Does leucocyte depletion during cardiopulmonary bypass improve oxygenation indices in patients with mild lung dysfunction?

S. V. Sheppard1,*, R. V. Gibbs2 and D. C. Smith3

1 Wessex Cardiothoracic Centre, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. 2 Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, UK. 3 Department of Anaesthesia, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK

* Corresponding author. E-mail: stuart.sheppard{at}suht.swest.nhs.uk

Accepted for publication August 2, 2004.


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Leucocyte-depleting arterial line filters have not dramatically improved lung function after cardiopulmonary bypass (CPB), but patients with pre-existing lung dysfunction may benefit from their use.

Methods. We randomized 32 patients with mild lung dysfunction having elective first-time coronary revascularization to either a leucocyte depleting or a standard 40-mm arterial line filter during CPB. The alveolar arterial oxygenation index was calculated before and 5 min after CPB, then at 1, 2, 4, 8, and 18 h after surgery. Time to extubation on the ITU was recorded. Preoperative, immediate postoperative, and 24 h postoperative chest x-rays were scored for extravascular lung water.

Results. Postoperative alveolar–arterial oxygenation indices were better in the patients who received leucocyte depletion during CPB (1.65±0.96 in the study group vs 2.90±1.72 in the control group, P<0.05). The duration of postoperative mechanical ventilation was less in the leucocyte-depleted group (4.8±2.1 vs 8.3±4.7 h in the control group, P<0.05). The extravascular lung water scores immediately postoperatively were 13.0±8.6 in the study group vs 19.6±10.8 in the control group (P=0.04), and at 24 h postoperatively, 9.7±7.7 vs 15.2±9.9 for controls.

Conclusions. For patients with mild lung dysfunction, a leucocyte-depleting arterial line filter improves postoperative oxygenation, reduces extravascular lung water accumulation, and reduces time on artificial ventilator after CPB. There may be an economic argument for the routine use of leucocyte-depleting filters for every patient during CPB.

Keywords: blood, leucocyte depletion ; heart, cardiopulmonary bypass ; lung, dysfunction


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Extracorporeal circulation of blood is not physiological, and results in activation of the complement system and leucocytes with consequent organ damage.13 The technique of leucocyte depletion was developed in response to this, with early studies using either cell separator technology, or leucocyte-depleting transfusion filters incorporated into the extracorporeal circuit.47 The key benefits of leucodepletion are improved cardiac and lung function, especially an increased postoperative .4 5

The LeukoGuard LG-6 arterial line filter (Pall Biomedical, Portsmouth, UK), removes leucocytes from the circulation, although the systemic neutrophil count may5 810 or may not be reduced.1113 Although one study demonstrated that the LG-6 removed mainly activated neutrophils,12 markers of inflammation9 13 and serum elastase,11 are not reduced by leucocyte depletion.

Leucocyte depletion during cardiopulmonary bypass (CPB) may improve oxygenation in the early postoperative period in comparison with controls,5 11 13 14 and the duration of postoperative mechanical ventilation may also be reduced,5 11 although some of these studies have insufficient power15 to detect the measured difference in main outcome variables. Also, the benefit of leucocyte depletion may be small if the duration of bypass is short.16 Whilst there is a growing body of research concerned with the depletion of leucocytes during CPB, the majority of published work has concentrated on leucocyte depletion in patients with normal preoperative lung function. We undertook this prospective randomized study to evaluate the effect of leucocyte depletion in patients who have mild (sub-clinical) lung dysfunction.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Following local Ethics Committee approval and informed written consent, we studied 32 patients presenting for elective coronary artery bypass grafting. The exclusion criteria for the study are shown in Table 1.


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Table 1 Exclusion criteria used during this study

 
Lung function is not routinely measured preoperatively in our unit unless the patient has respiratory symptoms or a significant smoking history, so the patients were identified in the operating room from the first arterial blood-gas measurement taken before bypass. Lung dysfunction was defined as an alveolar–arterial oxygenation index13 (AaOI, see below) greater than 1.25 (normal value in this age group is 0.2–0.55). All patients had normal preoperative haematology and biochemistry screening.

