Thore Pedersen

Intraaortic Balloon Pump in Open Heart Operations: 10-Year Follow-up With Risk Analysis

BACKGROUND The intraaortic balloon pump (IABP) is the primary mechanical device used for perioperative cardiac failure. METHODS We analyzed the prognostic predictors and long-term survival of 344 patients undergoing cardiac operations who required the perioperative use of an IABP at our institution from January 1980 to December 1989. Hospital survivors (163 patients) were followed up for a mean of 7.45 years (range, 1 month to 15.3 years); cumulative follow-up included 1,167 patient-years. RESULTS The early mortality rate was 52.6% (181 patients). From parameters available at the time of IABP insertion, logistic regression analysis identified preoperative serum creatinine level, left ventricular ejection fraction, perioperative myocardial infarction, timing of IABP insertion, and indication for operation as independent predictors of early (30-day) death (p < 0.05). Cox regression analysis of hospital survivors identified timing of IABP insertion, perfusion time, and preoperative serum creatinine level as independent prognostic factors for late death (p < 0.05), whereas patient age was only marginally significant (p < 0.06). There was no association between IABP-related complications and death. Survival analysis demonstrated a 10-year actual survival rate of 22.04% +/- 0.023%, with 57 patients still at risk and significantly improved survival among those who received an IABP before operation (p < 0.02). CONCLUSIONS The early mortality rate in patients who received an IABP was high. Hospital survivors had a relatively good long-term prognosis. The significantly better short- and long-term survival of patients who received an IABP before operation may justify more liberal preoperative use of the IABP in high-risk patients.

Clinical evaluation of duraflo II heparin treated extracorporeal circulation circuits (2nd version): The European working group on heparin coated extracorporeal circulation circuits

OBJECTIVES To evaluate whether the application of heparin treated circuits for elective coronary artery surgery improves postoperative recovery, a European multicenter randomised clinical trial was carried out. METHODS In 11 European heart centers, 805 low-risk patients underwent cardiopulmonary bypass (CPB) with either an untreated circuit (n = 407) or an identical but heparin treated circuit (n = 398, Duraflo II). RESULTS Significant differences were found among participating centers with respect to patient characteristics, blood handling procedures and postoperative care. The use of heparin treated circuits revealed no overall changes in blood loss, blood use, time on ventilator, occurrence of adverse events, morbidity, mortality, and intensive care stay. These results did not change after adjustment for centers and (other) prognostic factors as analysed with logistic regression. In both groups no clinical or technical (patient or device related) side effects were reported. Because female gender and aortic cross clamp time appeared as prognostic factors in the logistic regression analysis, a subgroup analysis with these variables was performed. In a subpopulation of females (n = 99), those receiving heparin treated circuits needed less blood products, had a lower incidence of rhythm disturbances and were extubated earlier than controls. In another subgroup of patients with aortic cross clamp time exceeding 60 min (n = 197), the amount of patients requiring prolonged intensive care treatment (> 24 h) was significantly lower when they received heparin treated circuits versus controls. CONCLUSION These findings suggest that improved recovery can be expected with heparin treated circuits in specific higher risk patient populations (e.g. females) and when prolonged aortic cross clamp time is anticipated. Further investigations are recommended to analyses the clinical benefit of heparin treated circuits in studies with patients in different well defined risk categories and under better standardised circumstances.

Duraflo II coating of cardiopulmonary bypass circuits reduces complement activation, but does not affect the release of granulocyte enzymes : a European multicentre study

