What is hemolysis and why do mechanical heart pumps cause hemolysis?

Impella blood compatibility

Hemolysis is the breakdown of red blood cells (RBC), resulting in the release of hemoglobin into blood plasma. Hemolysis is a consequence of blood movement through mechanical circulatory support (MCS) devices. RBCs experience high shear force as they pass through narrow openings in MCS devices. The RBCs traveling through unobstructed regions, such as regions away from the cannula wall, travel at higher speeds compared to RBCs in contact with the cannula wall. This difference in speed at which RBCs move past each other results in high shear force. When the shear force exceeds a critical level, RBC membranes rupture, resulting in hemolysis.1,2 Both the magnitude and duration of exposure to high shear force in addition to collision between cells and with various parts of the device may contribute to hemolysis.2

How is hemolysis measured?

Hemolysis is measured by detecting biomarkers representing disintegration of RBCs with release of the cells’ chemical contents such as plasma-free hemoglobin (PFH), lactate dehydrogenase (LDH), haptoglobin, indirect bilirubin, or by the presence of clinical signs such as hemoglobinuria. However, the sensitivity and specificity of the different markers for measurement of hemolysis vary widely. For example: LDH level can increase in response to any type of tissue injury, and is frequently elevated in myocardial infarction and cardiogenic shock (AMICS), thus LDH is not a specific marker for hemolysis. Therefore, LDH should not be used in isolation to assess for hemolysis in AMICS.

There are currently no published recommendations for measurement of hemolysis in patients treated with acute mechanical circulatory (AMCS) devices such as Impella® heart pumps. The commonly used definition for hemolysis assessment with AMCS devices is PFH > 40 mg/dL on more than 2 measurements taken at least 8 hours apart.11

The INTERMACS definitions (summarized below) were developed for durable ventricular assist devices (VADs) and use PFH levels assessed 72 hours after VAD placement to distinguish hemolysis resulting from operative procedures from that resulting from the durable VAD itself.

Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) defines hemolysis as:3

Minor Hemolysis: PFH greater than 20 mg/dL or a serum lactate dehydrogenase (LDH) level greater than two and one-half time (2.5x) the upper limits of the normal (ULN) range at the implanting center occurring after the first 72 hours post-implant in the absence of clinical symptoms or findings of hemolysis or abnormal pump function.

Major Hemolysis: PFH value greater than 20 mg/dl or a serum lactate dehydrogenase (LDH) level greater than two and one-half times (2.5x) the ULN at the implanting center occurring after the first 72 hours post-implant and associated with clinical symptoms or findings of hemolysis or abnormal pump function. Major Hemolysis requires the presence of one or more of the following conditions:

  • Hemoglobinuria (“tea-colored urine”)
  • Anemia (decrease in hematocrit or hemoglobin level that is out of proportion to levels explainable by chronic illness or usual post-VAD state)
  • Hyperbilirubinemia (total bilirubin above 2 mg/dL, with predominately indirect component)
  • Pump malfunction and/or abnormal pump parameters

Esposito et al.4 studied the predictive value of PFH or LDH as markers of hemolysis during LV support with Impella 5.0 or Impella CP in 23 patients with cardiogenic shock (mean age 62 years, mean duration of support 5.4 days). These investigators found that pre-device LDH was greater than 2.5 times upper limit of normal (ULN) in 71% (5/7) of patients receiving Impella 5.0 and 29% (4/14) of patients receiving Impella CP. Also, pre-device PFH was greater than 20mg/dL in 14% (1/7) of patients receiving Impella 5.0 and 25% (4/16) of patients receiving Impella CP. Using a hemolysis definition of PFH > 40mg/dL within 72 hours post-Impella implantation and presence of clinical signs resulted in identification of hemolysis in 30% (7/23). In addition, they reported that an increase in PFH by >27mg/dL within 24 hours after Impella implantation was highly predictive of hemolysis with sensitivity of 57% and specificity of 93%. Taken together, the study identified a change in PFH, not LDH, as sensitive and specific marker for hemolysis in patients receiving Impella support.

How is Impella designed to minimize hemolysis?

Shear stresses are determined by the speed of flow and geometry within the MCS device. Several engineering elements have been incorporated in Impella’s design and manufacturing to minimize hemolysis. The maximum speed of blood flow in Impella devices (irrespective of pump size) has been limited to 10 m/s, ensuring that the shear stress generated is well below 400 Pa (shear stress threshold of normal RBCs).2,5 In addition, flow channels, gaps and the surfaces of the pump are optimized to reduce damage to RBCs and any blood component in general.

