Strategies for Left Ventricular Decompression During Venoarterial Extracorporeal Membrane Oxygenation - A Narrative Review

ARTICLE IN PRESS Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 111

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Review Article

Strategies for Left Ventricular Decompression During Venoarterial Extracorporeal Membrane Oxygenation A Narrative Review Suneel Ramesh Desai, MBChB, MA, FRCA, EDIC, FFICM*,y, Nian Chih Hwang, MBBS, FFARCSI, GDAcu*,z,1 *

Department of Cardiothoracic Anaesthesia, National Heart Centre, Singapore Department of Surgical Intensive Care, Singapore General Hospital, Singapore z Department of Anaesthesiology, Singapore General Hospital, Singapore

y

Extracorporeal cardiopulmonary resuscitation involves the application of venoarterial extracorporeal membrane oxygenation for patients in cardiac arrest who have received good quality conventional cardiopulmonary resuscitation, and who are deemed to have a reversible cause and no contraindications. Systemic perfusion is maintained by the extracorporeal life support, allowing time for the underlying cause to be treated and the heart to recover. Specific considerations to promote cardiac recovery are discussed, including the maintenance of sinus rhythm, promotion of cardiac ejection, management of pulmonary hypertension, management of intravascular volume, and prevention of ventricular distention. Advanced strategies for ventricular decompression including atrial septostomy and percutaneous ventricular assist devices are discussed. Ó 2019 Elsevier Inc. All rights reserved. Key Words: left ventricular distension; extracorporeal cardiopulmonary resuscitation; intracardiac thrombus; Tandem Heart; Impella; upper body hypoxemia

PATIENTS RECEIVING venoarterial extracorporeal membrane oxygenation (VA-ECMO) are typically in cardiogenic shock or cardiac arrest. Approximately one-third of patients who receive VA-ECMO will survive to discharge from hospital, and there is some data to suggest that VA-ECMO may result in a higher survival rate compared with conventional cardiopulmonary resuscitation, particularly for in-hospital cardiac arrest. Wilson-Smith et al.1 presented a meta-analysis of 52 studies including 17,515 patients undergoing VA-ECMO for refractory cardiogenic shock. Overall survival rate was found to be 36.7%, 34.8%, 33.8%, and 29.9% at 1, 2, 3, and 5 years, respectively. Ahn et al.2 described a meta-analysis of 7 studies including 38,160 patients, comparing outcomes of patients who received conventional cardiopulmonary resuscitation (CCPR) with extracorporeal cardiopulmonary resuscitation (ECPR). There were no significant differences in 1 Address reprint requests to Nian Chih Hwang, Department of Anaesthesiology, Singapore General Hospital, Outram Road, 169608, Singapore. E-mail address: [email protected] (N.C. Hwang).

https://doi.org/10.1053/j.jvca.2019.08.024 1053-0770/Ó 2019 Elsevier Inc. All rights reserved.

mortality or neurologic outcomes for out-of-hospital cardiac arrest patients. However for in-hospital cardiac arrest patients ECPR was found to result in superior survival and neurologic outcomes (cerebral performance category 1-2 or Glasgow outcome scale 1) than CCPR (survival: odds ratio [OR] 2.40, 95% confidence interval [CI] 1.44-3.98; and neurologic outcome: OR 2.63, 95% CI 1.38-5.02). Chen et al.3 performed a prospective observational study comparing ECPR (n = 59 patients) with CCPR (n = 113 patients) for patients undergoing resuscitation for longer than 10 minutes for in-hospital cardiac arrest with a primary cardiac cause. Survival to discharge, 30-day survival, and 1-year survival were all significantly higher in the ECPR group compared with patients who received CCPR, with and without propensity matching. The intention of VA-ECMO support is to sustain systemic perfusion and oxygenation, allowing time for the underlying cause to be treated, and assessment of cardiac, neurologic, and systemic organ failure recovery.4,5 However early restoration of ventricular ejection is vital to prevent intracardiac thrombosis or refractory ventricular distention, both of which may result in an adverse

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outcome. The authors present a literature review advocating a stepwise approach for prevention, monitoring, and selective intervention for left ventricular distention during VA-ECMO. Methodology A narrative review was conducted. PubMed was searched combining the search terms “venoarterial extracorporeal membrane oxygenation” and “extracorporeal cardiopulmonary resuscitation,” “left ventricular dilatation,” “left ventricular distention,” “left ventricular unloading,” “left ventricular decompression,” “non ejecting heart,” “inotrope*,” “pulse pressure,” “pulsatility,” “intraaortic balloon pump,” “IABP,” “atrial septostomy,” “Tandem heart,” “Impella,” and “echocardiography.” Articles were filtered based on title and abstract, and reference lists were traced to identify additional articles of relevance. All article types were included, including case reports, case series, observational or interventional studies, position statements, clinical guidelines, and review articles. As this is a narrative review, included articles were selected based on the authors’ subjective determination of relevance to the overall theme of this paper. Implications of Left Ventricular Distention During VAECMO Left ventricular dysfunction develops rapidly following the institution of VA-ECMO, irrespective of central or peripheral cannulation.6 Initiation of VA-ECMO increases mean arterial pressure and systemic perfusion, in proportion to the VA-ECMO flow rate. However, an adverse effect of the increase in mean arterial pressure is a corresponding elevation in left ventricular afterload. This results in a detrimental increase in left ventricular end-diastolic volume and pressure, which reduces transmural myocardial perfusion, and impairs myocardial recovery and function.7-9,10-12 Other complications may include intracardiac thrombosis, pulmonary hypertension, pulmonary edema, and reduced likelihood of biventricular recovery and successful weaning from VA-ECMO.13-17 In order to maximize the likelihood of cardiac recovery, some authors recommend routine left ventricular decompression18 during VA-ECMO, whereas others propose a more selective approach.19 The difference in approach may depend on the primary indication for VA-ECMO. In cardiogenic shock there is usually some preservation of left ventricular ejection, in which case inotropic and vasoactive therapy, and intra-aortic balloon pump counterpulsation (IABP) may be reasonable first line options. However when VA-ECMO is used for ECPR there may be minimal or no cardiac ejection, and a specific unloading strategy may be required, depending on the recovery of left ventricular function. Tonna et al.20 conducted a survey of practice patterns of all centers in the United States that offered an ECPR service. The overall response rate was 70 out of 99 centers, of which 36 performed ECPR in the emergency department. The use of left ventricular decompression strategies varied, with the majority of centers favoring atrial septostomy (30.6%) or the left ventricular Impella device (33.3%). Only a minority of centers did not routinely decompress the

