Open-heart surgery patients are at risk from a number of adverse reactions that may be attributed to white blood cells or leucocytes. Some of the reactions ascribed to leucocytes may occur infrequently, but can be expensive to treat. Others are more prevalent, but not nearly as expensive to manage. Taken together, however, the price of implementing state-of-the-art filtration technology with a view towards totally controlling the exposure of the open-heart surgical patient to the variety of leucocytes they are normally presented with may be far less expensive than the costs incurred to treat leucocyte-mediated adverse reactions. This is a hypothesis as well as a programme of treatment referred to as total leucocyte control (TLC). A discussion of TLC follows, including a description of the variety of leucocytes to which the cardiac surgery patient is exposed, the different types of adverse reactions each type causes, the cost of treating these reactions and the potential to accrue savings by controlling their frequency of occurrence with TLC.

As a hypothesis, TLC views open-heart surgical patients as being uniquely at risk from costly leucocyte-mediated morbidity originating from at least three distinct components and/or procedures of open-heart surgery; leucocytes present in transfused homologous (or allogeneic) blood products, the patient's own (autologous) leucocytes, more specifically the neutrophils, activated by cardiopulmonary bypass (CPB) and presented to the systemic circulation through the arterial line, and neutrophils presented to the myocardium during the administration of blood cardioplegia.

As a programme of treatment, TLC is implemented with the use of leucocyte-reducing filters. Homologous transfusion products may be passed through leucocyte-reducing transfusion filters, either prior to storage of the blood product, in the operating room or at the bedside in the Intensive Care Unit (ICU). The patient's neutrophils, known to be activated by the process of CPB, may be controlled with leucocyte-depleting arterial line filters and dedicated leucocyte-reducing filters for the blood cardioplegia line. The positioning of filters, used to approximate best TLC during bypass surgery, is illustrated in Figure 1.

Figure 1. Diagrammatic representation of the types and locations of filters employed during CPB in an effort to achieve total leucocyte control and maximal protection against filterable matter. LG, leucocyte-reducing arterial line filter; BC1B, leucocyte-reducing blood cardioplegia filter - leucocyte-reducing transfusion products, although represented as a filter on a blood bag with an intravenous line, are, of course, never provided to the patient in this fashion and is illustrated merely for clarity; CPS02, 0.2 micron filter complements the BC1B by ensuring the crystalloid component of blood cardioplegia is free of bacteria and other particles in excess of 0.2 microns; ORO1H, a bacterial-retentive gas line filter.

Types of leucocytes of concern during open-heart surgery

The nature of the reactions that develop depend upon not only the quantity, but the type of leucocytes presented to the patient. Autologous products are viewed by many clinicians as 'safe blood'. In contrast, most sources of transfused blood are donors other than the patient. These homologous blood products are considered unsafe largely because of the popularized threat of viral transmission, including the human immunodeficiency virus (HIV). Transfusion products (packed red blood cells and platelets) harbour high levels of leucocytes formerly viewed as relatively innocuous passengers of a component blood product. More recently, however, the transfusion of allogeneic blood has been correlated with at least five leucocyte-mediated adverse reactions that comprise over 90% of the frequency of occurrence of all adverse reactions associated with transfusions. Among these five reactions, both transfusion-associated immunosuppression and transfusion-transmitted cytomegalovirus (CMV) infection are of particular importance in cardiac surgery. Each can lead to very costly complications and they may be controlled using leucocyte-depletion filtration technology. Evidence suggests transfusion-related immunosuppression may predispose patients to an increased risk of postoperative infections and, thereby, prolong hospital stay. Cytomegalovirus has been shown further to retard the recuperative process of patients who develop deep sternal wound infections called mediastinitis.² Combined, these reactions to homologous leucocytes lead to complications that are very expensive to manage.

Unlike other surgical procedures, most open-heart operations require the patient to be put on CPB. Two important consequences develop from this action. First, blood is directed out of the body through the heart-lung machine and, second, blood flow to the heart and lungs is reduced. Both bear significant impact upon the development of costly clinical sequelae.

