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12 July 2013 No. 23 INTRODUCTION TO ECMO G. GOVENDER Commentator: N. Moodley Moderator: S Goga DISCIPLINE OF ANAESTHETICS CONTENTS INTRODUCTION ................................................................................................... 3 HISTORY OF ECMO............................................................................................. 3 INDICATIONS FOR ECMO ................................................................................... 4 CONTRAINDICATIONS ........................................................................................ 6 TYPES .................................................................................................................. 6 MAINTENANCE AND CARE OF PATIENTS WITH ECMO .................................. 9 SPECIAL CONSIDERATIONS ............................................................................. 9 CRITERIA FOR WEANING OR DISCONTINUING ECMO ................................. 10 COMPLICATIONS .............................................................................................. 10 FUTURE ADVANCEMENTS............................................................................... 11 RESULTS OF RANDOMIZED TRIALS OF EXTRACORPOREAL MEMBRANE OXYGENATION FOR ACUTE RESPIRATORY DISTRESS SYNDROME ......... 12 CONCLUSION .................................................................................................... 13 REFERENCES.................................................................................................... 14 Page 2 of 15 INTRODUCTION TO ECMO INTRODUCTION Extracorporeal membrane oxygenation (ECMO) is unfamiliar to many of us in South Africa due to its nonexistent use in the public sector and its limited use in the private sector.This technology is used primarily in neonates with respiratory failure, particularly those with Hyaline Membrane Disease. The concept of ECMO is not to cure disease but rather to allow the lungs to rest which promotes quicker recovery times. Due to its success with the paediatric sector, this modality is now more frequently used in adult intensive care units around the world.In recent years, pivotal progress has been made in the conception and construction of ECMO circuits. They are now simpler, safer, require less anticoagulation and are associated with fewer bleeding complications. The encouraging results of the efficacy and economic assessment of conventional ventilatory support versus ECMO for severe adult respiratory failure (CESAR) trial performed in the United Kingdom and the good outcomes of patients who received ECMO as rescue therapy during the H1N1 influenza pandemic, in which the latest generation of ECMO technology was used, reignited interest in ECMO for severe acute respiratory distress syndrome (ARDS).In order for us to mirror our counterparts internationally in terms of standards of care, we should be familiarizing ourselves with novel concepts like ECMO, this being the motivation behind my choice of topic. HISTORY OF ECMO As early as 1935 have John Gibbon, Clarence Dennis (1), and others pursued the development of a mechanical device to take over the function of the heart and lungs to permit surgical operations on the heart and great vessels. Their inspiration came from a patient who demised from a pulmonary embolus. Gibbon was the first to use a roller pump which remains in general practice today. To substitute the lung, he used direct exposure of blood to oxygen which proved successful. Subsequently this technique was modified by Dennis, Morrow, Cross, DeWall, Rygg (7), and many others, leading to the single-use, disposable, direct gas interface oxygenators which are widely used today. Gibbon was the first to use the prosthetic heart/lung machine for a cardiac operation paving the way for success of extracorporeal circulation for cardiac surgery.However, during the 1950’s, with more frequent use it became clear that this life supporting device could also be lethal. Deterioration of organ function occurred in proportion to the amount of time on cardiopulmonary bypass. It was hypothesized that the direct exposure of blood to oxygen gas was responsible for this apparent toxicity. Page 3 of 15 The development of dimethylpolysiloxane membranes in 1957 was a major advance. This unique material allows for the transfer of carbon dioxide and oxygen at rates in excess of ten times that used through other plastics. Using this silicone rubber, blood oxygenators were constructed which were quite efficient and successful. Starting with Gibbon, all the studies on extracorporeal circulation have been conducted with the use of heparin anticoagulation, using a dose sufficient to produce an infinitely long clotting time (1). In 1971 a San Francisco Surgeon named Donald Hill (7) l used a modified extracorporeal bypass called “extracorporeal membrane oxygenation” (ECMO) to treat an adult who was dying from acute respiratory insufficiency. The patient was a young man who sustained a ruptured aorta and other injuries in a motorcycle accident in Santa Barbara, California. This was the first