Articles
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Pulse Oximeters: The Invention that Changed the Paradigm of Patient Safety Around the World

June 10, 2021

Katsuyuki Miyasaka, M.D., Ph.D.

Pulse Oximeters

Adapted from Special Feature on Pulse Oximeters: The invention that changed the paradigm of patient safety around the world. (LiSA (1340-8836) vol28 No3 Page237-308, 2021.03 (in Japanese)

View more articles from this special collection hosted by the APSF on Pulse Oximetry and the Legacy of Dr. Takuo Aoyagi.

Disclaimer: The information provided is for safety-related educational purposes only, and does not constitute medical or legal advice. Individual or group responses are only commentary, provided for purposes of education or discussion, and are neither statements of advice nor the opinions of APSF. It is not the intention of APSF to provide specific medical or legal advice or to endorse any specific views or recommendations in response to the inquiries posted. In no event shall APSF be responsible or liable, directly or indirectly, for any damage or loss caused or alleged to be caused by or in connection with the reliance on any such information.

Preface

Dr. Takuo Aoyagi

Dr. Takuo Aoyagi

I feel greatly honored to have been asked by the editorial board to organize a special memorial issue on Dr. Takuo Aoyagi. I would like to thank the editorial board for their wise decision to take this timely opportunity to tell the world about the great contribution Dr. Aoyagi made to humanity. Many contributors are from countries other than Japan, all of whom showed great interest in this project. They kindly agreed to search their files and memories from 40 years ago and send their memorial contributions on a tight schedule so that we would have time to translate their articles into Japanese. Drs. David J. Steward, Jeffrey Cooper and others sent their manuscripts in record time, some as short as six days and I am very grateful for the great interest shown by all.

As you read through this collection of articles, many of you will find new information and developments previously unknown to the public. I hope that this memorial will give all of us the opportunity to reconfirm what we know of the great legacy left to us by the late Dr. Aoyagi.

Oximetry: Principle, but no theory

First, I would like to share with you one of Dr. Aoyagi’s final wishes. The pulse oximeter is a very special type of patient monitor that still, as of this date, has no standard method of calibration. Dr. Aoyagi always used to say “It is the role of researchers like me to establish a theory, but without a theory, there are limits to what devices can do. It concerns me that clinicians and society at large do not understand how this affects them.” As an engineer and a developer, Dr. Aoyagi depended on clinicians like me to play an educational role and I believe that this memorial edition is important for letting people know about Dr. Aoyagi’s vision.

I am from a generation that experienced anesthesiology before the development of pulse oximeters. I was studying abroad in North America from 1973, when Dr. Aoyagi thought of the principle of pulse oximetry, until the end of 1977. This was just about the time when Minolta began selling a finger type device, and I knew nothing of Dr. Aoyagi’s existence or the idea of pulse oximeters. At that time, it was hard to get up to date information. International telephone calls cost 8000 yen for 3 minutes (the equivalent of 50,000 yen or US$500 now). Japan was just starting to shed the image of Made in Japan = cheap and poorly made. The HP 8-wavelength ear oximeter was already in use at a research laboratory. Although it appeared accurate, it seemed to be cumbersome for clinical use.

It wasn’t until six years after returning to Japan that I met Dr. Aoyagi at a Japanese Subcommittee of the International Organization for Standardization. We attempted, unsuccessfully, to establish a standardized calibration method. In the 36 years since I have had the privilege of learning from him, and having lived through the same generation as a clinician and a developer, I feel a responsibility to record his achievements. I am most grateful for being entrusted with recording how his great invention was born and how it grew.

I hope that by translating the English articles for this memorial into Japanese, a wide range of medical professionals in Japan will learn more about the birth and development of pulse oximetry. At the same time, I hope to use the occasion of publication of this memorial to enable people overseas to learn how this invention, conceived in Japan, has developed and the issues left to be resolved by publishing all the articles in this compilation in English so it is accessible to all.

This memorial issue is being published in order to honor Dr. Aoyagi on the first anniversary of his death. Due to time constraints, the authors did not have much time to write and I appreciate their cooperation. The authors, myself included, are not historians and most never thought they would be called upon to write a memorial article on short notice. There was not enough time to check for objectivity and consistency. There is no doubt that some uncertain statements, based on memories from long ago, are included. I hope you will understand the reasons for this and see there is great meaning in publishing this compilation in terms of further development of pulse oximeters, just as Dr. Aoyagi wished. A short introduction to each of the authors can be found at the end of the compilation.

I am truly grateful to the editorial board for making the publication of this memorial issue possible in a timely fashion, just before the first year after Dr. Aoyagi’s death.

May Dr. Takuo Aoyagi rest in peace.

 

Katsuyuki Miyasaka, M.D., Ph.D.
Executive Advisor to the Dean, Wayo Women’s University
Professor Emeritus, St. Luke’s International University
Tokyo, Japan
March 28, 2021


In summary and in closing this special feature

Background of the contributors and how things developed in Japan: From the inception to the present
☆ Contributors to this memorial issue are noted with this star.

Pulse oximeters can be used on all people no matter their color, race, age, body shape, place of measurement, or type of device. By merely turning on a switch, a clear number from 0-100% is displayed stably and in healthy people a number that “seems right” shows up. But according to Dr. Aoyagi, the basis for the numbers displayed just “happen to look right,” and in order to correctly interpret the results, clinicians must also consider the background in which the number gets displayed. In other words, besides the safety, stability and ease of use of the device, it is important not to overlook the precision and reliability of the measurement parameters, and also to understand the physiological and medical issues involved in order to correctly interpret the number displayed.

Pulse oximeters measure oxygenation, not respiration, but ordinary people and even some medical people tend to overlook this.1 In patients receiving oxygen during sedation for procedures, a display of 100% is not cause for relief. It is a percutaneous measurement subject to various factors, but is highly reliable when there is no body movement with a good pulse. In cases of extremely low measurements, sometimes it is better to believe the numbers than the patient’s clinical presentation. It is known that such lack of knowledge can have unhappy results.2

As has been seen in the COVID-19 pandemic, there are indications that it is possible for such things to occur, as overlooking silent hypoxia in patients with no symptoms3,4 or perhaps in patients under observation at home or other places outside a hospital who suddenly collapse or die.5 Dr. Aoyagi was strongly concerned about the lack of understanding of pulse oximeter measurements, even before the devices became popular with the general public. This concern guided his research on establishing a theory of pulse oximetry in his later years. Even if you don’t consider the pandemic, it has been reported that it is possible that moderate hypoxia in black people is overlooked almost three times as much as it is in white people.6 While skin color may not be a problem in Japan where there is little diversity, it is possible that other such reports will come out from other areas of the world.