left ventricle (5.6%). Russo et al.21 performed a meta-analysis of 17 observational studies including 3,997 patients supported with VA-ECMO. Overall mortality in the entire cohort was 60%, and a dedicated left ventricular unloading strategy was used in 1696 patients (42%), which included an IABP in 91.7%, percutaneous ventricular assist device in 5.5%, and pulmonary vein or trans-septal left atrial decompression in 2.8%. Patients who received a left ventricular unloading strategy had a lower mortality than those who received VA-ECMO alone (54% v 65%, risk ratio [RR] 0.79; 95% CI 0.72-0.87), however the incidence of hemolysis was higher in the left ventricular decompression group. No other differences in complications were identified. Truby et al.22 retrospectively reviewed data related to left ventricular distention from 121 patients who received VA-ECMO. Left ventricular distention was identified as severe (requiring immediate left ventricular decompression) in 9 patients (7%), and subclinical (pulmonary edema on chest x-ray with a pulmonary artery diastolic pressure >25 mmHg) in 27 patients (22%). The severity of left ventricular distention was inversely related to the likelihood of myocardial recovery, and event-free survival (death or transition to an alternative support device). The requirement for left ventricular decompression was significantly higher in patients receiving VA-ECMO for ECPR (OR 3.64, 95% CI 1.21-10.98). Possible outcomes in survivors of VA-ECMO may include cardiac recovery (with or without neurologic impairment),23,24 heart transplantation or transition to a durable left, right, or biventricular assist device.25-28 Conversion of VA-ECMO to a percutaneous left and/or right ventricular assist device may be considered as an interim bridge to decision, in patients with refractory cardiac dysfunction and pulmonary edema, to allow further time for evaluation of cardiac recovery, neurologic prognosis, and recovery of systemic organ failures. Hence some authors advocate a stepwise approach starting with femoral VA-ECMO for emergency support in view of the speed of cannulation, followed by strategies to optimize left ventricular ejection while on VA-ECMO support, and if required sequential conversion to a percutaneous left and/or right ventricular assist device.25,26 A proposed workflow is outlined in Figure 1. Monitoring Cardiac Ejection During VA-ECMO After initiation of VA-ECMO for cardiogenic shock or cardiac arrest, ECMO flow is titrated to optimize systemic perfusion and mean arterial pressure, and reversible causes are identified and treated. A deterioration in cardiac ejection is associated with reduced systolic pulsation of the arterial and pulse oximetry waveforms, and a reduced end-tidal carbon dioxide level.29 The development of pulmonary edema may be signified by pink frothy fluid emerging from the endotracheal tube, infiltrates on chest X-ray, or characteristic B-lines on transthoracic ultrasound.30-32 An immediate echocardiographic evaluation is warranted to assess left and right ventricular end diastolic volumes and systolic function. Absent systolic opening of the aortic valve leaflets confirms a loss of cardiac ejection. Aortic valve evaluation also must include

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Fig 1. Proposed workflow for prevention and management of left ventricular dilatation during venoarterial extracorporeal membrane oxygenation. IABP, intraaortic balloon pump counterpulsation; LVAD, left ventricular assist device; MAP, mean arterial pressure; RVAD, right ventricular assist device; VA-ECMO, venoarterial extracorporeal membrane oxygenation.

exclusion of aortic regurgitation, as this predisposes to significant left ventricular distention during VA-ECMO. Echocardiography Assessment of Left Ventricular Unloading A combination of point-of-care ultrasound, transthoracic, and transesophageal echocardiography may be useful in guiding vascular cannulation,33,34 optimal placement of devices to decompress the left ventricle,35,36 and detecting complications during VA-ECMO support.37 Echocardiographic assessment also allows detection of left ventricular distention and spontaneous echo contrast, exclusion of significant aortic regurgitation, and identification of patients with minimal or no cardiac ejection who may benefit from left ventricular decompression strategies.38 Unai et al.39 analyzed the echocardiographic findings in 98 patients supported with VA-ECMO for cardiogenic shock, of whom 22 (22%) developed spontaneous echo contrast (SEC). Factors associated with the development of SEC included a lower left ventricular ejection fraction (8.0% v 29%; p < 0.001), and a lower ratio of arterial pulse pressure to mean arterial pressure (pulsatility index) (0.13 § 0.14 v 0.26 § 0.22; p = 0.009). Patients who developed SEC also had a higher incidence of intracardiac thrombus (46% v 13%; p = 0.002) and stroke (36% v 7.9%; p = 0.002). The presence of SEC, intracardiac thrombus, and low pulsatility were all found to be risk factors for the development of stroke. Bhat et al.40 described a case report of a patient who developed a new right heart thrombus during VA-ECMO support after a pulmonary embolectomy. Alhussein et al.41 presented a case series of 3 patients who developed intracardiac

