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#203 - The Giants of Neonatology - Fighting for Air (Pr. Ola Didrik Saugstad)

Updated: 15 hours ago



Hello friends 👋

Hey everyone, it's Ben here. In our latest episode of The Incubator podcast, Daphna and I had the privilege of interviewing Professor Ola Didrik Saugstad, a true giant in the field of neonatology. Professor Saugstad took us on a fascinating journey, sharing his groundbreaking research on hypoxanthine as a marker for asphyxia in newborns and his pioneering work on resuscitating babies with room air instead of pure oxygen. It was incredible to learn how he challenged the long-standing dogma of using 100% oxygen for resuscitation, despite facing initial skepticism from the medical community. Through his unwavering determination and collaborative efforts with researchers worldwide, Professor Saugstad's findings ultimately led to a paradigm shift in neonatal resuscitation guidelines. He emphasized the importance of being receptive to new ideas, conducting rigorous studies, and promoting teamwork in research. We also discussed the challenges of conducting clinical trials in an increasingly complex era and the crucial role of ongoing international collaboration in addressing the remaining questions in neonatology, especially concerning optimal oxygen use in preterm infants. Professor Saugstad's inspiring story showcases the remarkable impact that dedicated researchers can have on enhancing care for our most vulnerable patients.

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Short Bio: Ola Didrik Saugstad (born 1947) earned his MD (1973) and PhD (1977) from University of Oslo, Norway. In 1980–81 he was post doc with a Fogarty grant from National Institutes of Health at Division of Neonatology, Department of Pediatrics, School of Medicine, University of California, San Diego. From 1986–2017 he was senior consultant of Neonatology at Oslo University Hospital and from 1991–2017 professor and Director of Department of Pediatric Research, University of Oslo. He was visiting research associate at the Cardiovascular Research Institute at University of San Francisco 1986 and from 2018 Adjunct Professor of Pediatrics, (Neonatology) at Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago Illinois. His research in Sweden and Oslo, and how this changed the present concept that newborns in need of resuscitation at birth instead of given pure oxygen should be given air. This discovery resulted in new international guidelines, improved resuscitation routines, and prevented the death of several hundred thousand newborns each year. Saugstad has traveled all over the world giving lectures about newborn resuscitation and health. He has been given numerous international and national awards, such as the Landmark Award by American Academy of Pediatrics (Perinatal section). He is an appointed honorary member of a number of national associations and an honorary doctor and professor at international institutions. In addition to his engagement for the smallest among us, Saugstad has been involved in the debate about Biotechnology and Chronic Fatigue syndrome.


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Here are some of Pr Saugstad's many publications:


Aasen AO, Saugstad OD.Circ Shock. 1979;6(3):277-83.PMID: 498432

 

Meberg A, Saugstad OD.Scand J Clin Lab Invest. 1978 Sep;38(5):437-40. doi: 10.1080/00365517809108448.PMID: 705228

 

Saugstad OD, Bo G, Ostrem T, Aasen AO.Eur Surg Res. 1977;9(1):23-33. doi: 10.1159/000127922.PMID: 14834

 

Saugstad OD, Aasen AO, Hetland O.Eur Surg Res. 1978;10(5):314-21. doi: 10.1159/000128021.PMID: 30633

 

Saugstad OD, Ostrem T.Eur Surg Res. 1977;9(1):48-56. doi: 10.1159/000127924.PMID: 844465

 

Saugstad OD.J Oslo City Hosp. 1977 Mar;27(3):29-40.PMID: 845718 No abstract available.

 

Saugstad OD, Schrader H, Aasen AO.Brain Res. 1976 Aug 6;112(1):188-9. doi: 10.1016/0006-8993(76)90349-8.PMID: 947488 No abstract available.

 

Saugstad OD.Pediatr Res. 1975 Apr;9(4):158-61. doi: 10.1203/00006450-197504000-00002.PMID: 1143950

 

Saugstad OD.Pediatr Res. 1975 Jul;9(7):575-9. doi: 10.1203/00006450-197507000-00004.PMID: 1161346

 

Saugstad OD, Hallman M, Abraham JL, Epstein B, Cochrane C, Gluck L.Pediatr Res. 1984 Jun;18(6):501-4. doi: 10.1203/00006450-198406000-00002.PMID: 6610852

 

Saugstad OD, Rootwelt T, Aalen O.Pediatrics. 1998 Jul;102(1):e1. doi: 10.1542/peds.102.1.e1.PMID: 9651453 Clinical Trial.

