Assessment of an extracorporeal life support to LVAD bridge to heart transplant strategy

Assessment of an Extracorporeal Life Support to LVAD Bridge to Heart Transplant Strategy Francis D. Pagani, MD, PhD, Keith D. Aaronson, MD, David B. Dyke, MD, Susan Wright, RN, Fresca Swaniker, MD, and Robert H. Bartlett, MD Section of Cardiac Surgery, Division of Cardiology, and Section of Surgical Critical Care, University of Michigan, Ann Arbor, Michigan

Background. Extracorporeal life support (ECLS) is an effective technique for providing emergent circulatory assistance. However, its use in adult patients is associated with poor survival when myocardial function fails to recover. Due to the prolonged waiting times for heart transplantation, ECLS as a bridge to transplant is associated with poor survival. In addition, ECLS has been reported to be a significant risk factor for death after bridging to an implantable left ventricular assist device (LVAD). After acquisition of the HeartMate LVAD (Thermo Cardiosystems, Inc) in October 1996, we began using ECLS as a bridge to an implantable LVAD and subsequently transplantation in selected high-risk patients. Methods. From October 1, 1996 to December 1, 1999, 60 adult patients presenting with cardiogenic shock were evaluated for circulatory assistance. Results. Twenty-five patients (group 1) with cardiac arrest or severe hemodynamic instability and multiorgan failure were placed on ECLS. Eight patients survived to

LVAD implant, 1 was bridged directly to transplant, and 4 weaned from ECLS. Nine patients in group 1 survived to discharge. Thirty patients (group 2) underwent LVAD implant without ECLS. Twenty-three were bridged to transplant, with 22 surviving to discharge. Five patients (group 3) were placed on extracorporeal ventricular assist with 3 bridged to transplant and all surviving to discharge. One-year actuarial survival from the initiation of circulatory support was 36% (group 1), 73% (group 2), and 60% (group 3). One-year actuarial survival from the time of LVAD implant in group 1, conditional on surviving ECLS, was 75% (p ⴝ NS compared with group 2). Conclusions. In selected high-risk patients, LVAD survival after initial ECLS was not different from survival after LVAD support alone. An initial period of resuscitation with ECLS is an effective strategy to salvage patients with cardiac arrest or extreme hemodynamic instability and multiorgan injury. (Ann Thorac Surg 2000;70:1977– 85) © 2000 by The Society of Thoracic Surgeons

E

xtracorporeal life support (ECLS) is a wellestablished method of providing emergent circulatory assistance for primary respiratory or cardiac failure [1–7]. However, application in adult patients with primary cardiac failure has been associated with poor survival when myocardial function fails to recover [2]. This poor outcome has been attributed to a high complication rate of stroke, infection, and progressive organ dysfunction that occurs after long durations of ECLS. If myocardial function does not recover after ECLS, transplantation is currently the only option for long-term survival [8]. Due to the current donor shortage and prolonged waiting times for transplantation, the use of ECLS as a bridge to transplant is generally not feasible [2]. Alternatively, patients who fail to recover myocardial function while supported by ECLS may be bridged to a long-term support device (eg, an implantable left ventricular assist device [LVAD]) that offers increased patient rehabilitation and a significantly lower risk of thromboembolic

events [8 –13]. However, previous reports have indicated that prior ECLS is a significant risk factor for death after LVAD implant [14]. Without a satisfactory endpoint to ECLS, there may be considerable reluctance to use ECLS in situations in which myocardial recovery is not likely (eg, cardiac arrest in a patient with end-stage heart disease and listed for heart transplantation) [2]. The reluctance to use ECLS may persist in circumstances in which patients are in need of immediate circulatory support, but are not candidates for alternative forms of circulatory assistance (implantable LVAD or extracorporeal ventricular assist) because of significant risk factors, severe hemodynamic instability, or insufficient time to mobilize resources in the operating room. After acquisition of the HeartMate LVAD (Thermo Cardiosystems, Inc, Woburn, MA) in October 1996, we initiated a strategy of ECLS to LVAD bridge to heart transplant to resuscitate and salvage patients with severe cardiogenic shock or cardiac arrest [15].

Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.

Material and Methods

Address reprint requests to Dr Pagani, Heart Transplant and Circulatory Assist Program, Section of Cardiac Surgery, University of Michigan, Taubman 2120, Box 0344, 1500 E Medical Center Dr, Ann Arbor, MI 48109; e-mail: [email protected].

