J Thorac Cardiovasc Surg 2006;132:675-680
© 2006 The American Association for Thoracic Surgery
Surgery for Congenital Heart Disease |
Failure of surface-modified bypass circuits to improve platelet function during pediatric cardiac surgery
Paul M. Kirshbom, MDa,*,
Bruce E. Miller, MDb,
Kathy Spitzer, CCP, CCTd,
Kirk A. Easley, MS, MApStatc,
Christine E. Spainhour, RN, CCRCe,
Brian E. Kogon, MDa,
Kirk R. Kanter, MDa
a Division of Cardiac Surgery, Emory University School of Medicine, Atlanta, Ga
b Division of Cardiac Anesthesiology, Emory University School of Medicine, Atlanta, Ga
c Department of Biostatistics, Rollins School of Public Health, Emory University School of Medicine, Atlanta, Ga
d Perfusion Services, Children's Healthcare of Atlanta, Atlanta, Ga.
e Cardiac Research Department, Children's Healthcare of Atlanta, Atlanta, Ga.
Presented at the Forty-second Annual Meeting of the Society of Thoracic Surgeons, Chicago, Ill, Jan 30–Feb 1, 2006.
Received for publication March 30, 2006; revisions received May 2, 2006; accepted for publication May 8, 2006.
* Address for reprints: Paul M. Kirshbom, MD, 1365 Clifton Rd, Suite A2100, Emory Clinic A, Atlanta, GA 30322. (Email: paul.kirshbom{at}emoryhealthcare.org).
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Abstract
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OBJECTIVE: Surface-modified cardiopulmonary bypass circuits have been shown to improve platelet function and decrease postoperative bleeding after heart surgery in adults. Two surface-modified cardiopulmonary bypass circuits are approved and commercially available for pediatric cardiac surgery. There have been few studies demonstrating the efficacy of these modifications for children. We performed a prospective, randomized trial comparing surface-modified cardiopulmonary bypass circuits to a standard unmodified circuit in pediatric cardiac surgery.
METHODS: Sixty-nine children (median 6 months old) undergoing first-time cardiac surgery were enrolled and randomized to an uncoated circuit or one of the two commercially available surface modified circuits for their operation. Blood samples were collected at baseline, on cardiopulmonary bypass, at the end of rewarming, after protamine, and at 18 to 24 postoperative hours. Platelet count, ß-thromboglobulin, and thromboelastography with and without abciximab were measured. Postoperative chest tube outputs and blood product utilization were also analyzed.
RESULTS: The platelet counts, ß-thromboglobulin levels, thromboelastographic measures of platelet function, and postoperative bleeding were not significantly different between the surface-modified cardiopulmonary bypass circuit groups and the control group.
CONCLUSION: Currently available surface-modified cardiopulmonary bypass circuits do not significantly improve platelet function or clinical outcomes after routine pediatric cardiac surgery.
Abbreviations and Acronyms ß-TG = ß-thromboglobulin; CPB = cardiopulmonary bypass; SM-CPB = surface-modified cardiopulmonary bypass
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Introduction
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The use of cardiopulmonary bypass (CPB) during cardiac surgery results in damage to both the cellular and humoral components of the coagulation system. This multifactorial process includes platelet activation and protein denaturation at the blood-surface interface, hemodilution, and activation of the fibrinolytic pathways.1,2
Pediatric patients are at particular risk for postoperative coagulopathy because of the increased hemodilution inherent in pediatric CPB, the relatively higher ratio of CPB circuit internal surface area to patient blood volume, and such preexisting patient factors as chronic cyanosis and polycythemia, which are more common in patients with congenital heart disease.
Modification of the blood-contacting surfaces in CPB circuits has been shown to improve platelet number and function,3–5 decrease fibrinolysis,3,5 and decrease the inflammatory response6 after cardiac surgery in adults. There are two surface-modified CPB (SM-CPB) circuits widely available for pediatric patients: the PMEA circuit, which incorporates an amphiphilic polymer coating (poly-2-methoxyethylacrylate) on the blood-contacting surfaces of the tubing and oxygenator (Terumo Corporation, Tokyo, Japan), and the SMART circuit, which includes a combination of phosphorylcholine coating with polycaprolactone-polydimethylsiloxilane additives to the base polymer resin (COBE Cardiovascular, Inc, Arvada, Colo). These SM-CPB circuits have been tested extensively in adult patients, but there are few data available documenting their efficacy for the pediatric patient population. This prospective randomized trial was designed to compare the pediatric PMEA and SMART SM-CPB circuits against a standard unmodified circuit with regard to platelet number, platelet function, and clinical outcome.
