Complement activation with bubble and membrane oxygenators in aortocoronary bypass grafting

Thirty-three patients admitted for coronary bypass grafting were randomized to cardiopulmonary bypass with a bubble oxygenator (Cobe or Polystan) or a membrane oxygenator (SciMed). Plasma concentrations of C3 activation products and the terminal complement complex were measured using enzyme immunoassays. Both variables increased almost linearly after onset of cardiopulmonary bypass, with maximal concentrations at closure of the sternum. From a baseline of 7.5 to 12.0 arbitrary units (AU)/mL (medians), the concentrations of C3 activation products increased by 117.5 AU/mL (Cobe), 120.5 AU/mL (Polystan), and 213.3 AU/mL (SciMed). The increase in the membrane group was significantly higher than in the two bubble oxygenator groups (p less than 0.01). From a baseline of 0.9 to 1.3 AU/mL, the concentrations of terminal complement complex increased by 5.4 AU/mL (Cobe), 6.6 AU/mL (Polystan), and 7.7 AU/mL (SciMed) (differences not significant). The higher C3 activation caused by the membrane oxygenator may be explained by differences in flow profile and surface area in contact with blood. The study cannot confirm the general assumption that membrane oxygenators lead to lower complement activation than do bubble oxygenators.     

Complement activation in cardiopulmonary bypass, with special reference to anaphylatoxin production in membrane and bubble oxygenators

Complement activation by cardiopulmonary bypass (CPB) was studied in 82 patients divided into membrane (MOG) and bubble oxygenator groups (BOG). The influence of primed homologous to circulating autologous blood volume (H/A) ratio was also evaluated. C4a increased very slowly during CPB in both groups, maintaining slightly higher levels in the BOG than in the MOG, with the exception of a marked initial rise in the BOG with a high H/A ratio (greater than or equal to 20%). Anaphylatoxin C3a levels increased more steeply in the BOG than in the MOG. An obvious rise in anaphylatoxin C5a production was observed in the BOG alone. The influence of high H/A ratio perfusion on complement activation was milder in the MOG than in the BOG. In 20 monkeys (Macaca fascicularis), continuous intraaortic infusion with bubbled autologous blood increased C4a and C3a levels, while autologous blood extracorporeally contacted with nylon increased C3a levels alone. In vitro studies revealed that human immunoglobulin fractions denatured by oxygen bubbling produced C4a, C3a, and C5a in a dose-dependent manner, although human albumin treated identically as human immunoglobulin did not produce these complements. It was thus inferred that (1) during CPB, complement is predominantly activated via the classical pathway in the BOG and via the alternative pathway in the MOG; (2) higher anaphylatoxin levels in the BOG than in the MOG are related to mode and grade of blood trauma; (3) anaphylatoxin level differences in both groups tend to increase with high H/A perfusion; and (4) immunoglobulin-free sera may reduced classical pathway activation.     

Complement activation during cardiopulmonary bypass

We researched complement activation of fifteen patients who had open heart surgery and on ten patients who had closed heart surgery. Our results showed that the complement system was partially activated by the anaesthesia and partially by tissue damage. This activation was aggravated when plasma contacted the pump-oxygenator system, continued in the intensive-care unit and became normal in the 24th hour after the operation. Complement activation occurred both via the alternative and classical pathways but the alternative pathway was activated more than the classical with increase in bypass time. Pulmonary sequestration of leucocytes which occurred due to the complement activation and the complement derived inflammatory mediators could have contributed to the pathogenesis of the post-pump syndrome.     