thrombosis during VA-ECMO, either in the left or right ventricle and the pulmonary circulation. Multiple etiologies were postulated, and both groups of authors suggested that prevention should focus on early recognition using echocardiography, anticoagulation strategy, biventricular decompression, and maintenance of cardiac ejection during VA-ECMO. Ortoleva et al.42 reviewed their echocardiographic database of 175 patients supported with VA-ECMO to identify characteristics associated with survival. Although there was no significant difference in baseline left and right ventricular function, survival was associated with an improvement in echocardiographic grade of biventricular dysfunction during VA-ECMO support (p < 0.01). Huang et al.43 analyzed 3D datasets of right ventricular function in 46 patients undergoing a VA-ECMO weaning trial, of whom 28 patients were successfully weaned. Right ventricular ejection fraction >24.6% was associated with successful weaning (area under the curve 0.9, p < 0.001), whereas right ventricular ejection fraction 24.6% was associated with increased 30-day all cause mortality (hazard ratio 15.86; 95% CI 3.56-70.73). Pappalardo et al.44 reviewed the echocardiography and hemodynamic records of 129 patients on VA-ECMO support, of whom 49 (38%) were successfully weaned, however 15 (31%) of these patients subsequently died after decannulation. Factors associated with successful weaning from VA-ECMO support included an improvement in pulse pressure, left ventricular ejection fraction 35% (interquartile range 25th-75th percentile, 22%-55%; p < 0.001), right ventricular systolic function, and a reduction in inotrope requirements.

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Aissaoui et al.45 reviewed 51 patients who underwent a VA-ECMO weaning trail, of whom 20 were successfully weaned. Factors associated with successful weaning from VAECMO included higher systolic arterial and pulse pressures, left ventricular outflow tract velocity time integral 10 cm, left ventricular ejection fraction >20% to 25%, and lateral mitral annular tissue Doppler S’ velocity 6 cm/s at minimal VA-ECMO flow. Management of VA-ECMO Flow and Mean Arterial Pressure The aim of VA-ECMO support is to balance flow rate and mean arterial pressure, in order to optimize systemic perfusion, whilst regulating left ventricular afterload. Camboni et al.46 presented a strategy aimed at promoting forward flow and a selective approach to left ventricular decompression in <2% of patients in a series of 600 patients receiving VA-ECMO support. Overall 37% of patients survived to discharge with this approach, despite 50% of patients requiring VA-ECMO support for ECPR. The authors promoted a strategy of strict afterload reduction, allowing a low mean arterial pressure <50 mmHg for the first 24 hours or more and limiting flow rates to 3 to 4 L/min provided that lactic acidosis was improving, as well as a restrictive approach to fluid management and a high positive end-expiratory pressure lung protective ventilatory strategy to reduce pulmonary edema. The authors advocated monitoring left ventricular recovery with echocardiography and evaluating global perfusion, as well as overall prognosis in deciding whether to perform an intervention to decompress the left ventricle. If overall prognosis was deemed to be favorable, but left ventricular recovery remained poor, they suggested an early transition to a durable left ventricular assist device, or transplantation, rather than persisting with VA-ECMO support in this situation. Kondo et al.47 described a case report where a “high flow/ vasodilatation method” was used in a patient with dilated cardiomyopathy complicated by cardiogenic shock and multiple organ failure. When the VA-ECMO flow rate was increased to optimize systemic organ perfusion, the elevated mean arterial pressure of 85 mmHg resulted in a loss of pulsatility of the arterial pressure waveform, with echocardiographic evidence of a dilated, non-ejecting left ventricle with persistently closed aortic valve. This was managed with the addition of vasodilators to regulate the mean arterial pressure and reduce left ventricular afterload, upon which left ventricular ejection returned, with a pulsatile arterial waveform and echocardiographic evidence of left ventricular ejection and aortic valve opening and closure, as well as a reduction in pulmonary artery pressure. However, this patient subsequently did not survive. Huang et al.48 describe a retrospective case series of 188 patients supported with VA-ECMO without placement of a left heart vent, of whom 22 patients (12%) developed prolonged cardiac standstill for longer than 6 to 8 hours despite correction of metabolic and temperature abnormalities. This was managed by increasing the VA-ECMO flow by 23 § 15% above baseline and limiting the rise in mean arterial pressure

