The Artificial Lung: The Past. A Personal Retrospective
2004; Lippincott Williams & Wilkins; Volume: 50; Issue: 6 Linguagem: Inglês
10.1097/01.mat.0000147960.14376.d5
ISSN1538-943X
Autores Tópico(s)Pleural and Pulmonary Diseases
ResumoBefore the now ubiquitous membrane artificial lung became available, surgeons for years employed diverse approaches to permit survival during potentially lifesaving procedures that required partial or total cessation of systemic blood flow. The patients’ metabolic demands were commonly greatly reduced through induction of moderate body hypothermia.1 For the delivery of oxygen and removal of carbon dioxide, several techniques/technologies were applied, including controlled cross-circulation,2 the use of canine lungs as oxygenators,3 as well as non-biologic screen–filming,4 bubble,5 and rotating disc oxygenators.6 The clinically useful pump-oxygenator of today evolved step by step, cautiously, with the developers trying to avoid errors that could have seriously set back progress. It was clear to anyone who participated in the early studies that major problems had to be solved, before there would be any hope of using such devices safely for days, weeks, or months. The potential for such devices yet to be invented was equally clear, i.e., the ability/power to improve greatly the quality of patient care during and following cardio-pulmonary bypass, as well as during acute and perhaps even chronic respiratory failure. The Membrane Artificial Lung Observations during the earliest clinical use of artificial kidneys of the Kolff design showed that venous blood (or modestly desaturated arterial blood), upon passing through an artificial kidney, becomes bright red, highly enriched with oxygen. These observations were the first to suggest potential for oxygen/carbon dioxide exchange across a plastic membrane and led to the use of polyethylene membrane in the design of a small, coiled membrane lung7 (Figure 1).Figure 1.: An early model of the membrane artificial lung, based on the Kolff artificial kidney.Cleveland, Ohio, was at that time a center of research dealing with blood oxygenators and cardiovascular surgery. It was no great surprise that the possibility to develop a membrane artificial lung was further explored just across the Cuyahoga River by Dr. G.H.A. Clowes Jr., in the Department of Cardiothoracic Surgery at the Cleveland City Hospital. My involvement began with an accidental encounter of unforeseeable, long term bondage. And so it was when I, a first year medical student at Western Reserve University (WRU) – now Case Western Reserve University – first met Dr. G.H.A. Clowes, Jr. Medical education at WRU was undergoing major changes in structure and content, as part of a novel experiment in medical education. It centered on exposing first year medical students to both earliest patient contact and medical research, which made a lot of sense. All first year medical students were asked to visit any of the university medical research laboratories to learn about their research programs, to select a field of interest, and to become involved in independent research, that was expected to continue throughout each student’s medical school years. I was fascinated by what I saw in Dr. Clowes’ laboratory, located in the basement of the Cleveland City Hospital. Between two thick acrylic plastic plates were two layers of polyethylene membrane just 0.0008“ thick, on either side of which was a sheet of vinyl-coated fiberglass screen to provide passage of air (or oxygen). Blood flowed from the femoral vein through a cannula into a venous reservoir and then was propelled by a finger pump through two layers of the membrane, where it progressively changed in color from dark red to bright red; and was then returned into the femoral artery. The goal of the study, which continued for many hours, was to identify plastic films with high oxygen and carbon dioxide permeability and to devise a membrane artificial lung suitable for cardiopulmonary bypass during open-heart procedures, without time limits imposed by the disc/bubble oxygenator that caused hemolysis and blood protein denaturation (Figure 2).Figure 2.: Right: appearance of plasma pumped through a membrane artificial lung for several days. Note absence of particulate material in suspension. Left: appearance of plasma exposed to a bubble oxygenator for same duration. Note particulate material in suspension.Among the many laboratories I visited, this project seemed to me of greatest interest, and that is where I spent my medical school time away from my regular classes, working with Mr. Howard Peacock, a most talented laboratory technician, to whom I owe so much. It occurred to me that, rather than measuring gas exchange across a membrane with the assembled membrane lung, it would be much simpler to test each membrane in a small diffusion chamber, with blood on one side of the membrane and the other side exposed to 100% oxygen. The test cell was to be vigorously shaken/rotated to effect good mixing of blood. Both oxygen and CO2 transport across the membrane could readily be calculated, and each membrane evaluated rapidly and conveniently. Later, that fall, I was surprised to learn that a short paper had been presented by Dr. Clowes at the founding meeting of the American Society for Artificial Internal Organs (ASAIO) in Atlantic City, N.J., and published in the ASAIO Transactions in 1955 with my name included as a co-author.8 I witnessed in person the many attempts in that laboratory to improve on the stacked plate membrane artificial lung that consisted of using many C-clamps, assembling, then degassing, cleaning and re-assembling/sterilizing a bulky adult size device weighing well over 50 pounds; it was clear that a more practical solution was necessary (Figure 