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Contemporary Outcomes of Venoarterial Extracorporeal Membrane Oxygenation for Refractory Cardiogenic Shock at a Large Tertiary Care Center

Truby, Lauren; Mundy, Lily; Kalesan, Bindu; Kirtane, Ajay; Colombo, Paolo C.; Takeda, Koji; Fukuhara, Shinichi; Naka, Yoshifumi; Takayama, Hiroo

doi: 10.1097/MAT.0000000000000225
Adult Circulatory Support

Refractory cardiogenic shock (RCS) is associated with significant morbidity and mortality, and current mainstays of medical therapy appear inadequate. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) represents an increasingly accepted therapy for RCS. Demographics, past medical history, preoperative characteristics, outcomes, and adverse events were collected for consecutive patients who received VA-ECMO support for RCS at our institution from March 2007 to December 2013. One hundred and seventy-nine patients with a mean age of 56.9 ± 16.1 years were included. Etiologies of RCS included postcardiotomy shock in 70 patients (39%), acute myocardial infarction in 46 patients (26%), primary graft failure in 17 patients (10%), and acute decompensated heart failure in 24 patients (13%). Mean arterial pressure before VA-ECMO support was 59.4 ± 22.8 mm Hg and 30.7% (n = 55) were undergoing active cardiopulmonary resuscitation at the time of cannulation. Overall, 38.6% of patients (n = 69) survived to discharge and 44.7% of patients (n = 80) survived to 30 days. Myocardial recovery was achieved in 79.7% of survivors (n = 55) and 39.1% were transitioned to a more durable device. Univariate analysis identified age (p = 0.002) and etiology of RCS (p = 0.041) as the most significant predictors of in-hospital mortality. Venoarterial extracorporeal membrane oxygenation for RCS appears successful as salvage therapy. Age and etiology should be considered when evaluating patients for VA-ECMO.

From the *Department of Surgery, Columbia University Medical Center, New York, New York; and Department of Medicine, Columbia University Medical Center, New York, New York.

Disclosures: Yoshifumi Naka receives consulting fees from Thoratec Corp. The remaining authors have nothing to disclose.

Correspondence: Hiroo Takayama, 177 Fort Washington Ave, New York, NY 10032. Email: hirofu2@hotmail.com.

Cardiogenic shock (CS) represents a severe form of acute heart failure characterized by the inability of the heart to maintain adequate cardiac output regardless of filling pressures.1 Despite advances in medical management, in many patients, pharmacologic therapy fails to prevent irreversible end-organ damage in this low flow state. As current mainstays of therapy for CS have recently come into question,2,3 venoarterial extracorporeal membrane oxygenation (VA-ECMO) has emerged as a promising means of cardiac and pulmonary support in this high-risk population.4 In adult cardiac patients, VA-ECMO is effective in ameliorating circulatory collapse that complicates 7–10% of acute myocardial infarctions (AMI),5 for refractory cardiogenic shock (RCS) that occurs following 0.5–5% of cardiac surgeries,6 as well as acute decompensated heart failure (ADHF) and primary graft failure. Despite its increasing use, the available evidence supporting this therapy is based only on single-center small case series. Thus, many questions regarding optimal patient selection, timing of device implantation, and noninferiority when compared with alternative percutaneous ventricular assist devices (VAD) remain unanswered.

We therefore examined our institution’s 6 year experience with VA-ECMO for RCS, addressing the characteristics of our patient population, the changing trends in device usage, and the analysis of clinical outcomes including survival and complications of support.

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Methods

Patient Population

From March 2007 to December 2013, 182 consecutive patients received VA-ECMO for RCS at our institution. Venoarterial extracorporeal membrane oxygenation runs for respiratory failure were not included. Among these, three patients received two device runs during the study period. The second device run was excluded from analysis to prevent confounding by indication. Demographics, past medical history, laboratory, and hemodynamic parameters as well as clinical outcome data were collected retrospectively during an extensive chart review. This study was approved by the Institutional Review Board at Columbia University. Informed consent was waived due to the retrospective nature of the study.