The hemolytic effects of the Impella pumps is determined in vitro by assessing modified index of hemolysis (MIH), according to American Society of Testing and Materials (ASTM) standards.6 MIH is a ratio of RBCs destroyed during passage through the pump to the total number of RBCs through the system. Impella pumps are tested in vitro using mock circulation loop using porcine blood maintained at 37⁰C for 3-6 hours. MIH is calculated from the slope of the PFH concentration versus time plot. The mean MIH of Impella pumps is about 5, well below the MIH upper limit of 20 for use of blood pumps in clinical setting. 6

What factors most likely cause hemolysis with Impella in the clinical setting?

Obstruction to blood flow is the most likely cause of hemolysis with Impella in the clinical setting. Hemolysis can occur due to interference to blood flow at the inlet, through the pump, and outlet of the pump.

If the flow of blood is obstructed at the inflow due to suboptimal Impella positioning (for example: inflow position in the posterior portion of the LV behind a papillary muscle causing inflow obstruction) and the pump operates at the same speed, blood will travel slower through the pump thus increasing the exposure time to the higher shear stresses near the impeller.

Obstruction within the pump (for example: fiber or clot on impeller) creates flow disturbances near the impeller resulting in high shear and hemolysis.

If the outflow windows are obstructed by the aortic valve, blood will exit the pump at higher speeds from unobstructed regions and will make contact with the aortic valve and other obstructing structures, resulting in high shear force and hemolysis.

Impella pumps have been tested under simulated conditions of inflow and outflow obstruction. Conditions mimicking inlet obstruction (continuous or diastolic suction) resulted in increase in MIH by 2.5 times while conditions of outlet obstruction increased MIH by 6 times. These results suggest that high levels of hemolysis with Impella more likely result from conditions blocking the Impella outlet. Hence, proper maintenance of optimal positioning of Impella devices is key to preventing the occurrence of hemolysis.

How does the rate of hemolysis with Impella devices compare to other heart pumps in pre-clinical/bench testing?

Impella devices have lower rates of hemolysis compared to static blood and other heart pumps in bench testing. Impella heart pumps are the most blood compatible heart pumps.

Impella pumps were tested in bench test settings to demonstrate equivalence in hemolysis rates with other heart pumps. PFH levels measured at 6 hours with heart pumps was compared with static blood maintained under the same testing conditions. PFH level of Impella 5.0® was 2.2 times, Impella CP® and Impella 2.5® were 2.7 times each, and Impella RP® was 3.5 times the value of static blood.7-12 In contrast, Tandem Heart, Centrimag, and industry standard bypass pump had higher PFH levels at 3.6 times, 4.1 times, and 5.8 times that of static blood (see graph).7

How does the rate of hemolysis with Impella devices compare to other heart pumps in clinical setting?

Impella devices have lower rates of hemolysis compared to ECMO based on published clinical studies.

Currently, there are no published recommendations for hemolysis assessment in patients treated with AMCS devices such as Impella. Hence, the definition of hemolysis varies widely between studies of AMCS devices making clinical comparisons challenging. The rates of hemolysis also vary based on the duration of Impella use which is determined by the clinical indication for Impella support. Based on surveillance of published literature, the reported rates of hemolysis with Impella and other MCS devices are as follows:

MCS DeviceImpella 2.5
Hemolysis (%) 0.16% - 10.3%
Study TypeRCT and observational studies
MCS DeviceImpella CP
Hemolysis (%) 8%-11.9%
Study TypeRCT and observational study
MCS DeviceImpella RP
Hemolysis (%) 7%-13.3%
Study TypeObservational studies
MCS DeviceIABP
Hemolysis (%) 7.1%
Study TypeRCT
MCS DeviceTandemHeart
Hemolysis (%) 5.2%
Study TypeRCT
MCS DeviceECMO
Hemolysis (%) 18%
Study TypeMeta-analysis of observational studies
Impella 2.5

Rates of hemolysis with use of Impella 2.5 in high-risk PCI were reported in two prospective trials and retrospective study based on the USpella registry.