with vasodilators. This strategy was found to be sufficient for left and right ventricular decompression in all patients, and none required placement of a left heart vent. Nine of these patients (41%) were able to be weaned from VA-ECMO support, however only 6 patients (27%) subsequently survived to hospital discharge. Spontaneous echo contrast and intracardiac thrombus developed in 6 patients (27%), and in 3 of these patients this situation resolved within 5.7 § 3.5 days of management with a higher heparin anticoagulation target, aiming for an activated partial thromboplastin time of 50 to 65 seconds. Of these 3 patients, 2 survived to discharge from hospital, and 1 subsequently succumbed to an intracranial hemorrhage. There was no significant difference in survival rate and total cardiac standstill time between patients with or without SEC and intracardiac thrombus. In addition to identifying ventricular distention, it also would be reasonable to exclude heparin resistance as a possible cause for intracardiac thrombus noted on echocardiography.49 Pharmacologic Management of Ventricular Dysfunction The general principles of pharmacologic management are similar to the management of cardiogenic shock or separation from cardiopulmonary bypass. This includes treatment of arrhythmias to restore a regular heart rate and preferably sinus rhythm, inotropic therapy, as well as optimization of biventricular preload, afterload, and contractility. Pharmacotherapy is coupled with treatment of the underlying cause, and systemic organ support, including management of oxygenation and ventilation, optimizing pulmonary vascular resistance, optimizing hematocrit, correction of acidosis and electrolyte abnormalities, and renal replacement therapy if required.50-52 An inodilator strategy is generally preferred in cardiogenic shock and after initiation of VA-ECMO support, with the aim of improving biventricular contractility without increasing afterload. This may include single agents such as milrinone, dobutamine, or levosimendan, or combinations of agents such as epinephrine with nitroglycerin, often in conjunction with a loop diuretic53 and inhaled nitric oxide54 for the management of right ventricular preload and afterload, respectively.55,56 Epinephrine is rapidly titratable and generally considered first-line therapy. However, dosage may be limited by the risks of tachycardia, arrhythmias, myocardial ischemia, and left ventricular outflow tract obstruction, which may occur in the presence of interventricular septal hypertrophy or systolic anterior motion of the anterior mitral valve leaflet. Levy et al.57 compared epinephrine with norepinephrine in a randomized controlled trial of 57 patients with cardiogenic shock. There was no significant difference in arterial pressure or cardiac index, however epinephrine was associated with a higher incidence of refractory cardiogenic shock (epinephrine 37% v norepinephrine 7%; p = 0.008), defined as sustained hypotension, end organ hypoperfusion, hyperlactatemia, and high inotrope and vasopressor dosage requirements. This led to early termination of the study. Epinephrine also was associated with greater tachycardia and rate pressure product, as well as lactic acidosis in the first 24 hours. Leopold et al.58 performed a

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meta-analysis of 2,583 patients treated with inotropes and vasopressors for nonsurgical cardiogenic shock. Data was included from 14 published studies and 2 unpublished data sets. Epinephrine was associated with a higher mortality (OR 3.3, 95% CI 2.8-3.9). Perkins et al.59 performed a randomized controlled trial of epinephrine compared with placebo in outof-hospital cardiac arrest. Epinephrine was associated with a higher 30-day survival with more severe brain damage compared with placebo, however there was no significant difference in survival to discharge between groups (epinephrine 2.2% v placebo 1.9%; unadjusted OR 1.18; 95% CI 0.86-1.61). Milrinone has valuable lusitropic and vasodilator properties with minimal effects on heart rate and may be useful for afterload reduction in pulmonary hypertension. However, it may accumulate in renal failure, and dosage may be limited by the development of vasoplegia. If vasopressors are required, vasopressin is preferred over norepinephrine, as it has a predominantly systemic site of action, with minimal effect on the pulmonary circulation.60 Other novel strategies may include methylene blue and hydroxycobalamin,61-63 or the combination of hydrocortisone, vitamin C, and thiamine for sepsisrelated vasoplegia and adrenal insufficiency.64 Lewis et al.65 retrospectively reviewed outcomes of 50 patients treated with milrinone compared with 50 patients treated with dobutamine as first-line agents for cardiogenic shock. There were no significant differences in time to resolution of shock, or hemodynamics. Dobutamine was associated with a higher incidence of arrhythmias (62.9% v 32.8%, p < 0.01), whereas both groups had a similar incidence of hypotension (milrinone 49.2% v dobutamine 40.3%, p = 0.32) and requirement for adjunctive vasopressors. There was no significant difference in the rate of discontinuation of either drug or adverse events, however reasons for discontinuation differed between the 2 groups, with milrinone being more commonly stopped for hypotension (13.1% v 0%, p < 0.01), and dobutamine more frequently being stopped for arrhythmia (0% v 11.3%, p < 0.01). The authors concluded that both drugs were equally effective for cardiogenic shock, however the choice of agent may be determined by their side effect profiles. Levosimendan has significant lusitropic and inodilator effects and may facilitate weaning from VA-ECMO. Affronti et al.66 compared weaning outcomes of 6 patients who received levosimendan 24 hours before a VA-ECMO weaning trial, with a retrospective control group of 11 patients in the same institution before introduction of the levosimendan protocol, who received traditional inotropes. The levosimendan group had a higher incidence of successful weaning (83.33% v 23.3%), higher survival (66.66% v 36.4%), and a lower incidence of patients requiring inotropic or vasopressor agents after separation from VA-ECMO (50% v 100%). A recent Cochrane review67 identified 13 trials including 2,001 patients, and 2 ongoing studies of inotropic and vasodilator therapy in cardiogenic shock. The majority of studies were small, and few robust recommendations could be made regarding the superiority of any particular drug combination over another, including comparisons of epinephrine versus dobutamine-norepinephrine, and phosphodiesterase inhibitors. In 6 studies including 1,776 patients, levosimendan was found to

