Outcomes of Venoarterial Extracorporeal Membrane Oxygenation Patients Requiring Multiple Episodes of Support

ARTICLE IN PRESS Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 15

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Original Article

Outcomes of Venoarterial Extracorporeal Membrane Oxygenation Patients Requiring Multiple Episodes of Support Yvonne Lai, MD*, Jamel Ortoleva, MDy, Mauricio Villavicencio, MDz, David D’Alessandro, MDz, *, Ken Shelton, MD*, Gaston D. Cudemus, MD 1 , Adam A. Dalia, MD, MBA, FASE* *

Department of Anesthesiology, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA y Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, Boston, MA z Department of Cardiothoracic Surgery, Massachusetts General Hospital, Boston, MA

Objectives: This study describes the largest North American single-institution experience with adult patients requiring multiple extracorporeal membrane oxygenation (ECMO) runs in the same admission and aims to describe outcomes of survival and complication rates in this patient population. Design: A retrospective chart reviewbased study in a single quaternary care center of venoarterial (VA) ECMO patients cannulated multiple times on ECMO support to assess for outcomes and survival (both of ECMO therapy and survival to discharge). Setting: Single quaternary academic center for ECMO. Participants: All patients undergoing VA ECMO who were at least 18 years of age from 2011 to 2019, composed of a total of 14 patients requiring multiple cannulations. Interventions: None, this was a retrospective chart review. Measurements and Main Results: Of the 326 patients reviewed, 14 patients (4.3% of all patients in the database) had multiple ECMO therapies. The average patient age was 55.2 § 10.99 years of age, and 57% were female; 4 of the 14 (28.6%) patients survived to hospital discharge. The top 2 indications for initial VA ECMO therapy were cardiogenic shock after myocardial infarction (35.7%) and after cardiotomy shock (35.7%). For repeated cannulation, the most common cause was hypoxia (64%, 9 patients), with 6 of these patients requiring a right ventricular assist device plus oxygenator. Other causes for repeated cannulation included post-cardiotomy shock (14%), recurrent ventricular tachycardia (14%), and cardiogenic shock (7%). All patients who required continuous venovenous hemofiltration during their first run of ECMO did not survive to discharge. Conclusions: Fourteen of 326 patients in the authors’ VA ECMO database required additional ECMO therapy after decannulation; this represents at least 1 to 2 cases per year at higher-volume centers. Despite the small number of patients in this retrospective review, it seems that certain patients are reasonable candidates for additional ECMO therapy should their cardiopulmonary function again decline. The findings of renal replacement therapy and infection being more common during a second ECMO run are logical, but larger cohorts (ideally multicenter or from within the Extracorporeal Life Support Organization registry) are required to validate these preliminary findings. Ó 2019 Elsevier Inc. All rights reserved. Key Words: ECMO; extracorporeal membrane oxygenation; multiple cannulations; critical care; cardiogenic shock; ECLS; extracorporeal life support

Y. Lai and J. Ortoleva have contributed equally as first authors to this manuscript. 1 Address reprint requests to Adam A. Dalia, MD, MBA, FASE, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E-mail address: [email protected] (A.A. Dalia). https://doi.org/10.1053/j.jvca.2019.12.007 1053-0770/Ó 2019 Elsevier Inc. All rights reserved.

EXTRACORPOREAL MEMBRANE oxygenation (ECMO) is a type of mechanical circulatory support used for support of refractory cardiopulmonary dysfunction in both pediatric and adult populations and comes in the form of venoarterial (VA) or venovenous ECMO.1 In the adult population, the most common