Protect I was a prospective feasibility trial investigating Impella 2.5 in 20 patients undergoing high-risk PCI.13 Two patients (10%) developed mild, transient hemolysis without clinical sequelae. In 1 patient, hemolysis was observed during pump use (peak plasma-free hemoglobin 75.8 mg/dL 1 hour after insertion). The plasma-free hemoglobin had returned to normal 24 h after the device was removed. In the other patient, the plasma-free hemoglobin was normal at device removal, but the level was elevated 14 h after removal (67.8 mg/dL). Neither patient required treatment or had any clinical sequelae.

Protect II was a prospective, multicenter, randomized trial comparing hemodynamic support with Impella 2.5 versus IABP in high-risk patients undergoing PCI.14 Cohen et al, reported hemolysis in 0.9% of 216 patients randomized to Impella 2.5 in Protect II trial.15 They also reported hemolysis in 0.16% of 637 patients in the USpella registry treated with Impella 2.5 during high-risk PCI.15

O’Neill et al reported hemolysis in 154 patients treated with Impella 2.5 for acute myocardial infarction and cardiogenic shock from the real-world cVAD registry.16 Hemolysis defined as PFH > 40 mg/dL or presence of hematuria was observed in 10.3%.

Impella CP

Ouweneel et al, compared IABP (n=24) with Impella CP (n=24) in patients with cardiac arrest and mechanical ventilation. Hemolysis requiring device extraction was reported in 0% with IABP and 8% with Impella CP. However, definition of hemolysis was not specified.17

Jensen et al, performed a single-center retrospective analysis of Impella use for profound cardiogenic shock in 109 patients.18 Impella CP was used in 97 patients (89%). Hemolysis was observed in 11.9%, however definition of hemolysis was not specified.

Impella RP

Recover Right was a prospective, open label, multicenter trial assessing the efficacy of Impella RP in 30 patients with RV failure and refractory to medical treatment.19 Hemolysis defined as PFH > 40mg/dL in two consecutive measurements after 24 hours of support was observed in 13.3%.

Hall et al, assessed the use of Impella 5.0 as bridge to decision in 58 patients with decompensated advanced heart failure.20 Hemolysis was defined as 2 consecutive measurements of PFH > 40mg/dl within a single 48-hour period or the combination of clinical signs such as hematuria and laboratory testing, including reduced hemoglobin, elevated LDH, and elevated indirect bilirubin. Hemolysis was observed in 7%.

Lima et al, investigated the use of Impella 5.0 as a bridge to cardiac transplantation or durable LVAD in 40 patients.21 Hemolysis defined as abnormal PFH > 40 mg/dL or presence of hematuria was observed in 8%.

Other MCS Devices

Burkhoff et al, conducted a prospective randomized study comparing Tandem Heart (n=19) with IABP (n=14) in patients with cardiogenic shock.22 Based on the definition of hemolysis of PFH > 40 mg/dL on more than 2 measurements taken at least 8 hours apart, hemolysis was observed in 5.2% with Tandem Heart and 7.1% with IABP. Based on meta-analysis of retrospective studies reporting on patients treated with ECMO, Zangrillo et al. reported hemolysis in 18% of 610 patients on ECMO.23

What are the clinical implications of hemolysis related to Impella?

High rates of hemolysis can result in anemia and the increased levels of PFH can cause renal dysfunction.24 Consistent with low rates of hemolysis with Impella, reports of anemia secondary to hemolysis are rare in the literature. Bianco et al, performed a retrospective analysis of 69 patients treated with Impella for cardiogenic shock. Hemolysis was reported in 29%, however the definition of hemolysis was not specified. The authors also assessed the impact of hemolysis on clinical course and prognosis. The results demonstrate that presence of hemolysis was not associated with increased rate of acute kidney injury, the need for renal replacement therapy, or mortality at 6 months, but was associated with prolonged ICU and total hospital length of stay.25

