Contemporary practice of cardiac surgery encounters

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1 Effects of Combined Conventional and Modified Ultrafiltration in Adult Patients Ugursay Kiziltepe, MD, Adnan Uysalel, MD, Tumer Corapcioglu, MD, Klara Dalva, MD, Hamdi Akan, MD, and Hakki Akalin, MD Department of Cardiovascular Surgery, School of Medicine University of Ankara, Turkey, and Department of Hematology, School of Medicine University of Ankara, Ankara, Turkey Background. Modified ultrafiltration (MUF) improves hemodynamics and postoperative recovery in children. Ultrafiltration (UF) may have similar benefits in adults. The purpose of this study was to investigate the effects of UF in adult patients. Methods. A total of 40 adult patients undergoing cardiac surgery were randomized into a study group of conventional UF during bypass venovenous MUF after bypass and a control group with no UF. Perioperative clinical variables, cytokines, and endothelin-1 levels were compared between groups. Results. There was no mortality in either group. The patients in the study group had a greater rise in hematocrit (5.7% 2.4% vs 1.2% 1.9%, p < 0.001), hemoglobin ( mg/ml vs mg/ml, p < ), and platelet levels (27,800 29,200 vs 9, , p < 0.001). Mean arterial blood pressure and CI increased after MUF (from mm Hg to mm Hg, p 0.05, and from to , p < 0.03, respectively). Postoperative oxygenation was better in the study group (alveolo-arterial PO 2 tension gradient mm Hg vs mm Hg, p 0.03). Ultrafiltration reduced postoperative bleeding ( ml vs ml, p < 0.003). Conclusions. A combination of conventional and modified UF is effective and safe in adult patients undergoing cardiac surgery. Ultrafiltration improved hemodynamics, hemostatic, and pulmonary functions. We recommend the use of combined UF in high-risk adult patients. (Ann Thorac Surg 2001;71:684 93) 2001 by The Society of Thoracic Surgeons Contemporary practice of cardiac surgery encounters an increasing number of patients who are both older and sicker than previously. Patients with certain risk factors have had higher mortality and morbidity following open heart surgery. Undesirable effects of cardiopulmonary bypass (CPB) may contribute to this increased risk. Cardiopulmonary bypass produces a whole body inflammatory response characterized with capillary leak and increased body water, which is most pronounced in children. The development of edema may cause dysfunction of vital organ systems and significant morbidity [1]. Cytokines and other inflammatory mediators contribute to the evolution of reperfusion injury, myocardial dysfunction, and ischemia [2 4]. Modified ultrafiltration (MUF), first described by Naik and colleagues [5], reduces total body water and improves postoperative recovery in children after open heart surgery [5 9]. These effects could be attributable to the removal of the inflammatory mediators with modified ultrafiltration (MUF) [10 13]. We believe that there may be theoretical benefits of MUF in selected adults. Ultrafiltration may improve myocardial, pulmonary, and other organ functions and may reduce morbid complications such as perioperative Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31 Feb 2, Address reprint requests to Dr Kiziltepe, Sokollu Cad. Nakis Sok. 8/14 Dikmen, Ankara, Turkey; uk9316@hotmail.com. myocardial infarction, adult respiratory distress syndrome, and low cardiac output syndrome after MUF in adult patients at risk. The goal of this study was to investigate the potential benefits and safety of UF in high-risk adult cardiac surgery patients. Material and Methods Patient Population and Selection Criteria From February 1999 to July 1999, 40 adult patients undergoing open heart surgery were prospectively randomized to a study group (n 20) with UF and a control group (n 20) without UF. The two groups were comparable with regard to sex, age, body weight, risk factors, and other demographic variables (Table 1). The study was approved by the institutional review board and informed consent was obtained from each patient. Patients were selected according to following risk factors for mortality [14] for the study group and control group, respectively: age greater than 70 years (5 patients in study group and 2 in control group), female gender (7 and 6), chronic renal failure (1 patient in study group), extracardiac arteriopathy (1 vs 2), chronic obstructive lung disease (8 and 7), severe neurologic dysfunction (1 patient in control group), previous cardiac surgery (3 and 1), recent myocardial infarction or unstable angina (6 and 7), left ventricular ejection fraction (EF) of less than 35% or chronic congestive cardiac failure (9 and 8), pulmonary 2001 by The Society of Thoracic Surgeons /01/$20.00 Published by Elsevier Science Inc PII S (00)