Inflammatory system activation during cardiopulmonary bypass as an indicator of biocompatibility: a randomized comparison of bubble and membrane oxygenators

As the exposure of blood to foreign material during cardiopulmonary bypass (CPB) leads to triggering of inflammatory systems, the inflammatory response was used as an indicator of the biocompatibility of oxygenators. Activation of complement and neutrophil granulocytes during CPB was studied in 96 patients undergoing coronary bypass, with randomized comparisons between four different oxygenators, two of bubble and two of membrane type. Seven patients undergoing thoracotomy without CPB served as controls. During CPB there was significant complement activation, measured as changes in the ratio C3d/C3, with no demonstrable difference between the bubble and membrane oxygenator groups. Such change was not seen in the controls. Neutrophil granulocytes released significant amounts of the granule proteins lactoferrin and myeloperoxidase during CPB, but not during thoracotomy without CPB. The plasma concentrations of lactoferrin and myeloperoxidase were significantly lower in the membrane oxygenator groups, possibly indicating better biocompatibility. The strong inflammatory response with both oxygenator types, however, indicates that presently used CPB devices have unsatisfactory biocompatibility.     

Complement activation in extracorporeal circulation. Comparison of nylon versus polyester bubble oxygenators

Complement activation during cardiopulmonary bypass is well known and may influence postoperative morbidity. As nylon can particularly induce complement activation, its influence was assessed by measuring total haemolytic complement and B, C3 and C4 factors, during cardiopulmonary bypass with bubble oxygenators for coronary surgery, comparing "nylon" circuits (20 patients, Bentley BOS 10) versus "polyester" circuits (19 patients, Shiley S 100 A). Complement activation began with induction of anaesthesia and surgical procedures, B, C3 and C4 levels falling significantly (respectively 15, 17 and 20% from baseline values). The alternative pathway was activated before the classical pathway. Complement activation continued during cardiopulmonary bypass, with no more consumption of complement factors (slight variations of about 0 to 3% of the levels found after anaesthetic induction and surgical procedures). No statistically significant difference appeared between the two groups. This suggested that nylon did not significantly increase complement activation during cardiopulmonary bypass. The bubble oxygenator material cannot therefore be considered as a criterion for choosing the type of equipment.     

Complement activation and lung permeability during cardiopulmonary bypass

Pulmonary dysfunction after cardiopulmonary bypass has been attributed to the damaging effects of complement activation on the lung. To further explore this phenomenon, we measured plasma levels of activated complement components (radioimmunoassay), assessed neutrophil n-formyl-methionyl-leucyl-phenylalanine (FMLP) receptor status (radioligand saturation binding assay), and quantified pulmonary epithelial permeability as radioaerosol lung clearance of technetium 99m-labeled diethylenetriamine pentaacetic acid in a series of 8 patients undergoing cardiopulmonary bypass. Significant elevations of plasma C3adesArg, C4adesArg, and C5adesArg levels were seen just after CPB, indicating activation of both the classic and alternate complement pathways. Neutrophil activation was evident as increased expression of neutrophil FMLP surface receptors after bypass. Despite the presence of complement and neutrophil activation, increased pulmonary epithelial permeability was not seen. These data support the hypothesis that complement and neutrophil activation during cardiopulmonary bypass is not associated with acute lung injury, at least not pulmonary epithelial injury. One can therefore infer that increased pulmonary epithelial permeability in patients at high risk for and experiencing sepsis-induced and trauma-induced adult respiratory distress syndrome may be due to factors other than complement and neutrophil activation.     

Washin and washout of isoflurane administered via bubble oxygenators during hypothermic cardiopulmonary bypass

Washin and washout of a volatile anesthetic given through the oxygenator during hypothermic (23.4 +/- 2.1 degrees C) cardiopulmonary bypass were studied in nine patients. The authors administered isoflurane and measured its partial pressure in arterial (Pa) and venous (Pv) blood and the gas exhausted from the oxygenator (PE) at 1, 2, 4, 8, 16, 32, and 48 min during washin. These measurements were repeated during washout, which coincided with rewarming. During washin, PE, Pa, and Pv progressively rose toward inlet gas partial pressure (PI). Equilibration of Pa with PI was 41% after 16 min, 51% after 32 min, and 57% after 48 min of washin. During washout, Pa declined to 24% of its peak after 16 min and to 13% after 32 min. Washin and washout were considerably slower in mixed venous blood. Washin of isoflurane appeared to occur more slowly during cardiopulmonary bypass than during administration via the lungs in normothermic patients, presumably because hypothermia increases tissue capacity, compensating for the effect of hemodilution that otherwise would decrease the blood/gas partition coefficient. During rewarming, washout appeared to occur as rapidly as from the lungs of normothermic patients. This may have resulted from the declining blood/gas partition coefficient (due to rewarming) and relatively limited tissue stores of isoflurane. The relationship between exhaust and arterial partial pressures was reasonably consistent; for clinical purposes, measurement of PE can be used to estimate Pa.     