OBJECTIVE This study was carried out to: (a) compare complement and granulocyte activation during cardiac operations in patients operated with cardiopulmonary bypass coated with heparin by the Duraflo II method, with activation in patients operated with uncoated circuits; and (b) relate complement, and granulocyte activation to selected adverse effects. METHODS In a multicentre study among Rikshospitalet, Ullevaal Hospital in Norway and Uppsala University Hospital in Sweden, plasma concentrations of the complement activation products C4b/iC4b/C4c (C4bc), C3b/iC3b/C3c (C3bc), the terminal SC5b-9 complement complex (TCC), and the granulocyte proteins myeloperoxidase and lactoferrin were assessed in two groups of patients undergoing aortocoronary bypass. Seventy-six patients underwent surgery operated with circuits coated by the Duraflo II heparin coating and 75 uncoated circuits. The same amount of systemic heparin was administered to all patients. RESULTS In both groups a significant increase in C4bc was first seen by the end of operation, from 86.7 +/- 12.5 to 273.0 +/- 277.4 nM in controls and from 86.9 +/- 18.5 to 320.2 +/- 190.5 nM in the control group, confirming previous documentation that the classical pathway is not activated during CPB, but as a consequence of protamin administration. The formation of C4bc did not differ significantly between the two groups. In the uncoated group the C3bc concentration increased from 124.0 +/- 15.3 to a maximum of 1176.1 +/- 64.7 nM (P < 0.01) and in the coated group it increased from 129.8 +/- 16.1 to a maximum of 1019.4 +/- 54.9 nM (P < 0.01) during CPB. Summary values but not peak values differed significantly between the groups. In the uncoated group the TCC concentration increased from 0.52 +/- 0.03 to a maximum value of 8.09 +/- 0.57 AU/ml (P < 0.01) while in the coated group the TCC concentration increased from a baseline of 0.53 +/- 0.03 to a peak value of 5.2 +/- 0.24 AU/ml (P <0.01). The difference between the peak values was statistically significant (P = 0.00002). In both groups a significant increase in myeloperoxidase and lactoferrin release was observed by the end of operation. There was no difference in myeloperoxidase or lactoferrin release between the two groups. TCC levels were compared to the occurrence of perioperative infarction, development of lung or renal failure, postoperative bleeding, time on ventilator and days in hospital. Three patients developed perioperative infarction; the peak levels of TCC were significantly higher in these patients than in the 148 patients that did not develop infarction. The reduction in TCC formation in the heparin-coated group was not associated with differences in any of the other clinical parameters. Few adverse effects occurred in the study. The peak values of C3bc were higher in the patients needing inotropic support that in those who did not, the relevance of this finding remains uncertain. CONCLUSION It is concluded that the Duraflo II heparin coating reduces complement activation, particularly TCC formation, during CPB, but not the release of specific neutrophil granule enzymes. No certain correlation was established between complement and granulocyte activation and clinical outcome.

Original ArticlesIntraaortic Balloon Pump in Open Heart Operations: 10-Year Follow-up With Risk Analysis 1

BACKGROUND The intraaortic balloon pump (IABP) is the primary mechanical device used for perioperative cardiac failure. METHODS We analyzed the prognostic predictors and long-term survival of 344 patients undergoing cardiac operations who required the perioperative use of an IABP at our institution from January 1980 to December 1989. Hospital survivors (163 patients) were followed up for a mean of 7.45 years (range, 1 month to 15.3 years); cumulative follow-up included 1,167 patient-years. RESULTS The early mortality rate was 52.6% (181 patients). From parameters available at the time of IABP insertion, logistic regression analysis identified preoperative serum creatinine level, left ventricular ejection fraction, perioperative myocardial infarction, timing of IABP insertion, and indication for operation as independent predictors of early (30-day) death (p < 0.05). Cox regression analysis of hospital survivors identified timing of IABP insertion, perfusion time, and preoperative serum creatinine level as independent prognostic factors for late death (p < 0.05), whereas patient age was only marginally significant (p < 0.06). There was no association between IABP-related complications and death. Survival analysis demonstrated a 10-year actual survival rate of 22.04% +/- 0.023%, with 57 patients still at risk and significantly improved survival among those who received an IABP before operation (p < 0.02). CONCLUSIONS The early mortality rate in patients who received an IABP was high. Hospital survivors had a relatively good long-term prognosis. The significantly better short- and long-term survival of patients who received an IABP before operation may justify more liberal preoperative use of the IABP in high-risk patients.

