© Borgis - New Medicine 1/2003, s. 16-22
Leszek Bęc, Maciej A. Karolczak
Prime leukocyte filtration combined with conventional ultrafiltration in paediatric cardiopulmonary bypass
2nd Department of Cardiac and General Paediatric Surgery, University Medical School of Warsaw
Head of Department: Prof. Maciej A. Karolczak
Background. Cardiopulmonary bypass (CPB) results in development of a systemic inflamatory response. Preventing ”post-pump” syndrome during surgery improves the postoperative recovery of patients. We sought to compare conventional ultrafiltration (CUF) and prime leukocyte filtration in paediatric patients operated on for congenital heart defects using CPB.
Methods. 40 paediatric patients were divided into three groups: prime leukocyte filtration (n=10), prime leukocyte filtration combined with conventional ultrafiltration (n=10), and a control group (n=20) with no filtration or CUF used. The arterial blood samples were obtained after induction of anaesthesia, after commencing CPB, and 1 hour and 24 hours after surgery. The levels of proinflamatory interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNFα) were measured and compared with postoperative findings. The ultrafiltration supernatant was sampled to determine the content of cytokines.
Results. We found no cytokines in the supernatant. The levels of IL-6, IL-8 were significantly higher in the ultrafiltration group compared with leukocyte filtration and control groups. The plasma levels on TNFα were also elevated, with no statistical differences between groups, however. The higher levels of cytokines were associated with increased total blood loss and a higher number of patients with pleural effusions as well.
Conclusion: The machanism of conventional ultrafiltration is not cytokine elimination. High plasma levels of proinflamatory cytokines augment total blood loss and pleural effusions in patients treated with conventional ultrafiltration. The use of leukocyte filters improves renal function, and diminishes the risk of pleural effusions in paediatric patients operated on with the use of a cardiopulmonary bypass.
Cardiopulmonary bypass (CBP) is associated with a risk of development of systemic inflammatory response with increased morbidity and morality, especially in neonates and infants operated on for congenital heart defects. It has been assumed that postoperative treatment of these patients should be focused on minimizing post-perfusion syndrome. The prevention of systemic inflammatory response is well documented by various methods. The rationale of leukocyte filtration is to eliminate leukocytes from the CPB circuit by filters located in various parts of the circuit (arterial, venous, or cardioplegic line). The filters may also be applied to filter the blood used for priming the circuit. Ultrafiltration is the method developed to reduce total body water (TBW) after CPB, by the process of removing excessive plasma water and low molecular weight solutes from the bypass circuit. Conventional ultrafiltration (CUF) is carried on during the rewarding phase of CPB – with a haemofilter located between the venous reservoir and the oxygenator. In the modified (MUF) type the haemofilter is used immediately after CPB and connected to the arterial line.
The aim of this study was to compare leukocyte filtration and conventional ultrafiltration, and their influence on the post-op period in children operated on with the use of CPB. The study was based on the measurement of levels of proinflammatory cytokines: interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor-alpha (TNFα), as well as clinical findings.
Materials and methods
Forty patients aged 7 days-14 years (mean value 31 months) were operated on for various of congenital heart defects in the 2nd Department of Cardiac and General Paediatric Surgery, University Medical School of Warsaw, Poland, between January 1st, 2000 and April 30th, 2001. Fourteen patients were male and twenty-six were female. The spectrum of defects involved atrial septal defect type secundumIpartial anomalous pulmonary vein drainage (ASD2/PAPVD), ventricular septal defect (VSD), atrioventricular septal defect (AVSD), tetralogy of Fallot (F4), right venttricular outflow tract obstruction (RVOTO), pulmonary vein stenosis, and anomalous origin of the right coronary artery from the pulmonary artery (Bland-White-Gerland syndrome, BWG).
The patients were assigned to one of three groups. In 10 patients ((LF) group; simple defects) pre- and post-bypass leukocyte filtration was applied and the whole blood used for priming was filtrated with a leukocyte removal device. In ten patients ((LF + CUF) group; low body weight patients, <5kg, or complex defects) both leukocyte filtration and conventional ultrafiltration were used. The remaining 20 patients were the control group (CTRL) with neither filtration nor ultrafiltration applied.
The extracorporeal circulation was performed using membrane oxygenators (Dideco, Mirandola, Italy) in all patients. The circuit was primed with Ringer acetate (100-500mL), 20% Mannitol (1mg/kg), 5% Albumin (100-200mL), 20% Albumin (100 ml), 8.4% sodium bicarbonate (20-40 mL) and heparin (1 mg/kg). The fresh (max. 72hr. old) blood used for priming (520 ml) was in groups (LF) and (LF + CUF) delivered to the circuit throught a high efficiency rapid-flow leukocyte removal filter (Purecell RC 400. Pall, Newquay, Cornwall, UK).
