TRANSPLANTATION
Extracorporeal Life Support in Heart and Lung Transplantation Desmond Bohn Extracorporeal life support is a technology that is being increasingly used to support children with cardiac and respiratory failure who fail conventional measures. Both extracorporeal membrane oxygenation and ventricular assist devices have been used In cardiac failure with the opportunity to support patients who fail repair of congenital heart disease and in primary myocardial disease. Outcomes in the latter are superior to the surgical patients which has lead to increasing use of extracorporeal life support as a bridge to transplantation. Experience with membrane oxygenation as a support mode after lung transplantation is limited to adult series with similar outcomes. Copyright IC 2001 by W.B. Saunders Company
Key words: Extracorporeal membrane oxygenation, ventricular assist devices, transplantation, myocarditis, cardiomyopathy.
T he
Mechanical Circulatory Support in Cardiac Failure
From the Department ojCritieal Care Medicine, The Hospitalfor SICk Children, Toronto, Canada. Addms repnnt requeJtJ to Desmond Bohn, MB, The Department oj entieal Care Medicine, The Hospitalfor Sick Children, 555 Univer· Jlry Ave, Toronto, Ontario M5G IX8, Canada. Copyright © 2001 fry W.B. Saunders Company 1092·9126/01/0401 ·0005135.00/0 dOl: JO.I053/pcJu .2001.23733
The use of mechanical circulatory support with ECMO or ventricular assist devices (VADs) can be life saving in patients with severe myocardial dysfunction following repair of congenital heart disease,l-8 in patients with acute viral myocarditis or cardiomyopathy presenting with cardiogenic shock,9 and in heart transplant patients either as a bridge while awaiting an available organ or following graft failure after transplantation. 10,1 1 Although the technique is highly invasive, with the potential for significant technical and patient complications, there are now well-documented cases of the successful use of mechanical support in patients following prolonged cardiac arrest both after repair of congenital heart disease 1,4 and in primary myocardial disease. 9 A successful approach to these patients requires careful consideration at several key points in a decision algorithm regarding the institution of mechanical circulatory support, details of management while on support, and careful consideration of the optimal time for weaning with the expectation of return of native
use of mechanical support has an established place in the management of patients with acute cardiorespiratory failure. Extracorporeal life support (ELS) has been used in adults with acute hypoxic respiratory failure since the 1970s and in neonates since the early 1980s. The Extracorporeal Life Support Organization database now contains outcome data on more than 18,000 patients treated with extracorporeal membrane oxygenation (ECMO) with survival rates of more than 80% in neonates and 40% to 50% in older children and adults with acute hypoxic respiratory failure. In the past 10 years ELS has been increasingly used as a cardiac support mode in children with severely compromised myocardial function. This chapter will review the use of this technology to support children with acute cardiorespiratory failure associated with heart or lung transplantation.
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heart function versus the need for cardiac transplantation. The initial presentation of acute viral myocarditis is frequently impending circulatory collapse with pulmonary edema or heart block following a flu-like illness which is frequently misdiagnosed as gastroenteritis because vomiting is a common symptom. This disease is one of the common causes of sudden and unexpected death in otherwise healthy children. 12 The history is usually of brief duration and the heart size is rarely enlarged on chest x-ray, despite severely reduced function seen by echocardiogram. The presence of cardiomegaly suggests that the diagnosis is more likely to be an underlying cardiomyopathy. Children in the first year of life with metabolic diseases presenting as cardiomyopathy may be completely asymptomatic until the disease is unmasked by the stress of an intercurrent illness. In older children with idiopathic cardiomyopathy the symptoms usually consist of tachypnea and effort intolerance. However, their physiologic compensation mechanisms are extremely well developed so that they frequently do not present until the disease is well advanced and myocardial function is severely depressed. When contemplating initiation of ELS in children with primary myocardial disease it is important that the distinction is made between acute viral myocarditis and cardiomyopathy because in the first instance the use of a mechanical circulatory assist device can be a definitive treatment with exit from ELS following recovery of myocardial function without a transplant, while in cardiomyopathy ELS is used as a bridge to transplantation. For this reason we perform endomyocardial biopsies in this center in all children presenting with acute heart failure without structural heart disease.
