Introduction
Darwin famously said that it is not the strongest of species that survives, nor the most intelligent, but the one most responsive to change. Indeed we humans are the only creatures existing on this planet who have managed the feats of flying without wings, swimming without gills and even breathing without lungs which is in essence what an oxygenator helps us in doing.
Extracorporeal oxygenators are artificial devices that substitute the lungs by entirely taking on the function of delivering oxygen to and extracting carbon dioxide from blood. In as early as 1667, Robert Hooke speculated that it may be possible to oxygenate blood of animals by directly exposing it to oxygen and the inflation of the lungs may not be necessary to accomplish oxygenation.(1) This was followed by different attempts with varying degrees of success such as the attempt by Brown Sequard to perfuse the head of a dog by injection which showed that the brain could only survive ischemia for 5 minutes(2,3) and Lovell who perfused a kidney by injection in 1849.(4) Ludwig shook together defibrinated blood and oxygen in a balloon and succeeded in the first attempt at direct-contact artificial oxygenation. Other milestones included the discovery of heparin in 1916 by McLean, a medical student at John Hopkins which solved the obstacle of how to prevent blood from clotting during the oxygenation process and paved the way forward.(5)
Principles of Gas Exchange in Blood
When arterial blood plasma containing 0.3 ml of oxygen/ 100ml of blood, is exposed to tissue fluid, which contains 0.13ml of oxygen/ 100ml of fluid, diffusion takes place and at equilibrium the concentration of oxygen in the plasma will approach to the same levels as that in tissue fluid. At the same time the oxygen held in RBCs is in equilibrium with the oxygen dissolved in the plasma and since the oxygen in the RBCs is bound to hemoglobin, the concentration of the oxygen dissolved in the plasma and in the RBCs is not the same owing to which, 100ml of blood will supply 5ml of oxygen to the tissue.
In the lungs there is no direct contact between gas and blood since the two phases are separated by the alveolar capillary wall, and the gas transfer between the alveolar air and the pulmonary capillary blood follows the laws of diffusion.
The main principle used in designing an effective oxygenator is producing a structure as close as possible to the natural human lung, but it is difficult to produce a blood film as thin as that existing in the lung and hence it becomes imperative to maintain effective mixing of the blood in the thicker blood film used in oxygenators so that RBCs with low oxygen are constantly being brought into close proximity to the gas exchange surfaces of the oxygenator thereby maintaining efficient oxygen transfer by keeping the distance of gas transfer to a minimum.(14)
(14)
Early models of Oxygenators
The first whole body extracorporeal perfusion by isolating the heart was demonstrated in a canine model by the Russian scientists in 1929 and they used the quiescent isolated lung as an oxygenator to oxygenate initially the head and finally the whole body of the animal.(6,7,8)
The first bubble oxygenator came into being in 1882 and involved introducing air into a venous reservoir and the subsequent pressure increase in the reservoir forced oxygenated blood into an arterial reservoir, which caused perfusion of an isolated organ.(9)
Mayo Gibbon Pump Oxygenator
(14)
Gibbon carried out the first successful human intracardiac operation, which was the repair of an atrial septal defect, under direct vision in 1953 using a film oxygenator that he developed over 20 years. Film type oxygenators involve exposing a thin film of blood to oxygen in an a traumatic manner. The initial model filmed blood over the inner surface of a rotating cylinder in an oxygen atmosphere and later developments involved using a series of 6-8 wire mesh screens (60cm*10cm dimensions) arranged vertically and in parallel in a container down which the blood flowed which formed a stable film exposed to oxygen flow.(10, 11) Gibson’s model was further developed as the Mayo-Gibson pump oxygenator at the Mayo Clinic (1) and was used by Kirklin et al successfully in human intracranial operations in 1955 (12) which did produce satisfactory results but the apparatus was bulky and difficult to sterilise and operate and needed a large blood saline priming volume. (13)
Bubble-type oxygenators