3). There was, in the corner of the animal research laboratory, a Kolff coiled artificial lung, very compact and certainly disposable.7 But, that artificial lung had fatal problems: large blood volume required for priming, high resistance to blood flow across the full length of the coiled tubing, and poor gas transfer because of the thick blood film (Figure 1).Figure 3.: The four principal approaches to effect gas exchange across solid/liquid interfaces. From top: the plate based, stackable membrane lung; the capillary-based membrane lung; the spiral coiled membrane lung; and the liquid/liquid interface artificial lung.I found a large roll of 0.0008” thin, folded polyethylene tubing 10 cm wide, coiled onto a large spool. I pulled a 10 cm wide vinyl coated fiberglass screen through the flattened polyethylene tubing. Rather than blowing air/oxygen through the tubing, I applied suction to one end: the membrane was firmly sucked against the screen, forming the most beautiful smooth, very fine cobblestone-like surface imaginable, while providing fresh air/oxygen through the full length of the screen. And, because blood flow was a short 10 cm cross wise, the resistance to blood flow was very low. I knew, then and there, that such an approach would allow wrapping (coiling) of such envelope around a spool, to form a compact multilayered coil of many square meters – the forerunner of the spiral coiled membrane lung (Figure 4). Such design proved rather simple to assemble but suffered from low oxygen and carbon dioxide gas permeability because of low gas permeability of polyethylene; still, the concept was sound.Figure 4.: The spiral coiled membrane artificial lung.As anyone who has worked on membrane artificial lung design will tell you, availability of high gas permeability, pinhole free, fabric-reinforced membrane of continuous lengths was a major stumbling block. At times, investigators and I too, in desperation, built their own facilities to fabricate membranes to assure availability of pinhole-free, high gas-permeability membrane9 (Figure 5). In subsequent years, thin-walled plastic hollow fiber membranes became widely available, with the latter assuming a dominant role worldwide in the fabrication of hollow fiber membrane lungs of many designs,10 well suited for day-to-day clinical use.Figure 5.: A large-scale fabric reinforced, multilayer silicone rubber membrane casting facility.Studies to Explore Use of the Spiral Coiled Membrane Lung in Acute Respiratory Failure Previously, blood oxygenators had been exclusively used to provide brief cardio-circulatory support during the course of brief cardiac surgical procedures. It was apparent that a safe blood oxygenator (CO2 removal was considered of lesser priority) for weeks and months, could make it possible to support patients with acute respiratory failure, not amenable with conventional mechanical ventilation. Clearly, bubble/filming oxygenators were of no use, as hemolysis and protein denaturation precluded anything but short term use. When I was Medical Officer at the National Institute of Health, Lung and Blood Institute, Bethesda, MD, we showed that prolonged (days and weeks) of extracorporeal blood pumping was feasible in unanesthetized, unrestrained sheep lasting many days, or weeks with or without use of a membrane artificial lung11 (Figures 6, 7). Clearly, the duration/length of such studies was no longer limited by possible injury from blood pumping or to the use of a membrane artificial lung.Figure 6.: Laboratory study: Long-term bypass was readily accomplished for either venovenous (or venoarterial) bypass for respiratory or cardiorespiratory assist, lasting days, or weeks.Figure 7.: Early studies of total gas exchange in a preterm fetal lamb; blood flows from the umbilical artery through two small spiral coiled membrane lungs. The fetus is immersed in synthetic amniotic fluid. Left, Warren Zapol; right, author.It was only a matter of time before clinicians were ready to use a membrane artificial lung (the membrane lung) for the support of a patient with severe, acute respiratory failure who did not respond to conventional care. This opened the flood gates to wide clinical use, starting with the first long-term successful bypass by Hill et al. in 1972.12 The following year, Bartlett and co-workers first used the membrane artificial lung in a newborn with acute respiratory failure.13 It seemed that a new era had arrived, with a new technology to support patients with severe acute respiratory failure with total/partial gas exchange provided through the extracorporeal membrane artificial lung. In a burst of enthusiasm, a multicenter randomized study sponsored by the National Institutes of Health showed, surprisingly, no difference in survival between groups of patients treated conventionally and those treated conventionally, plus extracorporeal membrane lung gas exchange.14 A cursory review of the summary report of the ECMO study final report showed that lung management of both groups of patients in the controlled ECMO study – control and study groups – did not differ much between the two groups, i.e., that management of lungs was essentially the same: the membrane lung in the study group was expected to provide time for the lung to rest, to heal. Clearly, that did not happen. Shortly thereafter, our own extensive studies in sheep persuasively showed that healthy lungs ventilated at a peak inspiratory airway pressure of 50 cm H2O, as in many of the patients in the ECMO study, led in only 1–2 days to severe acute lung injury and respiratory failure, not responsive to treatment.15 Indeed, acute lung injury and respiratory failure can also develop at a peak inspiratory pressure as low as 30 cm H20,16 and even more surprisingly (and depressingly), earliest signs of