The best memorial to Dr. Aoyagi, who died before he could finish his work, would be for those of us in clinical research to spread correct understanding of pulse oximetry to medical professionals and society in general.

Dr. Aoyagi’s contributions and recognition both inside and outside Japan

The inventor of pulse oximetry, Dr. Takuo Aoyagi (1936-2020), died on April 18, 2020. He was 84 years old. The first case of the new corona virus (COVID-19) in Japan was found in mid-January, 2020 and seemed to show signs of being rampant in mid-February. In hindsight, the peak of the first wave (500 cases nationwide) just happened to coincide with Dr. Aoyagi’s demise. Vaccinations in some countries finally started at the end of 2020, but at that point about 83 million people around the world had been infected and 1,850,000 people had died.7 It is thought that pulse oximeters were used in almost all these patients, many outside medical facilities. Dr. Aoyagi didn’t live to see that day. It is regrettable that he left us before he could complete his work on multi-wave theory and its precision and reliability.

Dr. Aoyagi’s passing was reported immediately and widely by foreign media, such as the New York Times (US), Washington Post (US), Globe and Mail (Canada), and CNN (worldwide).8-10 I was struck by the sharp contrast between the high interest shown by those overseas with reporting in Japan.11, 12 I have attended quite a few conferences overseas with Dr. Aoyagi, and have been moved by how researchers around the world would come up to him each and every time to thank him for his invention. I also feel how inadequate was the recognition he was given in Japan. Against this background, the 4th IAMPOV (Innovations and Applications of Monitoring Perfusion, Oxygenation and Ventilation) international symposium was held in Dr. Aoyagi’s home ground, Japan. With the support of the Japan Association for Clinical Monitoring and other groups, a group of approximately 180 enthusiastic people (60 from abroad) gathered in Tokyo. It was a moving experience for 3 days, to see a group of people from all over the world, interested in the same issues, gather and discuss our research freely, with no restraint, regardless of specialty or affiliation. ☆ Comment 1

2015 Tokyo IAMPOV Symposium (Last day, Auditorium at St. Luke’s International University)<br /> (An international symposium on patient monitoring devices and technology related to circulation, oxygenation, and respiration)<br /> Left side: Dr. Takuo Aoyagi<br /> Central area, front row from left to right:<br /> P. Bickler (UCSF), S. Weininger (FDA), S. Barker (Masimo) K. Miyasaka (St. Luke’s)<br /> P. Kyriacou (U. London), B. Kopotic (Edwards), K. Shelley (Yale)

2015 Tokyo IAMPOV Symposium (Last day, Auditorium at St. Luke’s International University)
(An international symposium on patient monitoring devices and technology related to circulation, oxygenation, and respiration)
Left side: Dr. Takuo Aoyagi
Central area, front row from left to right:
P. Bickler (UCSF), S. Weininger (FDA), S. Barker (Masimo) K. Miyasaka (St. Luke’s)
P. Kyriacou (U. London), B. Kopotic (Edwards), K. Shelley (Yale)

Contributors from IAMPOV to this memorial issue are Dr. Bob Kopotic, from the secretariat, and Dr. Kirk Shelley, professor at Yale and the organizer of the 3rd IAMPOV in 2012. Dr. Kirk Shelley, told us how he nominated Dr. Aoyagi for the 2013 Nobel Prize in Physiology or Medicine. Unfortunately, with his death, Dr. Aoyagi will not get the Nobel Prize, but I would like to express my gratitude and respect for Dr. Shelley’s courage in telling us what happened, so that it will not disappear from history.

Dr. Aoyagi has received many honors. In 2015 he was awarded the prestigious IEEE (Institute of Electrical and Electronics Engineers) Medal for Innovations in Healthcare Technology (as prestigious as the Nobel Prize in his field).13 The American Society of Anesthesiology (ASA) voted to give him honorary membership, one of their rare honors, in 2020. ASA will present the award in his memory at their annual meeting in October 2021. On December 25, 2020 he was posthumously awarded the 4th Grand Prize for Medical Research and Development by the Prime Minister of Japan. Mr. Hirokazu Ogino, the CEO of Nihon Kohden received the award on behalf of Dr. Aoyagi. This is the most prestigious award in Japan in this field.14 It can now be said that the reputation of Dr. Aoyagi in Japan has finally caught up to what it is overseas.

Comment 1: IAMPOV (Innovations and Applications of Monitoring Perfusion, Oxygenation and Ventilation)

IAMPOV, an international symposium about medical devices and technology for patient monitoring of perfusion, oxygenation and ventilation started in 2002 as ISIAPOV in Germany by Dr. Ewald Konecny (1935-2019) of Lubeck University. It was an international conference attended by medical engineers, medical clinicians, technical developers from private companies, and officials of regulatory agencies on a volunteer basis. It was a place to talk freely about a wide range of topics related to patient monitoring, mainly pulse oximetry. The 2nd symposium was held in 2007 at Duke University in the US. The 3rd symposium was held as IAMPOV in 2012 at Yale University, sponsored by Dr. Kirk Shelley. The 4th symposium was held in Tokyo at St. Luke’s International University sponsored by Dr. Katsuyuki Miyasaka. The 5th symposium is planned for 2021 at London University in England.

Contributions of pulse oximetry to patient safety

In addition to the great recognition Dr. Aoyagi had previously (IEEE Award and nomination for the Nobel Prize), many others from abroad joined in to add their voices to his memory: Dr. Steve Greenberg of APSF (Anesthesia Patient Safety Foundation, Comment 2)15, Ms. Kitty Jenkin of LifeBox16, and five other individual contributors. One of the founders of the LifeBox Foundation was Dr. Atul Gawande, who was a pioneer in the development of the now indispensable Surgical Check List. The foundation works to make pulse oximeters available to operating rooms around the world. Ms. Kitty Jenkin, in charge of communications at the foundation, has contributed to this memorial issue signed by Dr. Gawande and all the members of the board, representing a wide spectrum of countries and backgrounds.

