Changes in Platelet, Granulocyte, and Complement Activation During Cardiopulmonary Bypass Using Heparin-coated Equipment

Abstract: The effects of heparin-coated cardiopulmonary bypass (CPB) systems on platelet, granulocyte, and complement activation were investigated during cardiopulmonary bypass. Thirty patients underwent coronary artery bypass surgery with a heparin-coated (Carmeda Bio-Active Surface, CBAS, Medtronic, U.S.A.) CPB system (HC group, n = 10), a heparin-coated oxygenator and uncoated CPB circuit (HO group, n = 10), or an uncoated system (UC group, n = 10). In the HO group, plasma C3a (1667 ± 632 ng/ml) and C4a (1088 ± 319 ng/ml) concentrations were significantly (p < 0.05) lower than in the UC group (2846 ± 1045 ng/ml and 1494 ± 480 ng/ml, respectively) 10 min after the administration of protamine, but there were no significant differences in the platelet or granulocyte counts. In the HC group, granulocyte elastase concentrations 120 min after the onset of CPB (365 ± 177 μg/L) and 10 min after the administration of protamine (676 ± 314 μg/L) were significantly (p < 0.05) lower than in the other 2 groups (820 ± 341 and 893 ± 303 μg/L and 1365 ± 595 and 1,258 ± 622 μg/L). In addition, the increase in the plasma C3a concentration in the HC group 60 (p < 0.05) and 120 min after the onset of CPB (p < 0.05) was significantly less than in the other 2 groups. The C3a and C4a concentrations 10 min after the administration of protamine were significantly (p < 0.005 and p < 0.05) less in the HC group than in the UC group. Platelet counts 10 min after the administration of protamine were significantly higher (p < 0.05) and plasma β-throm-boglobulin concentrations during CPB were significantly lower in the HC group than in the other 2 groups 5 (p < 0.05), 60, and 120 min (p < 0.005) after the onset of CPB. Postoperative blood loss during the first 12 h in the HC group was significantly (p < 0.05) less than that in the UC group. The heparin-coated oxygenator and uncoated CPB circuit reduced complement activation but demonstrated no significant effects on the platelet and granulocyte systems. However, the heparin-coated CPB circuit (with all components making blood contact) reduced platelet, granulocyte, and complement activation and significantly reduced postoperative blood loss. Therefore, heparin coating of CPB systems improves biocompatibility.     

Clinical role of blood heparin level monitoring during open heart surgery

Protamine has been used for neutralizing heparin and its dosage is decided by the initial fixed dose of heparin. Adequate protamine neutralization is very important to reduce complications. To attenuate excess reactions, in particular, whole blood heparin concentration during and after cardiopulmonary bypass was measured using Hepcon®, and the efficacy of optimal protamine dose in open heart surgery was evaluated. Twenty patients were randomly divided into two comparable groups, P and C. In the C group, heparin was neutralized with an initial fixed dose of protamine, 1.67 mg protamine per milligram total heparin (n = 8). In the P group, protamine dose was determined for residual heparin concentration (n = 12). In the P group, blood heparin concentrations at 60 minutes after the establishment of cardiopulmonary bypass, just after cardiopulmonary bypass and first protamine administration were 2.35 ± 0.14, 2.31 ± 0.17 and 0.13 ± 0.08 U/ml, respectively. Concentrations reached zero with the second protamine administration. The requirement of transfusion (659 ± 224 vs. 1559 ± 323 ml, p = 0.0314), pulmonary vascular resistance index just after the protamine administration (190 ± 22 vs. 286 ± 18 dyne·s·cm^?5·m², p = 0.0137) and the IL-8 levels (just after protamine: 26.9 ± 5.1 vs. 43.5 ± 5.9 pg/ml, p = 0.0499, 12 hours after cardiopulmonary bypass: 37.1 ± 12.1 vs. 86.8 ± 20.0, p = 0.0435) in the P group were significantly lower than those in the C group. These data suggested that heparin level monitoring in whole blood may be useful to determine the optimal dose of protamine resulting in the decrease of a requirement of blood components in open heart surgery and attenuating in transient pulmonary hypertension and excess protamine-induced inflammatory reactions.     