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reduce short-term mortality compared with dobutamine (RR 0.60, 95% CI 0.37-0.95). The authors concluded that the number needed to treat was 16 patients overall, or 5 moderate risk patients; however the quality of evidence was low, and long term follow-up data was not available to confirm this apparent benefit. IABP IABP is frequently used in cardiogenic shock to improve diastolic coronary perfusion, as well as reduce left ventricular afterload and pulmonary edema. When used together with VA-ECMO it may improve coronary and cerebral perfusion,68-71 facilitate left ventricular unloading and weaning from VA-ECMO,72 reduce hospital mortality,73 and reduce the risk of pulmonary edema74. Wang et al.72 conducted a systematic review and meta-analysis of 12 observational studies including 3,704 patients supported with VA-ECMO with or without an IABP for cardiogenic shock or cardiac arrest. A greater proportion of patients in the VA-ECMO + IABP group were successfully weaned from VA-ECMO, compared with patients who received VA-ECMO without an IABP (77.9% v 61.2%; RR 1.28; 95% CI 1.21-1.35). However, there was no significant difference in hospital mortality (59.7% v 65.8%; RR 0.90; 95% CI, 0.80-1.02). In a separate systematic review and meta-analysis Li et al.73 identified 29 studies including 4,576 patients. Patients who received VA-ECMO + IABP had a lower hospital mortality compared with patients who received VA-ECMO alone (RR 0.90; 95% CI 0.85-0.95). This finding also was observed in subgroups of patients who received VA-ECMO for ECPR, postcardiotomy cardiogenic shock, or ischemic heart disease. There were no significant differences in neurologic, gastrointestinal, vascular, or limb ischemic complications. Brechot et al.74 conducted a retrospective single center study of 259 patients requiring VA-ECMO support, of whom 104 also received IABP support. Chest X-rays were assessed, and pulmonary edema was graded according to the Weinberg radiologic score. Patients who received VA-ECMO + IABP had a lower risk of pulmonary edema, more ventilator-free days on VA-ECMO, and a nonsignificant trend toward lower mortality. Atrial Septostomy Atrial septostomy, with or without placement of a left atrial catheter, has been described in both pediatric and adult patients requiring VA-ECMO for left heart decompression and relief of pulmonary edema.75-78 This may be performed under echocardiographic guidance,79 reducing the need for fluoroscopy and transfer to the cardiac catheterization laboratory. Baruteau et al.80 retrospectively reviewed records for 32 adult and 32 pediatric patients who underwent a balloon atrial septostomy during VA-ECMO in 4 centers over a 14-year time frame. The primary indication was pulmonary edema or pulmonary hemorrhage with left ventricular distention. Balloon atrial septostomy resulted in a rapid resolution of pulmonary edema within 24 hours. The incidence of complications was 9.4%,

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including pericardial collection, arrhythmias such as atrial fibrillation, ventricular fibrillation, and transient complete heart block, and vascular trauma requiring endovascular treatment. Prasad et al.30 retrospectively reviewed the records of 9 out of 242 adult patients supported with VA-ECMO who required an atrial septostomy for refractory pulmonary edema and upper body hypoxemia. Atrial septostomy resulted in an immediate reduction in left atrial pressure, together with an improvement in oxygenation and radiographic features of pulmonary edema. Lin et al.81 retrospectively reviewed 15 adult patients with refractory pulmonary edema who underwent percutaneous atrial septostomy within 4.3 days of starting VA-ECMO. All procedures were performed in the cardiac catheterization laboratory under fluoroscopic guidance with a 24 to 27 mm Inoue balloon catheter, and successful creation of an atrial septal defect was confirmed echocardiographically. The average procedure time was 36.8 minutes, and there were no procedure-related complications. Rapid resolution of pulmonary edema occurred within 24 hours. Instead of performing just a balloon septostomy, Aiyagari et al.82 described a series of 7 patients ranging from 8 months to 28 years in age who underwent transatrial septum placement of a 8-F to 15-F percutaneous catheter, within 11 hours of starting VA-ECMO. The left atrial catheter was connected via a Y connector to the venous limb of the VA-ECMO circuit allowing biatrial drainage. Catheter placement was successful in all 7 patients, and left atrial decompression was achieved in 5 patients. However, left atrial decompression was not possible using this technique in 2 patients who ultimately died. Tandem Heart The Tandem Heart system, illustrated in Figure 2, is a percutaneous left ventricular assist device with a 21-F trans-septal

left atrial inflow catheter, and a 15-F or 17-F outflow cannula placed either percutaneously via the femoral artery, or surgically via a vascular graft to the axillary artery. The centrifugal pump can provide a maximum pump speed of 7,500 rpm and flow rate of 4.0 L/min.83-85 Placement of the left atrial transseptal inflow catheter via an internal jugular vein puncture together with outflow cannula placement via a vascular graft to the axillary artery allows decannulation of the femoral vessels, and conversion from standard VA-ECMO to a minimally invasive left ventricular assist device system. Jumean et al.86 described their experience with placement of a Tandem Heart cannula in addition to VA-ECMO in a patient with refractory ventricular fibrillation and a left ventricular thrombus. The Tandem Heart inflow cannula was placed in the left atrium via a percutaneous trans-septal puncture and connected to the venous limb of the VA-ECMO circuit via a Y connector, creating biatrial drainage in conjunction with VA-ECMO. Reduced biventricular filling pressures and end diastolic volume was confirmed on transesophageal echocardiography, and biventricular unloading resulted in resolution of refractory ventricular arrhythmias. Impella Numerous case series describe the use of the Impella device, for left ventricular unloading in patients supported with VA-ECMO. Outcomes reported include a reduction in mortality,36,87,88 pulmonary hypertension, and pulmonary edema.8992 However compared with VA-ECMO alone, there may be an increased incidence of hemolysis.8789 The Impella device, illustrated in Figure 3, is inserted via the femoral or axillary artery and features a microaxial pump mounted on a 9-F catheter and positioned across the aortic