 

Saugstad OD, Kroese A, Myhre HO, Andersen R.Scand J Clin Lab Invest. 1977 Oct;37(6):517-20. doi: 10.3109/00365517709101840.PMID: 10733408

 

Saugstad OD, Ramji S, Irani SF, El-Meneza S, Hernandez EA, Vento M, Talvik T, Solberg R, Rootwelt T, Aalen OO.Pediatrics. 2003 Aug;112(2):296-300. doi: 10.1542/peds.112.2.296.PMID: 12897277 Clinical Trial.


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The transcript of today's episode can be found below 👇


Ben Courchia MD (00:01.222)

Hello everybody. Welcome back to the incubator podcast. We are back today with a new episode from our series, The Giants of Neonatology. We have the pleasure of having on with us Professor Ola Saugstad from Norway. Daphna, how are you this morning?

Daphna Yasova Barbeau, MD (00:16.931)

I'm doing well. We love the Giants series and we certainly have a giant in the studio with us today, don't we?

Ben Courchia MD (00:24.922)

Absolutely. Dr. Saugstad, thank you so much for making the time to be on with us today.

Ola Saugstad, MD, PhD (00:29.582)

Thank you so much for having me. It's a great honor and a pleasure to be here as your guest.

Ben Courchia MD (00:36.354)

The pleasure is all ours. I could spend the hour reading your bio, so I'm going to try to give a cursory version so that people can get a glimpse as to the work that you've done and the impact that you've had on the field. You earned your medical degree in 1973 and your PhD in 1977 from the University of Oslo, and you went in 1980 to get your postdoc with a Fogarty grant from the National Institutes of Health at the Division of Neonatology, Department of Pediatrics at the University of California, San Diego.

You have done tremendous work when it comes to neonatal resuscitation. Your research in Sweden and Oslo has really changed the concept that newborns need resuscitation at birth with pure oxygen. You've allowed this transition to happen where we actually perform neonatal resuscitation with much less oxygen and closer to room air. You have traveled all over the world giving lectures about newborn resuscitation and health. You've been given numerous international and national awards, such as the Landmark Award by the American Academy of Pediatrics. You're an appointed honorary member of a number of national associations and an honorary doctor and professor of international institutions.


Dr. Saugstad, thank you so much for taking the time to be with us this morning. I wanted to begin this conversation by talking about the early stages of your life. You grew up in a very academic environment. Your father was a psychologist, and your mother was in education. Can you tell us a little bit what it was like to grow up in this environment?

Ola Saugstad, MD, PhD (02:26.766)

It was very stimulating, but when I was a boy, I didn't think about it. I have to mention also that I spent two years in Chicago when I was a small boy, from three to five years old, because my father took his PhD in psychology there.

Ben Courchia MD (02:46.371)

Did that have any lasting impact on you?

Ola Saugstad, MD, PhD (02:50.758)

I think so, because I always felt I had a very close emotional relationship to the United States. At that time, although I was only five years old, I spoke fluent American English, and then I forgot it. But I always felt the US is my second home country. When I grew older, I realized I was brought up in a special family. My father was a professor, I had two uncles who were professors, and my grandfather was a professor and director of the University of Oslo. Going back to my mother's family, there are academicians and priests for 200 years. Now when I'm older, I appreciate that background more and understand it was a privilege to be raised in such an environment.

Ben Courchia MD (04:08.062)

Considering the quality of the work that your parents accomplished, did they look down on your decision to pursue a career in medicine?

Ola Saugstad, MD, PhD (04:20.382)

No, I was very determined. From the time I was 12 years old, I decided I wanted to be a doctor, and there was no discussion about it. One of my privileges was that I learned very early in life that you should follow your calling and your interests. If young people come up to me and ask for advice, I say the same: follow your interest. I think that's the most important thing.

Ben Courchia MD (05:01.999)

Was there an experience that prompted you at the age of 12 to fall in love with healthcare and medicine?

Ola Saugstad, MD, PhD (05:09.178)

I don't think there was anything special. I also wanted to become an archeologist for a brief period of my life, but then I decided to become a doctor. I had two uncles who were doctors. I was interested in humans, but I was also interested in science, so I found medicine to be a unique combination.

