Historical Perspectives: Continuous Positive Airway Pressure (CPAP)

Abstract

In the 1960s, hyaline membrane disease (HMD) was the major cause of neonatal death in the United States. Boston, Geller, and Smith (1) reported 100% mortality if neonates had Pao2s of less than 100 mm Hg in the first 12 hours after birth, and Stahlman and associates (2) reported a 70% mortality if neonates were breathing 100% oxygen in the first 12 postnatal hours. Included among the deaths were infants who weighed more than 1,800 g at birth. Outcomes were similar in other centers. Available care often consisted of administering oxygen, intravenous fluids, and antibiotics and keeping patients warm. As a last ditch effort, some babies were mechanically ventilated.Knowledge of the physiology of neonates and of their disease processes increased rapidly during this period. Smith (3) and Nelson and colleagues (4) demonstrated that neonates who had HMD had low lung compliance and a reduced functional residual capacity. Stahlman, (5) Rudolph and associates, (6) and many others demonstrated abnormalities in ventilation or the cardiovascular systems of affected neonates. John Clements isolated surfactant from the lung, (7) and Mary Ellen Avery and Jerry Mead (8) demonstrated a deficiency of surfactant in the lungs of neonates who died of HMD. Surfactant deficiency was associated with atelectasis. In detailed pulmonary and cardiovascular studies of neonates who had HMD, Chu and associates (9) demonstrated that a significant portion of the problem with this disease was due to mismatching of ventilation and perfusion and that grunting was an effort to counteract atelectasis (Figure).The development of neonatal intensive care units (NICUs) in the early 1960s, such as that created by Dr. Mildred Stahlman at Vanderbilt University, provided an environment in which sick neonates could be cared for, questions could be asked and answered, and physiologic measurements (such as those used by Stanley James at Columbia University for research) (10)(11) could be made and used to treat patients. NICUs were an outgrowth of adult ICUs. In the late 1950s, surgeons and anesthesiologists in Sweden began to care for term postsurgical neonates in special areas of the adult ICU. (12)Because HMD was the major cause of death in neonates, especially those born preterm, treatment of neonates who had HMD became the major focus of many developing NICUs. Bill Tooley organized the NICU at the University of California, San Francisco (UCSF) in 1963. From the studies of Chu and colleagues (9) and the attempts by Rod Phibbs and Ernie Guy at San Francisco General Hospital and by Bill Tooley at the UCSF to mechanically ventilate neonates who had HMD in the winter of 1960, it became clear that for this form of therapy to be effective, well-trained nurses were required. Fortunately Teresa Porrier, RN, an outstanding nurse and organizer who had the wonderful ability to get people to do the right thing and make them think it was their idea, was the head nurse in the nursery. She was very important in the development of this unit. Dr. Julius Comroe’s understanding of the importance of NICUs for patient care and for research led him to provide a wide variety of help. John Clements offered the necessary constant questioning of what we were doing and unstinting help in research. John Severinghaus (the inventor of the carbon dioxide electrode) built a blood gas machine and placed it in the NICU to allow quick and frequent measurement of blood gases and pH. By the mid-1960s, we took this device to the delivery room to measure blood gases and pH in sick neonates immediately after birth.I was given the opportunity to work in the NICU at UCSF through a series of events. I had lived in student housing near Rod Phibbs, where we became friends. Bill Hamilton became the new chair of anesthesia at UCSF in 1967. He and Bill Tooley had worked together in the Cardiovascular Research Institute at UCSF some years before and were good friends. Hamilton had been interested in HMD and its treatment while he was at the University of Iowa. The three of them decided that I might have something to contribute to the NICU because I had worked in the adult ICU and mechanically ventilated patients during my residency. I also had spent a considerable amount of time in the NICU during my residency and was interested in applying what I had learned from adults to neonates. Bill Hamilton gave me the opportunity to work full-time in the NICU with Bill Tooley, Rod Phibbs, and Joe Kitterman. I met Joe Kitterman during my residency while resuscitating a baby. Joe, more than anyone, taught me to question things and accept nothing as fact. He also taught me much of what I learned about neonatology in the early days. Because of my experience with mechanical ventilation in adults, I was given responsibility for pulmonary care in the NICU.Most mechanical ventilators available at the time were built to ventilate the lungs of adults, not those of sick preterm neonates. Many of the machines were piston-driven and delivered a “constant” tidal volume. However, the compression volume of these piston-driven early machines often approached 1,000 mL. As a consequence, it was necessary to ventilate the lungs of neonates by setting the machine to deliver this 1,000 mL plus whatever tidal volume was estimated to be appropriate for the neonate (usually 10 mL/kg or 10 to 30 mL/breath). Obviously, this was dangerous because the volume delivered to the neonate could vary significantly, depending on lung compliance and airway resistance. The Baby Bird and Puritan Bennett ventilators were subsequently developed for neonates, but they were often difficult to use, and it was difficult to wean patients who did improve from these devices. To do so required removing the patient from mechanical ventilation for progressively longer periods of time. Because the lung quickly collapsed when mechanical ventilation was discontinued, weaning was long, arduous, and usually unsuccessful. In the end, many infants died because they could not be weaned from mechanical ventilation. Early experience at the University of Pennsylvania by Jack Downes, (13) at the Hospital for Sick Children in Toronto by Paul Swyer, (14) and at Stanford University by Penelope Cave-Smith and colleagues (15) demonstrated that some mechanically ventilated neonates (especially those requiring short-term mechanical ventilation) survived. However, many of the survivors had severe chronic lung disease (16) that persisted into adulthood. (17) It was obvious that we needed a better way to ventilate these neonates.We noticed, while