Eight Japanese people who have worked with Dr. Aoyagi directly have added their articles so that we cover Dr. Aoyagi’s career from his initial ideas to what we know of him today. I believe we have covered all the steps of the development of pulse oximeters and the important roles other people played. Fortunately, most people have clear memories and impressions, and I’m sure Dr. Aoyagi would have been very proud of what they wrote. ☆ Comments 2 and 3

Comment 2: The Anesthesia Patient Safety Foundation (APSF)

APSF works closely with the American Society of Anesthesiologists (ASA) and is dedicated to promoting patient safety in anesthesia. It has encouraged the use of pulse oximeters during anesthesia since the 1980s. The APSF Newsletter is currently distributed to 200,000 people all over the world who are working in anesthesia. The Japanese Society of Anesthesiologists has issued a Japanese translation of parts of the newsletter since 2017. The current editor in chief of this newsletter is Dr. Steve Greenberg, who participated in IAMPOV 2015.

Pulse oximetry: Two beginnings

The invention of pulse oximetry started in Japan and is now used in both medicine and by ordinary people around the world. Surprisingly enough, two patents were filed at almost the same time in 1974. Dr. Aoyagi, on behalf of Nihon Kohden (patent filed March 29, 1974) and Mr. Akio Yamanishi, on behalf of Minolta (patent filed April 24, 1974) came upon this idea completely independently.17, 18 Dr. Aoyagi’s device, that came first, used a dye densitometer on the earlobe to measure cardiac output. He came upon his idea during an experiment to eliminate superimposed pulsation noise. His light source was an incandescent lightbulb and his point of measurement was the earlobe, both of which made it difficult to develop a practical device and the project ended. Chances are that it was not pursued because the invention was a side product and did not align with the company’s main project. Comment 3

Dr. Aoyagi reported on his invention to his supervisor, and it just happened that a physician the supervisor was visiting heard about it and work on a prototype was started. They were less interested in the significance of oxygen saturation and were mainly looking at new methods of measurement. Dr. Aoyagi told me that once the paper was published, there was no more mention of turning it into a clinical device. I don’t know what really happened, but the result is as we know it. But Aoyagi continued his research into establishing a theory of measurement through the years, and after a break of about 10 years, Nihon Kohden renewed its development. They allowed Dr. Aoyagi to pursue his research until the end and Dr. Aoyagi fulfilled their expectations.

On another front, Mr. Akio Yamanishi’s group was taking advantage of the new LED technology to develop fingertip plethysmography, etc. and the development of a pulse oximeter was one of their primary projects. They succeeded in developing the world’s first fingertip pulse oximeter. Two contributors to this issue, Dr. Ikuto Yoshiya (Anesthesia Professor at Osaka University at the time) and Dr. Yasuhiro Shimada (Assistant Professor at the same university) were involved, but their contributions were limited to improving precision through analysis.19 Minolta started selling their device (OXIMET 1471) through Mochida Pharmaceuticals in June 1977, but rather than using LED as a light source, they used a combination of tungsten and fiberoptic cable, so although the device was usable, it was difficult to operate. It is possible that the red spectrum in LEDs at the time was not sufficient, but it was an unfortunate choice.

I would like to note that there was absolutely no sense of competition between Nihon Kohden and Minolta at the time. Minolta had been pursuing this project since the late 1960s at the time of the Apollo Project, so as part of the company’s protocols, they began to apply for a patent for Yamanishi’s group at the end of 1973. Dr. Aoyagi’s application, sent in before his presentation at a conference, just happened to arrive at the patent office a few weeks earlier. I can only imagine how shocked the Minolta group must have been. Dr. Aoyagi’s patent was restricted to within Japan, but Minolta obtained an international patent. I do not have detailed patent information and I have no idea how latecomers managed to overcome patent issues, but it was good for mankind that Dr. Aoyagi’s patent did not restrict the sound competition of pulse oximeter development.

Most of the information on Dr. Aoyagi is only in Japanese, and his company, Nihon Kohden, did not try to develop the product. In 1987, Dr. John Severinghaus discovered Aoyagi’s achievements and made him known to the world, including Japan which was unaware of his invention. The first serious published paper on pulse oximeters in English was written by Dr. Yoshiya in 198020 and influenced researchers and inventors all over the world (Pierce EC: ASA The 34th Rovenstine Lecture, 1995). This history is already well known, and on behalf of Dr. Severinghaus, who is advanced in years, Dr. Robert Kopotic, a central figure in IAMPOV, has written some of this history for us (photo from 2012).

3rd IAMPOV Symposium, 2012, at the award ceremony<br /> From left:<br /> Dr. Takuo Aoyagi, Professor John Severinghaus, Dr. Katsuyuki Miyasaka (the author)

3rd IAMPOV Symposium, 2012, at the award ceremony
From left:
Dr. Takuo Aoyagi, Professor John Severinghaus, Dr. Katsuyuki Miyasaka (the author)

Comment 3: Possible reasons Nihon Kohden stopped their development of the pulse oximeter

There are many possible reasons Nihon Kohden stopped their development of pulse oximeters, even while holding the rights to Dr. Aoyagi’s invention. Dr. Aoyagi himself often said it was simply because he couldn’t get the understanding of his co-workers at the company. He also said that the founder of the company, Dr. Yoshio Ogino, a physician and president of the company at that time, understood and encouraged him. It is not clear what he meant by “understanding.”

In any event, the project was put on hold for about 10 years. It seems strange when you think about how other companies in Japan and around the world continued with development during that period. But by reading what one of Dr. Aoyagi’s co-workers wrote in his contribution to this memorial issue, it starts to make more sense. Dr. Aoyagi’s invention was a by-product of research being conducted on dye dilution cardiac output measurement using a densitometer for the ear. The light source they used was an incandescent bulb that was received by a photo-transistor. It was problematic in terms of stability, but the project was not ready to try the brand-new LED technology.

The existence of LED technology was known at the time (1974) and the Minolta group was already using it in other devices. The device developed by Nellcor several years later used LED on the fingertip, and Biox, which had developed and was selling an early version of the pulse oximeter, used LED in their ear oximeter. These devices were technologically complete and of high quality. Perhaps the biggest problem in Japan was that there was little motivation to develop the idea into a clinical device. There was no system in place for the technology side to get clinicians involved, and the physicians themselves who were in a position to evaluate trial devices had little interest in or understanding at the time of the clinical significance of continuous monitoring of oxygenation.