Leucocyte filtration during cardiopulmonary bypass hardly changed leucocyte counts and did not influence myeloperoxidase, complement, cytokines or platelets

In some patients, coronary artery bypass surgery induces postoperative organ dysfunction despite an apparently adequate revascularization and good haemodynamic performance. This complication may be caused by activation of the body’s inflammatory systems on blood contact with large foreign surfaces in the extracorporeal circuit. Activated leucocytes may play an important role in organ damage, and it is conceivable that leucocyte removal by filtration may decrease the potential side-effects of cardiopulmonary bypass (CPB). The aim of the present study was to investigate possible effects of leucocyte filtration during the whole CPB period in elective coronary artery bypass surgery on biochemical and clinical parameters. Forty patients were randomized to extracorporeal circulation using a leucocyte-depleting filter (group L, n = 20) or to extracorporeal circulation with no leucocyte filter (group C, n = 20). In the leucocyte-depleted group, the mean total white blood cell counts increased from 6.3 (95% confidence interval, 5.5 - 7.0) × 109/l to 7.0 (5.7 - 8.3) × 109/l during extracorporeal circulation and in the control group from 6.3 (5.2 - 7.3) × 109/l to 8.5 (7.2 - 9.8) × 109/l. The intergroup difference was not statistically significant (p = 0.84). A substantial increase in concentrations of interleukin-6, myeloperoxidase and complement activation products were observed in both groups without statistically significant intergroup differences. It is concluded that the leucocyte-depletion filter did not cause a significant reduction of circulating white blood cells during CPB, and there were no significant differences between the groups with respect to the inflammatory markers studied.

Ultrafiltration after cardiopulmonary bypass in children: effects on hemodynamics, cytokines and complement

OBJECTIVES The purpose of the study was to evaluate the clinical and hemodynamic effect of intraoperative extracorporeal ultrafiltration (UF) and its potential in reducing the plasma concentration of circulating cytokines and complement activation products following open heart surgery in children. METHODS Eighteen children with congenital heart disease were prospectively randomized into a control group (n = 9) and a group who underwent UF (n = 9). Serial plasma samples for measurements of circulating cytokines (interleukin 6 (IL-6), tumor necrosis factor alpha (TNF), and its soluble receptor (sTNF receptor)), and complement factors (C3 activation products (C3a and C3bc) and terminal complement complex (TCC)) were obtained before, during and up to 48 h after cardiopulmonary bypass (CPB). A pulmonary artery thermodilution catheter was introduced preoperatively for hemodynamic monitoring. RESULTS Postoperative hemodynamics were similar in both groups. Plasma levels of IL-6, sTNF receptors, C3a, C3bc and TCC increased significantly perioperatively (P < 0.01) in both groups. TNF was detected transiently in 16 patients perioperatively and in 4 of the 9 ultrafiltrate samples in concentrations similar to the plasma levels. Complement activating products were not detected in the ultrafiltration samples except for small amounts of C3a in two cases. Compared to the control group the plasma levels of C3a, C3bc and TCC were unaffected by the ultrafiltration procedure. The level of IL-6 and sTNF receptors increased significantly after 15 min of UF but there was no significant difference between the two groups postoperatively. CONCLUSIONS In this study no clinical or hemodynamic effect was registered after UF. TNF and C3a were occasionally detected in the ultrafiltrate but we were unable to demonstrate reduction of these or any of the other markers tested in the group subjected to ultrafiltration.