Complement activation during cardiopulmonary bypass: mechanism and prevention

The mechanism of complement activation during cardiopulmonary bypass was studied for the prevention. In ten patients undergoing open-heart procedures, the serum levels of complement fractions (C3, C4, and C3 activator) were measured by a single radial immune diffusion method. In four of ten patients, the plasma levels of C3a, C4a, and C5a fractions were studied by the radioimmunoassay 2 antibodies method. The serum levels of C3, C4, and C3 activator decreased after cardiopulmonary bypass. The plasma levels of C3a, C4a, and C5a increased after bypass. The lower level of C3 activator shows that C3 activator was not excessively produced during cardiopulmonary bypass. Therefore it can be thought that much C4b2a from classical pathway as well as C3a over-production localizing extra-corporeal circuits and little inhibitors on alternative pathway resulted in increased complement activation. The prevention should be done from these etiologies.     

Complement activation before, during and after cardiopulmonary bypass

Plasma levels of the complement parent molecules C3, C4, and factor B and their split products, C3d, C4d, and Ba were measured in 12 patients undergoing cardiopulmonary bypass for coronary artery surgery. Alternative and common complement pathway activation, demonstrated by statistically significant rising levels of Ba (P less than 0.05), and C3d (P less than 0.05) and by elevated Ba:B (P less than 0.05) and C3d:C3 (P less than 0.05) ratios were found before the institution of cardiopulmonary bypass but following heparin administration suggesting that heparin may itself initiate alternative pathway activation. In addition, significant depletion of parent complement components and elevation of split product concentrations was seen during bypass suggesting classical and alternate pathway activation (P less than 0.01). This study clarifies the pathways of complement activation during bypass and presents evidence that heparin administration may initially activate the complement cascade.     

低温心肺转流中不同氧合器对儿童罗库溴铵药效动力学的影响

目的研究先天性心脏病学龄儿童心肺转流(CPB)中,不同氧合器对其罗库溴铵药效动力学的影响。方法选择6～12岁先天性心脏病患儿46例,随机分为膜式氧合器组(MO组,n=22)和鼓泡式氧合器组(BO组,n=24)。诱导后静脉给罗库溴铵600μg/kg行气管插管。CPB前、中、后三阶段,肌颤搐反应强度(T1)25%时,静注罗库溴铵200μg/kg。监测两组诱导期、CPB前、中、后期罗库溴铵的起效时间、无反应时间、T110%、T125%、T175%恢复时间及恢复指数等指标。结果两组患儿CPB前罗库溴铵肌松时效比较差异无统计学意义。CPB中,MO组和BO组的起效时间、无反应时间、T110%、T110%～25%、T125%分别为(3.72±2.10)、(29.45±7.67)、(46.36±7.26)、(14.12±2.62)、(60.57±6.31)和(3.62±1.78)、(24.95±6.93)、(43.07±7.99)、(13.04±2.46)、(56.68±6.82)min,组间比较差异无统计学意义。结论低温CPB中使用膜式氧合器与鼓泡式氧合器对罗库溴铵维持量的肌松时效影响差异无统计学意义。     

Postperfusion lung syndrome. Comparison of Travenol bubble and membrane oxygenators.

To examine the role of the oxygenator in the postperfusion lung syndrome, we studied 16 patients undergoing aorta-coronary bypass with a bubble oxygenator and 14 similar patients with a membrane oxygenator both before and for 2 days after the operation. To maintain the same pulmonary artery occluded pressure and hemoglobin level at the end of the surgical procedure, significantly more blood was required in the bubble than in the membrane group. Postoperative pulmonary dysfunction in the bubble group was characterized by increased pulmonary vascular resistance (PVR) and lung water. The increase in lung water was present after bubble oxygenation on three successive measurements, whereas there was no increase in lung water above control value at any measurement time in the membrane group. The bubble group had a significantly greater increase in PVR at the immediate postoperative study time than did the membrane group. PVR returned to control value for the duration of study. These differences in lung water and PVR measurements may be related to greater blood component trauma with a Travenol bubble oxygenator than with a membrane lung.     