Daphna Yasova Barbeau, MD (05:55.151)

A lot of us in medicine have children, and we talk a lot about whether our kids are going to go into medicine or how we balance wanting our kids to be successful without placing too much pressure on them. It sounds like you had quite a supportive family despite this academic pedigree. I wonder if there were any particular things that were really supportive in your childhood and adolescence that helped set you on this path? We have to foster this creativity in our rising scientists so that their minds stay open to new opportunities.

Ola Saugstad, MD, PhD (06:55.398)

Nobody really questioned my wish to become a doctor when I grew up because I didn't discuss it with anyone; I just decided I wanted to do it. When I went into high school, I changed schools because it was very competitive to get into medical school in Oslo. I had to really get good grades, so I was very determined. But I had another interest, which was as strong as my interest in medicine, and that was soccer. I was a passionate soccer player from the time I was eight or nine years old, and I was very ambitious. So I tried to combine that with medical studies.

Ben Courchia MD (08:00.03)

I'll have more questions about your perspective on football afterwards. Because as a Frenchman myself, I cannot say soccer! We'll stick with football. But why neonatology then? I was looking at your family history and I thought for sure psychiatry was in line for you with a father who was a prominent psychologist. At what point did you say, I want to treat children, I want to help kids and babies?

Ola Saugstad, MD, PhD (08:31.306)

That was during my medical studies, because I was extremely interested in biochemistry. From when I was young, I always felt I made contact with children and that children needed protection. I found this unique combination of children and biochemistry in pediatrics. I didn't have any clear wish to go into neonatology, but just by chance, I got an offer in my last year of medical school in Oslo to go to Sweden and start research on perinatal asphyxia with the famous professor of perinatal medicine, Gösta Rooth. That was serendipitous, but then I decided this is what I want to do. I wanted to dedicate my professional life to newborns.

Ben Courchia MD (09:59.966)

Your research work is obviously something that we wanted to talk to you about. You have truly made an impact on how we resuscitate babies at birth by moving us away from using 100% oxygen on babies who were suffering from asphyxia and hypoxemia. There's an interesting story between neonatology and oxygen. We used to love oxygen, then we learned to hate oxygen, then we recently have come to this middle ground where we understand that too much is probably not good and not enough is probably not good either. When you were embarking on this work looking at oxidative stress, was that something that was the trend at the time, or were you feeling like you were taking an unusual path in neonatal research?

Ola Saugstad, MD, PhD (11:04.322)

The history of oxygen in neonatology is fascinating and quite dramatic. I was not interested in oxygen per se. When I started my research, I was interested in asphyxia. The aim of my doctoral thesis, which I started in Sweden in Uppsala, was to find a biochemical indicator of asphyxia. At that time, we had the Apgar score and we had acid-base balance, but not much more than that. My supervisor had very high ambitions and told me I had to invent a biochemical Apgar score.

I started to measure a metabolite called hypoxanthine. Hypoxanthine is a purine metabolite; it's a breakdown product from ATP. I thought that if we can measure hypoxanthine in body fluids, you get an estimation of the energy status of the cell. Since ATP is intracellular, we cannot measure that in body fluids, so I thought hypoxanthine could reflect the ATP level.

The problem was that there were no methods to measure hypoxanthine in body fluids at that time. My supervisor was an expert on PO2 electrodes, and he suggested that we should measure the oxygen consumption when hypoxanthine is oxidized to uric acid in the presence of the enzyme xanthine oxidase. I established this method to measure hypoxanthine in the plasma of newborn babies using only 0.2 milliliters of plasma. I started measuring hypoxanthine in the umbilical cords of newborn babies who had suffered asphyxia compared with controls, and found that asphyctic babies had almost fivefold higher hypoxanthine levels. That was the starting point to finding a biochemical indicator of asphyxia.


Daphna Yasova Barbeau, MD (14:35.783)

I think it's such a good reminder of how far neonatology has come. The fact that you mentioned it was 0.2 mLs—we're so judicious about how much blood we take from babies, but this was a time where frequent labs were not a part of routine management. I wonder if you can speak a little bit then to how you got more involved with the resuscitation side of things?

Ola Saugstad, MD, PhD (15:12.118)

I went back to Oslo and wanted to pursue this new observation about hypoxanthine. I got a position as a research fellow at the Institute for Surgical Research at the University of Oslo. I started experimental studies, measuring hypoxanthine in animals, like piglets, during hypoxia, and was able to show that hypoxanthine is increased. Then we did a study measuring hypoxanthine during the resuscitation of animals with endotoxic shock. We were actually measuring proteolytic enzymes, but I asked a colleague if we could resuscitate the animals at the end of the experiments so I could take some samples.