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Patients and Methods
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This study was reviewed and approved by the Emory University School of Medicine and Children's Healthcare of Atlanta institutional review boards, with informed consent obtained from the legal guardian of each patient.
From September 2003 to April 2005, a total of 69 patients were enrolled in the study. Inclusion criteria were elective congenital heart surgery requiring CPB and weight between 5 and 10 kg. Exclusion criteria were urgent or emergency surgery, previous heart surgery, documented coagulation disorders, use of anticoagulant or antiplatelet drugs within 48 hours of surgery, and procedures requiring a return to CPB (2 or more CPB runs). The patients were then randomly assigned by drawing sealed envelopes that contained cards for the following groups: control, unmodified pediatric tubing and oxygenator (COBE Cardiovascular); PMEA, poly-2-methoxyethylacrylate coated tubing and oxygenator circuit (Terumo); SMART, phosphorylcholine-coated, polycaprolactone-polydimethylsiloxilane additive tubing and oxygenator circuit (SMARxT Biocompatible Circuit; COBE Cardiovascular).
The same uncoated arterial and venous cannulas were used for all three groups. The patient weight range was selected to allow the use of the pediatric (non-neonatal) circuit and oxygenator from each company. Although the anesthesia and intensive care unit teams were blinded to patient group, it was impossible to fully blind the operating surgeon because of the obvious differences between the circuits with regard to tubing texture and thickness.
Thirty-five patients were screened for the study and considered to be candidates but were not enrolled for the following reasons: parents refused consent (n = 12), logistic issues (insufficient equipment to perform two simultaneous studies or personnel unavailable, n = 11), patient enrolled in a conflicting research study (n = 4), non–English-speaking family with no translator available for consent (n = 3), and surgery added to the schedule late, precluding preparation of randomized circuit (n = 5).
CPB Technique
After routine anesthetic induction and orotracheal intubation, all patients received a bolus of heparin (400 U/kg), with subsequent doses titrated to maintain an activated clotting time longer than 480 seconds during CPB. The CPB pump prime for these circuits was 550 mL and consisted of the following: heparin (2000 units), sodium bicarbonate (25 mEq), albumin (25%, 50 mL), mannitol (1 g/kg), and packed red blood cells calculated to provide an on-pump hematocrit of 30%. The aorta and either the right atrial appendage or both vena cavae were cannulated, depending on the operative procedure. Packed red blood cells were administered during the procedure to maintain a hematocrit at or above 30% during CPB. After weaning from CPB, modified venovenous ultrafiltration was performed for as long as 10 minutes at the discretion of the operating surgeon. After modified ultrafiltration, or after weaning from CPB if ultrafiltration was not used, the heparin was reversed with protamine sulfate (4 mg/kg). The activated clotting time was then checked to confirm a return to baseline. The remaining CPB pump volume was then passed through a cell-washing system and transfused within 2 hours of the patient's arrival at the intensive care unit.
Blood Sample Collection and Assays
Blood samples (7 mL) were drawn at five time points: baseline (after anesthesia induction), on CPB (5 minutes after institution of CPB), end CPB (after complete rewarming but before weaning from CPB), post-CPB (5 minutes after administration of protamine), postoperative day 1 (drawn on the morning after surgery). The samples were divided for the following assays: complete blood cell count (hemoglobin, hematocrit, platelet count), ß-thromboglobulin (ß-TG) level (enzyme-linked immunosorbent assay; Diagnostico Stago, Asnieres, France), and thromboelastography with and without abciximab (Reopro; Centocor, Malvern, Pa), performed for the four intraoperative time points but not on postoperative day 1. Blood samples were drawn from the indwelling arterial line after aspiration of 5 mL to clear the line of heparin and were handled as follows: the sample for CBC was placed in a potassium–ethylenediaminetetraacetic acid tube; the ß-TG sample was placed in an iced citrate, theophylline, adenosine, and dipyridamole tube and centrifuged at 4°C at 2000g for 30 minutes, the plasma supernatant was then frozen at –70°C until analysis; and thromboelastographic assays were run immediately as described in the following section.