Effect of a Miniaturized Cardiopulmonary Bypass System on the Inflammatory Response and Cardiac Function in Neonatal Piglets

The cognitive impairment and hemodynamic instability after neonatal cardiac surgery with cardiopulmonary bypass (CPB) might be exacerbated by hemodilution. Therefore, this study investigated the impact of different bloodless prime volumes on the hemodynamics and the inflammatory response by a miniaturized CPB system in neonatal piglets. The bypass circuit consisted of a Capiox RX05 (Capiox Baby RX, Terumo Corp., Tokyo, Japan) oxygenator and 3/16 internal diameter arterial and venous polyvinyl chloride tubing lines, with a minimum 75 mL prime volume. Twelve 1‐week‐old piglets were placed on a mild hypothermic CPB (32°C) at 120 mL/kg/min for 2 h. The animals were divided into two groups, based on the volume of the prime solution. The priming volume was 75 mL in Group I and 175 mL in Group II. No blood transfusions were performed, and no inotropic or vasoactive drugs were used. The interleukin‐6 (IL‐6) and thrombin‐antithrombin (TAT) complex levels, as well as right ventricular and pulmonary functions, were measured before and after CPB. Group I had low levels of IL‐6 and TAT immediately after CPB (4370 ± 2346 vs. 9058 ± 2307 pg/mL, P < 0.01 and 9.9 ± 7.7 vs. 25.1 ± 8.8 ng/mL, P < 0.01, respectively). Group I had significantly improved cardiopulmonary function, cardiac index (0.22 ± 0.03 vs. 0.11 ± 0.05 L/kg/min, P < 0.001), and pulmonary vascular resistance index (7366 ± 2860 vs. 28 620 ± 15 552 dynes/cm⁵/kg, P < 0.01) compared with Group II. The miniaturized bloodless prime circuit for neonatal CPB demonstrated that the influence of hemodilution can reduce the subsequent inflammatory response. In addition, a low prime volume could therefore be particularly effective for attenuating pulmonary vascular resistance and right ventricular dysfunction in neonates.     

Cardiopulmonary bypass

The primary function of the cardiopulmonary bypass (CPB) machine is to provide oxygenated blood flow to the systemic circulation while providing the surgeon with a motionless, bloodless surgical field. The CPB circuit consists of a reservoir, blood pump, oxygenator, heat exchanger, arterial filter, cardioplegia delivery device and cannulae, interconnected by various sized tubing. The venous cannula directs blood away from the heart and lungs via the CBP circuit and the arterial cannula returns the oxygenated blood to the systemic circulation. A blood pump propels the blood volume forward through a membrane oxygenator and allows rapid transfusion of oxygenated blood back into the systemic circulation. The CPB flow needs to be enough to maintain an adequate cardiac output, therefore a flow of 1.8–2.2 litres/minute/m² is recommended when at normothermia, although these flows can be reduced if the temperature is less than 28°C. The mortality and neurological complications after cardiac surgery are similar using either normothermic or hypothermic CPB. Maintenance of anaesthesia on CPB is often achieved with a propofol infusion (sometimes with the addition of remifentanil), but the use of volatile anaesthetic is also possible through the CPB machine. A vaporizer can be attached to the CPB circuit and volatile anaesthetic delivered into the sweep gas passing through the oxygenator. A safety checklist before separation from bypass is essential, and it may include: optimal temperature, heart rhythm, de-airing, acid-base status, ventilation, electrolytes and patient position. If heparin was used to maintain anticoagulation, it should be reversed with protamine after the patient is stable off-CPB. Some patients require inotropic or mechanical support to facilitate ‘weaning’ from CPB.     

A Newly Developed Silicone-Coated Membrane Oxygenator for Long-Term Cardiopulmonary Bypass and Cardiac Support

Abstract: The surface of polypropylene hollow fiber was successfully coated with a very thin (0.2 μm) silicone layer. Experimental studies were performed in long-term (6 h) normothermic cardiopulmonary bypass (CPB) using 10 goats. A conventional membrane oxygenator (Mera Exce-lung HPO-lSH, MERA, Tokyo, Japan) was used for 5 goats as a control (Group C) and a new silicone-coated membrane oxygenator, which is of the same construction as that of the one used for Group C, for 5 (Group S). The O₂transfer and CO₂removal functions showed the same ranges. In the other parameters, there were no differences between the 2 groups. As for hemolysis, however, the plasma free hemoglobin of Group S was lower than that of Group C. Currently, 3 chronic percutaneous cardiopulmonary support (PCPS) experimental models have been conducted, and there has been no evidence of thromboembo-lism or deterioration of the oxygenator. In conclusion, this new oxygenator is suitable not only for CPB, but also for long-term cardiac support.     