time ECMO was used on an adult patient. The patient was managed on veno-arterial extracorporeal support for 3 days and survived. This was a very important discovery, especially for intensive care units, where acute renal and respiratory failure was the major concerns in critically ill patients.Similar to the use of haemodialysis in cases of renal failure, it was hoped that ECMO would offer a temporary period of life support with extracorporeal circulation that would allow the damaged lung to recover. INDICATIONS FOR ECMO Page 4 of 15 Respiratory Failure ECMO support has been proposed for patients with ARDS refractory to conventional mechanical ventilation, and in other severe conditions such as lung trauma, severe asthma, pulmonary emboli or patients with chronic lung disease awaiting lung transplantation.According to the extracorporeal life support organization (ELSO), ECMO is indicated in the following (2): Hypoxemic respiratory failure with a ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) of <100 mmHg despite optimization of the ventilator settings, including the Fraction of Inspired Oxygen (FiO2), positive end-expiratory pressure (PEEP), and inspiratory to expiratory (I:E) ratio ECMO should be considered when the risk of mortality is 50% more, and is indicated when the risk of 80% or greater. 50% mortality risk can be identified by a PaO2/FiO2 < 150 on FiO2 > 90% and/or Murray score 2-3 80% mortality risk can be identified by a PaO2/FiO2 < 80 on FiO2 > 90% and Murray score 3-4 The Murray Score is based on the following (2): PaO2/FiO2 in mmHg on 100% oxygen for at least 20 minutes. Number of quadrants with infiltration seen on chest x-ray. PEEP value on the ventilator Compliance (ml/cmH2O) which may be calculated as: (Tidal Volume) / (PIPPEEP) Page 5 of 15 Hypercapnic respiratory failure with an arterial pH <7.20, CO2 retention due to asthma or permissive hypercapnia with a PaCO2 > 80 or inability to achieve safe inflation pressures (Pplat ≤ 30 cm HO) Cardiac Failure Refractory cardiogenic shock - Inadequate tissue perfusion manifested as hypotension and low cardiac output despite adequate intravascular volume. The persistence of low cardiac output despite volume administration, inotropes and vasoconstrictors Typical causes of refractory cardigenic shock: acute myocardial infarction, myocarditis, peripartum cardiomyopathy, decompensated chronic heart failure, post cardiotomy shock. Other causes: biventricular failure, refractory malignant arrythmias, heart failure with severe pulmonary failure In some centres, ECMO may be used in septic shock Recovery: Acute MI after revascularization, Myocarditis, Postcardiotomy Failure to wean from cardiopulmonary bypass after cardiac surgery Cardiac transplantation As a bridge to either cardiac transplantation or placement of a ventricular assist device CONTRAINDICATIONS Most contraindications are relative, balancing the risks of the procedure vs. the potential benefits. These include: Conditions incompatible with normal life if the patient recovers Pre-existing conditions which affect the quality of life (CNS status, end stage malignancy, risk of systemic bleeding with anticoagulation) Age and size of patient Futility: patients who are too sick, have been on conventional therapy too long, or have a fatal diagnosis. TYPES There are two common types of ECMO i.e. Veno-atrerial (VA) or Veno-venous (VV)Peripheral veno-venous ECMO should be the modality of choice for severe hypoxic respiratory failure wherein no major cardiac dysfunction exists. Therefore, echocardiography should be performed before veno-venous ECMO placement to identify severe left ventricular dysfunction, which might necessitate the use of veno-arterial ECMO. Page 6 of 15 Veno- Arterial Usually indicated in cardiac failure Output canula drains from the venous system and the input canula drains into the arterial system thereby bypassing the entire cardio-respiratory system. Pulsatile flow is needed for this modality. Venous Canula is placed in the right femoral vein and arterial canula is placed in the right femoral artery. The disadvantage of this method is that pulsatile flow is needed to mimic cardiac output and large bore cannulation of an artery is needed which can be associated with complications. Veno-Venous Indication: Isolated Respiratory Failure Both input and output cannula is situated in the venous system This system extracts the CO2 from the venous system and oxygenates the venous blood. It still requires a functioning cardiac system to output the oxygenated blood. Cannulation for veno-venous ECMO may involve two sites or a single site. In the two-site approach, blood is typically withdrawn from the inferior vena cava through a drainage cannula in the femoral vein, and oxygenated blood is reinfused into the right atrium through a cannula in the internal jugular vein. This approach can result in recirculation of blood, which occurs when reinfused blood is drawn back into the circuit in a closed loop. Recirculated blood does not contribute to systemic oxygenation. The recent introduction of a bicaval dual-lumen cannula allows