2 Ann Thorac Surg KIZILTEPE ET AL 2001;71: MODIFIED ULTRAFILTRATION IN ADULTS 685 Table 1. Demographic Analysis and Preoperative Diagnoses Study (n 20) Control (n 20) p Value Age (y) (27 78) (44 77) NS a Sex (female:male) 7:13 6:14 NS b Weight (kg) NS a Ejection fraction (%) (25 58) (32 52) NS a Diagnosis Coronary artery disease NS b Valvular heart disease 5 5 NS b Prosthetic valve dysfunctions 3 1 NS b a Student s t test; b 2 test. hypertension (4 and 2), and procedure urgency and critical preoperative condition (4 and 5). Patients with normal ventricular function who were on immunomodulatory medications such as steroids or aprotinin were excluded from the study. Operative Techniques Fentanyl, etomidate, pancuronium, and isoflurane were used for anesthesia induction and maintainance. Arterial, central venous, and pulmonary artery pressures in addition to rectal temperature and urine output were monitored throughout the operation. All patients were operated through a standard midline sternotomy and no minimally invasive technique was used. The pump circuit consisted of a Sorin Monolyth oxygenator with a 40- m arterial line filter (Sorin Biomedica, Saluggia, Italy) and a roller pump (Pemco Inc, Cleveland, OH). The circuit was primed with Ringer s lactate and packed blood cells were added to the pump circuit if the estimated hematocrit was less than 20%. After commencement of the CPB, patients were cooled down to 28 to 32 C. Myocardial protection was achieved by means of antegrade or retrograde cold (4 C) crystalloid cardioplegia (Plegisol, Abbott Laboratories, Chicago, IL). Ice slush was used for topical cooling. Internal mammary artery and individual saphenous vein grafts were used for CABG. None of the patients received aprotinin, steroids, or drugs that could effect the inflammatory response during perioperative period. Perfusion and Ultrafiltration Techniques The flow rate and blood pressure were kept at 2 L/min and 50 to 80 mm Hg during CPB. Conventional UF (CUF) and MUF were combined in the study group, whereas standard CPB without UF was used in the controls. The venovenous technique was elected for MUF. A special 0.25-inch tubing set (Bıcakcılar AS, Ankara, Turkey) and a hemofilter (Diafilter D30-NR, Minntech Corporation, Minneapolis, MN) were used for MUF. Both the inlet and outlet of the filter were connected to two bifurcating tubings to use each arm for either CUF or venovenous modified ultrafiltration (VVMUF) without disconnecting and reconnecting the tubings during transition from CUF to VVMUF (Fig 1A and 1B). One arm of the tubing to the inlet of the hemofilter was connected to arterial line, whereas the other arm was given to the operative field and secured until commencing VVMUF. Likewise, the tips of the tubing from outlet of the filter were connected to the venous reservoir and to a large bore (8.5F) internal jugular introducer catheter. The CUF was conducted during the rewarming phase and whenever the level in the reservoir reached the maximum. During CUF, the inlet from the arterial line and the outlet to the reservoir was kept open, whereas the other arms of the tubings were clamped. To maintain the blood level in the reservoir during CUF, Ringer s lactate was added to the reservoir if the level is too low. After termination of CPB and achievement of a hemodynamically stable condition, VVMUF was started. The venous cannula (or cannulae) was removed, whereas the free end of the inlet tubing itself or a sump catheter was inserted through right atrial appendage down to the inferior vena cava. Protamine was not started until the completion of VVMUF. To convert the circuit from CUF to VVMUF, the two clamps were simply transferred to the other arm of each tubing (Fig 1). During VVMUF a roller pump was placed to the inlet side and used to run blood through the filter with a flow rate of 300 to 400 ml/min. Prefilter and postfilter pressures of circuit were monitored during the procedure. To increase the amount of ultrafiltrate, suction (200 mm Hg) was applied to the ultrafiltrate port. The target volume for ultrafiltrate removal was between 1200 and 1800 ml depending on the priming volume. The arterial line was used to transfuse contents from the reservoir when volume replacement was needed. When the level in the reservoir was too low, crystalloid was added to keep it primed until all of the blood in the tubings was transfused. Postoperative Care Intensive care unit (ICU) monitoring was standard for adult patients. The ICU staff members were blinded to patients groups. All patients received renal-dose dopamine infusion (2 to 4 g kg 1 min 1 ) during ICU stay. It was standard for patients without complications to be kept in ICU for at least 2 days and in the ward for 4 to 5 days. Clinical Variables Demographic variables of both groups were compared. Pre-, intra-, and postoperative variables were compared

3 686 KIZILTEPE ET AL Ann Thorac Surg MODIFIED ULTRAFILTRATION IN ADULTS 2001;71: Fig 1. (A) Schematic description of pump and ultrafiltration circuit during conventional hemofiltration. (B) Schematic description of pump and ultrafiltration circuit during venovenous modified ultrafiltration. (CUF conventional ultrafiltration; VVMUF venovenous modified ultrafiltration.) between groups. Hemodynamic measurements were made through a Swan-ganz thermodilution catheter and were obtained after anesthesia induction (designated T1), after termination of CPB (T2, before MUF), and after completion of VVMUF in study patients or 30 minutes after termination of CPB in controls (T3, after MUF), during skin closure, at hours 1, 6, 12, 18, and 24 postoperatively. Between T2 and T3, emphasis was given to not changing the amount of inotropic support so as to keep its effects on hemodynamic measurements unchanged. Hematologic measurements including hematocrit and hemoglobin levels as well as leukocyte and platelet counts were determined at T1, T2, and T3 for both groups The total amount of inotropic support in postoperative period compared between groups. For this purpose, a total drug dose for the first 24 