Patients were pre-medicated 1.5 h before the operation with morphine 10 mg i.m. and lorazepam 2 mg p.o.. Anaesthesia was induced with midazolam 2–4 mg, fentanyl 10–15 µg kg–1, and pancuronium 0.2 mg kg–1, and maintained using oxygen-enriched air ( 0.4) and isoflurane. Intermittent positive pressure ventilation was adjusted to maintain at 4.5–5.5 kPa with a tidal volume of 10–12 ml kg–1 and PEEP of 5 cm H2O. During the period of CPB, a propofol infusion was used at 2–3 mg kg–1 h–1 to maintain anaesthesia, and this was continued for sedation in the intensive care unit until extubation.

The CPB circuit consisted of a microporous hollow fibre oxygenator with integral cardiotomy reservoir (Dideco D703 Compactflo, Sorin Biomedica, Mirandola, Italy). The circuit tubing was made of PVC, with the exception of the pump head tubing, which was made of silicone. The circuit was primed with 2 litres of Hartmann's solution and 5000 iu of porcine heparin. The patients were prospectively randomized into two groups of 16 patients using a sealed envelope system. In the control group, the arterial line filter was a 40 µm woven polyester screen (D754, Sorin Biomedica), and in the study group a leucocyte-depleting arterial line filter (Leukogard LG-6, Pall Biomedical, Portsmouth, UK) was used. The LG-6 filter combines a 40-mm screen filter with a surface-modified fibre pack for the removal of leucocytes. Perfusion staff were aware of which filter was in the circuit, but surgical, anaesthetic, and theatre staff were not told which filter was being used. During CPB, all patients were cooled to a nasopharyngeal temperature of 31°C. Blood circulation was by roller pump (Stockert SIII, Munich, Germany) and pulsatile flow at 2.4 litre min–1 m–2, reducing to 1.8 l min–1 m–2 during the period of hypothermia.

Following surgery, the patients were transferred to a dedicated cardiothoracic ITU where the staff were blinded to the type of filter used. Ventilation was continued with a Manley MP2000 ventilator using a tidal volume of 10 ml kg–1 at 10–12 b.p.m and no PEEP. Crystalloid fluid(4% dextrose, 0.18% saline) was given at 1 ml kg–1 h–1 and colloid (Gelofusine, B Braun, Melsungen, Germany) administration was titrated to maintain the pre-bypass central venous pressure. Blood and blood product administration was governed by a standard protocol, with a transfusion trigger of 80 g litre–1. Patients were extubated by the anaesthetic resident on the ITU. The criteria for extubation were a nasopharyngeal temperature greater than 36°C, blood loss in the chest drains less than 1 ml kg–1 h–1, and greater than 9.0 kPa with an of 0.4 or less. Neuromuscular block was not monitored or reversed. The time to extubation was recorded.

Blood samples were taken from the radial arterial line and the was recorded at the following time points: 5 min after termination of CPB, and at 1, 2, 4, 8, and 18 h postoperatively. The AaOI (or respiratory index) was calculated from blood gas tensions using the formula:

Where: Pbar=barometric pressure in kPa; =inspired oxygen fraction; =saturated vapour pressure of water at 37°C in kPa; =arterial partial pressure of carbon dioxide in kPa; =arterial partial pressure of oxygen in kPa.

Chest x-rays were taken preoperatively, then immediately and 24 h postoperatively. These films were later scored for lung water content using the Pistolesi scoring system,17 by a radiologist blinded to the type of filter used. The Pistolesi system uses a number of easily identifiable markers on the chest x-ray to generate a numerical score for lung water content. The primary features are the number and distribution of Kerley's lines, and evidence of water accumulation around the bronchial tree (Table 2).


