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Keywords:

  • George Gregory;
  • continuous positive airway pressure;
  • hyaline membrane disease;
  • idiopathic respiratory distress syndrome;
  • neonatal respiratory distress syndrome

Summary

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References

George Gregory, M.D. (1934-), Professor Emeritus at the University of California, San Francisco, has made numerous contributions to neonatology and pediatric anesthesia through his research efforts and authoritative textbook, Gregory's Pediatric Anesthesia. However he identified his defining moment as the occasion he saved the life of an infant suffering from neonatal respiratory distress syndrome by using continuous positive airway pressure (CPAP) ventilation. The development of CPAP by Gregory revolutionized the treatment of premature infants with respiratory failure. Prior to the creation of this treatment, the mortality rate of neonates with respiratory distress syndrome was >50%. The innovation markedly improved the ventilation of infants with respiratory distress and led to significant improvements in survival rates. Based on an interview with Dr. Gregory, this article describes the discovery of CPAP and reviews his career in advancing pediatric anesthesia and critical care medicine.

It was late at night when the junior anesthesiologist on call in the Intensive Care Nursery looked at the dying premature neonate. The newborn was in profound respiratory distress with a PaO2 of 30 mmHg. ‘This was a baby who by all of the published (criteria) at that time should have died,’ said Dr. George Gregory. What Gregory did next undoubtedly not only saved the baby's life, but also transformed the management of neonatal respiratory distress syndrome in premature infants.

‘The infant was in respiratory distress and actually went to the (cardiac catheter) lab because the cardiologists thought he had congenital heart disease. He didn't have congenital heart disease. The baby was breathing 150 times a minute, so I intubated his trachea and put an end expiratory pressure of 6–8 mmHg on the tube using a Jackson-Rees modification of the Ayres T-piece. Over the next hour, the PaO2 rose to about 230 mmHg,' recalled Gregory.

By his own account, this was a defining moment in Gregory's career. Now a Professor Emeritus at the University of California, San Francisco (UCSF), Gregory (Figure 1) has made numerous contributions to neonatology and pediatric anesthesia through his research on anesthetic requirement (MAC) in children and the neurologic effects of anesthesia on the developing brain. He is also widely known for his authoritative textbook, Gregory's Pediatric Anesthesia, now in its fifth edition. However, he identified the moment he saved an infant's life from idiopathic respiratory distress syndrome as his greatest achievement. This article reviews the career of this anesthesia pioneer and looks at his contributions to advancing pediatric anesthesia and critical care medicine.

image

Figure 1. Dr. George Gregory, Professor Emeritus at the University of California, San Francisco.

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Background history

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References

Born in Denver, Colorado, George Gregory moved with his family to San Diego during the Second World War, and then to Los Angeles where he grew up. Gregory's interest in medicine began early, at the age of 8, when he was treated for a leg abscess. His amazement at how his leg was anesthetized for the lancing of the abscess and alleviation of his pain triggered his motivation to pursue a career in medicine. He attended college at the University of California, Los Angeles (1955–59), attended medical school at UCSF (1959–63), and completed his internship at Los Angeles County Hospital (1963–64). After a year of surgical residency at UCSF (1964–65), he began his anesthesia residency (1965–67). Thereafter, Gregory obtained an anesthesia research fellowship in the Cardiovascular Research Institute, UCSF (1967–68) (Table 1).

Table 1. Personal history and timeline of Dr. George Gregory's career and contributions to pediatric anesthesia and critical care medicine
Birthdate: June 27, 1934
Place of birth: Denver, Colorado
Age when first became interested in medicine: 8 years old
Education
1955–1959: Undergraduate: University of California, Los Angeles
1959–1963: Medical school: University of California, San Francisco
1963–1964: Internship: Los Angeles County Hospital
1964–1965: Surgical residency: University of California, San Francisco
1965–1967: Anesthesia residency: University of California, San Francisco
1967–1968: Anesthesia research fellowship: Cardiovascular Research Institute, University of California, San Francisco
Clinical Practice: The University of California San Francisco, California
1968–1969: Clinical Instructor, Anesthesia
1969–1970: Assistant Clinical Professor, Anesthesia and Pediatrics
1970–172: Assistant Professor in Residence, Anesthesia and Pediatrics
1972–1975: Associate Professor in Residence, Anesthesia and Pediatrics
1975–1977: Associate Professor in Anesthesia and Pediatrics
1978–2001: Professor, Anesthesia and Pediatrics
2001–Present: Professor Emeritus, Anesthesia and Pediatrics
Directorship at The University of California San Francisco, California:
1976–1978: Director: Adult Intensive Care Unit
1981–1982: Director: Pediatric Intensive Care Unit
1991–1993: Acting Director, Liver Transplant Anesthesia
Most significant publications are ref. [23, 28, 29]
Additional significant publications
Frank LS, Boyce WT, Gregory GA, Levine J, Miaskowski C: Cardiorespiratory stability of very low birth weight premature neonates following postoperative administration of morphine. Acute Pain 1(4):7–16, 1998.
Vexler Z, Berrios M, Ursell PC, Sola A, Ferriero DM, Gregory GA: Toxicity of fructose-1,6-bisphosphate in developing normoxic rats. Pharmacol & Toxicol 84(3):17, 1999.
Litt L, Espanol MT, Hasegawa K, Chang LH, Gregory G, James TL, Beal ML, Chan P. NOS inhibitors decrease hypoxia-induced ATP reductions in respiring cerebrocortical slices. Anesthesiology 90(5):1392–1401, 1999
Major pediatric anesthesia textbook is ref. [27]