hours was calculated by adding the doses of dopamine and dobutamine (in micrograms per kilogram per minute) and assigning an arbitrary equivalent value of 10 g inotropic drugs per kilogram per minute for each 0.1 g of epinephrine per kilogram per minute [15]. Alveolo-arterial PO 2 gradient (A-a PO 2 ) and alveoloarterial PO 2 ratio (a/a PO 2 ) were calculated according to alveolar gas equation based on arterial blood gas analysis at postoperative hour 6. Inflammatory Mediator Measurements Interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin10 (IL-10), and endothelin-1 (ET-1) levels were measured. Arterial blood samples were drawn at T1, T2, T3, and at hours 2 and 24 after the operation. In addition, during CUF and VVMUF, hemofiltrate (for CUF) and ultrafiltrate (for VVMUF) samples were obtained. Blood samples were collected in sterile vacuum tubes containing EDTA and were centrifuged at 5,000 rpm for 15 minutes at 4 C to obtain an aliquot of plasma to store at 72 C until the assays were performed (ie, within 1 month). The IL-6, IL-8, and IL-10 (PharMingen, OptEIA, San Diego, CA) levels were measured with commercially available ELISA test kits with detection sensitivities of 4 pg/ml, 0.8 pg/ml, and 4 pg/ml, respectively. The ET-1 measurements were also performed with a commercially available ELISA test kit (Biomedica, Vienna, Austria) with a detection sensitivity of 0.05 fmol/ml. Statistical Analysis Results were summarized as mean standard deviation (SD). A p value of less than 0.05 was considered significant. When comparing the repeated measurements, differences of sequential values for each group were com-

4 Ann Thorac Surg KIZILTEPE ET AL 2001;71: MODIFIED ULTRAFILTRATION IN ADULTS 687 Table 2. Operative Variables and Pump Filtration Data Study (n 20) Control (n 20) p Value Operative procedure CABG NS a MVR 1 1 NS a AVR 0 3 NS a Redo MVR 3 1 NS a MVR TVR 1 0 NS a No. of anastomoses NS b Crossclamp times (min) NS c CBP time (min) NS c Amount of blood in prime (ml) NS c Pump prime (ml) NS c Amount of fluid removed with CUF ml... ( ml/kg) Amount of fluid removed with VVMUF mL ( ml/kg) Prefilter pressure (mm Hg) Post-filter pressure (mm Hg) Duration of VVMUF (min) Intraoperative urine output ml ml NS d ( ml/kg) ( ml/kg) NS d a 2 test; b Student s test; c t test for equality of means; d Mann-Whitney U Wilcoxon rank sum W test. AVR aortic valve replacement; CABG coronary artery bypass grafting; CPB cardiopulmonary bypass; CUF conventional ultrafiltration; MVR mitral valve replacement; TVR tricuspid valve replacement; VVMUF venovenous modified ultrafiltration. pared instead of values for each time point. Differences of the levels of inflammatory mediators between time points were analyzed as percent changes. The Wilcoxon matched pairs signed rank test was used for comparison of two consecutive measurements in same group, whereas the Mann-Whitney U Wilcoxon rank sum W test was used for comparison of the intergroup differences of two consecutive measurements. Continuous variables were evaluated by the Student t and Mann- Whitney U test where applicable. Differences between groups for discrete variables were evaluated by 2 and Fisher s exact test where applicable. All analyses were made using the SPSS statistical program (SPSS Inc, Chicago, IL). Results Both groups were well matched for age, sex, weight, functional capacity, and EF distribution (Table 1). The study group tended to have more patients with nonstructural dysfunction for valve reoperations (3:17 vs 1:19) and patients with poorer LV functions (EF, 25% or less), but the differences were not statistically significant. Otherwise preoperative diagnoses, number of patients with coronary artery disease, distribution of coronary lesions, and risk factors were similar. Intraoperative Variables Surgical procedures, cross-clamp and CPB times, and amount of priming of the circuit were similar in both groups. Data including the amount of fluid removed with CUF and MUF are summarized in Table 2. The study group tended toward slightly lower urine output during the intraoperative period but this failed to reach statistical significance. The pressures of the UF circuit did not reach excessive levels when flow rates up to 400 ml/min were used during VVMUF. The ultrafiltration procedures were completed in minutes. Hematologic Variables In both groups, hematocrit and hemoglobin levels at T2 were significantly lower than at T1 due to hemodilution with CPB (Table 3). In both groups, T3 levels of hemoglobin and hematocrit were elevated compared to those at T2. However the amount of elevation of those levels was significantly higher in the study group (p for hematocrit and p for hemoglobin levels). Similar elevations of leukocyte counts were encountered in both groups. Postbypass levels of platelets were significantly lower than T1 levels. Interestingly, the levels were increased significantly after VVMUF when T2 levels were compared with T3 levels in the study group (p ), whereas they continued to decrease in the control group. The differences in platelet levels for these two time points was significantly different between groups (p ). Hemodynamic Variables Mean arterial pressure (MAP) (p 0.05) and Cardiac Index (CI) (p 0.03) were increased after MUF, whereas Central Venous Pressure (CVP) and Pulmonary Capillary Wedge Pressure (PCWP) levels decreased slightly, suggesting an improvement in myocardial performance (Figs 2 and 3). These values did not change significantly in the control group. Interestingly, CI levels in both groups

