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Interact CardioVasc Thorac Surg 2008;7:75-79. doi:10.1510/icvts.2007.163659 © 2008 European Association of Cardio-Thoracic Surgery
Miniaturized cardiopulmonary bypass system in neonates and small infants
a Department of Cardiovascular Surgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan Received 23 July 2007; received in revised form 26 October 2007; accepted 29 October 2007
*Corresponding author. Tel.: +81-42-778-8111; fax: +81-42-778-9840.
Cardiopulmonary bypass (CPB) in children is associated with a capillary leak due to inflammatory response, which results in an increase in total body water. This study was designed to reveal that our miniaturized CPB system reduced the peri-operative systemic inflammatory response in small infants. In our institution, the priming volume has been reduced from 500 ml to 140 ml currently. Eighty consecutive patients weighing <5 kg were retrospectively reviewed. The postoperative peak C-reactive protein (CRP), body weight gain (%BWG), and the duration of postoperative mechanical ventilation (MVT) data were collected for each patient. Stepwise multiple logistic regression analyses were used to investigate which of the factors most affected the peri-operative inflammatory responses. A priming volume (coefficient: 0.060, P=0.01), most affected the postoperative peak CRP (mg/dl). A combination of priming volume (coefficient: 0.015, P=0.006), and bypass time (coefficient: 0.013, P=0.028), most affected %BWG (%). A combination of priming volume (coefficient: 0.05, P=0.001) and age (coefficient: –0.02, P=0.001) most affected the MVT (days). The miniaturized circuits reduced the peri-operative inflammatory response, resulting in reduced postoperative systemic edema, and postoperative mechanical ventilation time.
Key Words: Miniaturized cardiopulmonary bypass; Inflammatory response; C-reactive protein
Activation of systemic inflammation is a well-known adverse effect of cardiopulmonary bypass (CPB) [1]. Because the contact of blood components with CPB circuits is one of the major causes of inflammation. In neonates and small infants, the surface area of the CPB circuit is proportionately much larger than in adults, relative to the patients' size and blood volume. There is increasing evidence that the conventional extracorporeal circuits, which use large priming volumes, produce deleterious hemodynamic effects and postoperative cardiopulmonary dysfunction [2, 3]. The CPB in children is associated with a capillary leak due to inflammatory response, which results in an increase in total body water (systemic edema) after CPB. The systemic edema also affects patient's postoperative course and systemic morbidity. In our institution, the priming volume has been reduced from 500 ml in the year 2000 to 140 ml currently. This study was designed to reveal that our bypass system reduced the peri-operative systemic inflammatory response in neonates and small infants.
2.1. A miniaturized CPB system Our miniaturized CPB system was reported previously [4]. To achieve a low-priming-volume CPB system, a low-prime oxygenator and reservoir (Priming volume: 40 ml, Baby RX, Terumo Inc., Tokyo, Japan), arterial filters (15 ml, Filtia, JMS Inc., Hiroshima, Japan), and a smaller and shortened extracorporeal circuit were needed. In order to shorten the circuit, the CPB roller pump was placed close enough to the operative field to minimize tubing length. The biocompatible surface coating can reduce the inflammatory response and improve the outcome of cardiac surgery. Poly (2-methoxyethylacrylate) (PMEA) is one of the potential coating materials, and PMEA-coated circuits have already been reported to suppress the inflammatory response in clinical settings [5]. We have introduced the PMEA-coated bypass system to all patients since January 2005. The mean priming volume was 265±79 ml (range 200–500 ml). Blood gas management was performed using the pH-stat strategy. A high flow (150 ml·kg-1·min-1) normal-to-mild hypothermic (32 °C) CPB was used. Crystaloid cardioplegic solution (10 ml/kg) was given every 20 min. After termination of the bypass, modified ultrahemofiltration (MUF) was performed with a polymethylmethacrylate (PMMA) hemofilter in all patients. MUF was started with an ultrafiltration rate of 20 ml·kg-1·min-1 for 10 min. The heparinization was neutralized by protamine sulfate until the activated coagulation time had normalized. Solumedrol (30 mg/kg) was routinely given to all the patients before the bypass. Aprotinin was not used in this study. 2.3. Patients' demographic data From June 2000 to December 2006, in the Kitasato University Hospital, 80 consecutive patients weighing <5 kg, excluding simple ventricular septal defect (VSD) and atrial septal defect (ASD) were retrospectively reviewed. To clarify the influence of a low priming volume bypass system using coated circuits to peri-operative systemic inflammatory response, patients with more complicated procedures should be selected. There were 51 males and 29 females. The types of procedures and comprehensive Aristotle complexity scores [6] are shown in Table 1.