Choice of Device for Mechanical Support There are two options for mechanical support in acute myocardial failure: to use a
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pumping device with an oxygenator or to use a VAD to support either the left ventricle (LVAD) , right ventricle, or both ventricles without an oxygenator. The greatest experience is with the use of ECMO to support children with cardiorespiratory failure. Potential advantages to using this mode of support are familiarity with the technique in pediatric centers, the opportunity to avoid trans-sternal cannulation, the provision of biventricular support with two peripheral cannulation sites, and the presence of an oxygenator when hypoxemia complicates the clinical picture. Potential disadvantages are increased destruction of platelets and greater heparin requirements leading to bleeding, which may be particularly problematic if there has been a recent sternotomy. There also may be inadequate unloading of the left heart which may necessitate a balloon or blade atrial septostomy or opening the sternum to place a left atrial vent. Although most ECMO centers use a roller pump system, others prefer to use a centrifugal pump which allows for the flexibility to use either the ECMO or VAD option. Using a LVAD or bi-VAD has the advantages of automatically unloading the left heart by draining the left side and because there is no oxygenator in the circuit, less anticoagulation requirements, decreased destruction of platelets, and fewer circuit related complications. The principal disadvantage is that cannulae have to be placed within the chest which can result in significant bleeding and the risk of infection. The devices that have been used clinically to support patients with cardiac failure are listed in Table 1. 4,13-17
Cannulation: Sites and Techniques and Patient Management The choice of ELS device and cannulation technique wiII be influenced by factors such as the etiology of the myocardial dysfunction, the size of the patient, and the degree of urgency for instituting support. Extracorporeal membrane oxygenation provides greater flexibility in allowing rapid institution of sup-
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Table 1. Clinical Devices Used to Support Patients With Cardiac Failure Assist Device Avecor ' Biomedicus' Berlin Heart 'S Abiomed'3 BVS
5000
Type of Assist EcMO ECMO, LVAD, BIVAD BIVAD BIVAD
Thoratec'3 VAD Medos H.IA'S VAD Pierce-Donachy'4 VAD
Pump Type
Comments
Roller Centrifugal
Extensive experience with ECMO for adults and children Adult and pediatric experience for ECMO and VAD
Pneumatic Pneumatic
Adult and pediatric application Adult application only
Pneumatic Pneumatic Pneumatic
Adult application only Adult and pediatric application only Adult application only
port from a number of sites, utilizing vessels in the neck, groin or chest while the use of VAD necessitates transthoracic cannulation. The institution of ECMO via transthoracic cannulation provides excellent venous drainage and allows the direct insertion of a left atrial drainage cannula (vent). Because of the possible need for transplantation in many of these patients, neck or groin cannulation, while maintaining an intact chest cavity, may be preferred to decrease the risk of infectious complications. If extrathoracic option is chosen, cannulation for ECMO in neonates and small children « I 0 kg) is usually via the carotid artery and internal jugular vein as the femoral vessels are too small to accept adequate size cannulae. In older children, adolescents, and adults the femoral vessels are readily accessible and can be used during resuscitation in a cardiac arrest situation. ls There also are concerns about cerebral ischemia that may result from cannulation of the carotid artery in adults. The placement of cannulae in the neck vessels is via an oblique incision in the right side of the neck with the venous cannula advanced so that the tip is in the mid right atrium and the tip of the arterial cannula at the junction of the innominate artery and the aorta arch. Both vessels are tied off proximally. For femoral cannulation the venous cannula is advanced so that the tip is at the inferior vena cava/right atrial junction and the arterial cannula is advanced so that the tip is at the aortic arch. 'Vhen the trans-
sternal approach is used the venous cannula is placed directly into the right atrium and the arterial cannula is placed in the aortic arch. \Vhen LVAD is used the venous drainage cannula is placed through the left atrium or superior pulmonary vein. Pneumatic VAD systems use a trans-sternal atrial to aortic connection. The major objective in mechanical support is "heart rest." Therefore, for ECMO supported patients, the development of leftsided cardiac distension must be assiduously avoided by monitoring left-sided filling pressures and imaging the heart with echocardiography. To avoid this, many centers will routinely place a left atrial vent when the trans-sternal cannulation route is used. When cannulation is via the neck or groin left heart distension can be documented by echocardiogram or inferred if there is pulmonary edema. The left atrium can be decompressed with a balloon atrial septostomy which can be performed in the cardiac catheterization laboratory or at the bedside under echocardiographic guidance. I9-21 Adequate coronary artery oxygenation on ECMO support can be provided by continuing to provide ventilatory support when significant ventricular ejection occurs which insures that pulmonary venous and hence coronary arterial blood will be fully saturated. Avoiding left ventricular distension and providing fully saturated coronary blood flow gives ECMO-supported patients an improved chance for recovery of native ventricular