Early on, Gregory had a clinical interest in neonatology and idiopathic respiratory distress syndrome (RDS), otherwise known as hyaline membrane disease (HMD) or neonatal RDS. Serendipitously, his friend Roderic Phibbs, who was a Chief Resident in Pediatrics, introduced him to the Chief of the Intensive Care Nursery (ICN), William ‘Bill’ Tooley. Bill Tooley had been a fellow in the Cardiovascular Research Institute with William ‘Bill’ Hamilton, the Chair of Anesthesia at UCSF. Together they agreed that an anesthesiologist in the ICN would be beneficial, and that, given Gregory's experience in anesthesiology and critical care medicine, he would be a good fit. Therefore, after completing his anesthesia residency and research fellowship, Gregory began his career and research in the 1960s as one of the few anesthesiologists working in a neonatal intensive care unit anywhere in North America.

Intensive care medicine in the 1960s

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References

Although the 1950s and 1960s saw the early development of pediatric and neonatal intensive care, critical care medicine was still in its infancy [1, 2]. ‘(Pediatric) intensive care units were just being developed in North America. Newborn intensive care units were practically nonexistent,’ recalled Gregory. Laryngoscopy blades and endotracheal tubes for infants were developed in the late 1920s to 1940s [3-5], but their availability in every institution was limited. Residents were taught to intubate the trachea of infants by sticking their finger into the mouth and feeling the epiglottis, then sliding the tube along the finger into the trachea. ‘Once the endotracheal tube was in the trachea and ventilation was sufficient, the infant's pulse rate and color would often improve’, recalled Gregory.

Neonatal ventilation was very rudimentary. The invention of pulse oximetry was still years away [6], although, John Severinghaus's invention of the pH probe, carbon dioxide electrode, and blood gas analysis system [7] helped improve the monitoring of ventilation. Mechanical ventilation in premature infants posed great challenges due to the difficulty of weaning babies off the ventilators and iatrogenic complications such as pneumothorax. The Baby Bird ventilator, the workhorse of the neonatal and pediatric intensive care units, was yet to be invented [8]. Its predecessor, a Bird ventilator with a J-circuit, provided flow only during the inspiratory cycle. If patients inhaled between ventilator breaths, they would re-breathe their own exhaled gas, contributing to impaired ventilation and oxygenation. Prevention of this problem in neonates required mechanical ventilation at rapid rates, which often induced pulmonary trauma, and had a high incidence of cardiac and neurological complications [9]. ‘When I first started working in the ICN, babies were dying. Survival rates in infants with RDS were <30% with assisted ventilation’, stated Gregory.

The great killer

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References

In August 1963, President John F. Kennedy's son, Patrick Bouvier Kennedy, was born prematurely at 34 weeks; he weighed 4 pounds 10.5 ounces and suffered from neonatal RDS. Despite the best medical efforts, the infant died 2 days later [10, 11]. Neonatal RDS, is a syndrome caused by developmental insufficiency of surfactant production and structural immaturity of the lungs [12]. Shortly after birth, signs of RDS manifest as tachypnea, tachycardia, expiratory grunting, chest wall retractions, and cyanosis. Without support, affected infants rapidly develop hypercarbia, severe hypoxia, metabolic acidosis, chronic lung changes, and damage to other organs such as the brain and heart.