In vitro evaluation of new surface coatings for extracorporeal circulation

Cardiopulmonary bypass (CPB) exposes blood to large, foreign surfaces. This exposure may activate the cellular and humoral inflammatory systems, resulting in inflammatory reactions and organ dysfunction. Coating the inner surfaces of the bypass circuit may help alleviate these side-effects. The objective of this study was to determine the influence of two new surface treatments on blood cell and complement activation. Oxygenator and tubing sets coated with synthetic polymers (n = 7) or heparin (n = 7) were compared to uncoated sets (n = 7) in an in vitro model of CPB. The circuits were run at 4 l/min and recirculated for 120 min. The inflammatory response was assessed at regular intervals by platelet counts, and activation of complement, leucocytes and platelets. We found that the median platelet counts decreased from 127 to 122 × 109/l (not significant, NS) in the synthetic polymer sets, from 96 to 88 × 109/l (NS) in the heparin-coated sets, and from 93 to 54 × 109/l (p < 0.01) in the uncoated sets after 2 h of recirculation. There were significant differences in platelet counts between the coated sets and the uncoated set at end of experiments (p < 0.05). Beta-thromboglobulin (BTG) concentrations increased in the synthetic polymer sets from 166 to 352 ng/ml (p < 0.01), in the heparin coated sets from 336 to 1168 ng/ml (p < 0.01), and in the uncoated sets from 301 to 3149 ng/ml (p < 0.01) after 2 h of recirculation. The differences in BTG at termination of the experiments were significant among all three sets (p < 0.05). Myeloperoxidase (MPO) concentrations in the synthetic polymer sets increased from 63 to 86 μg/l (p < 0.01), in the heparin-coated sets from 90 to 208 μg/l (p < 0.01), and in the uncoated sets from 122 to 513 μg/l (p < 0.01) after 2 h of recirculation. The differences in MPO at termination of the experiments were significant among all three groups (p < 0.01). There were no significant differences at termination of the experiments among the three sets regarding complement activation as measured by C3 activation products and the terminal complement complex. We conclude that in the current in vitro model of a CPB circuit, the synthetic polymer coating and the heparin coating caused significantly less platelet loss and granulocyte and platelet activation than the uncoated surface (p < 0.05). The synthetic polymer coating caused significantly less granulocyte and platelet activation than the heparin coating (p < 0.05). There was moderate complement activation within each group, but no significant differences among the three groups.

Comparison of three oxygenator-coated and one total-circuit-coated extracorporeal devices

The present study was designed to compare the biocompatibility of three cardiopulmonary bypass setups with different surface coatings, and to determine if coating of the whole circuit with one of the coatings was more beneficial than coating of the oxygenator only. Extracorporeal devices entirely coated with synthetic polymers (Avecor, n = 6) were compared to oxygenators coated with synthetic polymers (Avecor, n = 6), end-point, covalently attached heparin (CBAS, n = 6) or absorbed heparin (Duraflo 2, n = 6) in an in vitro model of a heart-lung machine. The circuits were primed with fresh human whole blood and Ringer’s acetate and recirculated at 4 l/min at 30°C for 2 h. Test samples were obtained at regular intervals and analysed for myeloperoxidase (MPO), platelet counts, β-thromboglobulin, heparin, prothrombin fragment 1+2, plasmin-anti-plasmin complexes, and complement activation products. The mean MPO concentrations increased in the Avecor-coated oxygenator group (AV) from 247 at the start to 671 μg/l at the termination of the experiments, in the Avecor-coated total circuit group (AV-T) from 116 to 288 μg/l, in the Duraflo 2 coated oxygenator group (DU) from 160 to 332 μg/l, and in the CBAS-coated oxygenator (CA) group from 172 to 311 μg/l. The MPO concentrations increased significantly in all groups (p < 0.03). The increase in group A was significantly higher than in the other three groups (p = 0.007). The mean platelet counts decreased in the Avecor-coated total circuit group from 117 at start to 99 × 109/l at termination of the experiments, in the Avecor-coated oxygenator group from 119 to 103 × 109/l, in the Duraflo 2 group from 96 to 86 × 109/l, and in the CBAS group from 132 to 123 × 109/l. The platelet counts decreased significantly in all groups (p < 0.01), but the intergroup differences were not significant (p = 0.15). The mean β-thromboglobulin concentrations increased in the Avecor-coated total circuit group from 193 at the start to 754 ng/ml at the termination of the experiments, in the Avecor-coated oxygenator group from 474 to 1654 ng/l, in the Duraflo 2 group from 496 to 1280 ng/l, and in the CBAS group from 418 to 747 ng/l. The β-thromboglobulin increase was significant in each group (p < 0.01), but not between the groups (p = 0.49). The mean heparin concentrations in the Duraflo 2 group increased from 2460 at the start to 2897 IU/l at termination of the experiments, in the CBAS group from 2468 to 2518 IU/l. In the Avecor-coated oxygenator group heparin concentrations decreased from 2010 to 1968 IU/l, and in the Avecor-coated total circuit group from 2002 to 1927 IU/l. The differences in heparin concentrations were significant between the Duraflo 2 group and the other groups (p < 0.05). The mean prothrombin fragment 1+2 concentrations increased in the CBAS group from 0.4 at the start to 2.1 nmol/l at the end of the experiments, in the Avecor-coated oxygenator group from 0.4 to 0.6 nmol/l, in the Avecor-coated total circuit group from 0.3 to 0.4 nmol/l, and in the Duraflo 2 group from 1.2 to 1.3 nmol/l. The prothrombin fragment 1+2 increase was significant in all groups (p < 0.05), but there were no significant intergroup differences (p = 0.54). There were no significant differences at the termination of the experiments among the four groups regarding complement activation as measured by C3 activation products and the terminal complement complex. In the present in vitro model of a heart-lung machine, none of the three specific setups with different coatings was superior with regard to all test parameters. The CBAS group generated the highest levels of prothrombin fragment 1+2 formation, but least complement activation. The increasing plasma heparin concentrations in the Duraflo 2 group indicated more unstable heparin bonding. The Avecor-coated total circuit group were superior to the Avecor-coated oxygenator group regarding plasma concentrations of MPO, but not compared to the CBAS and Duraflo 2-coated oxygenator groups.