When a patient's blood is diverted from the body to the CPB circuit, the blood is exposed to the plastic surfaces which are foreign to blood. As a result, blood undergoes activation and, within the patient's own blood, the most prevalent circulating leucocytes, the neutrophils, become activated.^3-5 Neutrophils contain two major classes of highly reactive and potentially destructive chemicals known as oxidants and proteolytic enzymes.⁶ The combination of these two classes of destructive agents are particularly damaging to cells which receive less than a normal amount of oxygen and nutrients, that is, organs rendered ischaemic.^7,8 The two primary organs rendered ischaemic during CPB are the heart and lungs. Therefore, it is not surprising that the injury to organs that were once ischaemic and subsequently perfused or reperfused with blood containing activated neutrophils is called 'reperfusion injury'.

The primary manifestation of reperfusion injury is damage to the heart and lungs which causes them to function more poorly than they might if the neutrophil-mediated component of reperfusion injury were averted. From a practical point of view, when a heart does not perform well after surgery, it must be assisted with physical and/or pharmacological support. The use of intra-aortic balloon pumps are costly, as is the extended use of drugs, notably inotropes, which serve to strengthen the beat of a poorly functioning heart. When lung function is compromised, a patient cannot be removed from a ventilator as quickly and, thereby, requires additional time in the ICU. These services are very costly as well.

The most costly complications that develop following open-heart surgery

Studies have identified relationships between preoperative and intra-operative characteristics with morbidity; however, Taylor and coworkers correlate morbidity in open-heart surgery with postoperative hospital charges.⁹ Only three complications, namely, deep sternal wound infections, respiratory failure and left ventricular dysfunction, have been identified as the most costly complications of open-heart surgery. Leucocytes may play a pathogenic role in all three complications and the seminal literature related to these topics has been reviewed.^10-12

Costs of homologous leucocyte complications

The leucocytes present in transfused homologous blood products account for the immunosuppressive or 'transfusion effect' ^13,14 and are also capable of transmitting CMV infection.¹⁵ Both of these consequences of transfusion impact upon deep sternal wound infection, or mediastinitis, as well as other rather obvious indices of increased cost, including the development of postoperative infections that, in turn, correlate with prolonged hospital stay.

The transfusion of homologous blood products has been identified as a predictor of mediastinitis.¹⁶ The frequency of occurrence of mediastinitis ranges from 0.4 to 1.4%; although mediastinitis develops infrequently, it is the most expensive complication to deal with among cardiac surgical patients. Mediastinitis has been shown to increase average postoperative charges from $11,500 to well over $40,000.⁹ The extent to which the immunosuppressive effect of transfusion predisposes the patient to mediastinitis, compared with an independent effect of CMV on mediastinitis or some other correlate that remains to be identified, is not well understood. What is clear, however, is that the transfusion of homologous blood has been correlated with increased rates of mediastinitis. Leucocyte depletion of homologous blood products can effectively reduce the immunosuppressive effect as well as minimize the likelihood of transmitting CMV. So, whether the predominant influence of transfusion upon the rate of occurrence of mediastinitis is mediated by immunosuppression or CMV infection or a combination of the two, leucocyte depletion can address both adverse reactions and should reduce the rate of development of mediastinitis. At a cost of $40 000, prevention of just one case of mediastinitis per year may offset the cost of implementing TLC protection at a typical medical centre.

Perhaps the most relevant report of the relationship between CMV complications and leucocyte depletion derives from the work of Domart and colleagues which relates to mediastinitis.² They reported that, of 115 patients presenting with mediastinitis, those who were CMV viraemic had a higher mortality rate (35 versus 55%). Interestingly, of those patients who spent at least three weeks in the hospital, CMV viraemic patients had an average of 20 days added to their already long length of stay. Although the relationship between seroconversion and viraemia has not yet been studied in sufficient detail to draw conclusions concerning the potential cost savings that may be achieved by averting this complication, it would appear that the threat of acquiring CMV viraemia should be minimized in the cardiac patient population. In this regard, transfusion-associated CMV transmission may be abrogated by leucocyte depletion.¹⁷

The importance of CMV infection in routine open-heart surgery will likely attract more concern in the future. The literature points to an association between coronary artery disease and CMV.¹⁸ In a recent publication, CMV was shown to elaborate a protein, IE84, which inhibits an endogenous tumour suppressor gene, p53, that might account for part of the high rate of restenosis due to smooth muscle cell proliferation associated with angioplasty.¹⁹ The relationship between restenosis consequent to CPB and CMV serology is unstudied at this time, but could certainly represent an important point for consideration in long-term studies of the cost-effectiveness of leucocyte depletion. For if CMV can be shown to correlate with restenosis of vessels characterized by smooth muscle cell proliferation and IE84 elaboration, then prevention of a primary infection, reactivation of a latent infection or reinfection may make leucocyte depletion a cost-effective form of managing this complication of CPB surgery.

