Cardiogenic shock (CS) is a state of hypoperfusion caused by cardiac dysfunction that is seen in a wide variety of conditions such as acute myocardial infarction (AMI), postcardiotomy, myocarditis, and acute decompensated heart failure.
During the past decade, axial flow pumps have become widely available with the introduction of the Impella 2.5 system. As opposed to counterpulsation devices, axial flow devices unload the left ventricle throughout the cardiac cycle and partially replace myocardial function.1 For this reason, the Impella 2.5, CP, and 5.0 left ventricular assist device (LVAD) (delivering a constant flow of 2.5, 4, and 5 L/minute, respectively) have been increasingly used in CS as a bridge-to-recovery or advanced therapies.2 The Impella device was approved by the U.S. Food and Drug Administration (FDA) to provide short-term circulatory support in patients with CS after high-risk percutaneous coronary intervention (PCI). However, the device has been commonly used beyond 6 hours specifically patients with CS. Experts in our field frequently expresses that the incidence of hemolysis vastly outruns what prior registries have reported. The safety and efficacy of the Impella devices have been described elsewhere.3–5 Although, bleeding is the most common complication,6 increased rates of hemolysis have been noted with the prolonged use of the Impella.7,8 The purpose of this study is to determine the incidence of hemolysis when Impella is used longer than 6 hours in patients with CS.
We retrospectively studied all patients who required Impella (ABIOMED, Danvers, MA) support between April 2009 and September 2013 in two of our academic institutions (University of Miami Hospital and Jackson Memorial Hospital). Patients with less than 6 hours of support were excluded. Demographic data and hemolysis indicators were sampled and sorted according to support time and presence of CS. Cardiogenic shock was defined as persistent hypotension with end-organ hypoperfusion requiring pressors/inotropes or intra-aortic balloon pump. Patient’s data were then analyzed with GraphPad Prism software (GraphPad Software, La Jolla, CA) using paired t-test; a p value of less than 0.05 was considered statistically significant. A Kaplan–Meier curve was generated to describe survival. Renal replacement therapy in our study population was continuous veno-venous hemodialysis (CVVHD). The study was approved by the University of Miami’s Institutional Review Board.
A total of 118 devices were placed in 112 patients during this period of time (two of them were placed at an outside institution before transfer). In 46 patients with CS, the device was used for longer than 6 hours. Of them, five patients expired or had the device removed before laboratory testing was performed and one patient had concomitant bleeding because of an aneurysmal leak. Only 40 patients were included in our final analysis (35 patients had Impella 2.5, 3 had CP, and 2 had 5.0). Patient demographics are shown in Table 1. The patients were stratified depending on the precipitating event; the majority of them had ischemic heart disease (n = 24, 60%), and the device was placed after an AMI (n = 11) or an acute decompensation of ischemic cardiomyopathy (n = 13).
The 30 and 90 days of survival were 65% and 60%, respectively; three patients were referred to palliative care (and were included in the 30 days of mortality), three patients were bridged to heart transplantation, and four (10%) to a durable long-term LVAD. Two of our patients were lost in follow-up after discharge, and 90 days of survival analysis was performed using the Social Security Death Index updated until February 2014. Outcome characteristics are shown in Table 2. At 90 days, higher mortality was seen in patients with chronic ischemic cardiomyopathy (46%) and AMI (45%); however, the mortality was slightly lower (31.2%) in patients with nonischemic cardiomyopathy (Figure 1).
The average time of support was 86.63 hours (± 79.8) with the longest time being 361 hours. After 24 hours of support, the mean hemoglobin (Hb) decreased significantly from 11 to 9.8 mg/dl (p < 0.001), suggesting red blood cell (RBC) loss. Seven of the 40 patients (17%) received blood transfusion during the first 24 hours, and by the time of device removal, 26 of the 40 patients (65%) were transfused to maintain an adequate Hb level, significantly lower when compared with baseline (p = 0.0014) (Figure 2). A total of 205 units of RBCs were used throughout the support, with a mean of 7.5 units per patient transfused.
Hemolysis parameters, including lactate dehydrogenase (LDH), bilirubin, haptoglobin, and plasma free Hb, were evaluated and the results are shown in Figure 3; the LDH increased to 3,595 U/L (n = 21) within the first 24 hours of support. By the time of removal, the LDH increased to 5,201 U/L (n = 22; p = 0.0096), the mean bilirubin was 5.6 mg/dl (p = 0.008), and the haptoglobin level was 15.4 mg/dl (n = 25), suggesting persistent hemolysis.