single-site cannulation of the internal jugular vein. Venous blood is withdrawn through one lumen with ports in both the superior and inferior vena cava. Reinfusion of blood occurs through the second lumen and is directed across the tricuspid valve. The advantages of the single-site approach include avoidance of the femoral access site, improved patient mobility, and considerably reduced recirculation when the cannula is properly positioned. Page 7 of 15 Extracorporeal membrane oxygenation: a clinical update Page 8 of 15 MAINTENANCE AND CARE OF PATIENTS WITH ECMO Peripheral cannulation should be strictly percutaneous by Seldinger technique, which can be rapidly performed by nonsurgical staff and remotely without the need for specialized surgical equipment, requires no skin suturing, reduces bleeding and allows simple decannulation when ECMO has been weaned. The use of vascular ultrasound before and during the procedure enables immediate confirmation of venous vessel access, guidewire identification in the right atrium to exclude coiling in proximal vessels and optimization of cannulae positioning to reduce recirculation. Prerequisites Patients require management in an intensive care unit with a multidisciplinary team approach: Attention should be paid to the following factors: Fluid and electrolyte management Nutritional Support Infection Control Pain Relief and sedation if needed Anticoagulation Psychosocial considerations Maintenance of the Circuit Trained technician Medical staff with experience in ECMO use Circuit to be checked timorously and regularly SPECIAL CONSIDERATIONS Blood flow Maximum flow rates are used during VV ECMO to optimize oxygen delivery. VA ECMO must be high enough to provide adequate perfusion pressure whilst still being sufficiently low to provide preload so as to maintain left ventricular output. Diuresis Ultrafiltration can be added to the ECMO circuit Left ventricular monitoring Left ventricular output should still be closely monitored during VA ECMO as Left ventricular function may deteriorate. Page 9 of 15 CRITERIA FOR WEANING OR DISCONTINUING ECMO Patients with respiratory failure Radiographic improvement Better pulmonary compliance Increase in arterial oxyhaemoglobin saturation Patients with cardiac failure Improved Left ventricular output COMPLICATIONS Data are from the Extracorporeal Life Support Organization (ELSO) Page 10 of 15 Bleeding Occurs in more than 40% of patients, can be fatal Can be attributed to heparin infusion Risk of bleeding can be minimised with frequent monitoring of ACT according to patient target Thromboembolism More frequent with VA ECMO than VV ECMO because infusion is into the systemic circulation. Heparin infusion required Close circuit monitoring for clots is essential Cannulation-related Operator dependant Can include arterial dissection, distal ischemia and sepsis Heparin-induced thrombocytopenia When suspected, the heparin infusion is usually replaced by a non-heparin anticoagulant. Veno-Arterial specific complications Pulmonary haemorrhage Cardiac thrombosis Stasis of the blood which occurs if left ventricular output is not maintained can result in thrombosis. Coronary or cerebral hypoxia Preferential perfusion of the lower extremities due to catheter location FUTURE ADVANCEMENTS As mentioned above significant adverse events and potential complications can occur during extracorporeal life support. These are becoming less common and less severe with increasing experience and major technological developments, such as Heparin bounded circuits to prevent thromboembolism Left ventricular assist devices attached to the ECMO to improve CO2 removal Advances in circuit components such as oxygenators and pumps to improve simplicity of ECMO ECMO can also be used on cadavers to increase the viability of organs to be transplanted Page 11 of 15 RESULTS OF RANDOMIZED TRIALS OF EXTRACORPOREAL MEMBRANE OXYGENATION FOR ACUTE RESPIRATORY DISTRESS SYNDROME The first multicenter, randomized trial to evaluate ECMO for ARDS was conducted by the National Institutes of Health in the United States in the 1970s on 90 patients with severe ARDS refractory to conventional ventilation techniques. Patient survival in that trial was extremely low (<10%) and no improvement with ECMO was demonstrated. However, that study suffered from major methodological limitations.In the 1990s, Morris et al. in Utah conducted another randomized, controlled trial, which was a single-centre study using a device eliminating CO2.The study was stopped for futility after only 40 patients had been enrolled, and once again, the results did not advocate the use of this form of respiratory assistance. The most recent trial (CESAR) was conducted in the United Kingdom from 2001 to 2006. The patients randomized to receive ECMO support were transferred to a single centre (Glenfield, Leicester); where as the patients randomized to the control group were treated conventionally at designated treatment centres. Mortality or severe disability 6 months after randomization, the primary endpoint, was lower for the 90 patients randomized to the ECMO group (37 