Prostaglandin e biosynthesis during cardiopulmonary bypass

Initiation of cardiopulmonary bypass (CPB) causes immediate drop in blood pressure and peripheral vascular resistance (PVR) with activation of complex neurohumoral reflex mechanisms and redistribution of systemic blood flow. Prostaglandin E (PGE) is a potent vasodilator released during ischemia and low flow states. This study was designed to determine if CPB provided stimulus for PGE biosynthesis and its effect on PVR.Fourteen dogs were placed on CPB for 60 min at 80 ml/kg/min. Plasma PGE concentration and PVR were determined prior to and immediately after the start of CPB and at 15-min intervals. There were eight control animals (Group I) and six (Group II) had PGE inhibited by indomethacin (2.5 mg/kg). With the initiation of CPB, PVR decreased to 18 ± 1 U in both groups. In Group I, PGE increased from 404 ± 88 to 619 ± 256 pg/ml. In Group II, PGE levels dropped from 363 ± 94 to 218 ± 96 pg/ml after indomethacin block and did not change in response to CPB. At 15 min, Group I PVR rose to 30 ± 3 U while Group II PVR was higher at 42 ± 2 U (P < 0.001). PGE concentrations at this time were 652 ± 106 in Group I and 260 ± 92 pg/ml in Group II (P < 0.01). After 15 min, PGE returned to control in Group I but remained significantly elevated over Group II at 30 and 45 min. PVR continued to increase in both groups for the duration of CPB and Group II PVR remained significantly elevated (P < 0.05) compared to Group I.These data show that PGE is released in response to the initiation of CPB and is one of several factors affecting PVR during CPB.     

Biocompatibility of Heparin-Coated Circuits in Pediatric Cardiopulmonary Bypass

Abstract: In this study, we evaluated the biocompatibility of heparin-coated circuits in pediatric cardiopulmonary bypass (CPB). Eight patients were divided into 2 groups: the control group (Group C) and heparin-coated group (Group H). In Group H, CPB circuits, including the arterial pump, oxygenator, and cannulas were heparin-coated. Before, during, and after CPB, blood samples were obtained to assess the platelet counts (Plat), α2-plasmin plas-minogen inhibitor complex (PIC), thrombin-antithrombin III complex (TAT), C3 activation products (C3a), inter-leukin (IL)-6, IL-8, and polymorphonuclear neutrophil leukocyte (PMN) elastase. There was no significant difference in Plat, PIC, or TAT between groups. Group H showed significantly low levels of C3a (during and after CPB), PMN elastase (during CPB), and IL-6 (after CPB). These data demonstrated that in pediatric CPB, heparin-coated CPB circuits reduced the activation of complements and the production of PMN elastase and IL-6, suggesting the superior biocompatibility of the heparin-coated circuits.     

Hyaluronan based heparin free coated open and closed extracorporeal circuits for high risk coronary revascularization

This prospective randomized study compares the inflammatory response and fibrinolytic activation of fully coated/uncoated and open/closed extracorporeal circuits (ECC) in high risk patients. Over a 2-month period, 48 patients with EuroSCOREs 6 or greater undergoing coronary revascularization were prospectively randomized to one of the four perfusion protocols: Group 1: Closed and totally hyaluronan based heparin free coated (Vision HFO-GBS-HF, Gish Biomedical, Rancho Santa Margarita, CA) ECC with a soft-shell coated venous reservoir (SVR11S2-HFC, Gish Biomedical) and a hard-shell cardiotomy (CAPVRF44, Gish Biomedical) (n = 12); Group 2: Closed and totally uncoated identical ECC with soft-shell uncoated venous reservoir and a hard-shell cardiotomy (n = 12); Group 3: Open, totally hyaluronan based heparin free coated ECC (n = 12); and Group 4: Control-open, uncoated ECC (n = 12). Blood samples were collected at T1: Baseline; T2: 15 minutes after cardiopulmonary bypass (CPB) initiation; T3: before cessation of CPB; T4: 15 minutes after protamine reversal, and T5: in the intensive care unit. Serum IL-6 levels were significantly lower at T2 in all study groups, at T3 for coated groups, and T4 for closed+coated group (p < .05 versus control). Creatine kinase M-band (MB) levels in coronary sinus blood demonstrated well preserved myocardium after CPB in both coated groups versus Control (p < .05). Neutrophil CD11b/CD18 levels were significantly lower for all study groups versus control at T2, for both coated groups at T3 and only for closed + coated group at T4 (p < .05). Postoperative hemorrhage (mL) was 510 +/- 40 in closed + coated and 536 +/- 40 in open + coated groups (control: 784 +/- 48, p < .05). No significant differences in thrombin-antithrombin complex and free plasma hemoglobin were observed. Desorbed protein amount on ECC (mg/dL) was 1.7 +/- .01 in closed+coated, 2.01 +/- .01 in open+coated, and 3.3 +/- .015 in control groups (p < or = .05). Use of a closed and completely heparin free coated ECC may reduce neutrophil degradation, cytokine release characterized by improved clinical outcomes including reduced blood loss, reduced requirement for inotropes, and reduced atrial fibrillation.     