measuring pulmonary function in sick neonates in the delivery room, that increasing the ventilation rate during manual ventilation often resulted in an inadvertent positive end-expiratory pressure (PEEP) and improved blood gases. At the time, there was no simple, safe method of maintaining PEEP during mechanical ventilation or during weaning. Reducing the rate of ventilation led to atelectasis and hypoxemia. Gas trapping within the lung was considered a problem to be avoided by most physicians, based on work with normal lungs. Because the available mechanical ventilators frequently were ineffective, we and others sometimes ventilated neonates who had HMD by hand for 48 to 72 hours, using the Jackson-Reese system that commonly was employed to anesthetize infants and children. We learned early not to extubate the tracheas of these patients as soon as their blood gases improved because more than 80% required reintubation. Following reintubation, they often were worse off than if tracheal extubation was delayed until we could slowly reduce the rate of ventilation while maintaining adequate oxygenation and carbon dioxide partial pressures. Much of the hand ventilation was performed by the nurses.At this point, several things came together that favored the development of CPAP. We had an ICU with sufficient well-trained nurses. We could make measurements and act immediately on the data. We understood the pathophysiology of HMD. It was clear that surfactant deficiency was the problem. We knew from the studies of Chu and associates (9) that grunting respiration maintained a positive pressure in the lungs of neonates who had HMD. Our previous experience with inadvertent gas trapping and PEEP suggested that applying a positive pressure to the oral end of the endotracheal tube during expiration would decrease atelectasis and improve oxygenation. Others also probably had been applying PEEP inadvertently during mechanical or hand ventilation. Because we frequently measured airway pressures during ventilation, we knew when we were applying PEEP and could correlate the presence of PEEP with blood gas findings.The finding that really triggered the idea for CPAP in my mind was a paper by Harrison and associates from South Africa. (18) These authors demonstrated that when an endotracheal tube was inserted into the tracheas of neonates who had grunting respiration, Pao2 and pHa decreased and Paco2 increased. Removing the endotracheal tube and allowing the neonate to resume grunting respiration improved all of these variables. The respiratory tracings presented in their article clearly documented positive pressure in the airway during grunting respiration (except during the very short period of inspiration). The same evening that I read this article, a 1-day-old newborn was sent to us who had respiratory distress and a Pao2 of 28 mm Hg while breathing 100% oxygen. Initially he was believed to have cyanotic congenital heart disease and underwent cardiac catheterization. The heart was structurally and functionally normal. Based on our experience and that of others, this neonate had essentially a 100% chance of dying from his lung disease. We inserted an endotracheal tube and immediately attached a Jackson-Reese system to the endotracheal tube to generate a positive pressure during the expiratory phase of each breath while he breathed spontaneously. Within 5 minutes, his Pao2 had risen to approximately 78 mm Hg. In less than 1 hour, the inspired oxygen had been reduced from 100% to 58% while the Pao2 remained at 50 to 70 mm Hg. This was very unusual for an infant who had such serious HMD. Knowing that neonates who have HMD made and secreted surface-active material after 3 to 4 days of their disease, we maintained the applied end-expiratory pressure for 3 days before beginning to reduce the pressure. We subsequently weaned the neonate from CPAP in 5 days, and he made a complete recovery. He now runs a computer-related company in Japan.Based on the response of this infant, we subsequently confirmed that applying a positive pressure during expiration to the lungs of neonates who had HMD improved oxygenation, functional residual capacity, and airway resistance and had variable effects on lung compliance. The 20 infants reported in our initial paper on CPAP (19) had Pao2s of less than 50 mm Hg while breathing 100% oxygen, and many had apnea, cyanosis, and bradycardia before the initiation of CPAP. Based on our own data and the data of others, the mortality of these patients should have been nearly 100%. In contrast, 80% of these first 20 patients survived, including seven who weighed less than 1,500 g at birth. During this same time, Llewellyn and Swyer in Toronto (20) demonstrated that applying PEEP during the exhalation phase of mechanical ventilation improved oxygenation of sick neonates, and Ashbaugh and colleagues (21) reported similar changes in mechanically ventilated adults. Based on our results, Dr. Robert Kirby built the Baby Bird ventilator out of existing parts, a device that allowed time-cycled flow ventilation, a continuous flow of gas during expiration, and the maintenance of PEEP. This was a major advance in neonatal mechanical ventilation.Our original paper on CPAP was submitted to the New England Journal of Medicine, in great part to demonstrate the physiologic effects of CPAP. It was accepted for publication providing we placed the pulmonary function data in the archives. Ours was not a controlled trial; each patient served as her or his own control for physiologic measurements. We were still in the development stages of CPAP and continuing to refine it. One of the refinements was to add an underwater pop-off valve to the system to reduce the likelihood of causing a pneumothorax, which was done at the suggestion of John Clements. Until we had the system worked out, it was not possible to perform a controlled trial because once a trial started, the system could not be changed until the trial was complete. The tone of the paper changed when the pulmonary function data were eliminated; it had a more clinical than a physiologic bent.Looking back, one wonders why others did not develop CPAP earlier. All of the clues were there and in hindsight were obvious. I think the answer is related to the need for several factors to be in place: 1) an effective NICU where we could make measurements and act on them, 2) adequate numbers of nurses to provide needed care and make measurements frequently, and 3) an inquisitive environment where everything was questioned and there was no status quo. These were in place at UCSF, and I was given the privilege of working in this environment.