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function. Many institutions prefer to use ECMO because of the ability to be instituted via peripheral cannulation and the presence of an oxygenator for use in those patients with significant arterial hypoxemia. Flow rates for ECMO and VAD depend on patient size and may be limited by unfavorable venous cannula position, small cannula size, thrombus within the cannula, and hypovolemia. With the centrifugal pump systems negative pressures of more than 20 em H 20 in the venous line, frequently accompanied by "chattering" in the lines, indicates inadequate venous return to the pump and will result in hemolysis. A mixed venous (SV02) saturation of 65% to 70% and a normal blood lactate are indications of adequate pump flow. In-line SV0 2 measurements with an inline catheter in the venous line are useful for this but can only be interpreted when the left atrial vent is clamped. During mechanical assistance, inotropes may be discontinued but vasodilator therapy should be continued. Anticoagulation is maintained with a continuous heparin infusion with the objective of an ACT in the range of 180 to 220 seconds, which usually results in a heparin level of 0.3 to 0.5 U/mL. In the face of intrathoracic or mediastinal hemorrhage, a significant problem with trans-sternal cannulation, activated clotting time levels can be reduced to 160 to 180 seconds but this increases the risk of thrombus formation within the circuit.
Mechanical Support: Definitive Therapy Versus Bridge to Transplantation Despite profound ventricular dysfunction at presentation, many patients with acute viral myocarditis have sufficient return of ventricular function to allow device weaning and show normal ventricular function in nontransplanted survivors. 9•22 In addition, reports also have suggested that prolonged mechanical circulatory support may result in the recovery of ventricular function in some patients with dilated cardiomyopathy because of favorable influences
O~genation
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on the neurohormonal cardiovascular milieu and unloading of the left ventricle with normalization of ventricular geometry, a process termed "reversible remodeling."23.24 It is probable that the institution of mechanical circulatory support in patients with severe, primary myocardial disease can favorably impact these same factors resulting in ventricular recovery after relatively brief periods of support. However, a competing interest is the need to successfully procure a donor heart for those patients that fail to show return of ventricular function. Because of the scarcity of donor organs in 'the pediatric age group, timely listing for transplantation provides for the best chance for successful organ procurement. The period of support that optimally balances these competing interests should be highly individualized in each patient. An attempt should be made to identify patients who have return of native ventricular function sufficient for discontinuation of support by repeated attempts at weaning. The return of a pulsatile arterial waveform is an important sign marking the beginnings of return of function. At the time that weaning is attempted, all available diagnostic modalities should be brought to bear on the decision-making process. Visualization of myocardial contractility with surface or transesophageal echocardiography should be performed with each weaning attempt while monitoring the response of hemodynamic parameters (heart rate, blood pressure, atrial filling pressures). It should be noted that echocardiogram estimation of cardiac function is load dependent and requires adequate atrial filling. In addition, ventricular contractility on echocardiography remains markedly abnormal in many of these patients, despite their ability to be weaned. In each case the synthesis of all of the clinical parameters listed will determine the suitability for weaning. In borderline cases, patients may be maintained with the cannulas clamped in place for
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several hours with intermittent flushing while maintaining full systemic heparinization to safely assess stability after weaning from mechanical support. Identifying those patients that will require the use of ECMO or VAD as a bridge for transplantation is a clinical determination based on failure after repeated attempts at weaning as previously described. Extended bridging periods have been used successfully with more than 6 weeks of support to transplantation reported in one instance. 25 Prolonged periods of LVAD support in adult patients with dilated cardiomyopathy have been reported with reduction to normal in end-diastolic pressure-volume relations in some instances and separation from ELS without transplantation. 24,26 The development of pulsatile paracorporeal or implantable systems that have been used successfully in children in Europe will allow long-term support of patients presenting with profound ventricular dysfunction caused by acute myocarditis. 15 In a larger number of patients this approach may show that the majority can be supported long enough to allow return of native ventricular function, thereby avoiding transplantation.