Clinical performance and biocompatibility of novel hyaluronan-based heparin-bonded extracorporeal circuits

We tested documented in vitro and ex vivo advantages of novel hyaluronan based heparin bonded extracorporeal circuits in a prospective randomized study. During the period from June until September 2005, 40 patients undergoing reoperation for coronary artery bypass grafting were allocated into two equal groups (n = 20): Group 1 was treated with hyaluronan-based heparin-bonded circuits and group 2 was treated with uncoated control circuits. Complete blood count, fibrinogen, albumin, C3a, interleukin-2 levels, and thromboelastographic data were documented after induction of anesthesia (T1) and heparin administration before cardiopulmonary bypass (CPB) (T2), 15 minutes after initiation of CPB (T3), before cessation of CPB (T4), 15 minutes after reversal with protamine (T5), and the first postoperative day at 8:00 a.m. (T6). Hollow fibers were collected for consecutive biomaterial analysis by optical and scanning electron microscopy (SEM). Desorbed protein deposition on fibers was compared by spectrophotometry. Leukocyte counts were lower in T4-T6 in group 1 (p < .05). Platelet counts demonstrated significant differences at T4 and T5 in coated group (p < .05). Albumin and fibrinogen levels were better preserved in Group 1 at T4, T5 and T4, T6, consecutively (p < .05). C3a and IL-2 levels were lower at T3-T5 and T4-T5 in intervention group (p < .05). Postoperative hemorrhage was 412 +/- 50 mL in group 1 and 684 +/- 50 ml in group 2 (p < .05). Respiratory support time was shorter in group 1 versus control (p < .05). Platelet adhesion was significantly lower in intervention group. Amount of desorbed protein was 1.44 +/- 0.01 mg/dL in group 1 and 1.94 +/- 0.01 mg/dL in control (p < .05). SEM and spectrophotometry demonstrated better surface preservation in the hyaluronan coated group. Novel hyaluronan-based heparin-bonded circuits reduce platelet adhesion-aggregation and protein adsorption and provide better perioperative clinical parameters through platelet, albumin, and fibrinogen-sparing effects.     

Protamine reduces whole blood platelet aggregation after cardiopulmonary bypass

Objectives: Platelet dysfunction is an important cause of postoperative bleeding after cardiac surgery. Protamine is routinely used for reversal of heparin after cardiopulmonary bypass (CBP), but may affect platelet aggregation. We assessed changes in platelet function in relation to protamine administration. Design: Platelet aggregation was analyzed by impedance aggregometry before and after protamine administration in 25 adult cardiac surgery patients. Aggregation was also studied after in vitro addition of heparin and protamine. The activators adenosine diphosphate (ADP), thrombin receptor activating peptide-6 (TRAP), arachidonic acid (AA) and collagen (COL) were used.

Results: Platelet aggregation was reduced by approximately 50% after in vivo protamine administration; ADP 640?±?230 (AU*min, mean?±?SD) to 250?±?160, TRAP 939?±?293 to 472?±?260, AA 307?±?238 to 159?±?143 and COL 1022?±?350 to 506?±?238 (all p?<?0.001). Aggregation was also reduced after in vitro addition of protamine alone with activators ADP from 518?±?173 to 384?±?157 AU*min p?<?0.001, and AA 449?±?311 to 340?±?285 (p?<?0.01) and protamine combined with heparin (1:1 ratio) with activators ADP to 349?±?160 and AA to 308?±?260 (both p?<?0.001); and COL from 586?±?180 to 455?±?172 (p?<?0.05). Conclusions: Protamine given after CPB markedly reduces platelet aggregation. Protamine added in vitro also reduces platelet aggregation, by itself or in combination with heparin.     