This situation, where clinical needs are not necessarily assumed from the beginning, and where technology is of utmost importance for new devices, is one of the reasons clinicians show little interest until the device is already evaluated and a manuscript for publication is close at hand. This can be seen even now in academic physicians and is a problem not of the individual, but of the environment in Japanese medicine. I think the divide between clinicians and medical device developers was an influence.

The story of capnometers may look like the opposite is true. They have been used in anesthesia for 70 years. The rate of use in intubated patients is high, but their rate of use in non-intubated patients is still extremely low. I don’t think this is because the voice of clinicians is not reaching technology experts, but because there is no sense of awareness among clinicians of its importance.

When the use of pulse oximeters spread from the operating room to hospital wards, there was a big problem with frequent false alarms caused by body movement. The presence of anesthesiologists who understood the problem and could explain the necessity for and reasoning behind the device was very important, and I hope the same thing will happen to promote the use of capnometry in non-intubated patients. The success of the development of medical devices is not just dependent on technology, but needs a strategy with an all-encompassing view of the process from development to its clinical use.

Comment 4: Why didn’t Minolta succeed early on

Minolta had a very proficient technology team, that had helped work on the Apollo Project, and was working on new projects to develop new medical devices. They were working on finger plethysmograms using LEDs, so the development of pulse oximetry clearly would have been one of their goals. There is no doubt that Minolta was shocked by Dr. Aoyagi’s patent, but they continued development, certain of their superior technology compared to Nihon Kohden, indeed, compared to the world. We can assume that technology led their developmental process. While possessing the highest technology, their first device, MET 1471, did not use LEDs. It is not clear why they developed a completely analog device, except for the number display. I have had actual experience using MET 147121, and including measurements from the finger, it was a finely finished device. A) There was no problem with its use on patients under anesthesia who didn’t move, or on quiet infants.

While it was a technologically complete device, as a patient monitor, it was very difficult to use in terms of attaching probes and reading the number display (the display showed fractions of numbers, changing with every pulse beat, with a display of well over 100%). I thought the interface with humans needed quite a bit of work. I gave the developer a long list of things I thought should be improved when he came a few days later. Many years have passed since then, and now I know that my comments (list) never reached the team leader, Mr. Akio Yamanishi.22

The test device was offered for use in the US at the same time, but as it was introduced not by the technology development team, but by an outside trading company, it is believed that as a result, the technology could easily have been leaked. As it turns out, this was a good thing. Amidst all this, things just like I wrote in my list that most likely could only come from a pediatric anesthesiologist, were being shared with people involved in the project. While I remember being happy that my ideas were being heard, I was also quite surprised.

Clinical significance unrecognized in Japan

The OXIMET 1471 pulse oximeter that went on the market in 1977 seems to have been reviewed by several university academic anesthesiologists in Japan.23 However, while the device was judged to be useful at some level as a research measurement device, it seems that either there were no suggestions to help it spread as a clinical device or that if there were, they were not heeded. Only 200 devices in total were sold. Dr. Kunio Suwa (Associate Professor of Anesthesiology at Tokyo University) tried it out in 1992 on his own volition24, but unfortunately even then, as now, a structural problem existed in Japan’s medical device industry.

The very first time Dr. Aoyagi presented his invention, the pulse oximeter, to Japanese anesthesiologists was in 1989 at The Japan Society for Clinical Anesthesia Academic Meeting in Tokyo. At that time, most anesthesiologists in Japan had heard of Nihon Kohden, where Dr. Aoyagi worked, but it wasn’t until 2002 when the Japanese Society of Anesthesiologists gave Dr. Aoyagi an award for his contribution to society, that his name and Nihon Kohden’s pulse oximeter became familiar to anesthesiologists in Japan. The first person to tell the world about Aoyagi’s achievements was, as mentioned above, Dr. Severinghaus of UCSF.25,26 Dr. Severinghaus himself has made great contributions to the field of blood gas analysis and is known for his development of an electrode for partial pressure measurement of CO2.

Minolta’s OXIMET-1471 pulse oximeter goes to the US

A large Japanese trading company tried to sell Minolta’s OXIMET-1471 pulse oximeter in the US, and in connection with this, they offered use of the machine for evaluation to an anesthesiologist (Dr. Charles Whitcher) at Stanford University in 1977 and it was used clinically.27 (Personal communication from Mr. Akio Yamanishi) The development team at Minolta focused on scientific analysis of the tendency to overestimate at low oxygenation levels, but they were not particularly interested in making improvements to make the machine easier to use on patients in a clinical setting.

But this offering turned into an opportunity as it can be thought that Dr. William New saw the device. Dr. New, who later founded Nellcor and who used to work for HP as an engineer, played an extremely important role in the development of the currently used clinical pulse oximeter. Dr. New is an anesthesiologist who has a background in electrical engineering and biology. He was working in the same hospital as Dr. Whitcher at the time. Dr. New was very familiar with the HP ear oximeter.

HP Company ad for an ear oximeter (1973)<br /> 8 wavelengths (650-1050nm), heated ear probe to obtain arterialization<br /> It was accurate, but large and hard to operate. It was not a monitor

HP Company ad for an ear oximeter (1973)
8 wavelengths (650-1050nm), heated ear probe to obtain arterialization
It was accurate, but large and hard to operate. It was not a monitor

In 1980, Professor Whitcher’s group reported on the Minolta Oximeter Model 101 (OXIMET-1471) at the Annual Meeting of the American Society of Anesthesiologists (ASA). They clinically evaluated the device on 5 healthy male subjects and indicated the possibility of its being a clinically effective way to pinpoint the tendency to overestimate at low oxygenation levels. Their abstract quotes from an article by Suzukawa in 1978 (translated into English)23, but the presentation at ASA was not published.

Corning Medical was also involved in this research as they had just started to sell an invasive blood gas analyzer in Japan. I had a chance to visit Corning in October 1982 for a different reason and I was asked about it directly, but it is unclear how the relationship between Corning and Minolta developed afterward. This story is from the year before Nellcor started selling the N-100.

Minolta contributed to the initial spread of pulse oximeters and OXIMET-1471 was good enough. (Minolta played an important role in the initial spread of pulse oximeters and OXIMET-1471 was equipped with very high standard technology.) The precision was at research level and impressive, but without the system needed for Japanese anesthesiologists to give appropriate feedback on its usefulness as a clinical device, there was no way to improve it enough to take advantage of being the front runner.