When hemolysis was retrospectively diagnosed by Hb decrease and/or the need of blood transfusion, plus either increase in LDH or decrease in haptoglobin, the cumulative incidence of hemolysis during the support was 62.5%. When analyzing the patients according to the cause of CS, the patients with AMI had lower rates of hemolysis (4 of 11 patients [36%]) and required the least amount of RBC (18 units) compared with chronic ischemic cardiomyopathy (10 of 13 patients [76%], with 96 units) and nonischemic cardiomyopathy (11 of 16 patients [68.7%], with 91 units); this trend was also seen in patients who underwent PCI with 40% of hemolysis (6 of 15 patients) compared with 76% (19 of 25 patients) in the non-PCI group.
There was no difference at 30 and 90 days of survival in patients with or without hemolysis (Figure 4).
Although no significant increase in creatinine was noted, 42.5% were started or maintained on renal replacement therapy in the form of CVVHD caused by systemic hypotension. A slight but not statistically significant uptrend in creatinine was noted in nondialyzed patients (p = 0.17) (Figure 5).
Historically, CS attributable to AMI carried the highest mortality rate, as high as 80%.9 Furthermore, with early revascularization and wide use of intra-aortic balloon counter pulsation, a class IIa recommendation by the American College of Cardiology/American Heart Association guidelines for the management of AMI patients with CS,10 the mortality remained close to 50%11 and even lower when support with Impella 2.5 was initiated before PCI.2,12
Hemolysis is a common occurrence in patients with long-term Impella support for CS. The EUROSHOCK registry6 reports rates of 7.5% with an average support of 43 hours, 5–10% in Prospective Feasibility Trial Investigating the Use of the Impella 2.5 System in Patients Undergoing High-Risk Percutaneous Coronary Intervention (PROTECT I) trial in the first 24 hours, and 10.3% reported in USpella registry12 with a median duration of support of 23.7 hours. In our sample, hemolysis was evidenced by the persistent decline in Hb and haptoglobin as well as increase in LDH and bilirubin. Our results indicate that hemolysis was present at 24 hours and persisted until the time of removal (Figure 3).
Although patients with post-AMI had the lowest rates of hemolysis and blood transfusion, the small amount of participants in each group and the retrospective nature of the study do not allow us to draw any definitive conclusions. Furthermore, a lower incidence of hemolysis was seen in patients undergoing PCI, and hence, we hypothesize that post-AMI patients tend to receive aggressive anticoagulation, including dual antiplatelet therapy, thus decreasing the possibility of clot formation within the impeller, shear forces and/or device temperature, and lysing the erythrocyte. In this series of patients, a large number of them were started or maintained on renal replacement therapies and probably confounded the outcome while evaluating renal failure.
Longer Impella support is an option in patients with CS as a bridge to decision or recovery,1,13 but strict monitoring of hemolysis parameters at baseline and at frequent intervals is crucial. Although severe anemia secondary to hemolysis can be monitored with serial laboratory tests and treated with blood transfusions, it can also expose transplant candidates to different antigens, elevating the panel-reactive antibodies. Previous studies reported lower incidence of hemolysis with an early increase and subsequent decrease.3 This can be explained on the basis of relatively shorter duration of support and the half-life of the various LDH isoenzymes, which ranges from 6 to 48 hours.
Two recent publications reported decreased rates in mortality when short-term mechanical circulatory support was used in CS.2,12 Although our survival rates are comparable with the current trend, a major limitation to our study is the retrospective analysis of available data. We do not have pump analysis and other data points that may explain higher rate of hemolysis like pump placement signal, flow rate, motor current, and purge pressure alarms. Given that few patients had an Impella 5.0 or CP, we cannot draw conclusions with different devices. Furthermore, the comparison between them is outside the purpose of this study.
Our study highlights a significantly higher incidence of hemolysis in patients undergoing prolonged percutaneous Impella hemodynamic support for CS. To our knowledge, this is the first time effort has been made to quantify the incidence of hemolysis beyond 6 hours. Our observations suggest that higher amount of hemolysis occurring with prolonged Impella support does not affect overall short-term outcomes and can be used as a successful bridge for definitive therapy or recovery. Hemolysis indices, catheter placement, and device alarms should be closely monitored at baseline and at frequent intervals for the duration of support to aid in best patient outcomes.
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