Complement activation during major operations with or without cardiopulmonary bypass

Plasma concentrations of the complement products C3dg and the terminal complement complex, as well as the number of granulocytes (polymorphonuclear neutrophils), were assessed in patients undergoing aorta-coronary bypass with extracorporeal circulation, abdominal aneurysmectomy with implantation of an aortic graft, or thoracotomy without the introduction of synthetic material into the circulation. The concentration of terminal complement complex increased significantly only in the group undergoing extracorporeal circulation, with a corresponding drop in the number of granulocytes. In contrast, the C3dg concentration increased during both extracorporeal circulation and abdominal aneurysmectomy, which indicates that other factors than extracorporeal circulation may affect C3 activation during major operations. In the thoracotomy group, where the most pronounced increase in granulocytes was found, no complement activation was recorded. It is concluded that extracorporeal circulation activates the terminal pathway of complement and that assays detecting activation of both the initial and the terminal parts should be included when the pathophysiology of complement is examined during major operations and extracorporeal circulation.     

In vivo uptake and elimination of isoflurane by different membrane oxygenators during cardiopulmonary bypass

BACKGROUND: Volatile anesthetics are frequently used during cardiopulmonary bypass (CPB) to maintain anesthesia. Uptake and elimination of the volatile agent are dependent on the composition of the oxygenator. This study was designed to evaluate whether the in vivo uptake and elimination of isoflurane differs between microporous membrane oxygenators containing a conventional polypropylene (PPL) membrane and oxygenators with a new poly-(4-methyl-1-pentene) (PMP) membrane measuring isoflurane concentrations in blood. METHODS: Twenty-four patients undergoing elective coronary bypass surgery with the aid of CPB were randomly allocated to one of four groups, using either one of two different PPL-membrane oxygenators for CPB or one of two different PMP-membrane oxygenators. During hypothermic CPB, 1% isoflurane in an oxygen-air mixture was added to the oxygenator gas inflow line (gas flow, 3 l/min) for 15 min. Isoflurane concentration was measured in blood and in exhaust gas at the outflow port of the oxygenator. Between-group comparisons were performed for the area under the curve (AUC) during uptake and elimination of the isoflurane blood concentrations, the maximum isoflurane blood concentration (C(max)), and the exhausted isoflurane concentration (F(E)). RESULTS: The uptake of isoflurane, expressed as AUC of isoflurane blood concentration and a function of F(E), was significantly reduced in PMP oxygenators compared to PPL oxygenators (P < 0.01). C(max) was between 8.5 and 13 times lower in the PMP-membrane oxygenator groups compared to the conventional PPL-membrane oxygenator groups (P < 0.01). CONCLUSIONS: The uptake of isoflurane into blood via PMP oxygenators during CPB is severely limited. This should be taken into consideration in cases using such devices.     

Comparison of bubble and membrane oxygenators in short and long perfusions.