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Table 2 The Pistolesi scoring system for extravascular lung water (modified from17). The various scores for each item represent increasing presence of that item. The extravascular lung water score is the sum of the scores for the individual items present on the radiograph

 
Statistical analysis
Statistical analysis of the data was carried out in a spreadsheet (Excel 97, Microsoft Corp., USA) using Student's t-test and two-way analysis of variance (ANOVA). A P value of <0.05 was considered statistically significant. We considered a difference in AaOI between the two groups of 0.5 to be clinically significant, and the sample size was calculated to give a power in excess of 0.8 to detect this difference.15


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The two groups were comparable with respect to age, weight, body surface area (BSA), CPB time, aortic cross clamp time, and haematocrit during CPB (Table 3). No patient bled significantly, and there were no differences between the groups in the nasopharyngeal temperature on arrival in the ITU or the time taken to re-warm to 36°C.


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Table 3 Patient characteristics and bypass data for the two groups. Results are mean [range] or mean (SD). (BSA, body surface area; CPB, cardiopulmonary bypass duration; AoX, aortic cross clamp time; LG-6, leucocyte-depleted group)

 
Before the start of CPB, the AaOI was the same in both groups. Following CPB, the AaOI in the control group had increased significantly compared with baseline, while in the LG6 group it remained similar to the baseline value (between group difference, P<0.001 by ANOVA). This translates to a post-CPB of 19.6 (7.3) kPa in the LG-6 group compared with 12.5 (4.3) kPa in the control group (P=0.02), at an of 0.52 (0.19) and 0.53 (0.15), respectively. The difference in AaOI between the groups had disappeared by 18 h post-CPB (Table 4).


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Table 4 AaOI for the various time points studied, expressed as the mean (SD) (LG-6: leucodepleted group). Significance values are for between-group comparisons

 
The duration of postoperative ventilation was significantly shorter in the leucocyte-depleted patients, at 4.8 (2.1) h compared with 8.3 (4.7) h in the control group (P=0.041) (Table 4).

The Pistolesi scores were low in both groups before bypass (1.5 (1.1) in the leucodepleted group vs 1.3 (0.9) in the control group). There was a significant increase in the amount of extravascular lung water in both groups following CPB according to the Pistolesi scoring system (P<0.001 by ANOVA). However, the amount of lung water in the leucocyte-depleted patients was significantly less than controls both immediately following surgery (13.0 (8.6) vs 19.6 (10.8) for the control group, P=0.04), and at 24 h post-surgery (9.7 (7.7) vs 15.2 (9.9) for the control group, P<0.05).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In 1983, Kirklin introduced the concept of a whole body inflammatory response caused by the interaction between blood and the foreign surface of the extracorporeal circuit.18 This is known as material-dependent activation, and is characterized by activation of the complement system. As well as the immediate activation at the start of CPB, a second increase in complement activation is observed following release of the aortic cross clamp.19 This reperfusion injury has been termed material-independent activation, but the mechanism underlying this source of activation remains unclear. However, activated leucocytes are a part of the final common pathway in the inflammatory process.3

The duration of CPB was relatively short in our study, at between 60 and 65 min. This is of interest because, in low risk patients undergoing coronary revascularization, leucocyte filtration did not confer any significant preservation of lung function unless the duration of CPB exceeded 90 min.16 However, in our study the use of leucocyte depletion in patients with mild lung dysfunction provides some preservation of oxygenation irrespective of the duration of CPB.

During this study, the decision to discontinue mechanical ventilation was taken by the anaesthetist in the ICU, who was blinded to the type of filter used during CPB. Our results are in keeping with previous studies that demonstrated improved oxygenation in the early postoperative period in leucocyte-depleted patients compared with controls,5 11 1315 with a reduction in the duration of postoperative mechanical ventilation.5 11 Our routine practice at the time of this study was not to use PEEP, although this has now changed with the purchase of more sophisticated ventilators than those used for this study.

While the mean AaOI before CPB was around 1.8 in both groups (Table 4), these were all patients who had no symptoms of pre-existing pulmonary disorders, such as asthma or chronic obstructive pulmonary disease. It is possible that the reduction in exercise tolerance associated with coronary artery disease might have masked any symptoms that might otherwise be attributable to pulmonary dysfunction. However, although they may benefit from leucocyte depletion, these patients are difficult to identify preoperatively, so there may be an argument for the routine use of leucocyte-depleting arterial line filters during CPB.