In bubble oxygenators, gas in the form of bubbles is directly introduced into the blood. The large surface area of the bubbles helps oxygenation take place effectively making this one of the most simplest and effective oxygenators. However the mechanical stress caused by the introduction of air bubbles makes the trauma inflicted by this means of oxygenation the highest of all oxygenators. In addition, removal of the bubbles is necessary to avoid complications which is done by means of a settling chamber which permits air bubbles to dissolve out of the blood. This oxygenator was widely used for short-duration bypass procedures due to it being cost effective and easy to use.(14)
Clarke, Gollan and Gupta [27] reported in 1950 that even though small bubbles having a larger surface area to volume ratio favoured oxygen uptake, they were less buoyant making them less likely to rise spontaneously and more likely to remain in suspension causing a greater likelihood of air embolism (15) hence an optimum balanced size of bubbles needed to be used that were neither too big nor too small(around 2-7mm was optimum).(16,17)
(27)
The commercially available DeWall oxygenator(18) included a vertical column into which oxygen bubbled upwards at a high gas flow rate and the resultant foamy blood was made to enter a defoaming chamber, in which silicone-coated surfaces decreased the surface tension of the bubbles, making the smaller bubbles to coalesce into larger ones and these large bubbles were then eliminated in a helical tubular reservoir in which the bubbles floated upwards while the blood was being pumped downwards. This model slowly gained popularity and was being used in an estimated 90% of open heart operations worldwide in 1976.(19) Its advantages included being highly efficient because of large cumulative area of bubbles, simple design, easy to sterilise, disposable and requiring a very small priming volume. (20)
The DeWall oxygenator is considered as a ‘sequential bubble oxygenator’, i.e. the components (bubbler, defoamer, reservoir and pump) are arranged in a linear series while there are other variants which have come into existence such as ‘concentric bubble oxygenators’, in which the parts are arranged concentrically to maintain compactness of the system, and also ‘foam oxygenators’, which is an amalgamation of film and bubble type oxygenators in which gas exchange is achieved when blood films down a column forming a counter-current system.(21)
Disadvantages of direct oxygenators
The length of time that a film/bubble oxygenator could be used without inflicting serious complications was only about 4 hours. The principal limiting factor was the damage caused to blood constituents due to the direct contact of blood with air surfaces and the plastic and metal constituents of the circuit which led to traumatic destruction of RBCs and platelets, coagulation problems, protein denaturation, vascular problems, including diffuse capillary leakage, poor peripheral perfusion, acidosis and finally causing progressive organ failure(22). these disadvantages were acceptable due to the relatively short surgery duration but this became an obstacle for these oxygenators to find utility in conditions like infant respiratory distress. Attempts were made to use profound hypothermia to allow turning off of perfusion for an hour to allow prolonged intracranial surgery to be performed.(23,24)
Membrane Oxygenators
The idea of using a protective membrane between the blood and air in order to decrease the problem of blood trauma was introduced in by Kolff (25) who discovered that blood in their haemodialysis machine became oxygenated when exposed to aerated dialysates. However this had problems such as a dearth of suitable biomaterials to make the membrane, the membrane itself forming an additional barrier to the gas exchange, the problem of ensuring optimal distribution of flow of blood and gas to ensure efficient exchange.
The emphasis in early membrane oxygenator development was concentrated on finding suitable biomaterials. Ethylcellulose and polyethylene were the most permeable(27). Polyethylene was rolled into a coil to create the first experimental membrane oxygenator(28).
The disadvantage of hydrophilic membrane oxygenators was that they leaked plasma which severely shortened the duration of use and so to prevent this, hydrophobic polymers like Teflon were used to make membranes(31). With hydrophobic membranes came the secondary issue that carbon dioxide solubility in hydrophobic solids is very much decreased and to solve this problem silicone was proposed to be used in membrane lungs as it has a high permeability for both oxygen and CO2.