The anaesthesia was induced by Thiopenthal sodium and Pipecuronium bromide, and maintained with Fentanyl citrate, Izofluran and Pipecuronium bromide. The heparin (Heparium natricum, Polfa, Warsaw, Poland) at a dose of 3 mg/kg was given, and after achieving an activated clotting time of 400 seconds, the cardio-pulmonary bypass was commenced. The aorta was clamped and antegrade cold crystalloid cardioplegic solution (ST. Thomas) at a dose 20 ml/kg was administered. In the rewarming phase of CPB in the (LF + CUF) group, conventional filtration was performed with the use of a FH 22H Fiber Haemofilter (Gambro, Hechingen, Germany). After the CPB, Protamine sulfphate was applied to neutralize heparin. All procedures were performed by one surgeon (M.A.K.) employing the technique of bicaval cannulation, in moderate (27-32°C) hypothermia. The perfusion started at 2.8 l/min/m2 and was reduced to 1.9 l/min/m2 at 27°C.
All patients´ parents gave written informed consent participation in this study.
At various times, several samples (3 ml) of blood were collected from the arterial line of each patient. A baseline sample was obtained immediately after induction of anaesthesia. Sampling was also performed immediately after commencing cardiopulmonary bypass, and 1 hour and 24 hours after the end of CPB. An additional sample was obtained from ultrafiltration fluid (supernant). The samples were centrifuged at 2000g and plasma stored at -70°C until immunoassay. IL-6, IL-8 and TNFα were measured using commercially – available enzyme amplified sensitivity immunoassay kits (EASIA, Biosource Europe S.A., Nivelles, Belgium) according to the manufacturer´s instructions.
Data are presented as mean ą standard deviation. A significant difference between measurements was defined as p<0.5. To compare the dynamics of changes of IL-6, IL-8 and TNFα, Fridman´s ANOVA test was used white for comparing plasma levels of cytokines between groups, the Kruskal-Wallis ANOVA was used. The postoperative findings in the three groups of patients (diuresis, total blood loss) were investigated with one-way ANOVA.
A total of 40 patients underwent cardiopulmonary bypass. There were no early postoperative deaths any group. Mean cardiopulmmonary bypass and aortic cross clamp ing (aoCC) times were 68.7ą27.61 min (range: 26-139 min) and 38.82ą21.32 min (range: 7-92min), respectively. There was a statistically significant difference in CPB and AoCC times only between (CTRL) and (LF+CUF) groups (tab. 1).
Table 1. Clinical Findings in patients operated on with the use of cardiopulmonary bypass.
|Group||(CTRL) group||(LF) group||(LF+CUF)|
|Mean body weight (kg)||15.07 ? 13.14||8.74 ? 5.97||6.83 ? 5.39|
|CPB mean time min||60.35 ? 29.23||71.5 ? 34.98||89.4 ? 15.68*|
|Mean aortic cross-clamping time (min)||28.05 ? 0.88||35 ? 20||47.3 ? 17.96*|
* statistically significant (p < 0.05) when compared to CTRL group.
Cytokines: Plasma interleukin 6 was detectable preoperatively in none of the groups of patients. It was also not detectable 5 minutes after CPB commenced. In all groups, plasma levels were increased over 200pg/ml 1 hr after the end of cardiopulmonary bypass, and remained elevated 24 hours after surgery. There was, however, one significant difference: levels of IL-6 in the (LF+CUF) group were almost 2-fold higher than in groups without ultrafiltration (p<0.5) (Figure 1). Changes in interleukin 8 plasma levels are shown in figure 2. After CPB was established there was a decrease in IL-8 levels in all groups. One hour after CPB IL-8 levels rose, but they were 3 to 4-fold higher in the (LF+CUF)group than in the (LF) group or the (CTRL) group, respectively. They also remained elevated 24 hr after surgery, whereas in groups A and C a tendency to decrease was observed. Similary, plasma TNFα levels were decreased after the CPB was commenced. There was a significant release of tumour necrosis factor-alpha within 1 hr after the end of cardiopulmonary bypass in all groups (p<0.5). There were no statistically significant differences in TNFα plasma levels between groups. The levels still remained elevated in the (LF+CUF) group after 24 hours but with no statistical significance between groups (Figure 3).