From October 1, 1996, to December 1, 1999, 60 adult patients presenting to the University of Michigan Health System and at risk of death from primary myocardial

© 2000 by The Society of Thoracic Surgeons Published by Elsevier Science Inc

0003-4975/00/$20.00 PII S0003-4975(00)01998-6

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failure were treated with a flexible strategy of circulatory support that included either initial ECLS, extracorporeal VAD, or implantable LVAD followed by bridging to transplant when appropriate. Criteria for institution of circulatory support included: (1) refractory cardiogenic shock (cardiac index less than 2.0 L/min/M2 with systolic blood pressure less than 100 mm Hg, pulmonary capillary wedge pressure higher than 20 mm Hg and dependent on two or more inotropic agents with or without intraaortic balloon pump [IABP]), (2) cardiac arrest, or (3) risk of imminent death secondary to life-threatening recurrent ventricular arrhythmia or unstable angina with life-threatening coronary anatomy and severe left ventricular dysfunction not amenable to revascularization, along with no known existing absolute contraindications to heart transplantation and age less than 66 years. Patients requiring ECLS after failed transplant or ECLSassisted coronary angioplasty were excluded from analysis. Of the 60 patients, 25 (group 1) were initially placed on ECLS, 30 (group 2) were placed on LVAD support with the HeartMate LVAD (VE or IP 1000 model), and 5 (group 3) were referred to our institution on bi- or univentricular assist support with the ABIOMED BVS 5000 (ABIOMED, Inc, Danvers, MA). The choice for the type of device to initiate circulatory support was largely based on the presenting degree of hemodynamic instability, degree of organ injury, and clinical setting. Group 1 consisted primarily of patients presenting with cardiac arrest or severe hemodynamic instability (systolic blood pressure 75 mm Hg or less) with evidence of multisystem organ failure (MSOF) (defined as a serum creatinine level of 3 mg/dL or higher or oliguria; international normalized ratio (INR) more than 1.5 or transaminases more than five times normal or total bilirubin higher than 3 mg/dL; mechanical ventilation). Group 2 consisted primarily of patients presenting with refractory cardiogenic shock with stable hemodynamics associated with evidence of organ injury in fewer than two organ systems. Patients in group 3 were placed on Abiomed BVS 5000 bi- or univentricular assist support at other institutions, then referred to our center for further management. The ECLS circuit consisted of a membrane lung (Sci Med Life Systems, Minneapolis, MN), a servoregulated roller pump, and a heat exchanger [1, 2]. Arterial inflow to institute ECLS was obtained by right carotid artery cut-down in 9 patients, percutaneous femoral artery cannulation in 15 patients, and ascending aortic cannulation in 1. Five of the 15 patients (33%) with percutaneous femoral artery cannulation required arterial reinfusion to the profunda artery of the distal extremity through a side port of the arterial inflow cannula for limb ischemia. Venous drainage was obtained by right internal jugular cut-down in 8 patients, percutaneous femoral vein cannulation in 16 patients, and right atrial cannulation in 1. The determination of arterial or venous cannulation site was based on the degree of urgency to establish circulatory support. Atrial septostomy was the preferred method for left

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ventricular decompression and was performed in 7 of the 25 (28%) patients placed on ECLS. Early in the experience, atrial septostomy was performed in 3 patients after the development of pulmonary hemorrhage, with 1 patient surviving ECLS to LVAD implant. Based on this experience, atrial septostomy was performed after initiation of ECLS when there existed echocardiographic evidence of left ventricular dilation with pulmonary hypertension (mean pulmonary artery pressure higher than 30 mm Hg) assessed by Swan–Ganz monitoring. Using these guidelines, atrial septostomy was subsequently performed in 4 additional patients. No further episodes of pulmonary hemorrhage have occurred on ECLS using our current indications for atrial septostomy. Comparison of means was performed using one-way analysis of variance with post hoc Bonferroni adjustment and Tukey HSD multiple comparison tests to adjust for pairwise mean comparisons between groups when more than two groups were compared. Dichotomous outcome comparisons between groups were conducted using a ␹2 or Fisher’s exact test when appropriate. Actuarial survival was determined using the Kaplan–Meier method. Survival curves were compared by the log-rank test. Statistical significance was defined as p less than 0.05.

Results Mean age for all patients was 47 ⫾ 13 years (Table 1). There was no significant difference in age between survivors (survival to hospital discharge) and nonsurvivors or differences in age between groups. Within groups 2 and 3, survivors were significantly younger than nonsurvivors. Seventy percent (42 of 60 patients) of patients were men (Table 2). There were no significant differences in survival for gender for the entire cohort of patients. In group 2, survival was significantly higher for women. The cause of cardiac failure was nonischemic in 42% (25 of 60 patients), ischemic in 45% (27 of 60 patients), and postcardiotomy failure to wean in 13% (8 of 60 patients) (Table 3). Survival for patients with nonischemic cardiac failure was significantly higher compared with either nonischemic cardiac failure or postcardiotomy failure to wean. Within group 1, survival was significantly better in patients with ischemic cardiac failure. In group 2, there was a significantly improved survival for nonischemic cardiac failure. No patient placed on ECLS in group 1 after postcardiotomy failure to wean survived to hospital discharge. In 3 of 4 cases of postcardiotomy failure to wean in group 1, ECLS was initiated for hemodynamic deterioration postoperatively in the intensive care unit. Survival to hospital discharge was 50% (2 of 4 patients) for postcardiotomy failure to wean after initiation of biventricular or univentricular assist support in group 3. In all these cases ventricular assist support was initiated within 4 hours of the initial cardiac procedure. Overall, 30% of patients (18 of 60 patients) were in cardiac arrest or experienced a cardiac arrest event within 30 minutes of initiating circulatory support (Table 4). The incidence of cardiac arrest was significantly greater for group 1 as compared with groups 2 and 3. In