Heparin and protamine titration do not improve haemostasis in cardiac surgical patients

Purpose

Weight-based heparin and protamine dosing strategies for cardiopulmonary bypass (CPB) do not take into account interpatient variability in drug sensitivity and may result in bleeding complications. We compared the Hemochron® RxDx heparin and protamine titration system with standard weight based management with regard to heparin dose, protamine dose, and perioperative bleeding.

Methods

One hundred and thirty-five cardiac surgical patients were randomised into four groups. Group I received standard heparin and protamine management: Group 2 received heparin and protamine byin vitro titration. Group 3 had the heparin dose titrated, and group 4 had the protamine dose titrated. Coagulation tests, bleeding, and transfusion requirements were measured.

Results

The initial heparin bolus predicted by the titration was < 300 U· kg^?1 in all patients. Group 2 received a lower heparin bolus for the initiation of bypass but total heparin doses were not different among groups (group 1 = 365 ± 43, group 2= 348 ± 73 U · kg^?1, group 3= 394 ± 86 U · kg^?1, group 4= 376 ± 60; P = 0.06). Groups 2 and 4 received a lower initial and a lower total protamine dose (total dose group 1 = 4.03 ± 0.65 mg · kg^?1, group 2 = 3.56 ±1.11 mg · kg^?1, group 3= 4.22 ± 0.90 mg · kg^?1, group 4= 3.38 ± 0.98 mg· kg^?1,P = 0.001). The incidences of incomplete heparin neutralisation (P = 0.14) and heparin rebound (P = 0.1) were not different among groups. Postoperative bleeding and transfusion requirements did not differ.

Conclusion

In cardiac surgical patients, heparin and protamine titration did predict a lower protamine dose but did not result in a measurable improvement in haemostasis during the perioperative period.     

The calcium channel blocker nifedipine fails to inhibit leucocyte elastase release during cardiopulmonary bypass

Circulating concentrations of leucocyte elastase were measured in 16 adult patients undergoing cardiopulmonary bypass (CPB) with a flat-sheet membrane oxygenator. Eight patients (Group I) received the calcium channel blocker nifedipine (9 µmUg · kg^-1 · h^-1) during CPB. Eight patients (Group II) did not receive any calcium channel blocker during surgery and served as the control group. Elastase concentrations were measured at 7 time points: 2 before, 2 during, and 3 after CPB. The bypass procedure was associated with elevation in elastase concentrations (P<0.001). Comparing to baseline values elastase concentrations were significantly elevated (P<0.05) 60 min after the start of CPB and on all measurements done after CPB. Elastase concentrations correlated with the duration of CPB (rs = 0.76, P<0.001), and were not influenced by nifedipine infusion as revealed by comparing the two groups. This study demonstrates moderate elastase release during CPB with a fiat-sheet membrane oxygenator and fails to confirm inhibition of elastase release by nifedipine infusion during CPB.     

Haemostatic profile of small children during and following cardiopulmonary bypass

Objective: We evaluated changes of the haemostatic system during pediatric cardiac surgery during and after cardiopulmonary bypass (CPB).Method: Twenty-five children under 15 kg of body weight under-going open-heart surgery were divided into three groups; 9 patients (Group A), no bank blood was used throughout the surgery; 8 patients (Group B), packed red cells were used in the priming of CPB circuit; 8 patients (Group C) in cyanotic condition, for whom surgery was performed without bank blood. CPB caused a significant decrease of platelet counts in all three groups, the levels of which remained similar next morning.Results: Platelet counts decreased more significantly in Group C (59±27 k/mm³) than in Group A (119±42 k/mm³) and B (104±27 k/mm³). Platelet function-platelet activating factor test (HemoSTATUS^TM) did not significantly decrease throughout the perioperative period in Group A. Hemo-STATUS^TM value decreased during CPB and recovered after CPB in Group B and C. Prothrombin time international ratio (PT-INR) and activated partial thromboplastin time were significantly prolonged just after CPB and recovered until next morning in all three groups. PT-INR was more prolonged in Group C (2.92±0.62) than in Group A (2.08±0.27) and B (2.42±0.42). There was no significant difference in postoperative bleeding for the first 12 hours among the three groups.Conclusion: Although extreme hemodilution during CPB significantly impairs the coagulation and platelet system, these changes are usually transient and tolerable with minimal postoperative hemorrhage. However, a prolonged CPB and preoperative cyanotic condition may induce a critical decrease of platelet counts and increase postoperative bleeding.     