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diagnosis requiring VA ECMO support is cardiogenic shock (28.3%).2 This ensures adequate organ perfusion while awaiting myocardial recovery, a bridge to left ventricular assist device, or heart transplantation. Success after ECMO typically is defined as survival to hospital discharge; for acute respiratory failure, adult survival to discharge is 59%, whereas for cardiac or combined cardiopulmonary dysfunction, survival on average is 43%.1 Survival to discharge for cannulation during cardiac arrest, known as extracorporeal cardiopulmonary resuscitation (eCPR), is 29%.1 Additionally, the 5-year survival rate was 56% for the patients who were discharged successfully from the hospital and 63% for the patients surviving at 30 days.3,4 There has been a significant increase in ECMO usage in adult patients (up 433% in United States alone from 2006 to 2011) with a trend of improved survival rates.5 However, ECMO does not come without major complications including lower limb ischemia (10%-16.9%), neurologic complications (8%-13.3%), acute kidney injury (AKI) (47.4%-55.6% with 46%-52% requiring renal replacement therapy), infection (25.1%-30.4%), and bleeding (33%-40.8%).6-8 Additionally, there is a subset of patients that hemodynamically decompensate after ECMO weaning and decannulation. This can be due to a return of their initial pathology or a new-onset cardiopulmonary compromise requiring a second ECMO therapy. There are reports in the literature regarding outcomes for multiple ECMO cannulations in the neonatal and pediatric population, but data are lacking in the adult population.9 Neonatal data has shown that the survival rate decreases with the number of ECMO therapies, and complication rates increase by 20% (including Extracorporeal Life Support Organization [ELSO]-defined neurologic, infectious, renal, and metabolic complications).10 A similar outcome also has been shown in pediatric patients where survival rates decrease with multiple ECMO runs.1 The study the authors performed describes the largest North American single-institution experience with adult patients requiring multiple ECMO therapies in the same admission; the aim is to describe outcomes of survival and complication rates in this patient population.

Methods The institutional review board at Massachusetts General Hospital (Boston, MA) approved the retrospective review of medical records for the purposes of this study. All patients older than 18 years supported by ECMO between 2009 and 2019 were identified from the authors’ institutional ECMO database. The entire database contains 433 patients requiring ECMO with 326 of those patients requiring VA ECMO. Of those 326 VA ECMO patients, 18 required multiple ECMO therapies. Upon further review, 1 patient was removed owing to 2 runs from 2 separate admissions, and 3 were removed because they were transitioned in the operating room from central to peripheral cannulation, leaving 14 patients included in the study (Fig 1). A completed ECMO therapy was defined as successful weaning and decannulation from mechanical support (greater than 24 hours free of ECMO). Reinstitution of

433 Total Extracorporeal Membrane Oxygenaon Paents

326 Venoarterial Extracorporeal Membrane Oxygenaon Paents

14 Paents with Mulple Extracorporeal Membrane OxygenaonCannulaons

Fig 1. Database filtering workflow.

ECMO was defined as recannulation subsequently after the previous therapy. Readiness for ECMO decannulation was evaluated based on patient hemodynamics, echocardiographic assessment of cardiac function, degree of inotropic support to maintain cardiac output, gas exchange from arterial blood gas, and end-organ perfusion parameters. The decision for ECMO decannulation was determined by the cardiac surgical intensivist on service in addition to the cardiac surgeon after acquiring sufficient evidence that mechanical support was not needed. There was not a formalized protocol for ECMO decannulation at the time these patients were cared for; however, during the study period, one was created (Appendix A). Data collection included patient demographics, indication for ECMO, ECMO modality (VA or venovenous), duration of each therapy, central versus peripheral cannulation, and complications during hospital stay (renal failure, limb ischemia, bleeding, neurologic complications). Bleeding and hemorrhage were defined as gastrointestinal bleeding, cannulation site bleeding, or surgical site bleeding requiring more than 3 units of packed red blood cell transfusion in fewer than 24 hours. Neurologic complication was defined as seizure, ischemia orstroke, intraparenchymal or extraparenchymal hemorrhage, or brain death. Renal failure was defined as a serum creatinine greater than 1.5 mg/dL or initiation of renal replacement therapy. Limb ischemia was defined as lack of blood flow to the limb requiring intervention, including fasciotomy or amputation. Infection was defined as a documented microbiology sample with bacteria or fungus prompting antimicrobial intervention. Survival was defined as survival to hospital discharge to home, to the initial institution the patient was