Respiratory distress syndrome was one of the leading causes of neonatal morbidity and mortality. Although surfactant deficiency was described as the mechanism of RDS in 1959 [19], effective surfactant replacement therapy in premature infants did not begin until the 1980s [20].Studies published in the 1960s and 1970s described early attempts at the use of mechanical ventilation to rescue neonates with respiratory failure, but ventilator options were limited and devices were not widely available, resulting in minimal success [21] (Table 2). Mortality was particularly high in premature infants with very low birth weights. ‘If you had hyaline membrane disease and weighed 1800 g, you had a 50% mortality,’ Gregory recalled.

Table 2. Assisted ventilation for hyaline membrane disease in the 1960s: Rates of survival. Table courtesy of Dr. George Gregory
N Survival (%)ReferenceLocation
4030Adamson et al. [13]England
6633Heese et al. [14]South Africa
8039Stahlman et al. [15]USA
13036Martin-Bouyer et al. [16]France
16843Murdock et al. [17]Canada
20427Daily et al. [18]USA

Discovery of continuous positive airway pressure

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References

Gregory worked tirelessly in the ICN, often 7 days a week, trying to discover how to help these infants survive. After 6 months in the ICN, Gregory happened upon an article published in Pediatrics by Harrison et al. [22], which studied the effect of grunting by babies with RDS. The South African researchers measured the blood gas of infants with RDS who were grunting, then intubated the babies' tracheas and re-measured the blood gas. After intubation, the grunting ceased; however, the patients' condition worsened as they became more hypoxic and their arterial oxygen tension fell. Improvement in color and oxygenation occurred once the endotracheal tube was removed, and the infants resumed grunting. Harrison and his colleagues concluded that grunting was a modified Valsalva maneuver with a physiologic mechanism for maintaining functional residual capacity and improving alveolar ventilation [22].

Gregory recognized that if he put positive airway pressure on the end of the endotracheal tube, he could mimic this grunting and improve arterial oxygenation. The first patient to whom he applied this insight was the brother of a future colleague. The infant, who had been born prematurely, developed severe neonatal RDS. Gregory intubated the infant's trachea, but modified the then standard clinical practice by attaching the endotracheal tube to a Jackson-Rees modification of the Ayres T-piece. This allowed him to generate an end expiratory pressure of 6–8 mmHg (Figures 2 and 3a). The infant's PaO2 gradually improved over the subsequent hours, and the child survived (Figure 4a).

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Figure 2. System for applying continuous positive airway pressure through an endotracheal tube. A represents gas inflow, B oxygen sampling port, C Norman elbow (modified T piece), D endotracheal tube connector, E endotracheal tube, F Sommers T piece, G corrugated anesthesia hose, H Reservoir bag (500 ml) with open tail piece, I screw clamp, J aneroid pressure manometer, K plastic T connector, L plastic tubing (1 cm internal diameter), and M underwater ‘pop-off’. Arrows indicate direction of gas flow. Reprint with permission from the NEJM.

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Figure 3. (a) Photograph of infant with hyaline membrane disease intubated and treated with CPAP. The endotracheal tube is connected to a Jackson-Reese system, the same device commonly used to provide anesthesia for infants and children in the 1960s. Photo courtesy of Dr. George Gregory. (b) Patient, E.B., the first infant to be treated with CPAP without an endotracheal tube.Photo courtesy of Dr. George Gregory.

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Figure 4. (a) Patient C.K. at age 8.The first patient intubated and treated with CPAP. He is now the CEO of an educational computer company in Japan that aims to improve education in Asia. Photo courtesy of Dr. George Gregory. (b) Patient E.B. at age 14. He was the first patient treated with CPAP without an endotracheal tube. E.B. is currently the Chair of Fine Arts at a high school and has a PhD. Photo courtesy of Dr. George Gregory.

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Gregory's innovation saved not just one baby that night but subsequently improved the odds for countless other infants (Figures 3b and 4b). He and his colleagues presented their research at the Pediatric Research Society meeting in 1970 and published their findings in the New England Journal of Medicine in 1971 [23]. In this publication, Gregory and his coauthors described two continuous positive airway pressure (CPAP) devices: one was connected to an endotracheal tube, and the second was CPAP applied via a plastic pressure chamber without an endotracheal tube.

For the initial CPAP device, an endotracheal tube was connected to an Ayres T-piece, which was connected to a gas inflow line. Fresh gas was introduced into the system near this T-piece, which was connected via corrugate anesthesia tubing to a reservoir bag. The pressure in the system could be adjusted by varying inflow of gas or the degree of occlusion at the tail end of the reservoir bag. Because the system contained no valves, rebreathing of carbon dioxide was a possibility. Hence, fresh gas inflow needed to be in excess of twice the infant's respiratory minute volume to prevent rebreathing. A tube placed 30 cm under a column of water acted as a ‘pop-off’ valve to prevent excessive pressure that could create a pneumothorax. The pressure in the system was continually measured on an aneroid manometer (Figure 2) [23].