Evaluation of biocompatible cardiopulmonary bypass circuit use during pediatric open heart surgery

The contact of blood with nonbiological surfaces during cardiopulmonary bypass (CPB) induces a whole body inflammatory response and increases postoperative morbidity directly related to bleeding complications and end organ dysfunction. Methods to reduce these effects have included modification of extracorporeal circuits through biocompatible coating of disposables and the application of various pharmacological agents. Biocompatible coated surfaces are designed to mimic physiologic surfaces. This study was designed to ascertain the effects of using coated circuits during pediatric CPB. After Institutional Review Board approval and parent/guardian consent, patients undergoing CPB, weighing less than 15 kg, with target CPB temperatures more than 28 degrees C, were enrolled into the Coated Circuit Group using an entirely biocompatible CPB circuit with poly(2-methoxyethylacrylate) (PMEA) and a biocompatible coated oxygenator (n = 16). Those patients were retrospectively matched to control patients having the same congenital repair with respect to patient size, surgeon, anesthesiologist, bypass time, cross-clamp time, bypass temperature, and noncoated bypass disposables; (n = 16). CPB data collected included on-bypass platelet count, hematocrit (HCT), and CPB blood product use. Postprotamine data collected in the operating room included blood product use, time from initial protamine administration to chest closure, platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR). Postoperative intensive care unit (ICU) data included blood product use, HCT, chest tube output, platelet count, PT, aPTT, INR, blood gases, lactate, and ventilator settings at 1, 2, 4, 6, 12, and 24 hours. Other data collected included intubation time, length of time to chest tube removal, and length of ICU stay. Statistical significance (p < .05) was seen in units of platelets transfused postprotamine, ventilator peak inflation pressure (PIP) on admission to the ICU, postoperative day 0 packed red blood cells (PRBC) and fresh frozen plasma (FFP) transfused, and lactate at 1, 2, 4, 6, and 12 hours postoperative. Several parameters approached statistical significance, including PRBC transfused postprotamine, time from protamine administration to chest closure, postoperative day 0 platelets transfused, and ICU stay. The data suggest that PMEA biocompatible CPB circuits can be used safely during pediatric heart surgery, resulting in a decrease in postoperative blood product use, improved postoperative lung function, and a reduction in the time spent in the ICU.     

Anticoagulation for cardiac surgery in patients receiving preoperative heparin: use of the high-dose thrombin time

Patients receiving heparin infusions have an attenuated activated clotting time (ACT) response to heparin given for cardiopulmonary bypass (CPB). We compared patients receiving preoperative heparin (Group H) to those not receiving heparin (REF group) with respect to ACT, high-dose thrombin time (HiTT), and markers of thrombin generation during CPB. Sixty-five consecutive patients (33 Group H, 32 REF group) undergoing elective CPB were evaluated. ACT and HiTT were measured at multiple time points. Plasma levels of thrombin-antithrombin III complex and fibrin monomer were determined at baseline, during CPB, and after protamine administration. Transfusion requirements and postoperative blood loss were measured and compared. ACT values after heparinization increased less in Group H and were significantly lower than those in the REF group (P < 0.01). HiTT values did not differ significantly between the two groups. Blood loss and transfusion requirements were not significantly different between the two groups. Plasma levels of thrombin-antithrombin III complexes and fibrin monomer also did not differ between groups at any time, despite a lower ACT in Group H after heparinization and during CPB. Our data suggest that thrombin formation and activity are not enhanced in patients receiving heparin therapy, despite a diminished ACT response to heparin. The utility of ACT and the threshold values indicative of adequate anticoagulation for CPB are relatively undefined in patients receiving preoperative heparin. HiTT should be investigated as a safe and accurate monitor of anticoagulation for CPB in patients receiving preoperative heparin therapy. Implications: The diminished activated clotting time response to heparin, in patients receiving preoperative heparin therapy, poses difficulties when attempting to provide adequate anticoagulation for cardiopulmonary bypass. Current data suggest that heparin resistance is not observed when high-dose thrombin time is used to monitor anticoagulation and that a lower activated clotting time value in these patients may be safe.     