Before leaving the subject of the immunosuppression effect of transfused homologous blood, the impact upon the rate of postoperative infections other than mediastinitis should be considered. In a recent issue of BLOODLINK, Alter addresses the subject.²⁰ Some points are worth reviewing with a more focused view of the available data pertaining to costs. Transfusion-associated immunosuppression has been identified as a correlate of postoperative infection rates.²¹ These infections include not just mediastinitis, but the more prevalent infections like urinary and respiratory tract infections, bloodstream and surgical wound infections. In fact, there appears to be a dose-response relationship between the number of transfusions received and the rate of postoperative infections.²² Even a single unit of transfused homologous blood can prolong the length of hospital stay by a day and result in an infection rate of 14% compared with 3% in untransfused patients.²² It has been shown that patients provided with two or more homologous blood transfusions can have infection rates as high as 23%.^22,23 If homologous blood products are leucocyte depleted prior to transfusion, infection rates approximate those seen in patients transfused with autologous blood or those who have never been transfused at all, that is less than 5%.^23,24 Infection rates among CPB patients have been correlated with length of stay.^22,25,26 Williams and colleagues point out just how strong is the correlation between cost and the length of hospital stay.²⁷ Then, by inference, leucocyte depletion of homologous blood products for patients requiring transfusion may be expected to lower significantly the postoperative infection rate and, in turn, the costs associated with the management of these complications. Not only may leucocyte depletion be expected to impact on the rare but extremely costly complication of mediastinitis, but the overall frequency of other postoperative infections may be expected to be reduced as well and with them the cost of providing care to the open-heart patient population as a whole.

Autologous neutrophils activated on bypass contribute to morbidity

Results of a survey of board-certified thoracic surgeons ascribe prevention of reperfusion injury as the most important area for future research.²⁸ Reperfusion injury develops when one's own neutrophils, activated following exposure of blood to the CPB circuit, are presented to the pulmonary and coronary vasculature following a period of ischaemia.^3,4,8 The consequences, which can include pulmonary and myocardial dysfunction, may be attenuated by leucocyte depletion.^29-31

Pulmonary dysfunction following CPB is a significant determinant of increased costs

The incidence of postpump pulmonary dysfunction consequent to CPB is measurable³² and is believed, by some, to occur in all CPB patients.³³ A more severe complication identified as the adult respiratory distress syndrome (ARDS) may occur in as many as 1.3% of patients.³⁴ Upon retrospective examination of 630 consecutive patients at St Francis Hospital in Topeka Kansas, the incidence of pulmonary dysfunction, identified using the Society of Thoracic Surgeons criteria, was 9.5%.³⁵ Respiratory dysfunction can contribute to prolonged ventilator time, length of hospital stay and, in its extreme form, may present as respiratory failure. Respiratory failure drives the average postoperative charges up from $11,500 to over $28,000.⁹

Recent data show clinical safety, patient efficacy and cost-effectiveness may be achieved by applying leucocyte depletion within the arterial line of the bypass circuit.^36,37 These data have been corroborated using other techniques to effect leucocyte reduction.³⁸ A retrospective clinical study of 240 routine coronary artery bypass graft (CABG) patients confirmed the results of a previous study ³⁶ and extended the observations by reporting decreased length of hospital stay by 1.4 days among those in the group of patients who had undergone CPB with a leucocyte-depleting arterial line filter.³⁹ In addition, postoperative charges were reduced by an average of about $1900 per patient in whom leucocyte-depletion arterial fine filters were used.

More recent discussions of the potential for leucocyte-depleting arterial line filters to affect patient benefit in a cost-effective manner appeared in letters to the editor in a recent issue of the Annals of Thoracic Surgery. Allen and colleagues^4O reported that patients showed a trend towards improvement in pulmonary function consequent to bypass surgery when a leucocyte-depleting arterial line filter was used. A more impressive observation was noted by clinicians operating in a high altitude setting where low ambient oxygen pressure serves as an additional stress to the pulmonary vasculature of CPB patients. In this evaluation of a total of 188 patients, the frequency with which patients required supplementary nasal oxygen upon release from the hospital (using oxygen saturations below 90% as a criterion for oxygen therapy) was lower for patients undergoing CPB with a leucocyte-depleting arterial-line filter. In fact, among patients over the age of 70, the frequency of patients requiring supplementary nasal oxygen drops from 82% down to 33% with leucocyte-depletion filters employed in the arterial line.⁴¹ The authors conclude this technology is cost-effective in their practice.