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Variables and Definitions

Cardiogenic shock has been poorly defined across the reported series. In this study, RCS is defined as 1) a systolic blood pressure of less than 90 mm Hg, a cardiac index less than 2.0 L/(min·m2), pulmonary capillary wedge pressure over 16 mm Hg (or evidence of pulmonary edema in the absence of a pulmonary artery catheter), and evidence of end-organ failure, or 2) the inability to be weaned from cardiopulmonary bypass for postcardiotomy shock (PCS) despite maximal medical therapy with pharmacologic interventions and/or intraaortic balloon pump (IABP).

For those patients undergoing chest compressions at the time of cannulation, the hemodynamics assigned to the patients were: a systolic blood pressure of 60 mm Hg, a diastolic blood pressure of 20 mm Hg for a mean arterial pressure of 33 mm Hg.7 The etiology of RCS in each patient was categorized as PCS, AMI, primary graft dysfunction after orthotopic heart transplant, ADHF, or other.

Hemodynamics and laboratory parameters were collected immediately before and after 24 hours the initiation of support. Postoperative adverse events of interest were left ventricular distention requiring intervention in the form of left ventricle (LV) vent or Impella placement, limb ischemia requiring placement of distal perfusion cannula or fasciotomy, infection, bleeding, need for continuous veno-venous hemodialysis, and stroke. Bleeding events and significant infections were defined in accordance with INTERMACS definitions.8 Primary outcomes of interest included in-hospital mortality as well as 30 day and 3 month survival status. Myocardial recovery, defined by the ability to be weaned from mechanical circulatory support (MCS) and survival to either hospital discharge or to 30 days, transition to a more durable MCS device, and causes of death were noted. Follow up was based upon date of last contact with the patient; if a patient was lost to follow up they were censored from analysis after last date of contact.

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Patient Management

Our institution’s algorithm for the evaluation and management of patients with RCS has been reported elsewhere.9 In brief, MCS device therapy, either with VA-ECMO or short-term VAD, is considered for RCS. Venoarterial extracorporeal membrane oxygenation is typically reserved for those patients with CS who are either too unstable to go to the operating room, have an unknown mental status, or have severe coagulopathy. Depending on the clinical status of the patient as well as the emergent nature of the procedure, VA-ECMO is placed at the bedside, in the catheterization laboratory, or in the operating room. Absolute contraindications to MCS for RCS include the patient’s or family’s will against MCS, clinical judgment against MCS by the primary team, more than 30 min of ongoing cardiopulmonary resuscitation (CPR) before the VA-ECMO team’s arrival, septic shock, and extremely short-term predicted life expectancy due to comorbidities.

Venoarterial extracorporeal membrane oxygenation is established through arterial and venous cannulation. Peripheral cannulation is preferred whenever feasible. Femoral access is the first choice for peripheral cannulation although axillary arterial cannulation is used in selected cases (e.g., those who developed PCS after an aortic surgery in which axillary access had already been established). For PCS patients who develop RCS in the operating room, central cannulation is occasionally chosen. Arterial cannula sizes of 15–23 Fr and venous cannula sizes of 19–25 Fr are utilized. For emergent/urgent VA-ECMO cannulation, we preferentially use a 15 Fr arterial cannula to facilitate ease of cannulation procedure. The VA-ECMO circuit consists of Quadrox D oxygenator (Maquet, Wayne, NJ), Rotaflow (Maquet, Wayne, NJ), and smart-SMART-coated tubing (Sorin, Italy). A distal perfusion cannula is selectively inserted through a cut-down to the superficial femoral artery whenever there is lack of a strong Doppler signal on the ipsilateral foot. Once adequate hemostasis has been achieved after the procedure, the decision whether to begin systemic anticoagulation is considered on a case-by-case basis. This patient population is often significantly coagulopathic; etiologies include shock liver, loading of anti-platelet agents before percutaneous coronary intervention (PCI), etc. When the decision is made to utilize systemic anticoagulation, heparin is used with an activated partial thromboplastin time (aPTT) goal of 60–80. As with all patients, the risk of bleeding must be assessed against the benefits of preventing thrombus. Anticoagulation with IV heparin (goal PTT of 45–60 sec) is initiated as soon as bleeding is controlled. Device weaning is considered when the patient is improving clinically (evidence of end-organ recovery, neurologic recovery, etc). Once this occurs, overall myocardial function and ability to be weaned from VA-ECMO are evaluated under echocardiographic and hemodynamic monitoring. In most cases, the futility of device therapy in patients becomes clinically apparent very quickly. Support is terminated if a patient is deemed futile and the care is “withdrawn”. This decision is made by our multidisciplinary MCSD team based on many factors, such as other organ failure, CVA with significant clinical sequelae, presence of infection, psychosocial support status, etc.