acute lung injury can evolve within 1–2 days in sheep mechanically ventilated at a peak inspiratory pressure as low as 25 cm H20 (unpublished observations). While such early acute lung injury may still permit recovery, it points out the importance of not focusing on gas exchange alone, but also considering possible evolution of iatrogenic lung injury during aggressive ventilation of the lungs. Those findings were not surprising as, in the animal research laboratory, studies using mechanical ventilation last but a few hours; and, 24 h or longer of continuous animal study are uncommon. And yet, it is long term animal studies, and not those that last only few hours, that are directly applicable to long term care of a patient with severe acute respiratory failure. Providing adequate gas exchange and keeping peak inspiratory pressure in their normal range, under 25 cm H2O, can be a perplexing problem. I believe, however, that there is real benefit to low flow extracorporeal CO2 removal (ECCO2R), while providing some oxygen transport (extracorporeal membrane oxygenation). Unfortunately, such is not the current practice. Extracorporeal Life Support Organization A group of physicians, spread across the North American continent, should have had, and must have, an umbrella organization, to meet, establish working groups, and exchange news, experiences, results, and/or concerns. Dr, Robert Bartlett (University of Michigan, Ann Arbor) had the foresight, charisma, and organizational skill to establish such an umbrella organization in 1989, with meetings held annually. This has helped greatly to standardize treatment, provide training to groups wanting to become involved in clinical use of extracorporeal membrane oxygenation, and to provide a central repository for data collection. We all owe him many thanks. Ventilator Associated Pneumonia (VAP) A patient with acute respiratory failure who is admitted to a hospital rightfully expects that any treatment he/she is to receive will be safe and beneficial. Unfortunately, that is not always the case when treatment includes intubation and mechanical ventilation. There are, in addition, hazards directly related to the position of the patient, which is most often the “preferred” traditional semi-recumbent position, without considering the alternatives. Safety and expected benefits of any treatment or procedure are best explored first in the experimental animal research laboratory. One may ask, for example, whether it is possible in attempting to “recruit” collapsed regions of the lungs, to inadvertently over expand remaining healthy regions of the lungs, causing acute lung injury that may not manifest immediately. Or, for example, should the position of a patient in a hospital bed while mechanically ventilated be: supine, prone, recumbent, or semi-recumbent, etc? Irrespective of the fact that very few healthy humans ever sleep, at home, in the (now hospital preferred) semi-recumbent position, with head/neck raised at an angle of 30–45° above horizontal; by far the largest number of healthy humans sleep in the semi-lateral, or supine position, with head/neck elevated at an angle of some 10–15° above horizontal. Such choice would be reasonable, provided the patient is healthy; and most importantly, not intubated; hence retaining normal mobility to seek the most comfortable position while in bed and maintain normal tracheal mucociliary transport. However, in a patient intubated with the cuff inflated (with immediate major decrease in mucociliary transport), and absence of any mechanism of mucus transport except via intermittent (incomplete) mucus suctioning of the trachea and of the endotracheal tube with a suction catheter, both the upper trachea and the tracheal tube become within hours heavily colonized by potentially pathogenic bacteria, with the formation of bacteria laden biofilm lining the tracheal tube. In studies in intubated sheep, we showed that, when the endotracheal tube was oriented just below horizontal, all mucus spontaneously exited the trachea through the force of gravity, without need for deep tracheal suctioning and with absence of all bacterial colonization of the lungs17 (Figure 8). Hence, our well intentioned efforts at patient management during the adult ECMO study, with the patient kept in the semi-recumbent position, had not benefited from our more recently acquired knowledge regarding orientation of the endotracheal tube at, or below, horizontal whether on ECMO or off ECMO.Figure 8.: Above: in the experimental animal research laboratory, sheep intubated and mechanically ventilated, invariably develop ventilator associated pneumonia, after some 24 h of mechanical ventilation with the head/neck elevated above horizontal. Below: When the orientation of the endotracheal tube is horizontal/below horizontal, pneumonia does not develop.Future progress in membrane lung design, performance, blood access, and antithrombogenic surfaces is likely to allow both the support of the acutely failing lungs; and the support of the failing heart/lungs. Its future looks promising.18 In whatever we do clinically, we must adhere to the covenants of the World Medical Association Declaration of Helsinki, which reads, in part: “Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature.”19 The membrane artificial lung is, was, and will remain a most powerful tool in our armamentarium, both surgical and medical. Yet, we should apply it carefully, recognizing that any ancillary factors such as injuries from mechanical ventilation, or intubation/ventilator-associated nosocomial pneumonia, may well have been the primary cause for lack of survival/recovery of many of our patients.Figure: Theodor Kolobow, MD National Heart, Lung and Blood Institute
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