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transferred from, or to a chronic care facility. All of these definitions are derived from the ELSO registry.1 The data points were analyzed to compare those who survived to hospital discharge and those who did not. Acknowledging a small number of patients, statistical analysis was performed. Continuous data were compared using the t test (paired or unpaired where appropriate, and in the case of unpaired, homoscedastic or heteroscedastic depending on the result of the F test), and categorical data were compared using the Fisher exact test. A p value of less than 0.05 was considered statistically significant. Statistical analysis was conducted using Microsoft Excel, and data are summarized as means with standard deviations, and as numbers and proportions. Results Study Population

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patients) of all initial ECMO therapies. Repeat ECMO support most often transitioned to a temporary right ventricular assist device with an oxygenator (6 of 14 patients, 43%) followed by peripheral cannulation (5 of 14, 36%) (Table 2). The average duration of the first ECMO therapy was 9.8 § 8.3 days with an average interval of 15 § 18 days between the first and the second ECMO therapy. The second ECMO therapy had an average duration of 6 § 7.2 days. Complications were more prevalent during the second ECMO therapy. Every patient developed AKI during the second therapy, compared to 78.5% (11 of 14) of patients developing AKI during the initial therapy (p = 0.22 by Fisher exact test). All patients required continuous venovenous hemofiltration (CVVH) during their second therapy, compared to 43% (6 of 14 patients) during the initial ECMO run (p = 0.002 by Fisher exact test). The infection rate increased from 14% (2 of 14) to 78.5% (11 of 14) between the first and second run of ECMO (p = 0.002 by Fisher exact test).

Of the 326 patients reviewed, 14 patients (4.3% of all patients in the database) had multiple ECMO therapies. The average patient age was 55.2 § 10.99 years of age, and 57% were female; 4 of the 14 (28.6%) patients survived to hospital discharge (Table 1). The top 2 indications for initial VA ECMO therapy were cardiogenic shock post-myocardial infarction (35.7%) and post-cardiotomy shock (35.7%). Other indications included myocarditis, refractory arrhythmia, and sepsis (Table 2). For repeated cannulation, the most common cause was hypoxia (64%, 9 patients), with 6 of these patients requiring a right ventricular assist device plus oxygenator. Other causes for repeated cannulation included post-cardiotomy shock (14%), recurrent ventricular tachycardia (14%), and cardiogenic shock (7%) (Table 2). Patients were cannulated in different geographic locations within the hospital including the operating room, the cardiac catheterization lab, various intensive care unit locations; additionally patients who were transferred after cannulation at an outside institution were included in the analysis.

Differences Between Survivors and Nonsurvivors

ECMO Cannulation Strategy, Duration, and Complications

Extracorporeal membrane oxygenation is an effective treatment for severe cardiopulmonary dysfunction; VA ECMO is especially useful for patients in refractory cardiogenic shock or cardiac arrest to bridge to myocardial recovery, device implantation, or heart transplant. Early independent predictors of mortality after ECMO initiation include ECMO implantation during eCPR, severe liver or renal failure, and female sex.11 Conversely, the most significant predictor of survival is a reversible cause of cardiogenic shock including myocarditis.12,13 Acute coronary syndrome with or without ST-segment elevation accounts for up to 80% of cases with cardiogenic shock.14 Additionally, most acute coronary syndromerelated cardiogenic shock is due to left ventricular failure. The most common complication reported from the ELSO registry is cannula bleeding from peripheral VA ECMO and surgical bleeding from central ECMO.1 The use of ECMO has increased significantly, and survival after 1 run of VA ECMO for adults is 43% when not implemented during eCPR, according to the ELSO database.1 There is an increasing incidence of multiple ECMO runs with the

For the initial ECMO therapy, the most common cannulation strategy was peripheral, accounting for 64% (9 of 14 Table 1 Outcome Variables for Patients Undergoing Multiple ECMO Therapies

Mortality (%) Average age (y) Female (%) First cannulation (median d) Second cannulation (median d) Time off ECMO (median d) Neurologic complications (%) Renal failure during first cannulation (%) First cannulation SAVE score (median) Second cannulation SAVE score (median)

Survivors

Nonsurvivors

4 (28.5) 59 50 6 7 3 0 0 -2.75 -6.5

10 (71.5) 53.7 60 8.5 2 10 60 60 -7.9 -11

Abbreviations: ECMO, extracorporeal membrane oxygenation; SAVE, Survival After Veno-Arterial ECMO.

