Severe SIRS in cardiac surgery patients

cytoApproximately 1.5 million open heart surgeries are performed worldwide each year, with ~500,000 procedures in Europe and another ~500,000 procedures in the U.S. [1]. In Germany alone, ~84,000 open heart procedures using cardiopulmonary bypass (CPB) were performed in 2014 [2].
Although there have been significant advances in perfusion technologies and biocompatible materials used in CPB, patients undergoing complex cardiac surgery procedures such as re-operative coronary artery bypass grafting (redo-CABG), multiple interventions, aortic reconstruction, valve replacement due to endocarditis, or hypothermic circulatory arrest, remain at significantly higher risk of having complications, ranging from short-term organ dysfunction to multiple organ failure and death.
Factors such as the trauma of the surgical procedure, non-pulsatile blood flow, ischemia-reperfusion injury, and blood contact with air and artificial surfaces of the CPB system can lead to an activation of the complement system and a stimulus of inflammatory cytokine production. The concentration of these inflammatory mediators is directly correlated to the complexity, length, and invasiveness of the surgery and can lead to a post-operative systemic inflammatory response syndrome (SIRS) with SIRS-related complications such as acute kidney injury, respiratory and circulatory failure.
Furthermore, shear forces and cardiotomy suction can cause hemolysis resulting in the release of free hemoglobin, an important contributor to post-operative kidney injury [3]. Once released, free hemoglobin is a potent scavenger of nitric oxide (NO), and can lead to decreased renal blood flow, pulmonary hypertension, and increased systemic vascular resistance, putting stress on the heart. In addition, ferrous iron of the free heme is also a potent generator of oxygen radicals that can damage cell membranes and cause further renal tubule injury.
For example, acute kidney injury (AKI) occurs in up to 30% of patients undergoing on-pump cardiac surgery and is associated with mortality rates ranging from 7% to 38%. One to 5% of these patients will develop renal failure requiring hemodialysis with a substantially higher risk of death ranging from 50% to 90%. In addition to the increased mortality risk, post-operative AKI increases the direct cost of hospital care up to 42%, driven by the costs of increased ICU utilization, as well as pharmacy, laboratory, and radiology services [4].
Therefore, the reduction of inflammatory mediators such as cytokines and free hemoglobin by CytoSorb® represents a promising approach to reduce post-operative complications and costs. Unpublished in vitro data demonstrate the ability of CytoSorb® to remove a broad range of cytokines, C3a and C5a, as well as free hemoglobin. To date, CytoSorb® has been safely used intra-operatively in a bypass circuit in a heart-lung machine in more than 1,000 cardiac surgeries.
In a 40-patient retrospective case series in complex cardiac surgery patients undergoing hypothermic cardiac arrest and anterograde cerebral perfusion (20 cases using CytoSorb® intra-operatively vs 20 cases that did not), CytoSorb® was associated with statistically significant decreased levels of IL-6, fibrinogen, and procalcitonin during the post-operative period [5].
CytoSorb® has also been used hundreds of times with a standard dialysis machine to treat post-operative SIRS following cardiac surgery.
This flexibility in using CytoSorb® allows the treatment of a wide variety of cardiac surgery patients who are either at risk (intra-operative use) or who have developed post-operative SIRS (post-operative use).

In summary, the rationale for peri-operative CytoSorb® use in cardiac surgery includes:

  • Effective reduction of excessive cytokines and activated complement
  • Reduction of plasma free hemoglobin
  • Possible prevention or reduction of capillary leak syndrome
  • Possible improvement of hemodynamics (macro- and microcirculation) with a reduced need for vasopressors and/or post-operative extracorporeal membrane oxygenation (ECMO) or extracorporeal life support (ECLS)
  • Possible prevention or reduction of cytokine- and inflammatory mediator-induced organ injury
  • Other potential benefits such as improved myocardial function, liver function, and reduced incidence of cognitive dysfunction

 

Cardiac surgery patients that might particularly benefit from the pre-emptive (intra-operative) use of CytoSorb® may include those with high-risk profiles:

  • Age > 70 yrs (54.3 %*)
  • High risk procedures:
    – Combination procedures (valve repair/replacement, CABG) (13.4%**)
    – Redo procedures (8.4%)
    – Thoracic aortic surgery (7,117 cases in the year 2014 in Germany)
    – R/LVAD (915 cases in the year 2014 in Germany)
  • Long CPB duration expected (>120 min)
  • Endocarditis (approximately 1,100 cases in the year 2013 in Germany)
  • Pre-operative leukocytosis (> 12,000/µl) or hyperbilirubinemia

The intra-operative use of CytoSorb® could also be beneficial to patients with low primary risk but with unexpected intra-operative complications (e.g. SIRS, prolongation of CPB time).

* Percentage relates to the overall age distribution of cardiac procedures
** Percentage relates to the total number of open heart procedures using extracorporeal circulation


References 

[1] Importance of monitoring blood viscosity during cardiopulmonary bypass.
Holsworth RE Jr, Shecterle LM, St Cyr JA, Sloop GD.
Perfusion. 2013 Jan;28(1):91-2.

[2] Cardiac Surgery in Germany during 2014: A Report on Behalf of the German Society for Thoracic and Cardiovascular Surgery.
Beckmann A, Funkat AK, Lewandowski J, Frie M, Ernst M, Hekmat K, Schiller W, Gummert JF, Cremer JT
Thorac Cardiovasc Surg. 2015 Jun;63(4):258-69.

[3] Hemolysis during cardiac surgery is associated with increased intravascular nitric oxide consumption and perioperative kidney and intestinal tissue damage.
Vermeulen Windsant IC, de Wit NC, Sertorio JT, van Bijnen AA, Ganushchak YM, Heijmans JH, Tanus-Santos JE, Jacobs MJ, Maessen JG, Buurman WA
Front Physiol. 2014 Sep 8;5:340.

[4] Economic consequences of renal dysfunction among cardiopulmonary bypass surgery patients: a hospital-based perspective.
Callahan M, Battleman DS, Christos P, Efimba M, Whitelaw G
Value Health. 2003 Mar-Apr;6(2):137-43.

[5] New cytokine adsorber in use against SIRS and SEPSIS
Born F, Pichlmaier M, Peterß S, Khaladj N, Hagl C
Kardiotechnik 2/2014