Outcome The impact of the introduction of mechanical support on outcome in patients with cardiac disease is difficult to determine for a number of reasons. Reports in the medical literature are either anecdotal cases or case series with varying indications for the use of the technology and sometimes imprecise diagnosis. The largest published single-center experiences are from Boston and Columbus, OR, both of which show that the worst outcomes are in patients in which ELS was used for failed repair of congenital heart disease «30% survival) while in the bridge-to-transplant group survival was 40% to 60%.1,8 The largest case series of primary myocardial disease is the Extracorporeal Life Support Organization Registry database which reports
40% to 50% survival in patients in the diagnostic category myocarditis!cardiomyopathy.27 This database does not collect information on whether the exit from mechanical support is recovery of myocardial function or by way of transplantation. Undoubtedly, there have been some spectacular recoveries in children with myocarditis or cardiomyopathy who have deteriorated even to the point of cardiac arrest, placed on ECMO or LVAD after prolonged cardiac massage, with normal neurologic outcomes. I,17 The picture is different for ELS support in the congenital heart population. In a long-term follow-up study by Ibrahim et al 28 of children with cardiac disease supported with ELS, the incidence of neurologic injury was higher in patients in which ECMO was used, but most of these were small infants who had repair of congenital heart disease. Long-term outcomes with primary myocardial disease are much better. In a multicenter case series of children with acute viral myocarditis reported by Duncan et al,9 16 children with cardiogenic shock were placed on ECl\IO or VAD with 12 survivors, 7 of whom had return of native ventricular function. The median time of separation from mechanical support with ultimate return of ventricular function without transplantation was 140 hours (range, 115 to 400 hrs). Five others exited mechanical support by way of transplantation. Another remarkable feature of this series is that the duration of support was up to 10 days in one patient who regained normal function and the incidence of neurological damage was much lower. Similar experiences are reported from European centers with the use of pneumatically driven VAD systems. 15,29,30 This has implications for distinction between ELS as a definitive therapy or a bridge to transplantation. The situation with cardiomyopathy is more complex. Mechanical support in this situation is primarily a bridge to transplantation and outcome depends largely on donor organ availability, which implies size as well as tissue match in a child. Results tend to be poor
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in the case of ELS being used as a bridge to transplantation following unsuccessful repair of congenital heart disease or failure of the engrafted heart. This is because bleeding is always a major complication and perfusion to other organs is frequently compromised by periods of low cardiac output. In all instances survival, both short and long term, may depend on the avoidance of the complications of organ dysfunction and sepsis. 8
Extracorporeal Membrane Oxygenation in Heart-Lung and Lung Transplantation Oxygenation failure secondary to allograft dysfunction is not an uncommon situation following lung or heart-lung transplantation. 31 This may be caused by pulmonary edema secondary to reperfusion injury, pulmonary vascular endothelial abnormalities resulting in pulmonary hypertension, or rarely, primary nonfunction of the transplanted lung. Hypoxemia frequently can be reversed with mechanical ventilation with positive end-expiratory pressure, although at the risk of damage to the transplanted lung when high airway pressures and Fi02 levels are used. Inhaled nitric oxide also has been proven effective in this situation. 32 ,33 In the event that these measures fail to reverse the hypoxemia, there is an increasing experience in the use of ECMO in oxygenation failure following lung transplantation. While most of this experience comes from adult lung transplant programs, the principles are equally applicable to children.