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Table 1. Patient Characteristics Characteristic Age (y) (mean ⫾ SD) Survivorsd Nonsurvivors IABP (n) Intubated (n) Renal function Serum creatinine (mg/dL) BUN (mg/dL) Anuria or oliguria requiring dialysis or hemofiltration at institution of mechanical support (n) Liver function LDH ⬎ 5 ⫻ normal values (1,000 IU/L) (n) Mean (IU/L) AST ⬎ 5 ⫻ normal values (175 IU/L) (n) Mean (IU/L) ALT ⬎ 5 ⫻ normal values (225 IU/L) (n) Mean (IU/L) Serum bilirubin ⱖ 3.0 mg/dL (n) Mean (mg/dL) INR ⬎ 1.5 Mean a p ⬍ 0.05 compared with group 2. by hospital discharge.

ALT ⫽ alanine transaminase; international normalized ratio;

b

Group 1 (n ⫽ 25)

Group 2 (n ⫽ 30)

46 ⫾ 10 47 ⫾ 9 44 ⫾ 11 16 (64%) 25 (100%)a

45 ⫾ 15 44 ⫾ 15c 59 ⫾ 6 14 (47%) 7 (23%)

47 ⫾ 13 38 ⫾ 5c 61 ⫾ 4 0 5 (100%)

47 ⫾ 13 44 ⫾ 13 50 ⫾ 11 30 (50%) 37 (62%)

1.8 ⫾ 0.7 26 ⫾ 14a 10 (40%)a,b

1.6 ⫾ 0.6 42 ⫾ 21b 7 (23%)

1.1 ⫾ 0.7 20 ⫾ 12 1 (20%)

1.7 ⫾ 0.7 34 ⫾ 20 18 (30%)

13 (52%) 1,938 ⫾ 2,288a

2 (7%) 407 ⫾ 313

3 (60%) 1,593 ⫾ 1606

18 (30%) 1,155 ⫾ 1711

16 (64%) 990 ⫾ 1872a

2 (11%) 86 ⫾ 159

4 (80%) 698 ⫾ 849

22 (37%) 513 ⫾ 1292

10 (40%) 785 ⫾ 1,307a

5 (17%) 111 ⫾ 150

1 (20%) 296 ⫾ 468

16 (27%) 411 ⫾ 913

5 (20%) 1.7 ⫾ 1.2

5 (17%) 1.6 ⫾ 1.2

0 1.2 ⫾ 0.4

10 (17%) 1.6 ⫾ 1.1

14 (57%) 1.6 ⫾ 0.8

5 (17%) 1.4 ⫾ 0.5

2 (40%) 1.4 ⫾ 0.3

21 (35%) 1.5 ⫾ 0.5

p ⬍ 0.05 compared with group 3.

AST ⫽ aspartate transaminase; LDH ⫽ lactic dehydrogenase.

Table 2. Effects of Gender on Survival Following Initiation of Mechanical Circulatory Support

Male (%) n Female (%) n

Group 1 (n ⫽ 25)

Group 2 (n ⫽ 30)

Group 3 (n ⫽ 5)

All Patients (n ⫽ 60)

35% 17 38% 8

69% 23 86%b 7

50% 2 67% 3

54% 42 61% 18

a Survival defined at hospital discharge. male gender within that group.

b

p ⬍ 0.05 compared with

All Patients (n ⫽ 60)

p ⬍ 0.05 compared with nonsurvivors within group.

BUN ⫽ blood urea nitrogen;

group 1, no patient placed on ECLS after a cardiac arrest in the emergency room or in the postcardiotomy setting survived to hospital discharge. Two patients in group 2 placed on HeartMate LVAD support after a cardiac arrest in the operating room before LVAD implant did not survive to discharge. Survival to discharge was significantly decreased for all patients experiencing a cardiac arrest before initiation of circulatory support of any type (21% versus 71%, p ⬍ 0.05). Fifty percent of patients (30 of 60) were on IABP support and 62% (37 of 60 patients) were intubated at the

Survivala

c

Group 3 (n ⫽ 5)

d

Survival defined

IABP ⫽ intraaortic balloon pump;

INR ⫽

time of initiation of circulatory support (Table 1). The incidence of intubation before initiation of circulatory support was higher in groups 1 and 3 than in group 2. There was no significant difference in base line serum creatinine levels. Serum blood urea nitrogen (BUN) levels were significantly higher in group 2. The incidence of renal failure requiring dialysis or continuous venovenous hemofiltration (CVVH) after the initiation of circulatory support was significantly higher in group 1 as compared Table 3. Effects of Etiology of Cardiac Failure on Survival Following Initiation of Mechanical Circulatory Support Survival Nonischemic (%) n Ischemic (%) n Postcardiotomy (%) n

Group 1 Group 2 Group 3 All Patients (n ⫽ 25) (n ⫽ 30) (n ⫽ 5) (n ⫽ 60) 13% 8 62%b 13 0% 4

94%b 16 48% 14 ... 0

a Survival defined at hospital discharge. other etiologies within that group.