Eighty patients had cardiopulmonary bypass (CPB), half having short (109 +/- 11 minutes) perfusions and half having long (188 +/- 14 min) perfusions. Twenty patients in each group were perfused with bubble oxygenators (Bentley, Harvey, or Galen) and 20 with membrane oxygenators (Modulung or Teflo). Hemodilution to a hematocrit value of 22.5% +/- 1.4% and hypothermia to 28 degrees +/- 2 degrees C were used in all patients. Complete hemograms, sequential multiple analyzer 18 tests, coagulation profiles, blood gases and pH, three immunoglobulins, and two complement fraction proteins were sampled as follows: three times before perfusion, one to ten times during perfusion, 1 hour immediately after perfusion, and 4, 24, and 48 hours postoperatively. Data in concentration terms were compared statistically and reported as mean and standard error for each subset. Additionally, rates of gain or loss were calculated in terms of quantity per liter of blood pumped per minute. During perfusion for both duration sets, use of a membrane oxygenator resulted in greater pump flows (4.55 +/- 0.15 L/min versus 3.75 +/- 0.11 L/min), lower total peripheral resistances (1,125 +/- 63 dynes.sec.cm-5 versus 1,652 +/- 115 dynes.sec.cm-5), and greater urinary outputs (9.4 +/- 1.1 ml/min versus 2.2 +/- 0.6 ml/min) than in the bubble oxygenator subsets. Comparisons of measured and calculated data in the immediate postperfusion interval showed no differences between bubble and membrane oxygenator subsets for short perfusions. In long perfusions, the membrane subset had lower plasma hemoglobin and white cell concentrations and generation rates, smaller (3 to 8 1/2 times) losses of IgG, IgM, C3 and shed blood necessitating less transfusion, and greater C4 losses. The membrane oxygenator systems used were more complex and costly and offered no advantages for short perfusion in adults. In anticipated long perfusions or where bleeding may be a problem, a membrane oxygenator appears more efficacious than bubble systems. For perfusions of less than 2 hours, membrane oxygenators had no biochemical or hematologic advantage over the bubble devices used in this study.     

Cardiopulmonary bypass without systemic heparinization. Performance of heparin-coated oxygenators in comparison with classic membrane and bubble oxygenators

Performance characteristics of heparin-coated hollow-fiber membrane oxygenators (COATED HFMO, n = 5) were evaluated in an open-chest dog model without systemic heparinization. Four other oxygenators were evaluated with standard systemic heparinization (300 IU/kg, activated clotting time more than 400 seconds): a standard hollow-fiber membrane oxygenator (HFMO, n = 5), an inversed hollow-fiber membrane oxygenator (IHFMO, n = 5), a plate membrane oxygenator (PLATE MO, n = 5) and a bubble oxygenator (BUBBLE O, n = 5). The 25 dogs (36 +/- 12 kg) were perfused after cavo-aortic cannulation for 6 hours with a mean flow of 100 ml/kg body weight. At the end of perfusion without systemic heparin, heparin-coated equipment was replaced in three animals with standard uncoated equipment for control studies. Besides continuous hemodynamic evaluation with Mikro-Tip pressure transducers (Millar Instruments, Inc., Houston, Texas), a standard battery of analyses was performed before, after mixing, and every 30 minutes during bypass. All animals could be perfused in accordance with the protocol. Blood-gas values (pH, arterial oxygen tension, and arterial carbon dioxide tension) were maintained within physiologic ranges for all groups. After 6 hours of perfusion, plasma hemoglobin levels were as follows: 0.57 +/- 0.51 gm/L for COATED HFMO without systemic heparinization versus 2.65 +/- 1.02 gm/L for HFMO (p less than 0.05), 1.77 +/- 0.48 gm/L for IHFMO (p less than 0.05), 1.96 +/- 0.41 gm/L for PLATE O (p less than 0.05), and 1.5 +/- 0.40 gm/L for BUBBLE O (p less than 0.05) with systemic heparinization. Platelet levels were highest for COATED HFMO with 47% +/- 36% without systemic heparinization versus 33% +/- 9% for HFMO, 12% +/- 2% for IHFMO, 36% +/- 17% for PLATE O, and 19% +/- 12% for BUBBLE O with systemic heparinization. Activated clotting time for COATED HFMO without systemic heparinization was 135 +/- 75 seconds before bypass, 207 +/- 21 seconds after mixing, and 131 +/- 20 seconds after 4 hours of perfusion. There was no statistically significant increase of plasma heparin levels in the group perfused without systemic heparin. Determination of fibrin split products during perfusion without systemic heparinization did not show a significant increase. At the end of perfusion all devices were disconnected and gently rinsed with saline: There were no macroscopic clots in the COATED HFMO group perfused without systemic heparin. However, uncoated equipment introduced for control in animals perfused without systemic heparin showed major clotting.(ABSTRACT TRUNCATED AT 400 WORDS)