However silicon had low mechanical strength and formed pinholes in thin sheets which was surmounted by a new production process that increased the material strength.(32)
Newer Advances
The next limiting factor was the thickness of the blood column. The thicker the column the more tough it becomes for O2 to diffuse into inner layers. Capillary oxygenators was developed (33) whose small diameter allowed easier diffusion and configurations of blood inside the fibres and air outside and vice versa were tried of which the former was better.(34) The next bottleneck was when blood flows in a laminar flow the outer layers pose a barrier to diffusion of O2 into inner layers which was overcome by forcing blood into eddy currents by means of helical tubes (35) or surface elements(36)
The disadvantage of membrane oxygenators over direct ones was the lesser permeability of gases which was aimed to be minimised by microporous membrane oxygenators which allowed direct contact between blood and air through the pores. (31) Hollow fibre inverse flow(blood flowing outside) type oxygenators were a step ahead to maximise efficiency.(38)
The success of the hollow fibre inverse flow device led to the development of an intracorporeal oxygenator which is also known as IVOX and consists of a bundle of silicone-coated hollow fibres forming a non-microporous surface which is inserted into the IVC of a patient and O2 is pumped through these fibres. Secondary flows are achieved when venous blood makes its way through these fibres in the IVC.Further enhancements to these devices include incorporation of balloon pumps within the fibres to generate secondary flows and improve the gas exchange performance and this has been named the Intravascular Membrane Oxygenator (IMO). (39)
Conclusion
Extracorporeal Membrane Oxygenation has various applications and has shown immensely favourable results in doubling the survival rates of neonates with respiratory distress syndrome(37) however trials in adults yielded disappointing results.(40) It is indeed a tantalising thought that it may well be possible to overcome the hurdles of the current oxygenators and develop a long term ‘artificial lung in the near future which would definitely serve as a ray of hope to patients with chronic lung diseases who only key to life is a hard to obtain lung transplant that is often fraught with complications. The journey of evolution of oxygenators has been a long and interesting road full of ups and downs however the path ahead looks bright and promising indeed, with new innovations promising to open doors for more efficient processes that would definitely serve as a new lease of life for several patients.
References
(1) Lim MW. The history of extracorporeal oxygenators. Anaesthesia. 2006;61(10):984-995. doi:10.1111/j.1365-2044.2006.04781.x
(2) Wylie WD, Churchill-Davidson HC. A Practice of Anaesthesia, 3rd edn. London: Lloyd-Luke, 1972: 691–715.
(3) Brown-Sequard E. Du sang rouge et du sang noir, et de leurs principaux elements gazeuse, l’oxygene et l’acide carbonique. Journal of Anatomie (Paris) 1858; 1: 95.
(4) LobellCE.Deconditionibus quibus secretiones in glandulis perficiuntur, Diss Marburgi Cattorum: typ Elwerti, 1849.
(5) McLean J. The thromboplastin action of cephalin. American Journal of Physiology 1916; 41: 250–7.
(6) Probert WR, Melrose DG. An early Russian heart-lung machine. British Medical Journal of 1960; 1: 1047–8.
(7)Brukhonenko S. Circulation artificielle du sang dans l’ organisme entire d’un chin avec Coeur exclu. Journal of de Physiologie et de Pathologie Generale 1929; 27: 251–72.
(8) Brukhonenko S, Tchetchuline S. Experiences avec la tete isolee du chien. Journal of de Physiologie et de Pathologie Generale 1929; 27: 31–79.
(9) von Schro ̈der W. Uber die Bildungsta ̈tte des Harnstoffs Archiv Fur Experimentelle Pathologie und Pharmakologie 1882;15: 364–402.
(10) MILLER BJ, GIBBON JH, FINEBERG C. An improved mechanical heart and lung apparatus; its use during open cardiotomy in experimental animals. Med Clin North Am. 1953;1:1603-1624. doi:10.1016/s0025-7125(16)34927-6
(11) GIBBON JH Jr. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med. 1954;37(3):.
(12)KIRKLIN JW, DONALD DE, HARSHBARGER HG, et al. Studies in extracorporeal circulation. I. Applicability of Gibbon-type pump-oxygenator to human intracardiac surgery: 40 cases. Ann Surg. 1956;144(1):2-8. doi:10.1097/00000658-195607000-00002
(13)Moffit EA, Patrick RT, Swan HJC, Donald DE. A study of blood flow, venous blood oxygen saturation, blood pres- sure and peripheral resistance during total body perfusion. Anesthesiology 1959; 20: 18–26.
(14) Iwahashi H, Yuri K, Nosé Y. Development of the oxygenator: past, present, and future. J Artif Organs. 2004;7(3):111-120. doi:10.1007/s10047-004-0268-6
(15)Clarke LC Jr, Gollan F, Gupta VB. The oxygenation of blood by gas dispersion. Science 1950; 111 (2874): 85–7.
(16) Lillehei CW, DeWall RA. Design and clinical application of the helix reservoir pump-oxygenator system for extr- corporeal circulation. Postgraduate Medicine 1958; 23: 561– 73.