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Statistical Analysis

Continuous variables are presented as mean ± standard deviation or median (IQR) for those variables with nonnormal distributions. Categorical data are presented as counts and percentages. Among those patients with multiple device runs during the study period, the second device run was excluded from our analysis to prevent confounding by indication (n = 3). Landmark analyses were utilized based on 7 day and 8 week time points. To identify predictors of in-hospital mortality, univariate Cox proportional hazard regression analysis was performed utilizing clinical baseline variables. Significance was defined as p < 0.05. Those variables found to be significant on univariate analysis were entered into a multivariate Cox proportional hazard regression model. Two sample t-tests were used to compare continuous variables and χ2 used to compare categorical variables between survivors and nonsurvivors. Kruskal–Wallis analysis was utilized in those variables that were nonnormally distributed. StataSE version 13 (StataCorp, LP College Station, TX) was utilized for analysis.

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Results

Baseline Characteristics

Overall use of VA-ECMO for cardiac failure increased at our institution during the study period (Figure 1). In particular, the use of VA-ECMO for PCS has increased due to our aggressive approach to treating these patients (overall incidence of PCS remains low, complicating 1% of cardiac surgery cases at our institution). Baseline patient characteristics and etiology of CS have been summarized in Table 1. Overall, the most common indication for device run was PCS (39.1%, n = 70) followed by AMI (25.7%, n = 46). For those patients requiring VA-ECMO for PCS, common index operations included CABG in 16%, valve replacement in 30%, and aortic surgery in 11%. Survival to discharge differed substantially among etiologies (Figure 2). The mean patient age was 56.9 ± 16.1 years (range 19–90 years). Only patient age (52.7 ± 15.6 among survivors vs. 59.5 ± 15.9 among nonsurvivors; p = 0.006) and history of coronary artery disease (34.8%, n = 24 among survivors vs. 52.7%, n = 58 among nonsurvivors; p = 0.019) were found to be significantly different between those patients who survived to hospital discharge and those who did not.

Baseline hemodynamics and laboratory values are presented in Table 2. Overall mean arterial pressure was 59.4 ± 22.8 mm Hg with 37.4% (n = 67) of all patients having a baseline mean arterial pressure less than 60 mm Hg. Median arterial lactate was 5.5 mg/dl (IQR: 2.7–9.3) with almost two thirds of patients presenting with an arterial lactate greater than 4.0 mg/dl (74.9%, n = 134). Thirty-two percent of patients (n = 57) were being supported with an IABP before VA-ECMO cannulation and 30.7% (n = 55) were undergoing active CPR.

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Procedural Details

Cannulation was performed at the bedside (36.9%, n = 66) almost as often as the procedure was performed in the operating room (39.7%, n = 71). Twenty-five percent of patients were cannulated centrally (n = 45). Sites of arterial cannula placement included the femoral artery in 65.5% (n = 108), the aorta in 21.8% (n = 36), and the axillary artery in 12.7% (n = 21). For venous cannulation, the femoral vein (n = 126, 78.3%) was utilized more often than the right atrium (n = 28, 17.4%) and the internal jugular vein (n = 7, 4.4%).