100% 1 ... 0 50% 4 b

68% 25 54% 27 25% 8

p ⬍ 0.05 compared with

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Table 4. Influence of Cardiac Arrest and Location of Arrest on Survival Following Initiation of Mechanical Circulatory Support Group Group 1 (n ⫽ 25) No. with cardiac arrest Location of arrest Catheterization laboratory Coronary care unit Electrophysiology laboratory Emergency room Group 2 (n ⫽ 30) No. with cardiac arrest Location of arrest Operating room Group 3 (n ⫽ 5) No. with cardiac arrest a

Survival defined at hospital discharge. Groups 2 or 3.

Number

No. Survivinga

16 (64%)b

4 (25%)

3 8 1 4

1 (33%) 2 (25%) 1 (100%) 0 (0%)

2 (7%)

0 (0%)

2

0 (0%)

0 (0%) b

p ⬍ 0.05 compared with

with groups 2 and 3. Hepatic transaminases were significantly higher in group 1 as compared with group 2. There was no significant difference in base line total serum bilirubin levels or INR. Median duration of ECLS was 72 hours (range 0 to 369 hours). Overall, 36% of patients in group 1 (9 of 25 patients) survived to hospital discharge. Survival to hospital discharge was significantly decreased when the duration of ECLS support was either 48 hours or less or more than 168 hours (Fig 1). There were 12 deaths during ECLS. Of the 12 deaths, 1 patient died from delay in initiating ECLS due to technical difficulties at cannulation. Two patients had support discontinued within 24 hours after confirmation of intravenous cocaine use and sepsis [1] and massive pulmonary embolus [1]. Four patients had support discontinued 48 hours or less after initiating ECLS after findings of significant neurologic injury, believed attributable to the initiating cardiacrelated event, were confirmed by clinical examination, electroencephalogram, or brain blood flow study. Five additional deaths occurred while on ECLS and were

Fig 1. Percent survival to hospital discharge compared with duration of extracorporeal life support (ECLS) (48 hours or less, n ⫽ 9; 49 to 168 hours, n ⫽ 10; longer than 168 hours, n ⫽ 6).

attributed to stroke [2], pulmonary hemorrhage [2], or sepsis [1]. Four patients were weaned from ECLS, with 2 patients surviving to discharge and 2 dying before discharge from stroke (sustained during ECLS) and ventricular arrhythmia/sepsis. Eight patients placed on ECLS were bridged to a LVAD with 6 patients surviving to transplantation. All 6 patients survived to hospital discharge. Two deaths that occurred after LVAD implantation were attributed to sepsis [1] and MSOF [1]. The median duration of LVAD support for patients in group 1 after ECLS was 110 days (range 1 to 260 days). One patient placed on ECLS for cardiac failure after a postinfarct ventral septal defect was bridged directly to transplantation and survived to discharge. Overall, 9 patients in group 1 survived to discharge. There was a higher incidence of right-sided circulatory failure (RSCF) requiring mechanical assistance (right ventricular assist device [RVAD] or ECLS) after LVAD implant in group 1 (50%; 4 of 8 patients) as compared with group 2 (17%; 5 of 30 patients) or group 3 (0%; 0 of 3 patients). For group 1 patients experiencing RSCF, survival to hospital discharge after LVAD implant was 50% (2 of 4 patients) compared with 20% (1 of 5 patients) for group 2. Extracorporeal life support was used as right-sided circulatory support in 5 cases (40% survival to hospital discharge [2 of 5 patients]) and an ABIOMED RVAD was used in 4 cases (25% survival to hospital discharge [1 of 4 patients]). The arterial outflow for the ECLS circuit when used as right-sided support in conjunction with the HeartMate LVAD was femoral artery and left atrium [1], and left atrium only [4]. Levels of initial serum creatinine, serum BUN, urine output in the first 24 hours, lactate dehydrogenase (LDH), aspartate transaminase (AST), alanine transaminase (ALT), and total bilirubin were not significantly different in nonsurvivors as compared with survivors after initiation of ECLS (Figs 2, 3). However, no patient placed on ECLS with an initial LDH exceeding 4,200 IU/L, AST exceeding 2,300 IU/L, ALT exceeding 2,700 IU/L, and serum total bilirubin exceeding 3.3 mg/dL survived to hospital discharge. This observation also held true for group 3. No patient in group 2 had transaminase values that exceeded these limits. There was a trend toward increasing AST and ALT on day 2 of ECLS in nonsurvivors, but this trend was not statistically significant. Urinary output was significantly higher on day 2 of ECLS in survivors as compared with nonsurvivors. Survival to discharge was 47% for patients not requiring CVVH or dialysis while on ECLS and 20% for patients requiring renal support. Pulmonary compliance was a significant discriminator of survival in patients on ECLS for 5 days or longer (Fig 4). At days 5, 7, and 8 of ECLS, pulmonary compliance was significantly higher in patients who survived ECLS support to hospital discharge as compared with nonsurvivors. Seventy-seven percent (23 of 30 patients) in group 2 were successfully bridged to heart transplantation with 73% (22 of 30 patients) surviving to hospital discharge. There were 7 postoperative deaths in group 2 attributed to sepsis [2], RSCF [3], MSOF [1], and technical compli-