Cannulation and Patient Management The two alternatives available for ECMO support following heart-lung or lung transplantation are venovenous or venoarterial and both options have been used in published case series. 34•36 There are no established criteria for which is preferable accept that venoarterial support is more likely to be used following heart-lung transplant in patients with pulmonary vascular disease or
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those with significant myocardial dysfunction. Venovenous ECMO support in smaller children « 10 kg) can be accomplished through a single cannulation site using a double lumen venous cannula inserted through the internal jugular vein. These are available in sizes up to 17 guage and would supply sufficient flow (100 mLlkg) for pulmonary support. Venovenous support in larger children would require a double venous cannulation via the internal jugular and femoral veins. With either the double lumen cannula or a two cannula technique there is inevitably a degree of recirculation and oxygen saturation of 90% is the normal level. If ECMO is instituted in the first few days after surgery, hemorrhage from the surgical site will be a major risk factor. As in cardiac ELS, the balance is between sufficient heparinization to inhibit clot formation without causing significant bleeding. Activated clotting times in the region of 160 to 180 seconds are usually sufficient to achieve this balance. The use of heparin-bonded circuits may allow for lower systemic heparinization. Platelet consumption and destruction with membrane lungs is commonplace and platelet transfusions are frequently required to maintain counts at greater than 50,OOO/mm 3 • Ventilator parameters should be reduced to lung-rest settings, which means a slow rate (I O/min) while attempting to maintain some lung expansion with a positive end-expiratory pressure in the range of 10 em H 20 and an Fi02 of 0.3. Duration of support depends on the degree of underlying lung injury and the extent of any ventilator-induced lung injury. The best results are seen when ECMO support is instituted early. Recovery of lung function is heralded by clearing of the chest x-ray. When this point is reached, weaning from venovenous ECMO support can be attempted by reinstituting full mechanical ventilation while either reducing the blood flow in the circuit or the Fi02 concentration to the membrane lung (veno-venous ECMO). When venoarterial ECMO is being used, weaning can only be performed by re-
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ducing circuit flow before clamping the cannulas. Generally speaking, patients should not be separated from ECMO unless they can maintain oxygenation with ventilator settings of an Fi02 of less than 0.6 and a positive end-expiratory pressure less than 10 cmH20.
Outcomes Outcome data for ECMO support after lung or heart-lung transplantation consists of single case reports or case series from adult transplant centers. 34 ,36.46 Although there are a few case reports in children,47,4B although the largest case series are from two of the most high-profile adult lung transplant programs, the Washington University School of Medicine and the University of Pittsburgh. 35,36 Meyers et aP5 reported the need for ECMO support in 12 of 444 patients (2. 7%) following single or bilateral lung transplants with seven survivors to hospital discharge, while in the series by Glassman et al,36 ECMO was used in 16 of 215 (7.4%) of a similar mix of transplant patients with seven long-term survivors. The mean duration of support in both studies was 4 days and successful separation from ECMO was more common in patients in which separation was initiated early after surgery, which implies that ventilator-induced lung injury is a significant factor that impacts outcome. In both series a Biomedicus pump was used and the majority were venoarterial ECMO support. In some instances, the exit from ECMO was via a second transplant. There are very few survivors in the literature with recovery of lung function after more than 5 days of ECMO support. After this time the incidence of damage to other organs tends to rise. Failure to see improvement in graft function within this period should be an indication to perform a lung biopsy because the differentiation between rejection and infection can be very difficult.