vs. 53%). This is the first randomized trial showing better outcomes with ECMO for patients with severe ARDS. However, 22 patients randomized to the ECMO arm did not receive ECMO (died before or during transport, improved with conventional management at the referral centre or had a contraindication to heparin). The other major methodological problem was the absence of a standardized protocol for mechanical ventilation in the control group. Therefore CESAR is a good study, but does not convincingly prove ECMO is better than conventional therapy. What it did show was that transferring adult patients with severe but potentially reversible respiratory failure to a single centre specialising in the treatment of severe respiratory failure for consideration of ECMO significantly increased survival without severe disability. The role and proper use of ECMO for patients with ARDS have not been definitively established. The continued evolution of ECMO technology also limits the conclusions that may be drawn from recent studies. The role of extracorporeal carbon dioxide removal in ARDS, although potentially promising, remains to be defined. Although the CESAR trial provides some guidance for the use of ECMO, it is not clear which patients with ARDS are the best candidates for this treatment. The most favourable timing for the initiation of ECMO has not been established. Various strategies to achieve lung rest and their effects on the inflammatory process have not been compared, nor have any such strategies been shown to be superior to standard-of-care lung-protective ventilation during ECMO. The most appropriate strategy for weaning patients with ARDS from ECMO is also unknown. Page 12 of 15 The long-term effects of ECMO, especially potential neuropsychiatric effects, require further investigation. In short further and better studies are needed to evaluate ECMO, especially in ARDS. CONCLUSION ECMO is at present not available within the public sector and is rarely used in the private setting in our country. This modality is beneficial with good patient selection. Most data involves ECMO use within the paediatric population with promising results. Further studies amongst adult patients are recommended to guide ECMO use in this group.However, ECMO is costly and labour-intensive. In the CESAR trial, mean costs per patient in the group that could receive ECMO were more than twice as high as in the control group, at a mean of £73,979 over a period of 6 months.Optimal benefit from ECMO requires centralisation of services. Furthermore adequate staff training including experienced perfusionists, doctors and ECMO nurses are needed. This may prove difficult in a resource limited environment. Page 13 of 15 REFERENCES 1. Gibbon JH Jr. The development of the heart–lung apparatus. Am J Surg 1978; 135: 608-619. 2. Extracorporeal Life Support Organization. ECLS registry report, international summary. Ann Arbor, Mich: ELSO, 2009. 3. Hastings SL, Pellegrino VA, Preovolos A, Salamonsen RF. Survey of adult extracorporeal membrane oxygenation (ECMO) practice and attitudes among Australian and New Zealand intensivists. Crit Care Resusc 2008; 10: 42-46. 4. Mielck F, Quintel M. Extracorporeal membrane oxygenation. Curr Opin Crit Care 2005; 11: 87-93. 5. Marasco SF, Esmore DS, Richardson M, et al. Prolonged cardiac allograft ischemic time — no impact on long-term survival but at what cost? Clin Transplant 2007; 21: 321-329. 6. Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med 1972; 286: 629-634. 7. Bartlett RH. Extracorporeal life support: history and new directions. ASAIO J 2005; 51: 487-489 8. Bartlett RH, Roloff DW, Cornell RG, et al. Extracorporeal circulation in neonatal respiratory failure: a prospective randomized study. Pediatrics 1985; 76: 479-487. 9. O’Rourke PP, Crone RK, Vacanti JP, et al. Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective randomized study. Pediatrics 1989; 84: 957-963. 10.Bifano EM, Hakanson DO, Hingre RV, Gross SJ. Prospective randomized controlled trial of conventional treatment or transport for ECMO in infants with persistent pulmonary hypertension (PPHN) [abstract]. Pediatr Res 1992; 31: 196A. 11.Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008; 299:637–645. 12.Sud S, Friedrich JO, Taccone P, et al. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med 2010; 36:585–599. This reviews recent trials of prone positioning in severe ARDS. Page 14 of 15 13. 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Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. The Lancet 2009; 374:1351–1363. 18.Combes A, Pellegrino V. Extracorporeal membrane oxygenation for 2009 influenza A (H1N1)-associated acute respiratory distress syndrome. Semin Respir Crit Care Med 2011; 32:188–194. 19. Davies A, Jones D, Bailey M, et al. Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome. JAMA 2009; 302:1888–1895. 20. Kolobow T, Zapol W, Pierce JE, et al. Partial extracorporeal gas exchange in alert newborn lambs with a membrane artificial lung perfused via an A-V shunt for periods up to 96 h. Trans Am Soc Artif Intern Organs 1968; 14:328–334. Page 15 of 15