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Fig 2. Hepatic function during extracorporeal life support (ECLS). (A) Serum lactate dehydrogenase (LDH). (B) Serum total bilirubin. (C) Serum alanine transaminase (ALT). (D) Serum aspartate transaminase (AST). (■ ⫽ nonsurvivors; 䊐 ⫽ survivors.)

cations [1]. The median duration of LVAD support in all patients was 42 days (range 1 to 154 days), and was significantly shorter than the duration of LVAD support for group 1. Sixty percent of patients (3 of 5 patients) in group 3 survived to HeartMate LVAD implant. All three patients survived to hospital discharge after transplantation. There were 2 deaths while on ABIOMED BVS 5000 support attributed to MSOF [1] and gastrointestinal hemorrhage [1]. The median duration of ABIOMED BVS 5000 support was 4 days (range 2 to 7 days). The median duration of HeartMate LVAD support in patients in group 3 was 49 days (range 39 to 110 days). Median duration of follow-up for the entire cohort of patients was 6 months (range 0 to 38.5 months). Median duration of follow-up for groups 1, 2, and 3 was 0.4 months (range 0 to 26 months), 12 months (range 0.03 to 38.5 months), and 10.3 months (range 0.1 to 12 months), respectively. One-year actuarial survival for the entire group of patients from the time of initiation of circulatory support was 56% ⫾ 6% (mean ⫾ SE). One-year actuarial survival from the initiation of any mechanical support was 36% ⫾ 10% for group 1, 73% ⫾ 8% for group 2, and 60% ⫾ 21% for group 3 (Fig 5). Survival in group 2 was significantly higher compared with groups 1 and 3. Of those patients in group 1 (n ⫽ 8) surviving ECLS to LVAD

implant, 1-year actuarial survival was 75% ⫾ 15% (p ⫽ NS compared with group 2) (Fig 5).

Comment To optimize survival from cardiogenic shock, a variety of cardiac support options should be available to meet the diverse needs of a large patient population and different clinical settings. Extracorporeal life support is a wellestablished technology that provides circulatory support to patients presenting in cardiac arrest or with severe hemodynamic instability [1–7, 15]. The rationale for using ECLS as an initial method to establish circulatory assistance in our study was based largely on the premise that patients in group 1 represented a more acutely ill subset of patients, and that proceeding with LVAD implant was inappropriate at the time of evaluation (eg, in the circumstance of cardiac arrest) or that its use in the setting of MSOF would have been associated with poor outcome. This presumption was supported by the observation that there was a significantly higher incidence of cardiac arrest, intubation, IABP use, renal failure requiring CVVH or dialysis, and shock liver as compared with patients in group 2 or 3. Extracorporeal life support is not the only alternative to an implantable LVAD in providing emergent resuscitation. Other currently available options

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Fig 3. Renal function during extracorporeal life support (ECLS). (A) Serum creatinine. (B) Serum blood urea nitrogen (BUN). (C) Daily urine output. (■ ⫽ nonsurvivors; 䊐 ⫽ survivors; *p ⬍ 0.05 compared with nonsurvivors.)

for emergent circulatory support include centrifugal pumps, the ABIOMED BVS 5000, and Thoratec VAD (Thoratec Laboratories Corp, Pleasanton, CA). However, we believe ECLS offers some unique advantages in that it is readily available to rapidly resuscitate in-hospital patients with cardiac arrest. Sixty-four percent (Table 1) of the patients in group 1 were in cardiac arrest at the time of initiation of ECLS. Thus, instituting other forms of extracorporeal support in this scenario was not as feasible. In addition, ECLS is less costly at our institution compared with the other systems, does not require operating room resources, and avoids a sternotomy or ventriculotomy incision. Further, there are no data to suggest that ECLS is less effective in providing emergent circulatory support as compared with the abovementioned systems. The most important limitation of ECLS is its inability to provide long-term support because of the high incidence of complications [2]. When used in a bridge to transplant indication in adult patients, the use of ECLS is associated with an unacceptably low survival [2]. This limitation has previously prevented the use of ECLS at our institution in clinical situations in which myocardial recovery was not probable [2]. This major limitation of ECLS has been circumvented by a bridge-to-bridge strategy using a implantable LVAD for long-term support as a bridge to transplantation [8 –13]. One of the major findings in this study was our

continuing observation that LVAD survival after ECLS in a cohort of high-risk patients was not different as compared with a group of patients undergoing initial support with an implantable LVAD or LVAD implant after an extracorporeal VAD [15]. Previous reports by McCarthy and colleagues [14], however, demonstrated that ECLS before LVAD implant is a significant risk factor for death. The reasons for the different observations between these

Fig 4. Differences in pulmonary compliance in nonsurvivors and survivors in patients on extracorporeal life support (ECLS). (■ ⫽ nonsurvivors; 䊐 ⫽ survivors; *p ⬍ 0.05 compared with nonsurvivors.)

