Leukocyte Reduction of Blood Cardioplegia

Taylor et al¹ reported left ventricular dysfunction as the third most costly complication of open heart surgery increasing patient charges in excess of $5,000 per episode.Ventricular dysfunction may range from a failure to restore normal sinus rhythm to a severe decrement in ejection fraction. The pathogenesis of ventricular dysfunction may be viewed as compromised myocardial preservation with relative ischemia predisposing heart muscle to the risk of reperfusion injury.

There are considerable data pointing to leukocytes as the mediator of morbidity.² Evidence suggests that cardiopulmonary bypass causes complement and, in turn, neutrophil activation.^3,4 Activated neutrophils, when presented to ischemic tissue upon reperfusion of the vascular bed, lead to neutrophil adherence through the interaction of complementary cell adhesion molecules. With activated neutrophils held in such close proximity to vascular endothelium, neutrophil-derived oxidants and proteolytic enzymes can attain high concentrations in the space between these two cells (see Fig 1) and thereby mediate destruction of endothelial cells and parenchyma.

With ensuing endothelial cell destruction comes an increase in the release of cytokines with their accumulation in the interstitium. Interleukin-8, an endothelial cell-derived cytokine that is a chemo-attractant for neutrophils, is thought to accumulate in the interstitial fluid and promote extravasation of neutrophils into the interstitium and toward the parenchyma leading to myocardial cell dysfunction.

The value of keeping these leukocytes away from the target organ has been demonstrated clinically in both global^5,6 (transplantation) and regional (emergent^7,8 and routine^9-11 CPB) ischemia as summarized below.

Figure 1. Diagrammatic representation of neutrophil sequestration, endothelial destruction and extravasation of neutrophils leading to myocardial cell dysfunction.

Two studies demonstrated that the Pall leukoreducing filters (LeukoGuard^®) selectively reduce activated neutrophils.^12,13

Pearl et al⁵ showed that transplanted hearts reperfused with leukoreduced blood exhibited less ultra-structural damage than hearts perfused with whole blood. Biopsied subendocardial tissue was inspected microscopically and injury score assessed. The data show an increase in injury following transplantation that is prevented when the heart is presented with a short period of controlled reperfusion of the myocardium with leukoreduced blood prior to cross clamp removal.

Figure 2. Leukocyte-mediated ultrastructural damage is blunted with leukoreduced blood

A second article by the same authors⁶ showed improvements in myocardial preservation using biochemical markers. Creatinine phophokinase myocardial band (CPK-MB) and the vasocontrictor, thromboxane B₂ (Tx-B₂), were significantly lower in hearts perfused with leukoreduced blood.

Figure 3. Coronary sinus samples show reduced myocardial cell destruction with leukoreduced blood post transplantation

On the basis of these studies the authors concluded..."Reperfusion with amino acid enriched leukocyte depleted blood cardioplegia solution followed by leukocyte depleted blood alone is recommended for all transplanted hearts."

Sawa et al⁷ showed that leukocyte depleted terminal blood cardioplegia (LDTC) conferred protection to emergency patients with myocardial infarcts compared with whole blood (WB). Use of LDTC was associated with reduced peak CPK-MB, a lower requirement for inotropic support (dopamine) and a reduction in oxidative damage (reflected by lower levels of sino-atrial malondialdehyde or MDA).

Figure 4. Inotropic drug requirements decreased with leukoreduced blood reperfusion

Pala and co-workers⁸ reported similar findings and claimed that ..."In patients with LVD [left ventricular dysfunction] an oxidative stress occurs after aortic cross clamping, but leukocyte depletion of reperfusion can afford a better antioxidant defence."

Figure 5. Controlled reperfusion with leukoreduced blood reduces oxidant-mediated damage as measued by changes in arterio-venous MDA

Ichihara et al⁹ showed reduced levels of elastase (a product of neutrophil activation), lipid peroxides (a reflection of myocardial damage) measured in coronary sinus blood samples, and lower levels of peak CPK-MB post-operatively.

Figure 6. Leukoreduction is associated with lower plasma CPK-MB in routine bypass patients

Palatianos and Balentine¹⁰ showed a reduction in arrythmias and the incidence of low cardiac output with leukocyte reduced whole blood cardioplegia (LRWB).