5 688 KIZILTEPE ET AL Ann Thorac Surg MODIFIED ULTRAFILTRATION IN ADULTS 2001;71: Table 3. Perioperative Hematologic Measurements Measurement Hematocrit a Hemoglobin a Leukocytes (10 3 ) a Platelets (10 3 ) a Study Control Study Control Study Control Study Control Induction (T1) Pre-MUF (T2) b b b b b b c c Post-MUF (T3) d e d e d a Comparison of changes of levels from T2 to T3 between groups, Mann Whitney U-Wilcoxon Rank Sum W test; hematocrit, p 0.001; hemoglobin, p ; leukocytes, p NS; platelets, p b p T1 compared to T2, Wilcoxon matched-pairs signed-ranks test; c p 0.05 T1 compared to T2, Wilcoxon matched-pairs signed-ranks test; d p T2 compared to T3, Wilcoxon matched-pairs signed-ranks test; e p 0.05 T2 compared to T3, Wilcoxon matched-pairs signed-ranks test. Pre-MUF after termination of CPB and before VVMUF; Post-MUF after completion of VVMUF; other abbreviations as in Table 2. tended to decrease until postoperative hour 6, where CI increased in both groups (p for study and p 0.05 for controls). In the study group, after admission to the ICU, the systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) decreased significantly (p for SVR and p for PVR). Postoperative Variables and Pulmonary Function There was no hospital mortality in either group (Table 4). low cardiac output syndrome was encountered in 4 patients in each group. Although the total amount of inotropic support was higher in the control group, it failed to reach statistical significance. One patient with low cardiac output syndrome in the study group as well as 2 controls with perioperative myocardial infarction and low cardiac output syndrome needed intraaortic balloon counterpulsation support. The amount of urine output in the first 24 hours was similar in both groups. Perioperative myocardial infarction was seen in 2 controls. Transient ischemic changes in ECG without significant creatine kinase MB fraction and troponin I elevations were seen in 1 patient in the study group and in 2 in the control group. One patient from each group was reexplored early in the postoperative period. Total bleeding during the first 24 hours was significantly lower in the study group (p 0.005). Although total homologous blood transfusions were similar, the total amount of fresh frozen plasma transfusion was lower in the study group Fig 2. Hemodynamic measurements: (A) mean arterial pressures; (B) mean pulmonary artery pressures; (C) cardiac index measurements. (*Wilcoxon matched pairs signed ranks test; Mann-Whitney U Wilcoxon rank sum W test.)

6 Ann Thorac Surg KIZILTEPE ET AL 2001;71: MODIFIED ULTRAFILTRATION IN ADULTS 689 Fig 3. Hemodynamic measurements: (A) SVR measurements; (B) PVR measurements; (C) CVP measurements; and (D) PCWP measurements. (*Wilcoxon matched pairs signed ranks test.) (p 0.05). Both the a-a PO 2 gradient and a/a O 2 ratio were lower in the study group (p 0.05 for both). Although the total duration of intubation was lower in study group, it did not reach statistical significance. Time spent in the ICU and postoperative hospital stays were both slightly lower in the study group. Inflammatory Mediator Levels Plasma levels of cytokines and endothelin-1 are summarized in Figure 4. The IL-6 and IL-8 levels showed similar dynamics. The levels of both cytokines in the two groups started to elevate with the commencement of CPB, reached their highest values at postoperative hour 2, and were still high at postoperative hour 24. Although the amount of elevation between the induction and pre-muf IL-6 levels were significantly higher in the study group (p 0.005), higher base line values were noticeable in the control group. There was no decrease in the levels after MUF for both cytokines, and the levels obtained at T3 were higher than those at T2 in both groups. There were no significant intergroup differences in sequential measurements. Both were detected in the ultrafiltrate as well as the hemofiltrate. Higher levels of IL-6 were found in the hemofiltrate than in the ultrafiltrate. In both groups of patients, IL-10 levels reached their highest levels early after coming off of CPB. Because of the higher base line values of the study group, the elevation of levels between T1 and T2 seemed much more prominent in the control group (p ). For the rest of the time, percent differences in these levels with sequential measurements were statistically similar in both groups, although T3 levels were higher than T2 values in the study group and vice versa for the control group. Higher amounts of IL-10 were measured in the hemofiltrate than in the ultrafiltrate. Endothelin-1 levels also did not show significant intergroup differences over time. The peak values were reached just after termination of CPB, and levels decreased very quickly. Endothelin levels were not measured in either the ultrafiltrate or the hemofiltrate. Comment According to a recently published European system for cardiac surgical risk evaluation, the patients with a EuroSCORE of 1 to 2 had a predicted mortality of 0.8%, whereas if the score is more than 6, mortality would be up to 11.2% [14]. In contemporary cardiothoracic surgery practice, older and sicker patients are encountered more frequently than previously, and care of high-risk patients mandates the development of strategies to minimize the harmful effects of cardiac surgery.