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Fig 5. (A) Actuarial survival (Kaplan-Meier) for group 1 (n ⫽ 25; dotted line), group 2 (n ⫽ 30; solid line), and group 3 (n ⫽ 5; dashed line) from the time of initiation of mechanical circulatory support (p ⬍ 0.05, group 2 compared with group 1). (B) Survival in patients after left ventricular assist device implant (p ⫽ NS, group 1 compared with group 2 or 3; group 1 ⫽ dotted line; group 2 ⫽ solid line; group 3 ⫽ dashed line).

two studies may be many, but could simply reflect the initial severity of patient illness, differences in timing of ECLS to LVAD implant, or frequency of providing rightsided circulatory support in these circumstances. After ECLS, there was a need for right-sided circulatory support in 50% of patients undergoing LVAD implant. An increased incidence of MSOF has been associated with the need for an increased incidence of perioperative biventricular support [16 –18]. The finding in our study that prior ECLS is not a risk factor for death after LVAD implant should reduce the reluctance to use ECLS in clinical situations in which the likelihood of myocardial recovery is small and transplantation is ultimately needed for long-term survival. The strategy of applying ECLS followed by bridging to an implantable LVAD appears to offer immediate circulatory support to patients who might not otherwise have been considered for LVAD implant, or for ECLS in the absence of a long-term support option. This strategy prompted more aggressive consideration and utilization of ECLS for patients needing circulatory support. In addition, this strategy appeared to conserve LVAD resources and improve overall LVAD outcomes. Patients not surviving the initial period of ECLS, in all likelihood, would not have survived LVAD support. In 28% of patients (7 of 25) placed on ECLS, clear absolute contraindications to heart transplant were identified and ECLS was terminated within 48 hours. Most of these patients had significant neurologic injury, most likely sustained at the time of the initial shock event. Thus, costly LVAD implantations in patients unlikely to survive or unlikely to be a transplant candidate were avoided. The use of ECLS for cardiac failure in adult patients does have limitations. One concern is that left ventricular decompression may be inadequate, resulting in pulmonary hypertension, edema, and hemorrhage [19, 20]. To address this concern we have routinely obtained a transesophageal echocardiogram when pulmonary hypertension persists after initiation of ECLS to assess filling of the left ventricular cavity. In cases in which the left ventricle is not adequately decompressed we have performed an atrial septostomy (28% of cases). In addition, patients undergoing LVAD implant after ECLS had sig-

nificantly increased morbidity manifest as increased RSCF requiring RVAD support after LVAD implant and increased duration of LVAD support required for rehabilitation. The basis for the increased incidence of RSCF may be attributable to an exacerbation of lung injury caused by a heightened inflammatory response as a result of ECLS [21]. Alternatively, the degree of lung injury may simply be a manifestation of the degree of the initial hemodynamic insult, again supporting the notion that patients in group 1 were more acutely ill. An additional major observation in this study has been clarification of clinical measurements and scenarios that predict poor outcome after initiation of ECLS and optimizing the timing to bridge from ECLS to a LVAD. Due to the finite period of time that ECLS can be used without experiencing significant morbidity, it is unreasonable to expect complete resolution of all organ injury before the LVAD implant. Based on our experience, it appears that in most patients with survivable degrees of end-organ injury, reasonable recovery of organ function from the initial shock event occurs within 2 to 5 days of the initiation of ECLS. After 5 to 7 days, few patients have demonstrated significant further improvement in organ function and most begin to demonstrate progressive evidence of organ dysfunction with rising serum creatinine and BUN levels, decreasing urinary output, and rising bilirubin. This pattern may reflect a nonsurvivable degree of organ injury or an exacerbation of the organ injury by the inflammatory cascade initiated by extracorporeal support [21]. In the case of patients presenting with renal failure or who develop renal failure soon after initiating circulatory support, it is unlikely that significant renal dysfunction will improve during a short period of ECLS. In such cases we have presumed renal function will return once pulsatile flow is established with a LVAD and have not used renal function as a criterion to assess transplant candidacy or timing of LVAD implant. However, the duration of the initial shock event, degree of organ injury, and base line renal function before the shock event must be considered in this analysis. Recoveries of pulmonary and liver function are more important factors to be considered in the timing of LVAD implant. We have used an INR less than 1.5 and liver enzymes less