Fig 2. Tandem Heart inflow catheter placed via superior or inferior vena cava. IVC, inferior vena cava; LA, left atrium; RA; right atrium; SVC, superior vena cava.

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Fig 3. Impella and Impella RP devices. Ao, aorta; IVC, inferior vena cava; LV, left ventricle; PA, pulmonary artery.

valve. Echocardiography or fluoroscopy may be used to position the inflow port approximately 3.5 cm below the aortic valve annulus and the outflow port in the proximal ascending aorta. The Impella 2.5 features a 12.5-F pump capable of generating a flow rate of 2.5 L/min, whereas the Impella CP is a 14-F pump capable of up to 4 L/min flow.93-96 Addition of an Impella to VA-ECMO improves pulmonary perfusion and oxygenation and relieves postcapillary pulmonary hypertension. Eliet et al.90 demonstrated increased pulmonary artery Doppler velocity time integral and end-tidal carbon dioxide concentration, with lower left ventricular end diastolic dimensions on echocardiography, as Impella flow was increased in patients receiving both VA-ECMO and Impella support. End-tidal carbon dioxide concentration was closely correlated with pulmonary artery Doppler velocity time integral, and the authors suggested that capnography may be a useful monitor of pulmonary perfusion and left ventricular decompression in these patients. Similarly Lim91 found a reduced arterial to end-tidal carbon dioxide gradient, pulmonary artery pressure, and pulmonary capillary wedge pressure, with improved right ventricular stroke volume in patients receiving VA-ECMO and Impella CP support. Akanni et al.89 demonstrated lower pulmonary artery pressures, higher mixed venous oxygen saturation, higher PaO2/FIO2 ratio (374.51 § 170.97 mmHg v 148.55 § 67.69 mmHg, p = 0.043), and superior left ventricular unloading, with a nonsignificant trend toward improved 30-day survival. Pappalardo et al.88 performed a retrospective comparison of outcomes of 157 patients supported with VA-ECMO in 2 centers over a 2-year period. A subgroup of 32 patients treated with VA-ECMO and Impella support was compared with a propensity matched group of 42 patients who received VA-ECMO alone. Compared with VA-ECMO alone, the patients in the

VA-ECMO + Impella group had a lower hospital mortality (47% v 80%, p < 0.001), as well as a greater proportion of patients bridged to recovery or further support (68% v 28%, p < 0.001), with no major differences in bleeding rates between the 2 groups (VA-ECMO + Impella 38% v VA-ECMO alone 29%, p = 0.6). Renal replacement therapy was required more frequently (48% v 19%, p = 0.02) in the VA-ECMO + Impella group, however the authors suggest that this may reflect the greater rate of survival of this group of patients. Both Pappalardo et al.88 and Akanni et al.89 identified an increased incidence of hemolysis in patients receiving VA-ECMO Impella support compared with VA-ECMO alone (76% v 33%, p = 0.004; and 44.83% v 17.35%, p = 0.002, respectively). Tepper et al.92 retrospectively compared the outcomes of patients supported with VA-ECMO and 2 different approaches to left ventricular decompression, where 23 patients had VAECMO and percutaneous Impella support, and 22 patients had VA-ECMO with a surgically placed left ventricular vent. Pulmonary edema and pulmonary artery pressures were reduced in both groups, and there were no significant differences between the 2 groups in 30-day survival, discharge from the intensive care unit, vascular complications, VA-ECMO decannulation, or transition to a durable left ventricular assist device. In contrast, Patel et al.87 retrospectively found a lower mortality in patients requiring VA-ECMO support for refractory cardiogenic shock who received an Impella device for left ventricular decompression compared with selective placement of a surgically placed vent. Only 21/36 (58%) of patients in the VA-ECMO § surgical vent group received mechanical left ventricular decompression, compared with 30/30 (100%) of patients in the VA-ECMO + Impella group. Thirty-day mortality was significantly reduced in the VA-ECMO + Impella