What I saw was that hypoxanthine increases exponentially during the first 10 to 12 minutes. At the same time, I read the paper by Fridovich and McCord from the US showing that xanthine oxidase is an oxygen radical generator. When xanthine is oxidized to uric acid, oxygen radicals are generated, and hypoxanthine is the precursor. I understood that if you have a very high hypoxanthine concentration in the body fluids or tissues and you then give oxygen, it might be detrimental, because the more hypoxanthine you have, the more free radicals will be generated. We published this in 1979, and in 1980 I suggested this in another study. That was the first time we suggested the combination of hypoxanthine and oxygen might be detrimental.

Ben Courchia MD (18:51.552)

I think the connections you made are quite impressive, looking for this marker of hypoxia and realizing it could be a source of oxygen radicals. When exactly did you make that connection, and when did you clearly see that we need to use less oxygen during resuscitation?

Ola Saugstad, MD, PhD (19:58.662)

I finished medical school in 1973. This took seven years. I got my first grants around 1986 and 1987. I recruited some PhD fellows to test the effect of hypoxanthine on circulation. I also spent a semester in San Francisco at the Institute for Cardiovascular Research in 1986 with the late Abraham Rudolph, who was an extraordinary man. We started doing animal experiments with piglets, but they were not very successful. I had it in the back of my head to resuscitate with lower oxygen concentrations, but I wasn't determined to test it out yet.

One of my fellows was having problems with his experiments, so I suggested we try resuscitating with air. He did, and it went very well. The hemodynamic markers and acid-base balance did as well with air as with 100% oxygen. In 1991, we presented our first results with newborn piglets resuscitated with air versus 100% oxygen at the European Society for Pediatric Research in Zurich. It was a packed auditorium, and the audience was incredibly enthusiastic.

I realized I had to do clinical studies, but I had no experience with them. My old boss in Sweden, Gösta Rooth, put me in contact with Siddarth Ramji, who was running a big unit in New Delhi, India. Siddarth agreed, and very quickly he had resuscitated 84 newborn babies with either air or 100% oxygen. We found that outcomes were similar between the groups. We published that in 1993 in Pediatric Research. Then I organized the Resair 2 study, a multi-center study with 10 centers from six different countries (India, Philippines, Egypt, Spain, Estonia, Norway) with approximately 600 babies. Again, we showed that air-resuscitated babies did as well as those who received 100% oxygen.

Several others started to test it out, like Max Vento from Valencia. Around 2003, I spent a sabbatical with Max Vento, and we wrote a meta-analysis showing that mortality was actually 30% lower in babies resuscitated with air. That was a surprise to me; I only expected parity. The first Cochrane review in 2004 showed the same thing.

Ben Courchia MD (27:23.234)

There's a nice article by Max Vento in NeoReviews that mentions the response to your initial results was not always positive. In 1997, at a lecture in Hungary, somebody shouted at you. What was it like dealing with a portion of the community not thinking this was the right path?

Ola Saugstad, MD, PhD (28:09.142)

Many people said I was crazy. During my opening lecture at that European Congress in Hungary, a woman stood up and shouted that it was unethical. My answer was that using 100% oxygen had never been tested in a randomized study before, so if my approach was unethical, the standard practice was also unethical. In 2000, I was invited to the panel making the new international ILCOR guidelines in Dallas. It was said that if you don't have oxygen, you may start with air, which was progress. In 2005-2006, new ILCOR guidelines said you could choose between 100% oxygen or air. Canada and Australia quickly changed their national guidelines. The US was one of the last countries to change, possibly for legal reasons; people didn't dare deviate from the standard practice of care. But by 2010, ILCOR stated you should start with air for term or near-term babies.

Daphna Yasova Barbeau, MD (31:41.091)

It wasn't until 2015 that ILCOR recommended against hyperoxia. It's a perfect example of how long it takes from bench studies to clinical implementation. How can we shorten the lead time to get things to the bedside?

Ola Saugstad, MD, PhD (32:46.758)

I was often told I had to be more aggressive in promoting this, but I didn't feel it was my role to promote room air resuscitation. My role was to present data. I felt those who present data should not be the same ones forcing the changes. I appreciated that people were critical, and of course 30 years was too much time, but I wanted to ensure there were no subgroups that actually needed oxygen.