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than five times normal as important guidelines for the timing of LVAD implant. Total bilirubin is less important an indicator of the timing of LVAD implant as we observed frequently that the sustained elevations in bilirubin that occur during ECLS recover after LVAD implant. In addition, pulmonary compliance appears to be an important determinant of outcome: in ECLS patients with a sustained deterioration in pulmonary compliance (less than 25 mL/cmH2O), ECLS and subsequent LVAD outcomes were poor. This finding was consistent with previous findings that demonstrated that the degree of initial interstitial lung fluid is a predictor of ECLS outcome [22]. In addition, we have not achieved survival in clinical scenarios in which cardiac arrest occurred in the emergency room or in the postcardiotomy setting. In summary, ECLS to LVAD bridge to transplant therapy provides a flexible strategy of circulatory support for patients who might not otherwise be candidates for an implantable LVAD or for ECLS in the absence of a long-term support option. The observation that LVAD survival after ECLS is equivalent to survival after initial LVAD support, alone, should prompt more consideration of ECLS, even in clinical scenarios in which myocardial recovery is unlikely. Extracorporeal life support to LVAD bridge to heart transplant therapy improves use of LVAD resources by avoiding LVAD implantation in circumstances for which poor outcomes can be anticipated.

References 1. Anderson H, Steimle C, Shapiro M, et al. Extracorporeal life support for adult cardiorespiratory failure. Surgery 1993;114: 161–73. 2. Kolla S, Lee WA, Hirsch R, Bartlett R. Extracorporeal life support for cardiovascular support in adults. ASAIO J 1996; 42:M809 –19. 3. Magovern GJ Jr, Magovern JA, Benckart DH, et al. Extracorporeal membrane oxygenation: preliminary results in patients with postcardiotomy cardiogenic shock. Ann Thorac Surg 1994;57:1462–71. 4. Muehreke DD, McCarthy PM, Stewart RW, et al. Extracorporeal membrane oxygenation for postcardiotomy cardiogenic shock. Ann Thorac Surg 1996;61:684–91. 5. Magovern GJ, Simpson KA. Extracorporeal membrane oxygenation for adult cardiac support: the Allegheny experience. Ann Thorac Surg 1999;68:655– 61. 6. Wang SS, Chen YS, Chu SH. Extracorporeal membrane oxygenation support for postcardiotomy cardiogenic shock. Artif Organs 1996;20:1287–91. 7. Phillips SJ. Resuscitation for cardiogenic shock with extracorporeal membrane oxygenation systems. Semin Thorac Cardiovasc Surg 1994;6:131–5.

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8. Dembitsky WP. Bridging from acute to chronic devices. Ann Thorac Surg 1999;68:724– 8. 9. Frazier OH, Rose EA, McCarthy P, et al. Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system. Ann Surg 1995;222:327–38. 10. Oz MC, Argenziano M, Catanese KA, et al. Bridge experience with long-term implantable left ventricular assist devices. Circulation 1997;95:1844–52. 11. Frazier OH, Macris MP, Myers TJ, et al. Improved survival after extended bridge to cardiac transplantation. Ann Thorac Surg 1994;57:1416–22. 12. Oz MC, Rose EA, Levin HR. Selection criteria for placement of left ventricular assist devices. Am Heart J 1995; 129:173–7. 13. Oz MC, Goldstein DJ, Pepino P, et al. Screening scale predicts patients successfully receiving long-term implantable left ventricular assist devices. Circulation 1995;92(Suppl II):II169 –73. 14. McCarthy PM, Smedira NO, Vargo RL, et al. One hundred patients with the HeartMate left ventricular assist device: evolving concepts and technology. J Thorac Cardiovasc Surg 1998;115:904–12. 15. Pagani FD, Lynch W, Swaniker F, et al. Extracorporeal life support to left ventricular assist device bridge to heart transplant: a strategy to optimize survival and resource utilization. Circulation 1999;100(Suppl II):II206 –10. 16. Reinhartz O, Farrar DJ, Hershon JH, et al. Importance of preoperative liver function as a predictor of survival in patients supported with Thoratec ventricular assist device. J Thorac Cardiovasc Surg 1998;116:633– 40. 17. Farrar DJ, Hill JD, Pennington DG, et al. Preoperative and postoperative comparison of patients with univentricular and biventricular support with the Thoratec ventricular assist device as a bridge to cardiac transplantation. J Thorac Cardiovasc Surg 1997;113:202–9. 18. Kormos RL, Gasior TA, Kawai A, et al. Transplant candidate’s clinical status rather than right ventricular function defines the need for univentricular versus biventricular support. J Thorac Cardiovasc Surg 1996;111:773– 82. 19. Johnston TA, Jaggers J, McGovern JJ, et al. Bedside transseptal balloon dilation atrial septostomy for decompression of the left heart during extracorporeal membrane oxygenation. Cathet Cardiovasc Intervent 1999;46:197–9. 20. Seib PM, Faulkner SC, Erickson CC, et al. Blade and balloon atrial septostomy for left heart decompression in patients with severe ventricular dysfunction on extracorporeal membrane oxygenation. Cathet Cardiovasc Intervent 1999;46: 179– 86. 21. Plotz FB, van Oeveren W, Bartlett RH, et al. Blood activation during neonatal extracorporeal life support. J Thorac Cardiovasc Surg 1993;105:823–32. 22. Jamadar DA, Kazerooni EA, Cascade PN, et al. Extracorporeal membrane oxygenation in adults: radiographic findings and correlation of lung opacity with patient mortality. Radiology 1996;198:693– 8.