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Effect of Venoarterial Extracorporeal Membrane Oxygenation Support

Hemodynamic and laboratory values after 24 hours of support are summarized in Table 3. Mean arterial pressure improved by 15 mm Hg with an associated 11 mm Hg decrease in mean pulmonary artery pressures. Arterial lactate improved significantly after 24 hours of support (Δ - 2.73; p < 0.001), although hemoglobin decreased (Δ -1.10; p < 0.001). Mean arterial pressure remained significantly different between survivors and nonsurvivors after 24 hours of support (p = 0.041). Those patients that died during hospitalization were also found to have persistently elevated arterial lactate levels after despite VA-ECMO support (p = 0.038).

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Outcomes and Adverse Events

Outcomes are summarized in Table 4. Median length of support on VA-ECMO was 3.6 days (IQR: 1.6–5.9 days), with the median hospital stay being 29 days (IQR: 8.0–48.5 days). Overall, 38.6% of patients survived to discharge and 44.7% to 30 days (Figure 2). Landmark analysis demonstrated two distinct periods of risk, with 33% of patients dying within the first week of VA-ECMO initiation and additional 40% of those remaining dying during hospitalization. Once survival to discharge was reached, event rates remained low during the first year.

Adverse events were collected during device support. Left ventricular distention requiring intervention (LV vent, Impella, Abiomed Danvers, MA) occurred in 16 patients (8.9%). Clinically significant limb ischemia occurred in 13.9% (n = 25), with nine patients requiring placement of a distal perfusion cannula and two patients requiring fasciotomy for compartment syndrome. Infection was documented in 11.7% (n = 21), consisting of ventilator-associated pneumonia in 19 patients and two urinary tract infections. The most common adverse events were bleeding (40.8%, n = 73) and initiation of continuous veno-venous hemodialysis (29.6%, n = 52). Between survivors and nonsurvivors, there was a significantly higher incidence of need for renal replacement therapy (14.5% vs. 37.6%; p = 0.003) and bleeding events (23.2% vs. 51.8%; p = 0.000).

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Predictors of In-Hospital and 30 Day Mortality

Bivariate and multivariate Cox proportional hazard regression models are summarized in Table 5. When bivariate proportional hazard regression analysis was performed only age, etiology of RCS, low MAP, and a history of coronary artery disease were found to be significantly associated with in-hospital mortality. On multivariate analysis etiology of RCS (p = 0.017) was the only significant predictor of in-hospital mortality (Figure 2). Although, age did not reach significance, when it was further broken down into four categories, those over the age of 75 years appeared to be high risk (HR: 2.53, CI: 1.16–5.49). Relative hazard ratios were also calculated to predict risk of increasing age (Figure 3). Of note, active CPR was not significantly associated with in-hospital mortality on univariate or multivariate analysis (Figure 3).

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Discussion

This study addresses the contemporary outcomes of VA-ECMO for RCS at a large tertiary care center. It is one of the largest recently published series, and addresses outcomes of patients with various etiologies of RCS. The primary findings of interest were 1) survival to discharge of 38.6% (n = 69) and a 30 day survival of 44.7% (n = 80); 2) 35.8% of patients would achieve myocardial recovery, whereas 29.1% (n = 52) would require transition to a more durable device; 3) multivariate Cox proportional hazard regression analysis identified age to be the single most important predictor of in-hospital mortality, whereas hyperlipidemia and higher baseline hemoglobin were found to be protective.