2.4. Study protocol Patients' body weight gain was estimated by measuring the body weight before and after surgery in all patients. The body weight gain was expressed as percentile of body weight (%BWG) in this study. Blood examinations, including C-reactive protein (CRP) [7], white blood cell count (WBC), and platelet count (PLTC) were performed at 0, 12, 24, 48, and 72 h postoperatively for each patient. The %BWG, and postoperative peak CRP (p-CRP) and peak WBC (p-WBC) were obtained as indications of the peri-operative inflammatory responses. The lowest PLTC (min-PLTC) and the duration of postoperative mechanical ventilation (MVT) were obtained as the operative morbidity. The data of sex, body weight, priming volume, biocompatibility of CPB circuits (coated or uncoated), CPB time, the amount of blood transfusion, and the complexity of the procedure (Aristotle Score) were collected for all patients. Since January 2003, we have used the miniaturized bypass system <170 ml for 57 patients. There were 23 patients who used the conventional bypass system (with a priming volume of more than 200 ml). All the modification to the new was introduced at once. Because the new oxygenator itself is coated, circuits were also changed to coated ones. There were no transitional circuits. However, before the introduction of this system, we had gradually reduced the priming volume each year from 2000 when it was 500 ml to 200 ml in 2002 for 23 patients (the conventional group). First, descriptive statistics of the subjects were obtained. Second, univariate analyses were performed between for the miniaturzed bypass group and the conventional bypass group. The p-CRP, p-WBC, %BWG, min-PLTC, and MVT with the other variables were examined. Then, multivariate analysis was performed. The stepwise multiple regression analysis was employed to obtain a set of independent/explanatory variables which best predict the dependent variable (p-CRP, p-WBC, min-PLTC, %BWG, and MVT). Explanatory variables were entered and removed in a stepwise fashion at the significance level of P=0.05, to produce the best predictive model. When the explanatory variables in the final model were significantly correlated with the dependent variable, regression analysis was further pursued dropping those correlated variables, one by one, to check the robustness of the final model to collinearity. All dependent and independent/explanatory variables are listed in Table 2.
2.6. Institutional review board approval The institutional review board approved the utilization of the miniaturized bypass system. Data collection was performed according to the guidelines of the institutional review board.
There were four operative deaths (5.0%), and one hospital death. The mean CPB time was 160±62 min (range 41–360 min). The lowest hematocrit level was 26.0±3.0% (range 17.1–30.8%). Four patients (5.0%, TAPVC repair, AVSD repair, bidirectional Glenn shunt, and double-outlet right ventricle (DORV) repair) underwent transfusion-free procedures. The mean total volume of transfusion was 169±83 ml (range 0–355 ml). The patients' demographic data are shown in Table 3. There were no statistically differences in age, body weight, perfusion time, and Aristotle complexity score between the miniaturized CPB and conventional CPB groups, although there was a tendency that age and body weight of patients in the miniaturized CPB group were greater than those in the conventional group. The priming volume and blood transfusion in the conventional group were significantly greater than those in the miniaturized group (265±79 vs. 155±15 ml, P<0.00001, and 200±93 vs. 156±76 ml, P<0.05, respectively).
The p-CRP, %BWG, and MVT in patients with the conventional bypass system were significantly greater than those in patients with the miniaturized bypass system (Table 4). (P<0.01). There were no differences in p-WBC and min-PLTC between the two groups (Table 4).