Thromboelastography
Thromboelastography without abciximab was performed by mixing 350 µL whole blood with 10 µL 1% tissue factor in preheated disposable cups of a Thromboelastograph Coagulation Analyzer (Haemoscope Corp, Skokie, Ill). Thromboelastography with abciximab was performed by mixing 330 µL whole blood with 10 µL 1% tissue factor, 5 µL abciximab (2 mg/mL), and 20 µL 0.2-mol/L calcium chloride. The thromboelastographic tracing was then begun and allowed to run for at least 60 minutes after the maximum amplitude had been achieved. Two thromboelastographic values were manually measured and recorded by a single blinded author (B.E.M.): maximum amplitude values (the steady-state maximum amplitude of the thromboelastogram in millimeters, a measure of clot strength) and R values (measured from the beginning of the elastographic trace until an amplitude of 2 mm is achieved, a measure of rapidity of clotting). Thromboelastography without abciximab represents the clotting ability of whole blood, including platelet and fibrinogen contributions. When abciximab is added to the reaction mixture, the platelets are inactivated, and the thromboelastographic data is indicative of the fibrinogen contribution to clotting only.
Clinical Data
Intraoperative data collected included the procedure performed, total CPB time, aortic crossclamp time, and lowest temperature during CPB. Postoperative chest tube drainage, blood product use, ventilator time, and hospital stay were also recorded.
Statistical Analysis
The primary analysis of the data was performed according to original treatment assignment (an intention-to-treat analysis). Baseline characteristics were compared between treatment groups with the Kruskal-Wallis test for continuous variables and with the 
2 or Fisher exact test for proportions. Repeated-measures analyses for platelet count, ß-TG (natural log), and thromboelastographic outcomes (maximum amplitude with and without abciximab, R value with and without abciximab, natural log) were analyzed with a means model with SAS Proc Mixed (version 8; SAS Institute, Inc, Cary, NC), providing separate estimates of the means by time on study (baseline, on CPB, end CPB, off CPB, and postoperative day 1) and treatment group. An unstructured variance-covariance form among the repeated measurements was assumed for each outcome, and estimates of the standard errors of parameters were used to perform statistical tests and construct 95% confidence intervals. The model-based means are unbiased with unbalanced and missing data, so long as the missing data are noninformative (missing at random). Statistical tests were 2-sided.
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Results
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Patient demographic data are summarized in Table 1. Although there were no differences between groups with regard to gender distribution, weight, or body surface area, the patients randomly assigned to the control circuit were slightly older than the patients in the PMEA and SMART groups (median 7 [range 3–32] months vs 5 [range 3–17] months and 6 [range 3–20] months, respectively, P = .04). The procedures performed and perioperative data are summarized in Tables 2 and 3.
All patients underwent first-time cardiac surgical procedures typical for children in the 5- to 10-kg weight range, with most undergoing one of four procedures (atrial or ventricular septal defect closure, tetralogy of Fallot repair, or complete atrioventricular canal defect repair). There were no significant differences between groups for any of the perioperative variables, including CPB time, aortic crossclamp time, minimum temperature during CPB, postoperative chest tube drainage, blood product use, time to extubation, and hospital stay.
Platelet Number, Activation, and Function
There were no significant differences between groups with regard to platelet counts or ß-TG levels (Figure 1). Platelet counts decreased dramatically in all groups on initiation of CPB, with comparable levels of recovery by the following day.
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Figure 1. Serial changes in mean platelet counts (A) and mean ß-TG levels (B) through course of study by treatment group. Vertical bars indicate 95% confidence intervals for mean. Model-based means and 95% confidence intervals for ß-TG are reported from back transformation of log values to usual arithmetic scale. POD, Postoperative day.
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Thromboelastographic results are shown in Figures 2 and 3.
There were no significant differences between groups with regard to maximum amplitude (clot strength; Figure 2), but the R value at the off CPB time point without abciximab was significantly lower in the control group than in both the SMART (P = .006) and PMEA (P = .02) groups (Figure 3, A). This would suggest that the entire coagulation system, including platelet function, was able to form clot more rapidly in the control patients than in the study group patients after weaning from CPB.
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Figure 2. Serial changes in mean thromboelastographic results. Maximum amplitude without (A) and with (B) abciximab. Vertical bars indicate 95% confidence intervals for mean. POD, Postoperative day.
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Figure 3. Serial changes in mean thromboelastographic results. R value without (A) and with (B) abciximab. Vertical bars indicate 95% confidence intervals for mean. Model-based means and 95% confidence intervals for R value are reported from back transformation of log values to usual arithmetic scale. POD, Postoperative day.