    Acknowledgments
 
We thank Dr John Cook for scoring the chest radiographs.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 Chenoweth DE. Anaphylatoxin formation in extracorporeal circuits. Complement 1986; 3: 162–5

2 Wegmuller E, Kazachkinen MD, Nydegger UE. Complement activation during extracorporeal blood bypass. Plasma Ther Transfus Technol 1983; 4: 361–71[ISI]

3 Kazatchkine MD, Nydegger UE. The human alternative complement pathway: biology and immunopathology of activation and regulation. Prog Allergy 1982; 30: 193–234[ISI][Medline]

4 Romson JL, Hook BG, Kunkel SL, et al. Reduction of the extent of ischemia myocardial injury by neutrophil depletion in the dog. Circulation 1983; 67: 1016–23[Abstract]

5 Johnson D, Thomson D, Mycyk T, et al. Depletion of neutrophils by filtration during aortocoronary bypass surgery transiently improves postoperative cardiorespiratory status. Chest 1995; 107: 1253–9[Abstract/Free Full Text]

6 Bando K, Pillai R, Cameron DE, et al. Leukocyte depletion ameliorates free-radical-mediated lung injury after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990; 99: 873–7[Abstract]

7 Byrne JG, Appleyard RF, Lee CC, et al. Controlled reperfusion of the regionally ischaemic myocardium with leukocyte depleted blood reduces stunning, the no-reflow phenomenon, and infarct size. J Thorac Cardiovasc Surg 1992; 103: 66–72[Abstract]

8 Mihaljevic T, Tonz M, Von Segesser LK, et al. The influence of leucocyte filtration during cardiopulmonary bypass on postoperative lung function. J Thorac Cardiovasc Surg 1995; 109: 1138–45[Abstract/Free Full Text]

9 Chiba Y, Muraoka R, Ihaya A, et al. Leucocyte depletion and prevention of reperfusion injury during cardiopulmonary bypass: a clinical study. Cardiovasc Surg 1993; 1: 350–6[Medline]

10 Nanson JK, Sheppard SV, Kulkarni M, Smith DC. A comparison of sequential and activated white cell count in patients undergoing coronary artery bypass grafting, using cardiopulmonary bypass, with and without a white cell filter. Crit Care Forum 2000; 4: 3

11 Palanzo DA, Manley NJ, Montesano RM, et al. Clinical evaluation of the LeukoGuard (LG-6) arterial line filter for routine open heart surgery. Perfusion 1993; 8: 489–96

12 Thurlow PJ, Doolan L, Sharpe R, et al. Laboratory studies of the effect of Pall extracorporeal filters LG-6 and AV-6 on patients undergoing coronary bypass grafts. Perfusion 1996; 11: 29–37[Medline]

13 Hachida M, Hanayama N, Okamura T, et al. The role of leukocyte depletion in reducing injury to myocardium and lung during cardiopulmonary bypass. ASAIO J 1995; 41: M291–4[Medline]

14 Reeve WG, Ingram SM, Smith DC. Respiratory function after cardiopulmonary bypass: a comparison of bubble and membrane oxygenators. J Cardiothorac Vasc Anesth 1994; 8: 502–8[CrossRef][Medline]

15 Altman DG. How large a sample? In: Gore SM, Altman DG, eds. Statistics in Practice. London: British Medical Journal, 1982; 6–8

16 Sheppard SV. Mechanisms and technical aspects of leucocyte depletion. In: Matheis G, Moritz A, Scholz M, eds. Leukocyte Depletion in Cardiac Surgery and Cardiology. Basel: Karger, 2002; 16–32

17 Pistolesi M, Giuntini C. Assessment of extravascular lung water. Radiol Clin N Am 1978; 16: 551–74[ISI][Medline]

18 Kirklin JK, Westaby S, Blackstone EH, et al. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983; 86: 845–57[Abstract]

19 Wildevuur CRH, van Oeveren W. Blood interactions in extracorporeal circulation: tests to evaluate the activation of proteins and formed blood elements. Life Supp System 1987; 5: 85–91[ISI]





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