All patients who required CVVH during their first run of ECMO did not survive to discharge. All of the survivors did not experience neurologic complications, whereas 6 of 10 (60%) of the nonsurvivors suffered a major neurologic complication (p = 0.27 by Fisher exact test). Fifty percent of the survivors were female, whereas 60% of the nonsurvivors were female. Comparing initial Survival After Venoarterial ECMO (SAVE) scores between the survivors and nonsurvivors showed that survivors had higher SAVE scores, meaning higher estimated survival. Patients who received VA ECMO support during both therapies and survived had higher average SAVE scores during both the first and second runs; likely due to the small sample size, this result did not reach statistical significance (p = 0.166 by unpaired homoscedastic t test). Discussion

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Table 2 First and Second Diagnosis Requiring ECMO Support Along With Cannulation Location for Both First and Second Cannulation

First diagnosis

Second diagnosis

First cannulation location Second cannulation location

Postmyocardial infarction cardiogenic shock Postcardiotomy shock Arrhythmia/refractory ventricular tachycardia Myocarditis Sepsis Hypoxia Postcardiotomy shock Arrhythmia/refractory ventricular tachycardia Cardiogenic shock Peripheral Central Right ventricular assist device + oxygenator Peripheral (venoarterial) Central Peripheral venovenous (Avalon)

Number of Patients

Percentage of Patients

7 3 2 1 1 9 2 2 1 9 5 6 5 2 1

50 21 14 7 7 64 14 14 7 64 36 43 36 14 7

Abbreviations: ECMO, extracorporeal membrane oxygenation.

emergence of other mechanical circulatory support options, such as percutaneous ventricular assist devices or surgically implantable durable ventricular assist devices. Given the cost and resource utilization, it behooves clinicians to attempt to determine which patients can be salvaged with additional ECMO therapy. Most publications on multiple ECMO therapies are for neonatal and pediatric populations, showing equivalent or worse survival to hospital discharge compared with single-run ECMO patients.1,9,10 Additionally, in the pediatric literature, there is a higher incidence of complications during the second course of ECMO.10 In one study of all age ranges requiring multiple ECMO runs in the same admission, overall survival to discharge was 30% with no significance in survival difference between the adult and pediatric populations.9 A significant survival difference was noted between patients with and without renal failure requiring dialysis. The incidence of complications included neurologic (32.6%), hemorrhage (57%), infection (55.8%), and renal failure with hemodialysis (53.5%).9 Another study looked at repeat ECMO runs in the adult population; their quoted incidence was 2.4% or 6 of 246 patients.15 In this study, the in-hospital mortality rate between the single-run versus multiple-run ECMO groups was not found to be significantly different, with survival of 50% in both groups. Patient survival at 30 days postdischarge also was not found to be significantly different.15 The study concluded that outcomes for repeat ECMO patients compared favorably to the overall ECMO population, although it was underpowered (6 patients) to gauge this result. Based on this single-center retrospective analysis of adults requiring multiple ECMO cannulations, the incidence of survival is seemingly lower (28.5% or 4 of 14). Despite the small number of patients, a statistically significantly higher number of patients had infections and required continuous renal replacement therapy during the second ECMO run compared with the first. Given the prolonged course of critical illness and additional procedures, it is not surprising to note a higher incidence of renal failure and infection in these patients.

