math and I'm sure you've done this. I think if I recall the slide, your mortality, the raw mortality with the intervention dropped from something like 2% to 0.9% or something like that. When you multiply that out across the country of Rwanda or the world, how many lives saved is that from a simple warming device? Yeah, it's fun to do that math. I think what's really hard is that it's almost never that hypothermia is listed on the death certificate as the cause of death. So it's a contributing cause because once babies are hypothermic, they then develop all of these other problems. Their immune system doesn't work as well. They become brainacardic, they become coagulopathic, they don't eat well. And as I said, their brains don't go as well. So though this estimate that 40% of deaths hypothermia is a contributing cause, what's really not known as well is if you warm them up, how much better do they do? So actually one of the things I'm incredibly interested in because Rwanda has such great vital statistics that they keep is seeing what happens to the country. Like we're going to roll this out over the next year to the entire country and we'll be able to see what happens to their mortality rate. So it will really be sort of a living experiment. Unfortunately, they don't have great outcome like follow-up clinics like we have, so we won't be able to see a measure. We won't be able to measure the effect on outcomes. But we absolutely know that when babies don't get good nutrition, they don't have optimal outcomes. And so that piece I feel like has been proven so many times that there's no reason to think that wouldn't be the case there as well. But you do know what the neonatal mortality is in the group that you've treated, all cause mortality. And even if you don't have death certificates, our cause of death, and the cause of death doesn't trace back. Yeah. It's multiplied that 1% improvement in mortality. Yeah, if we think that the death rate fell by a third, that's what it did in our study. Then yes, you're right. That's going to be across the world, you know, millions of babies. That's the effect. And I guess just one other comment, I wish we're probably almost out of time, but one other thing is that one part of global newborn solutions is that we really want to make sure that we're not just settling a warmer, for example, in a pharmacy. We will do some of that, but we really want to be able to provide these sort of wrap around educational services. And this is where the open deviates curriculum will be so helpful so that people can not just know how to use the warmer, but the important use in general principles for thermal regulation and then broader principles for taking care of simple ways to take care of babies. So there's a whole chapter on respiration, on nutrition, on cardiovascular care, everything so that people can download that for free. It's a certificate program. We're actually just revising it to be able to take off the first sign that says it's the Oland Ministry of Health protocols and have it just be available. It's going to start being like just a PIE, novel consortium, and then we'll have another one that's just general care of the newborn. And the very last thing I'll say is that we're pairing up with this company that has a very amazing app that can both track all of this data and show you how to use the warmer and guide people through that should help us collect a whole bunch of data on how it's being used and what it's doing to thermal regulation, growth, and death. So having back in another 10 years and I'll tell you how it's going. We certainly will. I think I see Craig. Oh, I just, and we're speechless. And I've been looking forward to hearing what you've done and my goodness, we're overwhelmed. I felt like this morning, I wonder what it was like when they had Albert Schweitzer give grand rounds over Zoom and seeing that humility, the passion, the energy, and the creativity. Oh, my goodness. Thank you, Anne. Oh, thanks so much. And thank you all. This is the first time I've seen so many of you since COVID yet. So I was hoping you get to do it in person by now, but this has been really a wonderful honor for me. Thank you all. Thanks so much, Anne. And I guess the regulations on such unpacked work. Thank you. Bye, everybody. Thank you.