Daphna Yasova Barbeau, MD (34:36.376)

You wrote a book, The War Over Oxygen, describing this as one of the greatest scandals in the history of medicine. Can you speak a little bit to that?

Ola Saugstad, MD, PhD (34:47.926)

It was a dogma from the end of the 18th century. Oxygen was described as an element by Priestley around 1794, and very quickly they started treating newborn babies with it. Michael Obladen summarized this, noting that for 200 years, no one really questioned 100% oxygen. In 1992, the American Heart Association guidelines said there was no reason to be concerned about giving 100% oxygen during brief newborn resuscitation.

In 1998, I presented my data at Hot Topics in Washington. I was nervous because the elite of American neonatologists were there. After my lecture, Mary Ellen Avery stood up and supported me, saying she had always been concerned about using 100% oxygen. Getting the support of the queen of neonatology was so important. We became good friends until she passed away.

Ben Courchia MD (37:06.65)

Did any of the naysayers eventually turn around and apologize?

Ola Saugstad, MD, PhD (37:30.346)

No, I don't think so. But when it changed, it changed quickly. I came to Australia in 2007 and was cheered as a champion. It is important that people have criticisms and objections to new ideas. I was fortunate to have collaborators like Max Vento, who quickly started to study the same things.

Daphna Yasova Barbeau, MD (38:37.467)

Yours is a story of perseverance. How do we promote people looking at practices that haven't been well studied to prevent making these same mistakes?

Ola Saugstad, MD, PhD (39:15.97)

We have to be open to new ideas. If you question established routines, you have to study them in a proper way with randomized studies, pilot studies, and animal studies first.

Ben Courchia MD (40:05.094)

We had Professor Atle Moen at the Delphi conference recently, and he spoke about how neonatology has reached the era of complexity. How challenging is it becoming to continue to do randomized control trials in the current climate with complex patients? Where do you see research going in the next 10 to 15 years?

Ola Saugstad, MD, PhD (40:51.53)

Atle Moen was one of my first PhD fellows. Yes, situations are complex, but the basis is the same: you have to make very strict protocols. You have to ensure you have enough statistical power. I've seen many studies without power, which is a waste of time, money, and is unethical. I'm currently part of a large international group pursuing these unanswered questions about oxygen, adjusting for confounding factors and identifying weaknesses in our protocols.

Ben Courchia MD (43:35.022)

Speaking to people who have worked with you, they mentioned you are very competitive and draw from your passion for football to manage your research teams. Can you tell us about that?

Ola Saugstad, MD, PhD (44:49.518)

We can learn a lot from team sports like European football. You have to be a team and accept that your teammates make mistakes, just as you do. When I became head of the Department of Pediatric Research in Oslo, our national soccer team got a new coach and accelerated to being ranked number two in the world. I said, if they can do that with soccer in Norway, we can do it in research too. I've had 50 PhD fellows total. Being a big group made us very efficient, enthusiastic, and pioneering.

Daphna Yasova Barbeau, MD (47:17.207)

You were a role model in international collaboration before it was easy to hop on a Zoom call. How important is international collaboration to moving the field forward?

Ola Saugstad, MD, PhD (48:11.903)

Coming from a small country like Norway, I realized early on that I needed to collaborate with foreign groups. It's also vital that people follow the same track for 20, 30, or 40 years to know the history and see the future direction. I've been privileged to follow and develop one idea from the start of my research until today.

Daphna Yasova Barbeau, MD (49:47.947)

You've seen the entire history of oxygen in neonatology. Where do we go from here? What are the remaining holes in the story?

Ola Saugstad, MD, PhD (50:03.246)

We still have many unanswered questions, especially for immature babies less than 28 weeks. We don't know the optimal initial FiO2 for these babies. We know the most immature babies probably need some oxygen initially; we shouldn't start with air. We have suggested starting with 30% oxygen and titrating, but it might be that we need to start higher. The international group I'm part of is working on this, but we don't have the final answer yet.

Ben Courchia MD (51:24.07)

Dr. Saugstad, this is a great place to end on. Thank you so much for sharing your knowledge with us.

Ola Saugstad, MD, PhD (51:50.006)

Thank you for the interesting questions and for inviting me.

Daphna Yasova Barbeau, MD (52:02.399)

Our pleasure.


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