Finally, although not statistically significant, a neurologic complication likely contributes to mortality after multiple ECMO runs. The SAVE scoring system was developed to help predict survival after ECMO.16 The score is determined by 12 parameters, including etiology of cardiogenic shock, age, weight, pre-ECMO organ failure, chronic renal failure, duration of intubation before ECMO, pre-ECMO arrest, pulse pressure, and bicarbonate levels.16 In this cohort, the SAVE scores overall estimated a higher survival rate in both first and second ECMO runs in survivors compared with non-survivors, although statistical significance was not noted in this small cohort. Also, for all patients requiring VA ECMO for their first run, the survivors had higher SAVE scores compared to nonsurvivors. More work is needed on larger patient cohorts to determine the validity of the SAVE score in this patient population, which perhaps would be facilitated by a query of the ELSO database. Patients who required CVVH during their first run of ECMO did not survive to discharge; also, all patients experienced AKI during their second run. Renal failure, even in this small cohort, appears to be a potential marker for patients who may not benefit from additional ECMO therapy. Despite not reaching statistical significance, SAVE scores seemed to be a valid tool for multiple ECMO therapies, as this cohort of survivors had higher SAVE scores during both the first and second runs. A telling difference between those who survived multiple runs and those who did not was the amount of days between cannulations. Patients who survived multiple runs were recannulated sooner (3 days) compared to the nonsurvivors, who had a median 10-day period between the ECMO therapies. This may hint at some benefits to recannulating patients sooner who may be deteriorating after initial decannulation. The findings of renal replacement therapy and infection being more common during a second ECMO run are logical, but larger cohorts (ideally multicenter or from within the ELSO registry) are required to validate these preliminary findings. It seems likely that older age and neurologic complications also decrease survival in patients requiring multiple ECMO runs, but owing to small

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numbers this work could not prove that. The benefit of performing an outcomes analysis on this patient population is identifying patient characteristics that suggest a successful outcome if recannulation becomes necessary. Limitations of this study include the retrospective nature, the interprovider variability on the decision to wean ECMO therapy and variability in the decision to recannulate deteriorating patients, the small number of patients, and the period over which these patients were collected (2009-2019). Despite this, the scarcity of data on outcomes in adult patients requiring multiple ECMO therapies warrants retrospective review until a larger ELSO database can be analyzed and, ideally, data can be selected prospectively. This could be done by reviewing the ELSO database for patients who have multiple modes of ECMO on their ELSO Extracorporeal Life Support Registry form, which is an 8-page document for each patient at institutions that submit to the ELSO database containing detailed information on the ECMO therapy. On page 3 of that document, an “initial mode” is listed; subsequent to that mode on the following page, there is an option to “add a new conversion” that has accompanying start dates and times. Searching the ELSO database for all patients that had multiple conversions and separating patients with conversion start times different from the end time of the initial mode would be a way of determining which patients had multiple and separate ECMO therapies. Each run and each patient are assigned a unique number; this also can be cross-referenced to delineate those patients with multiple unique run numbers. This would provide a larger, more robust dataset for outcomes analysis in this patient population. A larger review also may assist in optimizing patient selection, a very important aspect of recannulation given that not all patients will be candidates for additional ECMO therapy. Adherence to a protocol for weaning of ECMO may decrease interprovider variability. A newly developed institutional protocol and checklist are presented in Appendix A; this protocol was developed by a multidisciplinary team.17 Other advancements that occurred over the course of this study period included the creation of a dedicated ECMO team and concentrating the physical location of VA ECMO patients to the cardiac surgical intensive care unit. Because of the complexity of ECMO patients and high risk for bleeding, an anticoagulation protocol also was developed, presented in Appendix B. As more data are collected, perhaps an algorithm can be proposed to determine which patients are the most ideal candidates for additional ECMO runs during the same admission Conclusion As ECMO use continues to expand, more providers will be confronted with the decision to perform additional ECMO support on patients who just were liberated from support. Given that 14 of 326 patients in a 10-year period in the authors’ VA ECMO database required additional ECMO therapy after decannulation, this represents 1 to 2 cases per year at higher-volume centers. Despite the small number of patients in this retrospective review, it seems that certain patients are reasonable candidates for additional ECMO therapy should their cardiopulmonary function