The impact of heparin-coated cardiopulmonary bypass circuits on pulmonary function and the release of inflammatory mediators

Reduction of the inflammatory reaction with the use of heparin coating has been found during and after cardiopulmonary bypass (CPB). The question remains whether this reduced reaction also decreases the magnitude of CPB-induced pulmonary dysfunction. We therefore evaluated the effects of a heparin-coated circuit versus a similar uncoated circuit on pulmonary indices as well as on inflammatory markers of complement activation (C3b/c), elastase-alpha(1)-antitrypsin complex, and secretory phospholipase A(2) (sPLA(2)) during and after CPB. Fifty-one patients were randomly assigned into two groups undergoing coronary artery bypass grafting with either a heparin-coated (Group 1) or an uncoated (Group 2) circuit. During CPB, a continuous positive airway pressure of 5 cm H(2)O and a fraction of inspired oxygen (FIO(2)) of 0.21 were maintained. Differences in favor of the coated circuit were found in pulmonary shunt fraction (P < 0.05), pulmonary vascular resistance index (P < 0.05), and PaO(2)/FIO(2) ratio (P < 0.05) after CPB and in the intensive care unit. During and after CPB, the coated group demonstrated lower levels of sPLA(2). After CPB, C3b/c and the elastase-alpha(1)-antitrypsin complex were significantly less in the coated group (P < 0.001). The coated circuit was associated with a reduced inflammatory response, decreased pulmonary vascular resistance index and pulmonary shunt fraction, and increased PaO(2)/FIO(2) ratio, suggesting that the coated circuit may have beneficial effects on pulmonary function. The correlation with sPLA(2), leukocyte activation, and postoperative leukocyte count suggests reduced activation of pulmonary capillary endothelial cells. IMPLICATIONS: Heparin coating of the extracorporeal circuit reduces the inflammatory response during cardiopulmonary bypass. Analysis of indices of pulmonary function indicates that use of heparin coating may result in less impaired gas exchange.     

Release of Proinflammatory Cytokines During Pediatric Cardiopulmonary Bypass: Heparin-Bonded Versus Nonbonded Oxygenators

Background. Heparin bonding of the cardiopulmonary bypass (CPB) circuit may be associated with a reduced inflammatory response and improved clinical outcome. The relative contribution of a heparin-bonded oxygenator (ie, >80% of circuit surface area) to these effects was assessed in a group of pediatric patients.

Methods. Twenty-one pediatric patients undergoing CPB operations were assigned randomly to receive either a heparin-bonded oxygenator (group H, n = 11) or a nonbonded oxygenator (group C, n = 10) in otherwise nonbonded circuits. The two groups were similar in pathology, age, weight, CPB time, and cross-clamp time. Plasma levels of the cytokines tumor necrosis factor-, interleukin-6, and interleukin-8, as well as terminal complement complex, neutrophils, and elastase, were analyzed before, during, and after CPB.

Results. Significant levels of tumor necrosis factor- were not detected in either group. Plasma levels of all other markers increased during and after CPB compared with baseline. Plasma levels of interleukin-6 peaked in both groups 2 hours after the administration of protamine but remained significantly higher in group C 24 hours after operation. Plasma concentrations of interleukin-8 peaked at similar levels in both groups 30 minutes after protamine administration and returned to baseline thereafter. Levels of terminal complement complex and elastase peaked in both groups 30 minutes after protamine administration. Plasma levels of terminal complement complex were significantly higher at the end of CPB and after protamine administration in group C. Elastase levels were significantly higher 2 and 24 hours after CPB in group C. The ventilation time of patients in group H was significantly lower than that of patients in group C: 10 (range, 3 to 24) versus 22 (range, 7 to 24) hours, respectively (p < 0.01).

Conclusions. The present study confirms the proinflammatory nature of pediatric operations and demonstrates a lessened systemic inflammatory response with the use of heparin-bonded oxygenators. This is achieved without bonding of the entire circuit, which could have significant cost-benefit implications by negating the need for custom-built heparin-bonded circuitry.     

Heparin-coated circuits (Duraflo II) with reduced versus full anticoagulation during coronary artery bypass surgery