DISCUSSION DR D. GLENN PENNINGTON (Winston-Salem, NC): It is a pleasure for me to discuss this excellent paper by Dr Pagani and his colleagues on the use of ECLS prior to the implantation of assist devices to bridge to transplant. This paper reflects a growing practice among cardiac transplant surgeons who implant devices to bridge patients to transplant. Extracorporeal life support provides a method of rapid resuscitation and a form of

triage that can help determine which patients will have sufficient organ viability to proceed to bridge. It is particularly gratifying to note that in the worst group, group 1, 9 patients were actually implanted with LVADs and from the time of the LVAD implant the survival was 75%, similar to those in group 2 who were not as urgent and underwent LVAD implant without ECLS. I suppose most importantly, of the

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patients transplanted there was apparently no mortality, proving again that circulatory support can convert even the sickest patients to excellent candidates for cardiac transplantation and, importantly, not wasting precious organ donors by putting hearts into the worst patients. I have several questions for the authors. In group 1, none of the patients who received ECLS after postcardiotomy failure to wean survived to hospital discharge. Would you now consider these patients unsuitable for ECLS and should they instead have been supported with assist devices after cardiac operation? Why not insert a Thoratec device in these postcardiotomy patients? The Thoratec device could provide right ventricular support, which you needed frequently, and a bridge to transplantation without the necessity of changing to another device. Additionally in group 1, no patient placed on ECLS after a cardiac arrest in the emergency room survived to hospital discharge. In fact, survival at discharge was significantly decreased for all patients experiencing a cardiac arrest. Would you now alter your decision about whether to actually institute extracorporeal membrane oxygenation in these desperately ill patients? You noted that of the patients requiring ECLS prior to LVAD there was a high incidence of the need for right ventricular support. In most series of LVAD implantation the need for right ventricular support does not bode well for a number of reasons. Could you tell us now whether when you need right ventricular support would you use ECLS, an Abiomed RVAD, or perhaps a Thoratec RVAD as your method of right ventricular support? Furthermore, you noted poor survival in patients with very high liver enzyme changes and in some of those requiring hemofiltration or dialysis. If you now had patients with combined liver and renal failure, would you not exclude those patients from ECLS support? You have also indicated that 5 to 7 days of ECLS support is usually the period during which success may occur. Would you now continue your support beyond that period of time if the patient has not improved or would you simply stop support because survival would not seem reasonable? Finally, I wish to congratulate you and your colleagues on an excellent paper. Many of us in the audience appreciate the

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incredible amount of work that went into these patients and we applaud you and your colleagues for an outstanding series. Thank you. DR PAGANI: I would like to thank Dr Pennington for the review of our manuscript and his insightful comments. With regard to his first question pertaining to postcardiotomy failure to wean, it is true that no patient placed on ECLS after a failed postcardiotomy operation survived. However, ECLS was instituted late, after the patients’ transfer from the operating room to the intensive care unit. So these were incidents of myocardial infarction or pulmonary edema that occurred late. I believe regardless of the type of device utilized, whether ECLS or extracorporeal VAD, the likelihood of survival in those circumstances would have been poor. We used ECLS because it allowed us rapid resuscitation of those patients in that particular setting. My personal bias is to utilize an extracorporeal VAD for postcardiotomy failure to wean. As you noted, no patient who arrested in the emergency room survived ECLS support. As we mentioned, the locations of the various arrests were the catheterization laboratory, the electrophysiology laboratory, the coronary care unit, and the emergency room. We had 4 patients who arrested in the emergency room with no patient surviving. I think this information will help us be more selective in the future as to who will receive ECLS. With regard to right-sided circulatory failure following ECLS, there was a higher need for right-sided support following LVAD implant: the incidence was 50% in group 1 compared with 17% in group 2. We utilized either extracorporeal membrane oxygenation or an Abiomed device for right-sided support depending on the clinical circumstances. If the patient had hypoxia, we tended to opt for ECLS; when oxygenation was adequate, we chose an Abiomed for right-sided circulatory support. As our experience grows we will be more selective in terms of patients, and I appreciate the comment that a patient presenting with combined liver and renal failure is unlikely to survive. I think we will be more selective in the future. Survival after 5 to 7 days of ECLS dropped precipitously. I think our willingness to continue ECLS after this period of time is limited. Thank you.