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again decline. Given the high intensity of resource utilization, an algorithm to assist in the determination of which patients can be salvaged with additional ECMO therapy would be very helpful to minimize prolonging a poor outcome and to assist in the appropriate allocation of this therapeutic modality. Conflict of Interest The authors have no disclosures or conflicts of interest to report. Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1053/j.jvca.2019.12.007. References 1 Extracorporeal Life Support Organization. Registry. Available at: https:// www.elso.org/Registry/Statistics.aspx. Accessed September 22, 2019. 2 Yeh TC, Chang HH, Ger LP, et al. Clinical risk factors of extracorporeal membrane oxygenation support in older adults. PLoS One 2018;13:e0195445. 3 Rastan AJ, Dege A, Mohr M, et al. Early and late outcomes of 517 consecutive adult patients treated with extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. J Thorac Cardiovasc Surg 2010;139:302–11;311.e1. 4 Smedira NG, Moazami N, Golding CM, et al. Clinical experience with 202 adults receiving extracorporeal membrane oxygenation for cardiac failure: Survival at five years. J Thorac Cardiovasc Surg 2001;122:92–102. 5 Sauer CM, Yuh DD, Bonde P. Extracorporeal membrane oxygenation use has increased by 433% in adults in the United States from 2006 to 2011. ASAIO J 2015;61:31–6. 6 Xie A, Phan K, Tsai YC, et al. Venoarterial extracorporeal membrane oxygenation for cardiogenic shock and cardiac arrest: A meta-analysis. J Cardiothorac Vasc Anesth 2015;29:637–45. 7 Cheng R, Hachamovitch R, Kittleson M, et al. Complications of extracorporeal membrane oxygenation for treatment of cardiogenic shock and cardiac arrest: A meta-analysis of 1,866 adult patients. Ann Thorac Surg 2014;97:610–6. 8 Zangrillo A, Landoni G, Biondi-Zoccai G, et al. A meta-analysis of complications and mortality of extracorporeal membrane oxygenation. Crit Care Resusc 2013;15:172–8. 9 Chou HW, Chang TI, Wang CH, et al. The outcome of patients requiring multiple extracorporeal membrane oxygenation: How many runs of ECMO is reasonable? Int J Artif Organs 2016;39:288–93. 10 Meehan JJ, Haney BM, Snyder CL, et al. Outcome after recannulation and a second course of extracorporeal membrane oxygenation. J Pediatr Surg 2002;37:845–50. 11 Combes A, Leprince P, Luyt CE, et al. Outcomes and long-term quality-oflife of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock. Crit Care Med 2008;36:1404–11. 12 Asaumi Y, Yasuda S, Morii I, et al. Favourable clinical outcome in patients with cardiogenic shock due to fulminant myocarditis supported by percutaneous extracorporeal membrane oxygenation. Eur Heart J 2005;26:2185–92. 13 Massetti M, Tasle M, Le Page O, et al. Back from irreversibility: Extracorporeal life support for prolonged cardiac arrest. Ann Thorac Surg 2005;79:178–83. 14 Reyentovich A, Barghash MH, Hochman JS. Management of refractory cardiogenic shock. Nat Rev Cardiol 2016;13:481–92. 15 Brady JJ, Kwapnoski Z, Lyden E, et al. Outcomes in patients requiring repeat extracorporeal membrane oxygenation. J Card Surg 2018;33:572–5. 16 Schmidt M, Burrell A, Roberts L, et al. Predicting survival after ECMO for refractory cardiogenic shock: The survival after veno-arterial-ECMO (SAVE)-score. Eur Heart J 2015;36:2246–56. 17 Dalia AA, Ortoleva J, Fiedler A, et al. Extracorporeal membrane oxygenation is a team sport: Institutional survival benefits of a formalized ECMO team. J Cardiothorac Vasc Anesth 2019;33:902–7.