7 690 KIZILTEPE ET AL Ann Thorac Surg MODIFIED ULTRAFILTRATION IN ADULTS 2001;71: Table 4. Postoperative Patient Data Characteristic Study (n 20) Control (n 20) p Value Mortality 0 0 NS a Low cardiac output 4 4 NS a syndrome Transient ischemia 1 2 NS a Perioperative 0 2 NS a myocardial infarction Total inotropic NS b support ( g/kg/24 h) Urine output NS b (ml/kg/h) Intraaortic balloon 1 3 NS a pulsation support Total bleeding, first b 24 h (ml) Total blood NS b transfused (ml) Total fresh frozen b plasma transfused (ml) a-a O 2 tension c gradient a/a O 2 ratio c Total intubation NS b time (h) Total intensive care NS b unit stay (days) Total hospital stay (days) NS b a Fisher s exact or 2 test; b Mann-Whitney U Wilcoxon rank sum W test; c t test for equality of means. In addition to surgical trauma, the exposure of the blood to nonhuman surfaces as well as ischemia and reperfusion of the organs, changes in body temperature, and the release of endotoxin all contribute to CPBinduced activations of a series of inflammatory cascades. These reactions may cause various postoperative complications such as respiratory and renal failure, bleeding disorders, liver dysfunction, and (ultimately) multiorgan failure. Although these events have been encountered more frequently in young infants, they may also increase the risk of cardiac surgery for adults at high risk. The production of inflammatory mediators precipitates the development of myocardial ischemia after uncomplicated surgical revascularization and reperfusion injury in addition to fluid accumulation and organ dysfunction [3, 4]. Currently the recommended strategies for decreasing inflammatory reactions includes steroid and aprotinin treatments, depletion of leukocytes, use of colloid-primed and heparin-coated extracorporeal circuits, and MUF for children [1]. Minimally invasive coronary artery bypass grafting without CPB probably can be added to this list [16]. Modified Ultrafiltration Initially the use of MUF was intended to reduce the CPBinduced increase in total body water. However, a series of reports also documented the improvement of myocardial, pulmonary, and hemostatic functions, as well as decreased postoperative bleeding [5 7], reduced postoperative morbidity after cavopulmonary connection [8], and improved cerebral metabolic recovery after circulatory arrest [9]. Modified Ultrafiltration Versus Conventional Ultrafiltration Successful modifications of CUF, such as zero balanced UF [17], have documented its effectiveness on the removal of fluid as well as inflammatory mediators. In their study Journouis and colleagues [17] concluded that the combination of both techniques resulted in better pulmonary function and more effective removal of inflammatory mediators than did MUF alone. Although they were performed in children, several studies have compared the two methods and found that MUF was more effective in reducing weight gain, lessening myocardial edema, and improving LV contractility compared to CUF alone [18]. Although we believe that MUF is more effective than CUF for reducing total body water, we preferred to perform CUF because we have documented the presence of inflammatory mediators in hemofiltrate. Modified Ultrafiltration in Adults When we have reviewed the English language literature we did not encounter detailed reports of the widespread use of MUF in adults. Although inflammatory reactions are not as pronounced in adults as in young infants, we believe that there is a proportion of adult patients at high risk for whom any additional measure to decrease operative risk is not only desirable but mandatory. In particular we believe that elderly patients and as well as patients with renal dysfunction, pulmonary disease, or poor ventricular function could be good candidates for MUF, and that they might benefit from the use of MUF given its efficacy in the pediatric population. Our findings support this hypothesis and document that MUF improves hemodynamic, hemostatic, and pulmonary function after open heart surgery in adult patients at high risk. Although total body water was not measured in this study, significant reversal of hemodilution was demonstrated (Table 3). Interestingly we also noticed the elevation of platelet counts after MUF, which may help to decrease postoperative bleeding. Although chest tube drainage was less in the study group, somehow this is not reflected in the use of homologous blood in the ICU, whereas fresh-frozen plasma transfusions were less in the study group (Table 4). We postulated that this could be related to the increased postoperative bleeding and transfusion needs of 2 patients in the study group. These patients had excessive postoperative bleeding due to an unclipped internal mammary artery side branch, nonneutralized heparin for borderline hemodynamics, and difficulty in weaning from CPB. Our findings also showed improvement in myocardial function, which correlated with increased MAP and CI (Fig 2) as well as decreased filling pressures after MUF (Fig 3). We have also noticed a decrease in size and an increase in contractility of heart visually with ongoing