Figure 7. Leukoreduction reduces clinical sequelae

The Pall BC1B leukoreducing blood cardioplegia filter contains a specifically designed medium for the removal of leukocytes. The device has been clincially tested.¹⁴

Figure 8. Characterization of the Pall LeukoGuard® BC (BC1B) BC1B filters

A recent study provides evidence to suggest myocardial preservation may be compromised by neutrophil-mediated reperfusion injury.¹¹ A leukoreducing filter was shown effective in lowering WBC’s while leaving platelets nearly unaffected (Figure 10).

Troponin-T is a heart muscle-derived protein that is normally present in low concentrations in the pre-operative blood sample of elective CPB patients. Following routine bypass, these levels were shown to rise more in patients without leukoreducing filters.¹¹

These data combine to suggest that myocardial preservation may be improved by incorporating leukocyte reducing filtration technology in the blood cardioplegia limb of the bypass circuit.

Figure 9. Leukoreduction with Pall LeukoGuard® BC (BC1B) Figure 10. Pall LeukoGuard® BC (BC1B) attenuates the rise in circulating CPK-MB and troponin-T.

1. Taylor GJ, Mikell FL, Moses HW, et al: Determinants of hospital charges for coronary artery bypass surgery; The economic consequences of postoperative complications. Am J Cardiol 1990; 65:309-313.
2. Weiss SJ: Tissue destruction by neutrophils. N Eng J Med 1989; 320:365-376.
3. Allen S: The role of leukocytes in the systemic inflammatory response and the potential impact of leukocyte depletion. Cardiovasc Eng 1997;2:34-54.
4. Bulkley GB. Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function. Lancet 1994; 344:934-936.
5. Pearl JM, Drinkwater DC, Laks H, et al: Leukocyte-depleted reperfusion of transplanted human hearts prevents ultrastructural evidence of reperfusion injury. J Surg Res 1992; 52:298-308.
6. Pearl JM, Drinkwater DC, Laks H, Capouya ER, Gates RN: Leukocyte-depleted reperfusion of transplanted human hearts: a randomized, double-blind clinical trial. Journal of Heart & Lung Transplant 1992; 11:1082-1092.
7. Sawa Y, Matsuda H, Shimasaki Y, et al: Evaluation of leukocyte-depleted terminal blood cardioplegia in patients undergoing elective and and emergency coronary artery bypass grafting. J Thorac Cardiovasc Surg 1994; 108:1125-1131.
8. Pala MG, Paolini G, Paroni R, et al: Myocardial protection with and without leukocyte depletion: A comparative study on the oxidative stress. [abstract] Presented at the Eighth Annual Meeting of the European Association for Cardio-Thoracic Surgery, The Hague, The Netherlands. Sept 25-28, 1994.
9. Ichihara T, Yasuura K, Maseki T, et al: The effects of using a leukocyte removal filter during cold blood cardioplegia. Surg Today Jpn J Surgery 1994; 24:966-972.
10. Palatianos G, Balentine G: Leukocyte-filtered blood cardioplegia and controlled reperfusion. [abstract] Presented to the Third International Congress of the Society for Cardiovascular Surgery. Berlin. Sep 6-9, 1994.
11. Suzuki I, Ogoshi N, Chiba M, Komatsu T, Moizumi Y: Clinicial evaluation of a leukodepleting blood cardioplegia filter (BC1B) for elective open-heart surgery. Perfusion, 1998;13:205-210.
12. Thurlow PJ, Doolan L, Sharp R, et al: Studies of Pall leukocyte filters LG6 and AV6 on an in-vitro simulated extracorporeal circulatory system. Perfusion 1995;10:291-300.
13. Hurst T, Johnson D, Cujec B, et al: Depletion of activated neutrophils by a filter during cardiac valve surgery. Can J Anaesth 1997;44:131-139.
14. Heggie AJ, Corder JS, Crichton PR, Hesford JW, Bingham H, Jeffries S: Clinical evaluation of the new Pall leukocyte-depleting blood cardioplegia filter (BC1). Perfusion 13:17-25,1998.

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