In the second CPAP system, the infant's head was enclosed in a plastic chamber with warmed, moisturized gas flowing into the chamber at 10–20 l·min−1 and escaping through an outlet tube (Figure 3b). With this device, pressures could be increased by squeezing the bag to intermittently sigh the patient. The pressure in this system was measured with an aneroid manometer. With both systems, initial pressure of 6 mmHg was applied to the airway and increased by increments of 2 mmHg to improve the infant's arterial oxygenation [23].

The physiological rationale and striking results were widely accepted, and the use of CPAP was rapidly adopted by neonatologists and pediatricians. ‘With this system, survival rates rose to 80%’, reported Gregory. The mortality from neonatal RDS declined rapidly.

Mentors and colleagues

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References

A number of individuals influenced Gregory's career and helped fuel his success. One was his friend and colleague, Roderic Phibbs, Chief Resident in Pediatrics, who initially introduced Gregory to Bill Tooley, Director of the ICN. In addition, Bill Hamilton, Chief of Anesthesiology, had the insight not only to appoint Gregory to the anesthesia staff, but to support his work in the ICN with Tooley, Joseph Kitterman, and Phibbs.

Gregory also identified his anesthesia residency classmates as great influences in his career. These included Ronald Miller, Robert Stoelting, Robert Hickey, Joseph Lee, John Wade, Cederic Bainton, and others. Out of his class of 12, 10 continued on in academic medicine careers. Other mentors included Phil Larson, who influenced Gregory to choose anesthesiology as a career, and anesthesia faculty mentors at UCSF, such as Stewart Cullen, Skip Way, John Clements, John Severinghaus, and Sol Shnider. His research mentor was Ted Eger, to whom he says he owes much.

Other life achievements

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References

Beyond his defining contribution of the discovery and development of CPAP in improving RDS survival rates, Gregory is known for helping to shape the modern-day subspecialty of pediatric anesthesia through research, clinical practice, and teaching. In 1968, Gregory and colleagues demonstrated the differing anesthetic requirements between children and adults (24–26). In 1980, he established and directed the first pediatric intensive care unit at UCSF. In 1983, the first edition of Gregory's popular textbook, Gregory's Pediatric Anesthesia, was published [27]. This book, now in its fifth edition, highlighted physiology and pharmacology as it related to clinical care.

For the last 10 years, Gregory has devoted his research career to studies of the developing brain, hoping to discover ways to prevent central nervous system damage in babies [28, 29]. Nowadays, he focuses on taking care of patients and teaching physicians in Latin American and Asian countries with his work through ReSurge International (formerly Interplast) [30]. He also still teaches residents and fellows and cares for pediatric patients in the operating rooms at UCSF.

‘My goal has always been to make the residents and fellows better than I am. I have thought that if residents and fellows finish the program and are not better than I am, I have failed. It doesn't always work, but many times people turn out as good or better than I am, which is enormously satisfying. Without that as a goal, you are wasting your time as an educator’.

Conclusion

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References

As Dr. Gregory reflects on his career, he states, ‘I was so bloody lucky to be in the right place at the right time, and I guess to have had enough sense and curiosity to take advantage of it’. He was in the right place with some of the true pioneers of the time. The field of neonatology and critical care medicine was so primitive that Gregory and colleagues developed and pioneered much of the subspecialty as we know it today. Through hard work, persistence, and ingenuity, Gregory applied physiology and technology into practice and communicated the innovation to his peers. His mentors kept him motivated, thinking, and searching for answers to the unknown. Sharing his keen insights was a major step in improving outcomes in neonates. ‘I've said many times, you don't have to be really smart to do what we do, but you have to have the right mindset. And the right mindset is to think of the problems a certain way. Having the curiosity gives you the mindset’.

Acknowledgments

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References

Special thanks to Dr. George Gregory for his time and efforts in this endeavor. Acknowledgements to the Society for Pediatric Anesthesia, Karen Bieterman and the staff of the Wood Library-Museum, and Claire Levine for her editorial assistance.

References

  1. Top of page
  2. Summary
  3. Background history
  4. Intensive care medicine in the 1960s
  5. The great killer
  6. Discovery of continuous positive airway pressure
  7. Mentors and colleagues
  8. Other life achievements
  9. Conclusion
  10. Acknowledgments
  11. Conflict of interest
  12. References