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with prolonged use ofbiventricular assist devices. Heart 82:237·240, 1999 30. Ishino K, Loebe M, Uhlemann F, et al: Circulatory support with paracorporeal pneumatic ventricular assist device (VAD) in infants and children. Eur J Cardiotho· rac Surg II :965-972, 1997 31. Khan SU, Salloum J, O'Donovan PB, et al: Acute pulmonary edema after lung transplantation: The pulmonary reimplantation response. Chest 116:187-194, 1999 32. Adatia I, Lillehei C, Arnold JH, et al: Inhaled nitric oxide in the treatment of postoperative graft dysfunction after lung transplantation. Ann Thorac Surg 57:1311-1318, 1994 33. Date H, Triantafillou AN, Trulock EP, et aI: Inhaled nitric oxide reduces human lung allograft dysfunction.] Thorac Cardiovasc Surg 111:913-919, 1996 34. Zenati M, Pham SM, Keenan RJ, et al: Extracorporeal membrane oxygenation for lung transplant recipients with primary severe donor lung dysfunction. Transpl Int 9:227-230, 1996 35. Meyers BF, Sundt TM III, Henry S, et al: Selective use of extracorporeal membrane oxygenation is warranted after lung transplantation. J Thorac Cardiovasc Surg 120:20·26, 2000 36. Glassman LR, Keenan Rj, Fabrizio MC, et al: Extracorporeal membrane oxygenation as an adjunct treatment for primary graft failure in adult lung transplant recipients. J Thorac Cardiovasc Surg 110: 723-727, 1995 37. Nelems jM, Duffin j, Glynn FX, et al: Extracorporeal membrane oxygenator support for human lung transplantation. j Thorac Cardiovasc Surg 76:28-32, 1978 38. Nguyen DQ, Kulick DM, Bolman RM III, et al: Temporary ECMO support following lung and heart-lung transplantation. j Heart Lung Transplant 19:313316, 2000 39. Vlasselaers D, Verleden GM, Meyns B, et al: Femoral venoarterial extracorpo-
real membrane oxygenation for severe reimplantation response after lung transplantation. Chest 118:559-561, 2000 40. Struber M, Haverich A: Extracorporeal membrane oxygenation-New developments. Thorac Cardiovasc Surg 47:304306, 1999 (suppl 2) 41. Chan CY, Chen YS, Ko \'1, et al: Extracorporeal membrane oxygenation support for single lung transplantation in a patient with primary pulmonary hypertension. j Heart Lung Transplant 17: 325-327, 1998 42. Ball j\V jr, Noon GP, Short HD, et al: Extracorporeal membrane oxygenation for early graft dysfunction in lung transplantation: A case report. j Heart Lung Transplant 16:468-471, 1997 43. Badesch DB, Zamora MR,jones S, et al: Independent ventilation and ECMO for severe unilateral pulmonary edema after SLT for primary pulmonary hypertension. Chest 107: 1766-1770, 1995 44. Slaughter MS, Nielsen K, Bolman RMD: Extracorporeal membrane oxygenation after lung or heart-lung transplantation. ASAIO J 39:M453-M456, 1993 45. Jurmann ~U, Schaefers Hj, Demertzis S, et al: Emergency lung transplantation after extracorporeal membrane oxygenation. ASAIO J 39:M448-1\1452, 1993 46. J urmann MJ, Haverich A, Demertzis S, et al: Extracorporeal membrane oxygenation (ECMO): Extended indications for artificial support of both heart and lungs. Int J Artif Organs 14:771·774, 1991 47. Koutlas TC, Bridges ND, Gaynor jW, et al: Pediatric lung transplantation-Are there surgical contraindications? Transplantation 63:269-274, 1997 48. Bridges ND, Mallory GB jr, Huddleston CB, et al: Lung transplantation in children and young adults with cardiovascular disease. Ann Thorac Surg 59:813-821, 1995