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group compared with the VA-ECMO § surgical vent group (57% v 78%; hazard ratio 0.51; 95% CI 0.28-0.94). The VA-ECMO + Impella group also required lower inotrope doses (p = 0.001). There was no significant difference in devicerelated complications. The relatively large sheath size required for percutaneous Impella placement may be a risk factor for distal limb ischemia. Kizner et al.97 describe a case series of 2 patients requiring VA-ECMO, as well as an Impella CP for left ventricular decompression, where a novel strategy for bilateral distal limb perfusion was utilized. Both legs were at risk of ischemia owing to bilateral femoral arterial cannulation for VA-ECMO and the Impella. Percutaneous cannulation of both superficial femoral arteries for bilateral antegrade distal limb perfusion was successfully performed to prevent limb ischemia. The adequacy of distal limb perfusion may be confirmed by sonography, with ultrasound evidence of contrast microbubbles sequentially appearing in the popliteal artery then the vein,34 or by using tissue oximetry.98,99 Management of Upper Body Hypoxemia During VAECMO Upon restoration of cardiac ejection, or if an antegrade venting strategy is used, there may be a risk of upper body hypoxemia until the pulmonary edema resolves. Upper body hypoxemia, or “North-South” or “Harlequin” syndrome, is most commonly seen during VA-ECMO support with femoral artery cannulation, in the context of hypoxemic respiratory failure with preserved left ventricular ejection, where the lower body is mainly perfused with oxygenated blood from the ECMO circuit, and the upper body (including coronary and cerebral circulations) is mainly perfused with deoxygenated blood returning from the lungs via the left heart.100,101 This may be monitored with cerebral oximetry, or a pulse oximeter placed on the ear, or arterial blood gas analysis from an intraarterial catheter in the right radial artery.29,102 Upper body hypoxemia may be managed by converting VA-ECMO to a veno-arterio-venous (VAV-ECMO) configuration, where a proportion of oxygenated blood is returned to the right atrium to augment mixed venous and pulmonary venous oxygen saturation, in addition to perfusing the systemic arterial circulation. Upper body hypoxemia is rarely seen in patients who receive VA-ECMO with axillary artery cannulation.103,104 Conversion from VA-ECMO to VAV-ECMO involves the addition of a right internal jugular venous cannula. This may be a single-lumen return cannula, or a double-lumen Avalon Elite cannula, which allows for bicaval drainage and right atrial return, with minimal recirculation between inflow and outflow ports.103 Cakici et al.105 reviewed data from 9 patients converted from VA-ECMO to VAV-ECMO for development of Harlequin syndrome during support for primary cardiogenic shock complicated by respiratory failure. Flow sensors and occluder devices were used to control differential flow rates via the return cannulas. The authors postulated that as a result of the lower resistance in the venous system compared with the arterial system, two-thirds to three-quarters of the oxygenated blood returned

via the internal jugular vein venous return cannula, with the remainder via the femoral arterial return cannula. Optimal hemodynamics and oxygenation could be achieved with calibrated occlusion of the internal jugular venous outflow tubing.

Percutaneous Right Ventricular Assist Devices A temporary right ventricular assist device may be necessary if right ventricular systolic function is slow to recover, such as after a pulmonary embolism or right coronary artery myocardial infarction. Percutaneous options for right ventricular support include the Tandem Heart Protek Duo cannula, and the Impella RP device. The 29-F percutaneous double-lumen Protek Duo cannula,106,107 illustrated in Figure 4, is placed via the internal jugular vein, with the inflow port positioned in the right atrium, and the outflow port in the main pulmonary artery. A maximum flow rate of up to 3.8 L/min is possible when connected to a dedicated centrifugal pump, allowing it to function as a percutaneous right ventricular assist device.108 An oxygenator also may be added if persistent respiratory failure is a significant issue.109,110 The Impella RP, illustrated in Figure 3, is another right ventricular assist device that may be considered to aid right ventricular forward flow.111 This is a 23-F microaxial pump mounted on an 11-F percutaneous right heart catheter, with the inflow port in the inferior vena cava, and the outflow port in the main pulmonary artery.112,113 Unlike the Protek Duo system, an oxygenator cannot be added, limiting its use in coexisting respiratory failure. In addition, the Impella RP requires femoral venous cannulation, which may limit patient mobilization.

Fig 4. Protek Duo double lumen cannula. PA, pulmonary artery; RA, right atrium.

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Summary Both Napp et al.25 and Camboni et al.26 recommend a stepwise approach to VA-ECMO cannulation, left ventricular decompression, and bridging to decision or alternative long-term support strategies. The majority of patients requiring VA-ECMO for cardiogenic shock can be managed simply with double cannulation (femoral vein and artery), standard inotropic and vasoactive therapy to promote left ventricular ejection, IABP, and treatment of the underlying cause. In particular, avoidance of hypertension, and judicious use of vasodilators may be helpful in reducing left ventricular afterload and promoting forward flow. In cases where cardiac ejection remains poor with refractory left ventricular distention and pulmonary edema, typically when VA-ECMO is used for ECPR, additional cannulation may be considered to decompress the left ventricle, including antegrade venting with the Impella 2.5 or CP, or retrograde venting with an atrial balloon septostomy or Tandem Heart system. In the presence of recovery of left ventricular function, with persistent respiratory failure and upper body hypoxemia, conversion of VA-ECMO to VAV-ECMO may be considered. An early evaluation of cardiac, neurologic, and systemic recovery is recommended, with conversion to percutaneous left and/or right ventricular assist devices, and a decision regarding transplantation, or durable ventricular assist device implantation for destination therapy. Declaration of Competing Interest The authors declare no conflicts of interest. References 1 Wilson-Smith AR, Bogdanova Y, Roydhouse S, et al. Outcomes of venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock: Systematic review and meta-analysis. Ann Cardiothorac Surg 2019;8:1–8. 2 Ahn C, Kim W, Cho Y, et al. Efficacy of extracorporeal cardiopulmonary resuscitation compared to conventional cardiopulmonary resuscitation for adult cardiac arrest patients: A systematic review and meta-analysis. Sci Rep 2016;6:34208. 3 Chen Y-S, Lin J-W, Yu H-Y, et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: An observational study and propensity analysis. Lancet 2008;372:554–61. 4 Ouweneel DM, Schotborgh JV, Limpens J, et al. Extracorporeal life support during cardiac arrest and cardiogenic shock: A systematic review and meta-analysis. Intensive Care Med 2016;42:1922–34. 5 Aneman A, Macdonald P. Venoarterial extracorporeal membrane oxygenation for cardiac arrest/cardiogenic shock. Intensive Care Med 2017;43:116–8. 6 Schiller P, Vikholm P, Hellgren L. Experimental venoarterial extracorporeal membrane oxygenation induces left ventricular dysfunction. ASAIO J 2016;62:518–24. 7 Olinger GN, Bonchek LI. Ventricular venting during coronary revascularization: Assessment of benefit by intraoperative ventricular function curves. Ann Thorac Surg 1978;26:525–34. 8 Roberts AJ, Faro RS, Williams LA, et al. Relative efficacy of left ventricular venting and venous drainage techniques commonly used during coronary artery bypass graft surgery. Ann Thorac Surg 1983;36:444–52. 9 Kanter KR, Schaff HV, Gott VL, et al. Reduced oxygen consumption with effective left ventricular venting during postischemic reperfusion. Circulation 1982;66:I50–4.