Nellcor appears on the scene

Nellcor was founded in 1981. A close copy of the fingertip device by Minolta was made into the prototype N-100A in 1982 and was being sold in 1983.28 It was significantly and overwhelmingly an excellent device in terms of performance, design, operability and clinical sensibility. A rise in the call for safety awareness in anesthesia also helped the device spread rapidly. The founder of the company himself was an anesthesiologist, but advice from pediatric anesthesiologists was taken into account during development. The latest and most important pulse oximeter for anesthesia to hit the market, and the one that played a major role, was Nellcor’s. Dr. William New, its founder, passed away in 2017 and unfortunately, none of the people close to him that I contacted were available to write an article for this memorial.

With great luck, I learned that Dr. David J. Steward (at that time at the Hospital for Sick Children in Toronto) had been asked directly by Dr. New to evaluate the prototype Nellcor N-100A. He agreed to write about what he knew and submitted an invaluable photo of the prototype N-100A. I knew Dr. R. Raphaely (staff at the pediatric anesthesia department of the Children’s Hospital of Philadelphia), the person who introduced Dr. New to Dr. Steward. I knew most of what happened after, but this was the missing link! The secret to the success of the Nellcor N-100 lay in the input from top level clinical pediatric anesthesiologists. There is no doubt that the spread of pulse oximeter use in a clinical setting was due to the proficient efforts of Nellcor in making early and skillful use of recently matured LED technology from Japan and putting everything together to make a practical clinical monitor.

There is also another factor, the raised social awareness of the number of malpractice cases charged against anesthesiologists in the US and the high cost of malpractice insurance for anesthesiologists in the US in the 1980s. Above all, in 1986 the ASA Guidelines for anesthesia monitoring included the use of pulse oximeters as one possible choice. These Guidelines spread, not just in the US, but all over the world and were a big turning point for anesthesia safety.

Increased momentum for awareness of anesthesia safety in the US

There were many factors in the movement to improve patient safety during anesthesia, boosted by Cooper’s study in the late 1970s.29 The high cost of malpractice insurance for anesthesiologists led to the discussion of formulating the “Harvard Guidelines,” drawn up by a group of people from the hospitals associated with Harvard University (1983). Other factors were ABC’s television documentary “The Deep Sleep: 6,000 Will Die or Suffer Brain Damage”(1982), the establishment of APSF, and incorporation of the ASA Guidelines. Dr. Jeffrey Cooper☆, known as the Father of Patient Safety, was involved in the formulation of the “Harvard Guidelines” and has written an article for this memorial.

He discusses the role played by numerous factors such as the possibilities of non-invasive measurement (inventions), the development of excellent devices based on human engineering (Nellcor N-100), and education about the clinical significance of monitoring (ASA Monitor Standards).

Japanese companies were left behind as they were unable to fathom the wave of the times. They couldn’t see the importance of the background of devices, in other words, it wasn’t just technology that was important, but the role of the people for whom the device is being created. There was a lack of understanding of the importance of such factors as cooperation between the developers of medical devices and the clinical setting, including social aspects. There was also a lack of understanding of the entire production process, including education and how products reach clinicians and are applied (concept of BioDesign).30

When the Harvard Guidelines started to be discussed in the early 1980s, one of the most important missions was to establish rules that anesthesiologists would have to adhere to, even in the country of the free. Discussion was focused on fundamentally important issues that no conscientious anesthesiologist could argue, such as having anesthesiologists be physically present, rather than introducing still arguable monitoring devices.

Thus, although incorporating the use of capnometers or pulse oximeters in the guidelines was discussed, they were eventually left out because they were still in the early stages of development.31 The ASA Anesthesia Standards from 1986 recommend the use of oxygenation monitors, but the requirement to use pulse oximeters didn’t come until 1989 when the standards were amended. Up until this point, the issue of anesthesia safety was centered mainly on activity in the US, just as Nellcor’s N-100 was playing a central role in the market.

But in 1984, the British giant BOC/Ohmeda procured an American firm Biox and new activity began in England. Biox products were widely used in Japan and played a central role.

Comment 5: Research measurement devices and clinical monitoring devices

Oxygenation values arbitrarily showed up from around 90% to 120% soon after attaching a probe to the patients finger in the early version of Minolta’s OXIMET-1471. The device had a calibration knob that adjusted digital number values making it possible to make appropriate adjustments at the bedside. You could set blood gas values to match the patient’s oxygenation at the start of measurement, so it would display correct values thereafter. The developers would say that if the display shows 100%, then you can believe that it really is 100%. The display also showed very specific values to one decimal point at each heartbeat (say 95.6%). In actual use however, after you calibrated the device to the patient’s blood gas levels, it was not unusual to see numbers from 100% or much more, baffling clinicians. Still, with further improvement, it was a device that had great possibilities as a monitor.

The person who brought the device to me at the time said, “You can calibrate it any time you need to. Since it doesn’t always show 100, it shows you can trust it.” Well certainly there was some truth to this, but the problem was you never knew when calibration would be needed. I explained “Clinicians want a monitor to tell them whether oxygenation is good or bad; we don’t need decimal level precision. Unless you can tell us whether it’s 100% or less than 90% from as soon as you attach the device, it cannot be used as a monitor. Also, displays that change every heartbeat are impossible to read.” He was not pleased, to say the least, and he never returned. Fortunately, after that, pulse oximeters in general developed along the lines I spoke about and their development continues to this day.

As time goes by, pulse oximeters that have fulfilled their role as non-invasive general monitors. It may now be necessary for people to think about what they want from measurement devices in terms of precision and stability. In order for this to happen, we need to establish the theory Dr. Aoyagi sought after. Interpreting the values displayed requires an understanding of medicine. This applies not only to medical professionals, but general society as well.

Influence of Biox/Ohmeda

The American market for oximeters started in 1979 with Biox’s (Denver) device, Biox II. According to Dr. Jonas Pologe (personal communication) who was involved in development at Biox, the device, an ear oximeter, was made after considerable study of both Aoyagi’s and Minolta’s published reports. I did clinical research on Biox III in the latter half of 1984 in Japan and found it to work in a clinical setting with good performance. I reported on this research in 1985.32 It was a stable and convenient patient monitor during anesthesia, and while it was better than Minolta’s or Nellcor’s devices, it was primarily a research device designed for respiratory internists. With little input from clinical anesthesiologists at Biox, Nellcor’s device, that came after, was clearly and overwhelmingly better for clinical use.