These are the results of the evolution of our efforts to decrease the priming volume. The volume of blood transfused to patients with the conventional CPB was significantly greater than that with the miniaturized CPB. Therefore, to eliminate these biases, stepwise multiple logistic regression analyses were needed to investigate which of the factors most affected the peri-operative inflammatory responses and operative morbidity. 3.2. Multiple regression analysis Multiple regression analyses results are shown in Table 5. The priming volume best predicts p-CRP. One unit change in priming volume (ml) increases the p-CRP (mg/dl) by the amount indicated by their corresponding coefficient values. A combination of priming volume and CPB time best predicts %BWG. These variables were all positively associated with %BWG (again, increase in priming volume (ml) and CPB time (min) by one unit is likely to increase body weight percentage by the amount equal to their regression coefficients). The p-WBC was best predicted by the coated circuit use and Aristotle score. A combination of CPB time and body weight best predicts min-PLTC. Finally, a combination of priming volume and age best predicts the postoperative MVT. One unit change in these variables increases (priming volume) or decreases (age) the MVT by the amount indicated by their corresponding coefficient values.
4.1. Miniaturized circuits It is well-known that the contact of blood components with CPB circuits is one of the major causes of inflammation [1]. There is increasing evidence that conventional extracorporeal circuits, which utilize large, priming volumes, produce deleterious hemodynamic effects and postoperative cardiopulmonary dysfunction [8]. The reduction of priming volume can improve postoperative hemodynamics [9]. Wabeke et al. [3] used vacuum-assisted venous drainage in a rabbit model of CPB and showed that the use of a smaller priming volume (90 vs. 330 ml) normalized resistance in the peripheral microcirculation. In this study, the priming volume most affected the postoperative peak CRP. The reduction of priming volume decreased postoperative inflammatory response in neonates and small infants. In our study, priming volume and CPB time most accurately predict body weight gain (systemic edema). The miniaturized bypass system and shorter bypass time reduce systemic edema caused by a capillary leak due to inflammatory response, resulting in reduction of the postoperative MVT. 4.2. Biocompatible PMEA coated circuits The CPB, through the exposure of blood to foreign surfaces as well as ischemia-reperfusion events that occur in specific tissue beds, results in an activation of the systemic inflammatory response [7]. The hyperinflammatory state is an important contributor to post-CPB organ dysfunction in neonates and small infants [4, 10]. Heparin-coated circuits, and more recently PMEA coating [7], may attenuate inflammation after infant CPB. Jensen et al. [10] showed that the use of a heparin-coated perfusion system reduced fibrinolytic activity after bypass in a prospective randomized trial of 40 children. A similar reduction in CRP and complement levels with PMEA-coated circuits was demonstrated by Ueyama et al. [11] in a prospective randomized study comparing heparin-coated, PMEA-coated, and conventional circuits. In the present study, PMEA-coated circuits themselves did not affect the postoperative peak CRP. Multivariate analyses showed that only the priming volume predicts the peak CRP. The reduced priming volume affected the postoperative inflammatory response more than PMEA coating use in the present study.Boning et al. reported that a smaller priming volume resulted in a higher platelet count [12]. Ninomiya et al. reported the PLTC was most affected by PMEA coating in a prospective randomized study comparing PMEA-coated and conventional circuits [5]. However, Kirshbom et al. recently reported that the surface-modified bypass circuits, including the PMEA- and SMART-coated circuits, did not significantly improve PLTC and function or clinical outcome in pediatric cardiac circuit affected peri-operative minimal PLTC [13]. Although comparing the advantages and disadvantages of the PMEA-coated circuits with the heparin-coated circuits requires further study, the price of the PMEA-coated circuits is the same as that of the uncoated circuits and is 33% lower than that of the heparin-coated circuits supplied by the same company (Terumo Inc., Tokyo, Japan). We performed MUF at the rate of 20 ml·kg-1·min-1 for 10 min in all patients. Intraoperative ultrafiltration has been reported to reduce the rise in total body water after CPB in pediatric patients and to reduce the duration of mechanical ventilation [14]. Modified ultrafiltration has the advantage of filtering only the patient's extracellular blood volume, resulting in greater hemoconcentration efficacy and a more rapid recovery of ventricular function [15]. The efficiency of filtration might have improved due to the reduced priming volume. This further resulted in the reduction of inflammatory responses and less body weight gain. The present study is a retrospective study, and the number of patients was small (n=80). Nevertheless, stepwise multiple regression analyses showed definitive results. During the past six years of this study periods, the perfusion strategy and postoperative care were unchanged; however, surgical techniques and procedures have improved year by year. The most important changes were the reduced priming volume and biocompatible, coated circuits. This evidence suggests that a more detailed prospective randomized study is warranted.
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Abstract
1. Introduction