BACKGROUND: Introduction of completely heparin-coated cardiopulmonary bypass (CPB) circuits combined with reduced systemic anticoagulation has been shown to reduce postoperative bleeding and requirements for allogeneic transfusions after cardiac surgery. However, some uncertainty exists whether this effect is due to the reduced amount of heparin or to the heparinized surface itself. Therefore, a retrospective study was undertaken, comparing two different anticoagulation protocols applied to coronary artery bypass patients treated with identical heparin-coated CPB equipment. METHOD: Over a 12 month period all coronary artery bypass patients operated with extracorporeal circulation were subjected to a Duraflo II heparin-coated circuit (Baxter Healthcare Corp, Bentley Laboratories Division, Irvine, Calif) and full heparin dose (activated clotting time [ACT] > 480 seconds; Group F, n = 651). Over the next 24 months, all coronary patients who were treated with an identical circuit combined with reduced systemic heparinization (ACT > 250 seconds) were included in Group R (n = 675). Except for the different anticoagulation protocols, all treatment regimens before, during, and after the operation remained unchanged throughout the study period. RESULTS: There were no statistically significant differences in any major demographic or operative parameters. In Group R, the postoperative bleeding was mean 665 +/- 257 ml versus 757 +/- 367 ml in Group F (p < 0.0001), and the perioperative decrease in hemoglobin concentration was significantly lower in Group R (22 +/- 1.2 gm/L versus 25 +/- 1.3 gm/L, p < 0.0001). The time for postoperative ventilatory support was shorter in Group R (1.7 +/- 1.3 hours versus 1.9 +/- 1.1 hours in Group F, p = 0.0006), and the incidence of new episodes of atrial fibrillation after the operation was lower (26.4% in Group R versus 32.8% in Group F, p = 0.01). There were no significant differences in the incidences of perioperative myocardial infarction, stroke, transient neurological disturbances, physical rehabilitation, or mortality. No technical or coagulation problems were recorded in either group. CONCLUSION: The use of Duraflo II coated circuits for CPB combined with reduced anticoagulation decrease postoperative bleeding and hemoglobin loss compared with full heparin dose treatment. In addition, the intubation time was shorter and the incidence of postoperative atrial fibrillation was lower in the patients treated with low heparin doses.     

Comparison of two protocols for heparin neutralization by protamine after cardiopulmonary bypass

Twenty patients undergoing cardiac operations were randomly assigned to two protocols for heparin neutralization by protamine after cardiopulmonary bypass. In all patients protamine chloride was given at a ratio of 1 unit of protamine to 1 unit of injected heparin. In Group I (10 patients) all protamine was infused within 10 minutes after termination of cardiopulmonary bypass. Group II (10 patients) received 75% of the calculated protamine dose within 10 minutes after termination of bypass and the remainder after transfusion of all blood in the heart-lung machine. Plasma heparin levels were significantly lower in Group II 5 minutes after transfusion of all blood in the heart-lung machine and were 0.13 units/ml (standard deviation 0.04) in Group I and 0.06 units/ml (standard deviation 0.05) in Group II (p less than 0.001) 60 minutes after bypass. Activated partial thromboplastin time mirrored the changes in plasma heparin, whereas activated clotting time (Hemochron) was too insensitive to detect these low plasma heparin levels. We conclude that the two-dose protocol resulted in more complete heparin neutralization than the one-dose protocol.     

Plasma Vasopressin Levels and Urinary Sodium Excretion during Cardiopulmonary Bypass with and without Pulsatile Flow

The use of pulsatile perfusion during bypass should create a more physiological milieu and thus attenuate the vasopressin stress response. To determine this, 20 patients scheduled for elective coronary artery bypass operation were studied in two groups. Group 1 had standard nonpulsatile perfusion, and in Group 2 a pulsatile pump was used. Measurements were made before and after anesthesia, after surgical incision, and at 15 and 30 minutes during and after cardiopulmonary bypass.In both groups, vasopressin levels were significantly elevated after sternotomy (4.5 ± 1.5 to 37 ± 10 pg/ml in Group 1 and 3.1 ± 1.2 to 33 ± 9 pg/ml in Group 2, p < 0.05) and during bypass (198 ± 19 pg/ml in Group 1 and 113 ± 16 pg/ml in Group 2) but were higher in Group 1 (p < 0.05). With comparable perfusion pressures in both groups, Group 2 required higher flow (4.5 ± 0.2 versus 3.5 ± 0.3 L/min, p < 0.05) and had lower resistance (1,351 ± 182 versus 1,841 ± 229 dynes sec cm^-5, p < 0.05) and higher urine Na⁺ (123 ± 5 versus 101 ± 8 mEq/L, p < 0.05). These data demonstrate that pulsatile flow can significantly attenuate the vasopressin stress response to bypass. Since vasopressin, at these concentrations, is a potent vasoconstrictor and is capable of producing a Na⁺ diuresis, this may partially explain the higher flow requirements and the decrease in Na⁺ excretion.