Effects on Complement, Granulocytes and Platelets of a Leukocyte-Depletion Filter During in vitro Extracorporeal Circulation

In an in vitro study, extracorporeal circuits equipped with either a leukocyte-depleting filter (n = 5) or a standard arterial-line filter (n = 5) were perfused for 120 minutes with fresh human whole blood. Leukocyte activation, leukocyte and platelet counts and complement activation were studied. Significant reduction of leukocyte and platelet counts and significant activation of leukocytes and of platelets were found in both groups, but without significant intergroup difference for any parameter after 120 minutes of perfusion. The leukocyte-depleting filters, however, were somewhat more effective in removing leukocytes during the initial 30 minutes of circulation.

Veno-venous bypass in liver transplantation: heparin-coated perfusion circuits reduce the activation of humoral defense systems in an in vitro model

We studied the effects of bypass circuit surface heparinization on kallikrein-kinin, coagulation, fibrinolytic and complement activation in a closed model system for simulating veno-venous bypass (VVBP) in orthotopic liver transplantation (OLT). The circuits were identical to those in routine use during clinical OLT in our institution. Fresh whole human blood diluted 1: 2 with Ringer’s acetate was circulated at a non-pulsatile flow (2 l/min) and at a constant temperature (37.5°C) for 12 h. In 10 experiments, the entire inner surface of the circuits was coated with end-point attached heparin (HC). In the remaining 10, non-treated PVC tubing was used (NC). Components of the plasma kallikrein-kinin, coagulation, fibrinolytic and complement systems were analyzed using functional techniques (chromogenic peptide substrate assays) and enzyme immunoassays at baseline, 3 and 12 h. Significant activation of the initial (C3bc) and terminal (TCC) components of the complement system were found in both the NC and HC groups after 3 and 12 h: C3bc: NC: baseline =4 (3.5-7.7), 3 h=17.3* (12.5-27), 12 h=31* (17.7-63.6), HC: baseline=4.9 (3.2-6.8), 3 h=9* (6-14.4), 12 h=13.7* (7.4-18.1). TCC: NC: baseline=0.4 (0.2-0.6), 3 h=5* (0.8-11.9), 12 h: 13.1* (4.2-25.7). HC: baseline=0.5 (0.1-0.6), 3 h=0.6* (0.1-0.8), 12 h=1.2* (0.3-2) AU/ml; median and range (*: p<0.05). The C3bc and TCC concentrations were significantly higher in the NC group at 3 and 12 h, compared to the HC group: C3bc (NC vs. HC group): 3 h,p<0.001; 12 h, p<0.001. TCC (NC vs. HC group): 3 h, p<0.001; 12 h, p<0.001. Significant increases in the values of thrombin-antithrombin complexes (p<0.003), prothrombin fragment 1+2 (p<0.006) and plasmin-α2-antiplasmin complexes (p=0.016) were found in the non-coated group, but not in the heparin-coated group during the observation period, showing that the coagulation and fibrinolytic systems were activated in the non-coated circuits. We conclude that heparin-coating of the internal surface of the extracorporeal perfusion circuit used for VVBP reduces activation of the plasma cascade systems in a closed venous system in vitro.