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96 Pappalardo F, Contri R, Pieri M, et al. Fluoroless placement of Impella: A single center experience. Int J Cardiol 2015;179:491–2. 97 Kizner L, Flottmann C, Horstkotte D, et al. Bilateral antegrade perfusion of the superficial femoral artery to prevent limb ischaemia during combined use of Impella CP left ventricular assist device and extracorporeal life support. Interact Cardiovasc Thorac Surg 2016;23:335–7. 98 Patton-Rivera K, Beck J, Fung K, et al. Using near-infrared reflectance spectroscopy (NIRS) to assess distal-limb perfusion on venoarterial (V-A) extracorporeal membrane oxygenation (ECMO) patients with femoral cannulation. Perfusion 2018;33:618–23. 99 Steffen RJ, Sale S, Anandamurthy B, et al. Using near-infrared spectroscopy to monitor lower extremities in patients on venoarterial extracorporeal membrane oxygenation. Ann Thorac Surg 2014;98:1853–4. 100 Alexis-Ruiz A, Ghadimi K, Raiten J, et al. Hypoxia and complications of oxygenation in extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth 2019;33:1375–81. 101 Cove ME. Disrupting differential hypoxia in peripheral veno-arterial extracorporeal membrane oxygenation. Crit Care 2015;19:280. 102 Koerner MM, Harper MD, Gordon CK, et al. Adult cardiac veno-arterial extracorporeal life support (VA-ECMO): Prevention and management of acute complications. Ann Cardiothorac Surg 2019;8:66–75. 103 Jayaraman AL, Cormican D, Shah P, et al. Cannulation strategies in adult veno-arterial and veno-venous extracorporeal membrane oxygenation: Techniques, limitations, and special considerations. Ann Card Anaesth 2017;20:S11–8. 104 Werner NL, Coughlin M, Cooley E, et al. The University of Michigan experience with veno-venoarterial hybrid mode of extracorporeal membrane oxygenation. ASAIO J 2016;62:578–83. 105 Cakici M, Gumus F, Ozcinar E, et al. Controlled flow diversion in hybrid venoarterial-venous extracorporeal membrane oxygenation. Interact Cardiovasc Thorac Surg 2018;26:112–8. 106 Ravichandran AK, Baran DA, Stelling K, et al. Outcomes with the Tandem Protek Duo Dual-Lumen Percutaneous Right Ventricular Assist Device. ASAIO J 2018;64:570–2. 107 Nicolais CD, Suryapalam M, O’Murchu B, et al. Use of Protek Duo Tandem Heart for percutaneous right ventricular support in various clinical settings: A case series. J Am Coll Cardiol 2018;71:A1314. 108 Schmack B, Weymann A, Popov A-F, et al. Concurrent left ventricular assist device (LVAD) implantation and percutaneous temporary RVAD support via CardiacAssist Protek-Duo TandemHeart to preempt right heart failure. Med Sci Monit Basic Res 2016;22:53–7. 109 Diaz-Guzman E, Sharma NS, Wille K, et al. Use of a novel pulmonary artery cannula to provide extracorporeal membrane oxygenation as a bridge to lung transplantation. J Heart Lung Transplant 2016;35:1051–3. 110 Gomez-Abraham JA, Brann S, Aggarwal V, et al. Use of Protek Duo Cannula (RVAD) for percutaneous support in various clinical settings. A safe and effective option. J Heart Lung Transplant 2018;37:S102. 111 Pieri M, Pappalardo F. Impella RP in the treatment of right ventricular failure: What we know and where we go. J Cardiothorac Vasc Anesth 2018;32:2339–43. 112 Shokr M, Rashed A, Mostafa A, et al. Impella RP support and catheterdirected thrombolysis to treat right ventricular failure caused by pulmonary embolism in 2 patients. Tex Heart Inst J 2018;45:182–5. 113 Kapur NK, Jumean M, Ghuloom A, et al. First successful use of 2 axial flow catheters for percutaneous biventricular circulatory support as a bridge to a durable left ventricular assist device. Circ Heart Fail 2015;8:1006–8.