8 Ann Thorac Surg KIZILTEPE ET AL 2001;71: MODIFIED ULTRAFILTRATION IN ADULTS 691 Fig 4. Inflammatory mediator measurements: (A) IL-6 levels; (B) IL 8 levels; (C) IL 10 levels; (D) endothelin-1 levels. ( Mann-Whitney U Wilcoxon rank sum W test.) MUF. Davies and colleagues [9] documented that MUF improves diastolic compliance in addition to improvement in intrinsic LV systolic function in children. This improvement of compliance may be especially helpful in the case of inadequate relaxation of ischemic myocardium. This may have crucial importance for patients with poor ventricle function as well as ischemic heart disease. Improvement in pulmonary function after MUF in adult patients was also documented along with better A-a PO 2 gradient and a/a PO 2 ratios in the study group, although the decreased intubation times in the study group failed to reach statistical difference. We believe that this may relate to decreased accumulation of fluid in the lungs. Circuit Design Although Elliot and colleagues described arteriovenous MUF [5], we chose to perform MUF in adult patients in a venovenous fashion, as we were familiar with this modification from our early experience with children. Theoretically there should be no reason for the significant differences in the efficiency and safety of the two techniques other than the possibility of cross-circulation with VVMUF. To prevent this we used the inferior vena cava (IVC) blood selectively for the inlet of the filter. One of our concerns with this circuit design was the possibility of elevated pressures in the circuit and resultant blood injury because of the return of the blood to the body through an internal jugular (IJ) catheter. However, this was not the case with flow rates between 300 and 400 ml/min, as the pressures in pre- and postfilter positions were within the physiologic limits. Another concern was the possible intolerance to removal of large amount of fluid from the circulation. This could cause acute hypovolemia, and consequent deterioration of the circulation and kidneys. However, no complication related to hypovolemia was encountered and the average urine output of the two groups was similar, with moderate amounts of removed water ( ml; ml/kg). This volume may seem lower compared with data from studies involving children (51.2 to 138 ml/kg) [6, 11]; however, even with this amount we were able to demonstrate clinically beneficial effects. For future reference, we believe that higher flow rates and higher amounts of removed ultrafiltrate volumes can be achieved safely. Cytokines Their release during CPB may related with ischemiareperfusion, complement activation, endotoxin release, and release of other cytokines [1, 2]. It was reported that the levels of proinflammatory cytokines were correlated with duration of CPB, myocardial ischemia, and the development of multiorgan failure, whereas antiinflammatory cytokines such as IL-10 have a suppressant effect on inflammatory response [1]. It is hypothesized that the

9 692 KIZILTEPE ET AL Ann Thorac Surg MODIFIED ULTRAFILTRATION IN ADULTS 2001;71: beneficial effects of MUF could be attributable to the removal and decreased levels of inflammatory mediators. This issue, however, is still controversial. Although some studies were able to demonstrate decreased levels of circulating cytokines [10] after UF, others were not [11, 12, 13]. Some authors also hypothesized that UF could be removing some mediators, which triggers the production of cytokines [17]. IL-6 is responsible from coordination of acute phase response. The raised levels were found to be associated with myocardial dysfunction after CPB and postoperative ischemic episodes in adults. IL-8 is involved with activation, chemotaxis, and sequestration of neutrophils in the lungs and with pulmonary injury after CPB [1]. We were unable to demonstrate different dynamics of the IL-6 and IL-8 levels between groups. Both were present in the ultrafiltrate and hemofiltrate, with small but similar amounts. In addition, IL-10 has a protective role with suppression of production of proinflammatory cytokines. We could not demonstrate significantly different levels between groups except for induction levels, which were higher in the controls. Small amounts were also found in both the ultrafiltrate and hemofiltrate. Endothelin-1 is released from the