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Discussion
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The role of the CPB circuit in the development of postoperative morbidity and mortality has been the subject of intensive research since the inception of mechanically assisted cardiac surgery. Progressive advancements in perfusion technology and techniques have played a major role in incrementally improving surgical outcomes. One area of research has been the blood–artificial surface interface within the CPB circuit. The first intensively studied CPB circuit surface modification was the heparin-coated circuit, which was found to decrease complement activation and improve clinical parameters in both children and adults.7–9
Subsequent innovations have included modification of the polymer resin during manufacture, coating the inner surface of the tubing and oxygenators with additives after they have been manufactured, and a combination of these strategies. Two of the SM-CPB circuits that have been tested in the adult population are the PMEA X-coated Circuit (Terumo Corp) and the SMARxT Biocompatible Circuit (COBE Cardiovascular).3–6,10,11 Both these circuits have been shown to decrease complement activation, platelet activation and deposition, and fibrinolysis in adult cardiac surgical patients; however, the clinical significance of these changes has been contradictory. Gu and colleagues10 tested the SMART circuit in a pilot study involving 20 patients randomly assigned to either uncoated or SMART for elective coronary artery bypass grafting. The only difference they found between groups was decreased deposition of platelets within the SMART circuits, and this did not result in any difference between the groups with regard to platelet counts, ß-TG levels, or postoperative bleeding. In a similar study, Sudkamp and colleagues12 evaluated the SMART circuit in 122 patients undergoing coronary artery bypass grafting and found slightly improved platelet function in the SMART group but no difference in platelet counts or postoperative bleeding. Defraigne and colleagues,4 on the other hand, performed a nearly identical study in 100 patients undergoing coronary artery bypass grafting and found that patients in the SMART circuit group had significantly higher platelet counts, lower ß-TG levels, a trend toward decreased postoperative bleeding, and significantly less postoperative use of fresh-frozen plasma and platelet transfusions.
There are very few data concerning the efficacy of these SM-CPB circuits in children, but because the ratio of the internal surface area of the CPB circuit to blood volume is higher in children, one would expect the clinical advantages of these circuits documented in adults to translate to the pediatric population. Unfortunately, the results of this randomized trial do not support this expectation. We found no significant improvements in the SM-CPB circuit groups with regard to platelet counts, ß-TG levels, postoperative bleeding, or blood product use. There were no differences between groups by thromboelastography other than a minor difference in the R value after CPB, which actually favored the control group. It should be noted that this study tested the efficacy of SM-CPB circuits in isolation, a circumstance in which they did not result in any significant improvements in this patient population. These circuits theoretically could, however, provide an incremental improvement if used in conjunction with other modalities, such as the routine use of antifibrinolytic agents, steroids, or modified ultrafiltration. We did not assess different combinations of potential interventions.
These data must be considered in light of the limitations of the study. Despite the randomization protocol, the patients in the control circuit group were slightly older than the study group patients. The effect of this minor age difference is unclear, because the weights of the patients and diagnoses were comparable, but it must be considered. Also, hemodilution had a major impact on platelet counts in this patient population, as would be expected, and this degree of hemodilution could have overwhelmed any improvement resulting from the SM-CPB circuits. However, the fact that the ß-TG levels were the same among groups suggests that platelet activation was comparable among groups, and until commercially available CPB circuits are miniaturized to a greater degree, hemodilution will remain a clinical reality that must be considered in any clinically relevant study for children. Regarding postoperative transfusions, the decision to transfuse was made in collaboration with the intensive care unit team, which was blinded to study group; however, the operating surgeons, who were not entirely blinded, were also involved in the decision to transfuse, so the potential for selection bias did exist. Several other limitations include the limited scope of the platelet functional assays, which may have missed subtle changes in platelet function, and the patient population selected for the study. This study intentionally excluded complex neonatal cases to increase the homogeneity of the patient population and limit diagnosis-related variability as much as possible.
In conclusion, this randomized trial demonstrated no significant advantages for the SM-CPB circuits relative to an uncoated circuit in elective pediatric cardiac surgery. The SM-CPB circuits did not significantly decrease platelet activation, improve platelet function, or improve postoperative outcomes. This study suggests that the advantages of SM-CPB circuits demonstrated in the adult population may not translate to the pediatric population.
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References
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- Edmunds LJ. Blood-surface interaction during cardiopulmonary bypass. J Cardiol Surg 1993;8:404-410.
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Abstract
Introduction