Myocardial preservation, compromised by activated neutrophils, may impact upon costs

Over 70% of open-heart procedures conducted in the USA employ blood cardioplegia²⁸ because the enhanced oxygen-carrying capacity of blood is believed, by many surgeons, to be important to provide optimal myocardial preservation. Present in blood, however, are activated neutrophils derived from the CPB circuit, which may participate in the development of reperfusion injury to the myocardium. This injury is presumed to manifest, in part, as the costly complication identified as left ventricular dysfunction, a complication that serves to elevate postoperative charges by over $5000.⁹

Data suggest a brief period of reperfusion of the myocardium with leucocyte-depleted blood can improve myocardial performance in animal models of regional ischaemia.⁴² Changes in morphological and biochemical indices of myocardial integrity suggest improvement with similar treatment among heart transplant patients.^43,44 More recently, routine CABG patients were shown to derive benefit from leucocyte depletion of the blood delivered to the myocardium compared with whole blood or terminal cardioplegia (10 mM K+) in terms of lower levels of malondialdehyde, a lipid oxidation product reflective of cellular destruction, measured following 20 minutes of reperfusion.⁴⁵ Palatianos and Balentine showed leucocyte-depleted blood presented to CABG patients improved outcomes with a significant reduction in the incidence of arrhythmias, improved cardiac output and a reduction of mean ICU length of stay was from 7.9 to 4.8 days.⁴⁶ Another recent report illustrates that controlled reperfusion of the myocardium with leucocyte-depleted blood in patients with poor left ventricular function initially protects the patient against oxidants that are generated by neutrophils and believed to be responsible for cellular damage.⁴⁷ Thus, morbidity may be reduced in all populations of CPB patients and not just transplantation or regionally ischaemic patients consequent to failed angioplasty. A new microaggregate removal and leucocyte-reducing filter has been characterized for use in the blood cardioplegia line, making it possible to provide a lower burden of leucocytes to the myocardium during blood cardioplegia administration on a routine basis.

TLC may effect tender loving care at a total lower cost

Social, economic and technological developments work together to elevate the recognition of TLC as an important hypothesis that merits investigation. Any open-heart programme has the opportunity to test the hypothesis that controlling the exposure of the open-heart surgical patient to all forms and sources of leucocytes normally present during surgery reduces morbidity. Moreover, clinical implementation of TLC as a technological advancement may be shown to be cost-effective.

Unfortunately, the pressure to contain costs precludes some cardiac surgeons and perfusionists from evaluating TLC in their practice. Hospital administrators, striving to improve their bottom line profits, have, perhaps, more by convention and instinct, reacted to the financial pressures by slashing budgets in every department of the hospital. Total leucocyte control can only effect cost savings by increasing one's budget (filter purchases) and saving in another area as a result of decreasing complications. The impact upon costs is the single, most important consideration for the successful incorporation of any change, like TLC, in medical practice today. Overcoming the intuitive and widespread reactionary policy to cut the budget of every department is the greatest obstacle to continued development of fiscally responsible medical products, procedures and practices. In terms of reperfusion injury, we are witnessing pressure from clinicians in many disciplines to bring all the laboratory animal data to bear in the clinical arena for the ultimate test,⁴⁸ clinical studies; a timely challenge indeed.

Note added in proof

In a prospective, randomized double-blinded clinical trial of cardiac surgery patients, the use of leukoreducing arterial line filters afforded transient improvement in pulmonary shunt fraction and mean blood pressure.⁴⁹ In addition, recent data show that leukoreduction initiated at the onset of bypass with a leukoreducing arterial line filter improves cardiac function; in a porcine model of regional ischaemia, improvement in wall motion scores and decreased infarct size were observed.⁵⁰

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*Presented at the Annual Seminar of the American Academy of Cardiovascular Perfusion, Palm Springs, 26-29 January 1995.

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