endothelium and is the most potent endogenous vasoconstrictor yet known. It is associated with pulmonary hypertension as well as with the regulation of arterial blood pressure. In this study, the peak levels were reached at the end of CPB. The levels showed similar dynamics in both groups. In our opinion, the beneficial clinical effects of combined UF can be attributable to a mechanism other than removal of the inflammatory mediators, as the levels were not lower after UF and did not show different behavior between groups. Contrary to our findings, Journouis and colleagues [17] reported that proinflammatory cytokines, TNF-, IL-1, IL-6, IL-8, and myeloperoxidase were significantly removed by UF; they also noted that complement activation was reduced significantly after CUF, although several other authors have agreed with us [11 13]. Myocardial Ischemia We noticed a higher but statistically insignificant frequency of ischemic episodes in controls than in study patients. As the relationship between cytokines and myocardial ischemia has been demonstrated [3, 4], it may be beneficial in reducing the inflammatory mediators on postoperative myocardial ischemia. Therefore, decreased incidence of ischemia in the study group may be related to removal of cytokines. We believe that this issue can be an important indication for MUF, especially in adult patients with ongoing ischemia. Limitations of the Study In this study, patients were selected according to the risk factors previously mentioned [14] and were randomized into two groups. Even with randomization, slightly higher-risk patients were enrolled in the study group, including 3 patients with nonstructural prosthetic valve dysfunction, 1 of whom needed an emergency reoperation for a stuck mitral prosthesis. Although the mean EF of both groups were similar, some study patients had values as low as 25%, whereas the lowest EF in the control group was 32%. For this heterogeneity of the groups, we elected to compare the differences of sequential measurements between groups instead of comparing the values for each time point. In this study we preferred not to remove larger amounts of fluid with higher flow rates through UF circuit to avoid blood injury and circulatory intolerance. Although we now believe higher flow through the filter and higher amounts of fluid removal can be tolerated, in our opinion future studies are needed to investigate these issues in adult patients. In this study we were able to demonstrate clinical effects of MUF; however, more sophisticated and specific studies are warranted to analyze its effects on those systems in addition to its possible effect on ischemia. We also were not able to perform a multivariate analysis to identify patient subgroups with maximal benefit from MUF because of an inadequate number of patients; future studies should also address to this issue. Another point of interest would be a comparison of VVMUF with arteriovenous MUF; we did not compare these techniques mainly because of time limitations. Our conclusion is that combined conventional and MUF is a safe, effective, and useful technique to improve postoperative recovery in high-risk adult patients undergoing open heart surgery. The authors thank perfusionists Ahmet Kunduroglu, Satilmis Turkmen, Altan Ada, Mustafa Zengin, Bunyamin Alkan, Aydin Kunduroglu, Semra Hopanci, and Ismail Kose for their help in conducting this study. References 1. Wan S, LeClerc J-L. Inflammatory response to cardiopulmonary bypass. Mechanisms involved and possible therapeutic strategies. Chest 1997;112: Kawamura T, Wakusawa R, Okada K, Inada S. Elevation of cytokines during open heart surgery with cardiopulmonary bypass: participation of interleukin 8 and 6 in reperfusion injury. Can J Anaesth 1993;40: Hennein HA, Ebba H, Rodriguez JL, et al. Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg 1994;108: Wan S, LeClerc J-L, Vincent K-L. Cytokine responses to cardiopulmonary bypass: lessons learned from cardiac transplantation. Ann Thorac Surg 1997;63: Naik SK, Knight A, Elliott M. A prospective randomized study of a modified technique of ultrafiltration during pediatric open-heart surgery. Circulation 1991;84(Suppl 3): Davies MJ, Nguyen K, Gaynor JW, Elliott MJ. Modified ultrafiltration improves left ventricular systolic function in infants after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1998;115: Friesen RH, Campbell DN, Clarke DR, Tornabene MA. Modified ultrafiltration attenuates dilutional coagulapathy in pediatric open heart operations. Ann Thorac Surg 1997;64: Koutlas TC, Gaynor JW, Nicolson SC, Steven JM, Wernovsky G, Spray TL. Modified ultrafiltration reduces postoperative morbidity after cavopulmonary connection. Ann Thorac Surg 1997;64:37 43.