References

  1. Leverett LB, Hellums JD, Alfrey CP, Lynch EC. Red blood cell damage by shear stress. Biophys J. 1972;12(3):257–273.
  2. Baskurt OK. Red Blood Cell Mechanical Stability. Engineering. 2012;5:8-10.
  3. Interagency Registry for Mechanically Assisted Circulatory Support, National Heart Lung and Blood Institute. INTERMACS Adverse Events Definitions: Adult and Pediatric patients. Available at http://www.uab.edu/medicine/intermacs/images/protocol_5.0/appendix_a/AE-Definitions-Final-02-4-2016.docx. Published May 15, 2013. Accessed July 22, 2018.
  4. Esposito M, Morine KJ, Annamalai SK et al. Increased Plasma-Free Hemoglobin Levels Identify Hemolysis in Patients With Cardiogenic Shock and a Transvalvular Micro-Axial Flow Pump. Artificial Organs 2018.
  5. Lee SS, Ahn HK, Lee JS et al. Shear Induced Damage of Red Blood Cells Monitored by the Decrease of Their Deformability. Korea-Australia Rheology Journal, 2004; 16(3):141-146.
  6. ASTM F 1841-97, ASTM 1830-97, American Society for Testing and Materials, Subcommittee F04.30 Annual Book of ASTM Standards (Vol 13.01.), ASTM, West Conshohocken, PA (1998).
  7. CentriMag/Industry standard data – Levitronix Website
  8. FDA Bench Test Data for Impella 5.0/LD PMA P140003
  9. FDA Bench Test Data for Impella CP PMA Supplement P140003/S004
  10. FDA Bench Test Data for Impella 2.5 PMA P140003
  11. FDA Comparative Bench Test Data for Impella 2.5 510(k) Clearance K063723
  12. FDA Bench Test Data for Impella RP PMA P170011
  13. Dixon SR, Henriques JP, Mauri L et al. A prospective feasibility trial investigating the use of the Impella 2.5 system in patients undergoing high-risk percutaneous coronary intervention (The PROTECT I Trial): initial U.S. experience. 2009; 2(2):91-6.
  14. O'Neill WW, Kleiman NS, Moses J et al. A prospective, randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: the PROTECT II study. Circulation. 2012;126(14):1717-27.
  15. Cohen MG, Matthwes R, Maini B, et al. Percutaneous left ventricular assist device for high-risk percutaneous coronary interventions: Real-world versus clinical trial experience. Am Heart J 2015; 170: 872-879.
  16. O'Neill WW, Schreiber T, Wohns DH, et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: results from the USpella Registry. J Interv Cardiol. 2014;27(1):1-11.
  17. Ouweneel DM, Eriksen E, Sjauw KD, van Dongen IM, Hirsch A, Packer EJ, et al. Percutaneous Mechanical Circulatory Support Versus Intra-Aortic Balloon Pump in Cardiogenic Shock After Acute Myocardial Infarction. J Am Coll Cardiol. 2017;69(3):278-87.
  18. Jensen PB, Kann SH, Veien KT, et al. Single-centre experience with the Impella CP, 5.0 and RP in 109 consecutive patients with profound cardiogenic shock. Eur Heart J Acute Cardiovasc Care. 2018;7(1):53-61.
  19. Anderson MB, Goldstein J, Milano C, et al. Benefits of a novel percutaneous ventricular assist device for right heart failure: The prospective RECOVER RIGHT study of the Impella RP device. J Heart Lung Transplant. 2015;34(12):1549-60.
  20. Hall SA, Uriel N, Carey SA, et al. Use of a percutaneous temporary circulatory support device as a bridge to decision during acute decompensation of advanced heart failure. J Heart Lung Transplant. 2018;37(1):100-106.
  21. Lima B, Kale P, Gonzalez-Stawinski GV et al. Effectiveness and Safety of the Impella 5.0 as a Bridge to Cardiac Transplantation or Durable Left Ventricular Assist Device. Am J Cardiol. 2016;117(10):1622-1628.
  22. Burkhoff D, Cohen H, Brunckhorst C, et al. A randomized multicenter clinical study to evaluate the safety and efficacy of the TandemHeart percutaneous ventricular assist device versus conventional therapy with intraaortic balloon pumping for treatment of cardiogenic shock. Am Heart J 2006;152:e1-e8.
  23. 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(3):172-8.
  24. Tanawuttiwat T, Chaparro SV. An unexpected cause of massive hemolysis in percutaneous left ventricular assist device. Cardiovasc Revasc Med. 2013;14: 66–67.
  25. Bianco CM, Burch AE, Mawardi G, Lamm MK, et al. The Impact of Hemolysis on Outcomes of Cardiogenic Shock Patients Supported With Impella Percutaneous Left Ventricular Assist Device. Journal of Cardiac Failure. 2016; Supplement 110, 22 (8),319.

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