Our survival rates compare favorably to reported outcomes in other large studies, including a meta-analysis of 1,763 patients reported 30 day survival rates ranging from 20.8% to 65.4% (mean 40.6%).10 Recently, Loforte et al.11 published their experience of 73 patients with RCS across all etiologies who were treated with VA-ECMO. They reported a 45.2% survival to discharge rate. Of note, however, patients with renal failure, as well as those that were centrally cannulated, two populations well-represented in our study, were excluded from analysis. Belle et al.12 described a similar cohort of 51 patients and reported only a 27.5% survival to discharge, likely due to the high percentage of patients cannulated in the setting of refractory cardiac arrest (47.1%). Flécher et al.13 recently published one of the largest series reporting outcomes of VA-ECMO for RCS with 260 patients. He reported a 41% survival rate to 30 days with only 15% of patients receiving CPR at the time of cannulation. Finally, the extracorporeal life support organization (ELSO) registry recently published their outcomes data of 2,312 cases of adult extracorporeal cardiac support of which 39% survived to discharge.14 Landmark analysis in this study revealed two distinct periods of risk in VA-ECMO patients: the first 7 days after VA-ECMO initiation and the first 2 months, which roughly corresponds to hospital stay. The outcomes of those patients who were transitioned to another short-term MCSD have recently been published elsewhere.15

When a multivariate Cox proportional hazard regression model was generated to assess the association between baseline variables and in-hospital mortality, etiology was the only variable significantly associated with outcome. Although age did not remain significant, the predicted relative hazard ratio of death increased steadily with age, without identification of a distinct point at which risk increased at a higher rate (Figure 3).

It must also be recognized that differing etiologies of RCS create four distinct subgroups of patients within our overall cohort, each of which have differing expected outcomes based upon previously reported data. For example, Bermudez et al.16 reported differing rates of 30 day survival between those patients with RCS secondary to AMI (64%) and ADHF (56%). Among AMI patients alone, rates of survival to discharge have been reported as high as 76%.17 In contract, PCS has historically been associated with poor outcomes, with outcomes at 30 days reported as ranging from 11% to 38%.6,13,18 In contrast to PCS, VA-ECMO utilization for primary graft failure is associated with high rates of survival to discharge and to 30 days.13 In this study, both AMI and primary graft failure trended toward better outcomes when compared with PCS (Figures 2, 3; Table 5). Our experience reveals a 48% survival to discharge among AMI patients, which appears lower than other centers’ experience despite a similar percentage of patients undergoing active CPR before VA-ECMO cannulation. Outcomes of PCS patients (31.4% survival to discharge) and primary graft failure (64.7% survival to discharge) at our institution appear comparable with previously reported series.

Despite its ability to improve survival in critically ill patients, VA-ECMO support is not without significant complications. A recent meta-analysis of 1,866 adult patients who received VA-ECMO support between 2000 and 2012 revealed significant pooled estimate rates of complications, including limb ischemia (16.9%), need for renal replacement therapy (46%), stroke (5.9%), bleeding(40.8%), and infection (30.4%).10 This study revealed similar rates of limb ischemia and bleeding, with lower rates of renal replacement therapy, infection, and stroke.

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Limitations

Many limitations native to retrospective studies were present in our analysis. Our study only includes those patients who were placed on VA-ECMO support, but excluded those evaluated for, but not offered, device therapy. As previously mentioned, side-by-side comparison of patients of similar risk, who were managed medically or supported with alternative percutaneous ventricular assist devices would greatly strengthen analysis and conclusions. Not all complications of support, including arrhythmias, device malfunctions, and hemolysis were collected during this study. Finally, comparing outcomes across studies is markedly difficult due to heterogeneous patient populations, indications for VA-ECMO, outcomes of interest, and definitions of adverse events.

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Conclusions

Although survival remains around 40%, VA-ECMO appears to be satisfactory as salvage therapy in what would otherwise be an almost uniformly fatal disease. Age and etiology of RCS appear most influential on outcome. A substantial fraction of patients rescued by this therapy required, and could be supported by, more durable heart replacement therapy. Venoarterial extracorporeal membrane oxygenation seems to be the only MCSD (other than IABP) that can be inserted at the bedside in patients too unstable to be transported to a procedural area. Because of these advantages, VA-ECMO is being increasingly applied beyond salvage therapy situations (INTERMACS 2 and 3 patients). We believe that this study adds to the existing body of literature working toward improvements in patient selection for salvage device therapy. Further studies are needed to establish optimal timing of device implantation, patient management, and noninferiority to other percutaneous devices.

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References

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mechanical circulatory support; venoarterial extracorporeal membrane oxygenation; heart failure

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