10 Ann Thorac Surg KIZILTEPE ET AL 2001;71: MODIFIED ULTRAFILTRATION IN ADULTS Skaryak LA, Kirshbom PM, DiBernardo LR, et al. Modified ultrafiltration improves cerebral metabolic recovery after circulatory arrest. J Thorac Cardiovasc Surg 1995;109: Journois D, Poupard P, Greeley WJ, Mauriat P, Vouhé P, Safran D. Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Anesthesiology 1994;81: Wang MJ, Chiu IS, Hsu CM, et al. Efficacy of ultrafiltration in removing inflammatory mediators during pediatric cardiac operations. Ann Thorac Surg 1996;61: Pearl JM, Manning PB, McNamara JL, Saucier MM, Thomas DW. Effect of modified ultrafiltration on plasma thromboxane B2, leukotriene B4, and endothelin-1 in infants undergoing cardiopulmonary bypass. Ann Thorac Surg 1999;68: Saatvedt K, Lindberg H, Geiran OR, et al. Ultrafiltration after cardiopulmonary bypass in children: effects on hemodynamics, cytokines and complement. Cardiovasc Res 1996;31: Nashef S, Roques F, Michel P, et al. European system for cardiac operative risk evaluation (EuroSCORE), Eur J Cardiothorac Surg 1999;16: Wernovsky G, Wypij D, Jonas RA, et al. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants: a comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 1995; 92: Struber M, Cremer JT, Gohrbandt B, et al. Human cytokine responses to coronary artery bypass grafting with and without CPB. Ann Thorac Surg 1999;68: Journouis D, Israel-Biet D, Pouard P, High-volume, zerobalanced hemofiltration to reduce delayed inflammatory response to CPB in children. Anesthesiology 1996;85: Daggett CW, Lodge AJ, Scarborough JE, Chai PJ, Jaggers J, Ungerleider RM. Modified ultrafiltration versus conventional ultrafiltration: a randomized prospective study in neonatal piglets. J Thorac Cardiovasc Surg 1998; 115: DISCUSSION DR J. WILLIAM GAYNOR (Philadelphia, PA): I would like to congratulate the authors on their excellent study. I thank them for the opportunity to review the manuscript and thank the Society for the opportunity to discuss this paper. Modified ultrafiltration was introduced in the early 1990s at Great Ormond Street by Martin Elliot and colleagues in an attempt to deal with the adverse effects of capillary leak syndrome and increased total body water, which led to organ dysfunction and adverse outcomes in infants undergoing repair of congenital heart defects. These infants are exposed to extremes of hemodilution, hypothermia, and often circulatory arrest. Because of dissatisfaction with the technique of conventional ultrafiltration and the inability to reverse the increase in total body water, the technique of modified ultrafiltration in which ultrafiltration is performed after separation from bypass was introduced. Numerous studies since that time have shown that the use of modified ultrafiltration in these high-risk infants can result in reversal of hemodilution, decreased postoperative bleeding, decreased need for transfusion, and, in some studies, improved hemodynamics. The mechanism by which modified ultrafiltration is beneficial has remained controversial. It clearly reverses hemodilution and decreases the need for blood transfusion. Some studies have suggested that there is a modulation of the inflammatory response to cardiopulmonary bypass by removal of inflammatory mediators. It is most effective in small infants in whom the blood volume is small in relation to the priming volume of the bypass circuit, and has been less effective in older patients in whom there is not this discrepancy. The authors have carefully evaluated the utility of this technique in a randomized group of adults undergoing cardiopulmonary bypass for coronary bypass grafting and valve surgery. The groups were well matched for baseline and operative characteristics. At the time of separation from bypass, however, the controls tended to have higher arterial pressure, increased cardiac index, and decreased filling pressures compared to the patients who would undergo modified ultrafiltration. Thus, although there is an increase in these hemodynamic parameters during modified ultrafiltration, it merely brings the patients up to the same level as the controls. Also, despite the use of conventional ultrafiltration in the study patients, hematocrit and hemoglobin tended to be higher in the control patients. Thus, again, although modified ultrafiltration reversed the hemodilution it merely brought the patients up to the level of the control patients. It is interesting that the authors removed a significantly greater amount of fluid during bypass than after bypass. This is in distinct contradiction to what is usually seen in children in whom there is usually a significant removal of fluid during the modified ultrafiltration after separation from bypass. Thus I would like to ask the authors the following questions: why they think that the hemodynamics tended to be better in the control patients, and the hemoglobin and hematocrit higher, despite the use of conventional ultrafiltration? In addition, how do they think they can modify their techniques: possibly, as they suggested, either by using arteriovenous modified ultrafiltration or by removing greater amounts of fluid to improve the clinical outcome? Although there were measurable benefits in terms of hemodynamics, these unfortunately did not translate into a significantly improved clinical outcome in terms of decreased hospital stay, decreased intensive care unit stay, etc. Thus it remains to be determined: is the technique worthwhile in adults, and is it worth the cost of an additional 15 to 20 minutes in the operating room? I feel that studies such as this should provide the impetus for further studies and that, in selected groups of patients and with modifications of the technique, modified ultrafiltration can be useful in subsets of adult patients and can provide a clear clinical benefit. Again, I would like to congratulate the authors on their study. DR KIZILTEPE: As it can be seen in our slides, we had those patient groups slightly different. There is more heterogeneity in the study group, which is lower ejection fractions and higher patients with older age and patients with more reoperations. Two of those reoperations were done under emergency conditions. Those two patients had structural valve dysfunctions (ie, stuck mitral valves), and they were really in bad shape before the surgery. Although when you look at it overall, there was no big difference between those groups. We accept, even with randomization, that there is slight heterogeneity. This may partly explain the worse hemodynamics in the study group just after coming off bypass. Again, lower hematocrit levels were observed in the study group and could be a reason for that heterogeneity, because those stuck mitral valves and other reoperations showed volume overload before the surgery. We wanted to remove as much volume as during cardiopulmonary bypass to increase the controversial removal of the cytokines. That is why we tried to make as much conventional ultrafiltration, and when we got the reservoir low with the volume we just replaced the volume. So we wanted to remove much more volume during cardiopulmonary bypass, because we believe conventional ultrafiltration also removes some of those cytokines. Thank you very much.