Fig. 1. IL-6 plasma levels. Almost 2-fold increase in IL-6 levels 1hr and 24hr after CPB in (LF+CUF) patients when compared to groups without CUF.
* p<0.05 when compared to remaining groups
Fig. 2. Changes in IL-8 plasma levels during CPB. Interleukin-8 levels in group with CUF used are significantly elevated 1 hr and 24 hr after CPB when compared to remaining groups.
* p<0.05 when compared to remaining groups
Fig. 3. Dynamics of TNFα is significantly elevated 1 hr and 24 hr after surgery. There are no statistically significant differences between groups.
Supernatant: We have not found interleukin-6, interleukin-8 or tumour necrosis factor-α in the ultrafiltration fluid (supernatant).
Clinical findings: The mean time of mechanical ventilation was 22.52ą31.2; 99.1ą94.6 hours in groups (CTRL), (LF), (LF+CUF), respectively. Significant differences were observed between the (LF+CUF) and (CTRL) groups and between the (LF+CUF) and (LF) groups. In comparing these data, one patient from the (CTRL) group with subglottial stenosis (requiring tracheostomy) was excluded. The total blood loss (substernal drainage) differed between (LF+CUF) and remaining groups; the highest mean values were noted in the group with both leukocyte filtration and conventional ultrafiltration. Diuresis in the first 24 hours after surgery was the highest in the (LF) group (51.57ą23.14 ml/kg/24 h; statistically significant when compared to the (CTRL) group). It was, however, suprisingly high in the (LF+CUF) group but with no statistical significance when compared to (CTRL). The lowest rate was found in the (CTRL) group. Pleural effusions needing surgical intervention were found in 15 patients, with 9 (45%), 4 (40%) and 2 (20%) patients in (CTRL), (LF+CUF) and (LF) groups, respectively (tab. 2). Exudation to the pericardial sac was foud in three patients (2 in [CTRL] and 1 in [LF+CUF] group). They were treated with drainage (n=1), non-steroid anti-inflammatory drugs (n=1), and steroids (n=1; patient operated on for BWG syndrome; Encorton 1mg/kg).
Table 2. Postoperative findings by group.
| ||CTRL group||LF group||LF+CUF group|
|Mechanical ventilation (h)||22.52 ? 15.9||30.88 ? 31.2||99.1 ? 94.6|
|Total postoperative blood loss (ml/kg)||14.65 ? 7.03||15.79 ? 9.18||28.08 ? 21.08|
|Mean diuresis (ml/kg/24 h)||34.48 ? 11.57||51.57 ? 23.14||40.25 ? 14.49|
|Patients with pleural effusions (%)||45%||20%||40%|
Data are expressed as mean ą standard deviation. P<0.05 was considered statistically significant.
Leukocyte filtration is a well-known method used to minimize post-pump syndrome. The elimination of neutrophils improves many postoperative parameters in patients after open heart surgery. Most trials, however are carried out on adult patients (1-4), and little is known about children (5, 6). Ultrafiltration (UF) (conventional as well as modified) is still on area of clinical studies. Many surgeons prefer only one type of UF or join them both (combined UF). We have found no study concerning a combination of leukocyte filtration and conventional ultrafiltration in paediatric patients operated on with the use of a cardiopulmonary bypass.
Interleukin-6 is synthesized in many types of cells: monocytes, macrophages, lymphocytes, endothienal cells, keratinocytes and smooth muscle cells (7, 8). It results in leukocytosis, fever, impaired nitrogen metabolism, higher endothelial permeability and acute phase protein synthesis in the liver (7, 9) we observed non-measurable IL-6 plasma levels at the start of surgery and a significant rise to 255 pg/ml and to 230 pg/ml 1hour after surgery in (CTRL) and (LF) groups, respectively. It was probably caused by comparable surgical trauma (simple heart defects). The leukocyte filtration had no influence on IL-6 plasma levels as filters do not stop cytokines (1). It is known, however, that IL-6 synthesis depends on CPB duration (10, 11); higher IL-6 levels should therefore be detectable in the (LF) group. The lack of a difference between these groups suggests only a minimal influence of perfusion time on IL-6 levels. The highest IL-6 plasma levels were found in (LF+CUF) with 400 pg/ml and 200 pg/ml 1hour and 24 hours after surgery, respectively. They were almost two-fold higher when compared to the remaining two groups. This finding is inconsistent with previous studies where cytokine (TNFα, IL-6, IL-8) filtration during UF was found (12). Gaynor suggests that conventional ultrafiltration is closely related to proinflammatory mediators removal (13).
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