(17)Nunn JF. Nunn’s Applied Respiratory Physiology, 4th edn. Oxford: Butterworth Heinemann, 1993.
(18) Hewitt RL, Creech O Jr. History of the pump oxygenator Archives of Surgery 1966; 93: 680–96.
(19) Lillehei CW. History of the development of extracorporeal circulation. In: Arensman RM, Cornish JD, eds, Extracorporeal Life Support. Boston: Blackwell Scientific Publications, 1993: 9–30.
(20) Hurt R. The technique and scope of open-heart surgery. Postgraduate Medical Journal 1967; 43: 668–74.
(21) Galletti PM, Brecher GA. Heart-lung bypass: principles and techniques of extracorporeal circulation. Thesis. New York: Grune & Stratton, 1962.
(22) Hurt R. The technique and scope of open-heart surgery. Postgraduate Medical Journal 1967; 43: 668–74.
(23) Drew CE, Anderson IM. Profound hypothermia in cardiac surgery, report of three cases. Lancet 1959; i: 748– 50.
(24)Boulton TB. Profound hypothermia by the Drew tech- nique. International Anesthesiology Clinics 1967; 5: 381– 410.
(25) Kolff WJ, Berk HT. Artificial kidney: dialyzer with great area. Acta Medica Scandinavica 1944; 117: 121–34.
(26) DeWall RA. Origin of the helical reservoir bubble oxygenator heart-lung machine. Perfusion. 2003;18(3):163-169. doi:10.1191/0267659103pf656oa
(27) Clowes GHA Jr, Hopkins AL, Kolobow T. Oxygen dif- fusion through plastic films. Transactions – American Society for Artificial Internal Organs 1955; 1: 23–4.
(28) Kolff WJ, Baltzer R. The artificial coil lung. Transactions – American Society for Artificial Internal Organs 1955; 1: 39–42.
(29) Clowes GH Jr, Hopkins AL, Neville WE. An artificial lung dependent upon diffusion of oxygen and carbon dioxide through plastic membranes. Journal of Thoracic Surgery 1956; 32: 630–7.
(30) Clowes GHA Jr, Neville WE. Further development of a blood oxygenator dependent upon the diffusion of gases through plastic membranes. Transactions – American Society for Artificial Internal Organs 1957; 3: 52–8.
(31) Aebischer P, Goddard M, Galletti PM. Materials and materials technologies for artificial organs. In: Materials Science and Technology – a Comprehensive Treatment, Vol. 14, Medical and Dental Materials, Chapter 4. In: Cahn RW, Haasen P, Kramer EJ Williams DF, eds. Cambridge: VCH Weinheim, 1992.
(32) Burns N. Production of a silicone rubber film for the membrane lung. Biomedical Engineering 1969; 4: 356–9.
(33) Bodell BR, Head JM, Head LR, Formolo AJ, Head JR. A capillary membrane oxygenator. Journal of Thoracic and Cardiovascular Surgery 1963; 46: 639–50.
(34) Wilson R, Shepley DJ, Llewellyn-Thomas E. A membrane oxygenator with a low priming volume for extra-corporeal circuit. Canadian Journal of Surgery 1965; 8: 309–11.
(35) Dorson W Jr, Baker E, Hull H. A shell and tube oxygenator. Transactions – American Society for Artificial Internal Organs 1968; 14: 242–9.
(36) Peirce EC 2nd, Dibelius WR. The membrane lung: studies with a new high permeability co-polymer membrane. Transactions – American Society for Artificial Internal Organs 1968; 14: 220–6.
(37) Bennett CC, Johnson A, Field DJ, Elbourne D, UK Collaborative ECMO, Trial Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation: follow-up to age 4 years. Lancet 2001; 357: 1094–6.
(38) Gaylor JDS. Membrane oxygenators: current developments in design and application. Journal of Biomedical Engineering 1988; 10: 541–7.
(39) Cox CS Jr, Zwischenberger JB, Traber LD, et al. Use of an
intravascular oxygenator ⁄ carbon dioxide removal device in an ovine smoke inhalation injury model. Transactions – American Society for Artificial Internal Organs 1991; 37: M411–3
(40) Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. Journal of the American Medical Association 1979; 242: 2193–6.
Nanditha’s Neural Nebula 