In 1984, Biox was bought by the British Company BOC, a world leader at the time in anesthesia related products. The fingertip model, Biox 3700, was introduced.33 In anticipation of selling in Japan, they sought input from Japanese sales offices and anesthesiologists. Improvements, such as waveform display and the shape of re-usable probes, were made. The efforts by Mr. Yasuhiko Sata (Tokibo) to use sales techniques unique to Japan were successful, and in Japan, Biox sold much more than Nellcor that had already captured the anesthesia market in North America and Europe. At this point, neither Nihon Kohden nor Minolta had products that were better than foreign ones. The domination of the Japanese market by foreign brands continued.

Widening interest in research

Approximately 50 world leaders in physiology and anesthesiology, including Dr. Jim Payne and Dr. John Nunn from England and Dr. John Severinghaus and Dr. Kevin Tremper from the US, gathered in Chartridge, a suburb outside London in May 1985.34 From Japan, Dr. Kunio Suwa (Tokyo University, Anesthesia Department) talked about the oxygen dissociation curve35, and Dr. Katsuyuki Miyasaka (National Children’s Hospital, Anesthesia Department), the sole pediatric anesthesiologist there, talked about his clinical experience with tragus probes adapted from adult earlobe probes for Biox III in pediatric patients.32 The conference provided an opportunity to discuss a wide range of issues from the definition of SpO2 and the categorization of oxygen saturation, to the clinical usefulness of pulse oximetry and the significance of biological research.

Top left: International conference at Chartridge Seminar House<br /> Held May 1985 at a suburb of London with 50 participants<br /> Definition of SpO<sub>2</sub>, discussion of how to think about oxygen saturation<br /> Bottom left: Published proceedings of the Chartridge Conference<br /> Top right: May 1987, Hakone Fujiya Hotel in Kanagawa Prefecture<br /> International conference on neonates and pediatric patients with about 20 participants<br /> From TcPO<sub>2</sub> to SpO<sub>2</sub><br /> Bottom right: Published proceedings of the Hakone Conference

Top left: International conference at Chartridge Seminar House
Held May 1985 at a suburb of London with 50 participants
Definition of SpO2, discussion of how to think about oxygen saturation
Bottom left: Published proceedings of the Chartridge Conference
Top right: May 1987, Hakone Fujiya Hotel in Kanagawa Prefecture
International conference on neonates and pediatric patients with about 20 participants
From TcPO2 to SpO2
Bottom right: Published proceedings of the Hakone Conference

In response to this, in 1986, Dr. Kunio Suwa☆ (Tokyo University, Associate Professor), Shosuke Takahashi (Kyushu University, Professor of Anesthesia) and Dr. Hiroshi Sankawa (National Children’s Hospital, head of the Anesthesia Department) were the primary movers to start the Japan Research Group on Pulse Oximetry.24 In 1987, Dr. Katsuyuki Miyasaka (National Children’s Hospital, Department of Anesthesia) organized an international conference (Hakone Conference) to discuss the use of pulse oximeters primarily in neonatal medicine.36 Sales of the Biox 3700 in Japan suddenly started to grow in the fields of anesthesia and NICU. Dr. Hiroshi Nishida (Tokyo Women’s Medical College, Professor Emeritus) recalls the important role that pulse oximetry played in increasing a healthy interest in such hot topics as prevention of retinopathy of prematurity, lung surfactant replacement therapy, and high frequency oscillation (HFO).

From Anesthesia to Critical Care

The Japanese Society of Anesthesiologists created their first safety guidelines (Monitoring Guidelines for Anesthesia Safety) and recommended use of pulse oximeters during anesthesia. This was 7 years after ASA released their first Monitoring Guidelines for Anesthesia in 1986 in the US.37 Professor Shosuke Takahashi played an important role, but more than half of physicians who engaged in anesthesia did not have access to even one pulse oximeter in their institutions. Domestic competition was practically non-existent. Interest in pulse oximeters grew rapidly in the field of anesthesia, but when their use expanded from during anesthesia when patients didn’t move to the recovery room, ICU and general wards, a big problem arose in how to deal with false alarms from body movement. When venous waves are superimposed on pulse waves, the convenient assumption of pulse oximeters that all pulsation is arterial pulsation no longer holds. In efforts to decrease false alarms, many strategies were tried such as temporarily freezing alarm information, prolonging the moving average time of the data, and extraction of the arterial waveform during synchronization with electrocardiograms, but none of these served as a fundamental solution.

A group from the Masimo Corporation, founded in 1989 by Mr. Joe Kiani, focused on the problem of false alarms from body movement (in other words how to deal with body movement and low perfusion) in pediatric patients with heart disease who tend to be agitated and move a lot, and unavoidable body activity in the PICU (Pediatric Intensive Care), as compared to adult ICUs or NICUs.

Emergence of Masimo Corporation

From the early 1990s, the Masimo Corporation, looking into cooperation with the major electronic company NEC, found little interest in the problem of body movement in the field of anesthesia in adults, so they developed deeper relationships with Dr. Katsuyuki Miyasaka and Dr. Yasuyuki Suzuki from the Intensive Care Department of the National Children’s Hospital (now the National Center for Child Health and Development). They were studying the reliability of and problem of false alarms in respiratory monitors in pediatric ICUs and respiratory therapy in home care pediatric patients.38 They had also introduced a project called the “Sound of Silence” to address the problem of alarm fatigue in pediatric anesthesia and pediatric ICUs such that all alarms were silenced within 3 times of beeping. Thus, they were able to obtain many hours of raw data and video recordings from pulse oximeters and patients. It was not a comparative study and it was not published, but this data on Japanese patients in pediatric ICUs helped strengthen strategies to deal with body movement, and thus low perfusion in adults. It helped in improving of Masimo SET (ver. 2.2) that functions well even in patients who move (2000).39,40

Even without a theory of pulse oximetry, they developed a method of measuring SpO2 using arithmetic chips and powerful statistical methods. They further added multiple wavelengths, and are introducing new monitor indices such as carboxyhemoglobin and other abnormal hemoglobins, total hemoglobin, oxygen reserve index (ORI), and various circulating blood volume indices. They are pioneering a road of their own. This is a little different from big data analysis, but by proceeding from special extractions and relative relationships, they found causal relationships and I hope this will result in the establishment of a theory.

Nihon Kohden starts development of pulse oximeters again; problems with multi-wavelengths and precision

In 1984, Dr. Aoyagi was put back in charge of the development of pulse oximeters at Nihon Kohen. Dr. Aoyagi formed a team including Mr. Masayoshi Fuse and Dr. Naoki Kobayashi. As opposed to the clinical, practical approach that helped Masimo succeed, Nihon Kohden followed a conservative, theoretical approach to achieve great precision.

The theory of multi-wavelengths (5 wavelengths) was proposed in 200841 and was established by Dr. Aoyagi in 2015, but they are still verifying the theory and no product has been made. However, this cautious approach is not necessarily a failure to act. A long term issue for the prevention and survival prognosis of neonatal retinopathy was about the need to adjust the threshold for low perfusion or adjust the fine calibration curve.42 In 2020, the topic of the clinical significance of measurement differences due to racial differences (skin color)6 came up, but there was little basis for discussion because there was no theory and no way to compare numbers using a standardized calibration. The only conclusion is that we’ve reached a limit. In other words, conveniently neglecting differences in skin color, race, adults, infants, body shape, place of measurement, device, etc. is not questioned for the sake of convenience. It is impossible to standardize calibration using actual measurements on human beings who can’t be standardized (no more than calibration can be standardized), between manufacturers and devices, different probes, etc. The road laid down for us by Dr. Aoyagi is of great importance to break the deadlock of the acceptance of differences of 1-2% especially in the low SpO2 range and to establish a theory, as emphasized by Nihon Kohden.

The challenge of in vitro calibration

Dr. Aoyagi and I have known each other since 1980. In our work for ISO TC-121 SC3 (mainly patient monitor devices), we came to be concerned about the precision of pulse oximeters that were being produced without regard for the lack of a method for standard calibration. As ISO searched for a solution for a standard, I suggested incorporating the device into an international standard, without fully understanding the reason for why there was no calibration standard. I ended up being put in charge. Fortunately, Mr. Yamanishi and Dr. Aoyagi were able to participate in the project. At the time I was using a small roller pump for development of the world’s smallest ECMO for pediatrics43, and I figured out that if I clipped a probe onto the circuit, I could get decent pulsation. Without sacrificing any people, I thought I could calibrate under extreme hypoxic conditions.

We might have a principle of pulse oximetry, but no theory

When I told Dr. Aoyagi my idea, he said in no uncertain terms “That’s pointless, pulse oximetry has a principle, but it doesn’t have a theory.” Struck by this Zen-like opinion, I was deeply shocked. In the 40 years since I’ve known Dr. Aoyagi, he never used strong words like that again. After a short discussion, I said, “Well, it’s your job to establish a theory or whatever. If you don’t, you won’t get a Nobel Prize.” In response to my young arrogance, his manner fell apart and he said, “Aah. You won that one.” Then he gave a carefree smile, and with a gesture of friendship, stopped the argument, and continued his considerate explanation with a pencil.

Research on multi-wavelengths

In the end, I never succeeded in establishing an in vitro calibration method44 for ISO, but this was the same as saying the theory had not been established. The most recent ISO standard ended up mandating empirical calibration using blood sampling in healthy adults who are exposed to a non-physiological level of hypoxia. Thus the accuracy of currently available pulse oximeters ignores such factors as race, age (adult or child), or individual devices. Dr. Hironami Kubota questions whether regular household devices really need to go through such a complicated calibration process. It is a very complicated issue.

Dr. Aoyagi started working on a complete theory and after verification with experiments with multi-wavelength simulation models that took into account light scattering and pulsation, and also the effect of surrounding tissue, he presented his work at IAMPOV 2015 (Tokyo).45 The main reason for his studies using multi-wavelengths was to improve precision. But since he wasn’t looking at such factors as abnormal hemoglobin, I think it is possible his research was not considered important enough to result in product development and never became a major project.

Research that was a stretch

Against this background, Dr. Aoyagi continued his experiments where a small number of subjects held their breath to create a state of hypoxia, sometimes for a long time. He came to my research lab at the hospital when he felt there was a chance that it would help to have a doctor around. The subjects usually were himself and Mr. Masayoshi Fuse, a long-time member of his team. Over 70 years of age, he felt the overstretched research was ghastly.46 As a result, the issues for Dr. Aoyagi’s multi-wavelength theory have not yet been fully verified or followed up. As someone who represents the researchers continuing Dr. Aoyagi’s work, Mr. Kazumasa Ito, who worked on Dr. Aoyagi’s later research, is committed to solving this difficult problem, and has submitted an article to this memorial issue that shows his dedication to this cause.

The spread of pulse oximeters in society and the issues involved

While Dr. Aoyagi was pleased with the widespread use of pulse oximeters, he feared that without a theory, the number displayed might take on a life of its own. It is not possible to rule out the influence this strong reluctance Dr. Aoyagi had about believing the reliability of the number displayed had on how he didn’t come up with a product. But under the shadow of the great usefulness of the device for COVID-19, it is a concern that pulse oximeters are being used not just in the operating room, but everywhere, by medical professionals and ordinary people alike, without a proper understanding of what it means.

Mr. Hironami Kubota, who once worked at Nihon Kohden at the same time as Dr. Aoyagi and engaged in the development of central patient monitoring systems, has added a discussion to his article in this memorial issue about how the use of pulse oximeters, developed for use on seriously ill patients in a special environment, does not match its current use elsewhere, from general patient wards to the non-medical general population. While pulse oximeters are classified as medical devices requiring regular maintenance in Japan, they are being used widely by the general population without being aware of what they are, or even escaping safety rules by being embedded in a large number of products. Their performance is improving as a common device and the difference between pulse oximeters for medical use is hard to understand. Noninvasive patient monitors, such as pulse oximeters in wearable form, will continue to flood the market and influence our daily lives. They cause little harm as electronic devices, but if you misinterpret the numbers displayed, critical harm can result. The current regulatory system to protect users from suffering this kind of harm is inadequate.

We, as clinicians, have to inform people of possible dangers from these devices. It is becoming more and more important to let people know how to interpret the number displayed. Although the device is not recommended for running or for measurements other than on the fingertip, they are used without a second thought if the number displayed looks right. There is no problem legally speaking if the number displayed is not on a device labeled for medical use. In the current state of affairs, where the appropriate use of pulse oximeters is not guaranteed, people won’t even be able to tell if a device is poorly made as long as the number looks right. When something that can be used by anybody by just clipping on a probe and reading a number, combined with the situation where pulsations of healthy people are strong, any product will show “normal” values. Even if there was a dangerous condition, no one would notice a problem as long as the number is within the “normal” range.

Even if you don’t call it a diagnosis, interpreting the number shown, or particularly judging the line between normal and not normal, requires medical understanding. While it is necessary to educate users about correctly understanding the number, the regulations demanding proper education of the general public in Japan are vague. The manuals included in the devices say “seek a doctor’s opinion if there is a problem,” but this warning is of no use to the lay public because as things are now, there is no way for them to know if there is a problem or not. However, people use the device to “find a problem.” Thus the user is left believing in the device without adequate understanding and no one including the company or government has responsibility for misuse of the device.

While the authorities in charge may be interested in the safety of electronic products, they are not interested in how the numbers displayed are interpreted or in the safety of the medical device embedded in the device. There are very few cases where clinicians are involved in product inspection. Our mission is to educate the public whenever we have a chance and provide them with the knowledge they need to evaluate products where medical quality and non-medical quality products are combined.

Epilogue

After participating in this memorial issue and reading all the manuscripts, I feel great gratitude for the immense contribution Dr. Aoyagi made to human health. When I think how the lives of so many people have been saved and how many more will be saved in the future, I feel incredibly fortunate to have lived and worked with Dr. Aoyagi. In 2000, I co-authored a paper, “Theory and applications of pulse spectrophotometry,”47 which raised my expectations as a clinical researcher for the future of pulse oximetry in the next generation of patient monitors. I realized how privileged I was to have helped develop pulse oximetry for 30 years, but I felt how much regret Dr. Aoyagi had for leaving his task unfinished, while the rest of us continued to treat cavalierly the lack of the true basis of measurement, the theory. Planning for this memorial issue has helped me realize that on the other side of his great contribution to clinical medicine, was the limited number of clinicians directly involved.

It is not that Dr. Aoyagi was untalkative or anti-social, but he definitely didn’t talk much about things other than his research. I knew him for the better part of 35 years, but even if we talked a bit about art, I don’t remember ever talking to him about his family or him personally. I guess I too belong to an era of Japan where that was not unusual.

I must make special note of the fact that I never once stepped into Dr. Aoyagi’s research lab. He always came alone to the room where I worked in the hospital, waiting to talk in between patients. Sometimes he would let me know ahead of time and send documents for me to read, and sometimes I had the chance to hear him discuss things for hours. That time was so special, but I couldn’t share it with my staff because it was not possible to fit it in around our work schedules. Truthfully, I didn’t know what Dr. Aoyagi’s position was in his company or what his research and development goals were. I don’t think he had the opportunity to let his supervisors in his company know what was really on his mind. The fact that it was not possible to create a structure to join the forces of a top-class research developer from a privately-owned company with a physician like me, working in a national hospital, is typical of the limitations faced by scientists trying to develop new medical devices in Japan.

There is a distinct difference between evaluating “finished” pharmaceuticals and “unfinished” developing medical devices. How to apply carries of paramount importance in medical device development and user and developer to work together in developing new medical devices is essential. Unfortunately, even now there is no such system of cooperation in public hospitals in Japan, rather it is restricted.

Dr. Aoyagi’s explanations and his presentations at conferences had a very unique style using Excel for projection and hand-written explanations. His unique structural style was convincing. You can see this in his invention notes from 1973.48 Somehow he reminds me of Maestro Herbert Blomstedt, the 93 year old conductor (Honorary Conductor Laureate of the NHK Symphony Orchestra) in manner and looks. The Dr. Aoyagi I know outside of work is a person with deep knowledge of music and art. Sometimes he surprised me with his extraordinary knowledge of art history and the arts. He was like a pure young man who threw himself fully into whatever interested him.

Figure 5: Dr. Aoyagi showing his work to Dr. Byron Aoki of the University of Hawaii<br /> At the author’s office,<br /> Head of the department of anesthesia and ICU<br /> National Center for Child Health and Development, 2002

Figure 5: Dr. Aoyagi showing his work to Dr. Byron Aoki of the University of Hawaii
At the author’s office,
Head of the department of anesthesia and ICU
National Center for Child Health and Development, 2002

I have a special memory from being with him at a meeting of ISO in September 1987 in Moscow, part of the previous Soviet Union. At the time, the Soviet Union was subject to the ups and downs of perestroika, a bit like what things are like in North Korea now. Dr. Aoyagi arrived at the Moscow airport on a different plane from me and was supposed to give me my visa. But he forgot and had passed through immigration, leaving me in the hands of Soviet immigration for an entire day at the airport. He never realized the seriousness of my situation at the time.

During the same trip, I had a chance to go to the Hermitage Art Museum in St. Petersburg with him. We entered the main hall and he just stood there, back straight, white mask, and not moving. It was rather suspicious drawing the attention of the secret police. He was looking on, blissfully unaware of what was going on. He continued his tour of the museum for several hours happily without noticing the turbulence behind him.49 Things in Russia are very different now, and it would not be unusual to see an Asian person or even a Russian person in a mask. As far as Aoyagi was concerned, he was just overwhelmed by the sheer number of famous paintings. I was faced with the unlucky task of standing up to the KGB, but in the face of Dr. Aoyagi’s childlike innocence, I couldn’t get myself to try to explain things to him. I will never forget this.

In closing

Dr. Aoyagi presented his principle of pulse oximeters for the first time at a conference in 1974. The session was chaired by Dr. Tatsuo Togawa (Professor of Medical Engineering at the Tokyo Medical and Dental University), a prominent scientist in the field. Dr. Togawa stated in 2011 that pulse oximeters have developed much more than could be imagined even then from Dr. Aoyagi’s presentation.50 The possibilities for pulse oximetry using multi-wavelengths are many, including the establishment of a standard method of calibration, improvement in the precision of measurements during low perfusion or body movement, and by including the measurement of other substances or metabolic situations. It may even be possible for it to act like pulse spectrophotometry.47 This may not be as easy as it sounds to a clinician, but placing our hopes with the scientists following Mr. Aoyagi, I would like to express my gratitude for the great contributions made by Dr. Takuo Aoyagi in this field.

May he rest in peace.

 

Katsuyuki Miyasaka, M.D., Ph.D.
Executive Advisor to the Dean, Wayo Women’s University
Professor Emeritus, St. Luke’s International University
Tokyo, Japan
March 28, 2021

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Read more articles from this special collection hosted by the APSF on Pulse Oximetry and the Legacy of Dr. Takuo Aoyagi.