The systemic inflammatory response to cardiopulmonary bypass

Although our understanding of the basic pathophysiology of systemic inflammatory response to CPB has significantly advanced in the last 2 decades, these experimentally derived ideas have yet to be fully integrated into clinical practice. Treatment of the systemic inflammatory response to CPB is also confounded by the fact that inhibition of inflammation might disrupt protective physiologic responses or result in immunosuppression. Although it is unlikely that no single therapeutic strategy will ever be sufficient in of itself to totally prevent CPB-associated morbidity, the combination of multiple pharmacologic and mechanical therapeutic strategies, each selectively targeted at different components of the inflammatory response, may eventually result in significantly improved clinical outcomes following cardiac surgery.     

体外循环心脏手术围术期肺的炎性反应

目的 研究体外循环心脏手术过程中肺的炎性反应和观察术后肺功能受损的程度。方法 择期心脏瓣膜置换患者20例,在CPB前,主动脉开放心脏复跳1、3、5、10 min分别采右心房与肺静脉血检测PMN、CD11b、IL-8、IL-10、MDA和SOD水平以及对术后肺功能进行观察。结果 血中上述物质的水平,肺静脉明显高于右心房,主动脉开放心脏复跳后各时点较CPB前显著性升高(P<0.05)。与CPB前比较,术后各时点所有患者肺泡OI、VD/VT及P(A-a)O2分别较CPB前增大(P<0.05),CaO2、SaO2和PaO2均呈下降趋势(P<0.05)。结论 体外循环过程中肺发生了炎性反应并造成肺损害,肺损伤后肺功能的改变为亚临床性。     

The effects of cardiopulmonary bypass temperature on inflammatory response following cardiopulmonary bypass.

OBJECTIVES: The inflammatory response to cardiopulmonary bypass is believed to play an important role in end organ dysfunction after open heart surgery and may be more profound after normothermic systemic perfusion. The aim of the present study was to investigate the effects of cardiopulmonary bypass temperature on the production of markers of inflammatory activity after coronary artery surgery. METHODS: Forty-five low risk patients undergoing elective coronary artery surgery were prospectively randomized into three groups: hypothermia (28 degrees C, n = 15), moderate hypothermia (32 degrees C, n = 15), and normothermia (37 degrees C, n = 15). All patients received cold antegrade crystalloid cardioplegia and topical myocardial cooling with saline at 4 degrees C. Serum samples were collected for the estimation of neutrophil elastase, interleukin 8, C3d, and IgG under ice preoperatively, 5 min after heparinisation, 30 min following start of CPB, at the end of CPB, 5 min after protamine administration, and 4, 12 and 24 h postoperatively. RESULTS: Patients were similar with regard to preoperative and intraoperative characteristics (age, sex, severity of symptoms, number of grafts performed, aortic cross clamp time, cardiopulmonary bypass time). Neutrophil elastase concentration increased markedly as early as 30 min after the onset of cardiopulmonary bypass and peaked 5 min after protamine administration. Levels were not significantly different between the three groups. A similar finding was apparent for C3d release. Interleukin 8 concentrations also demonstrated a considerable increase related to cardiopulmonary bypass in all groups, but there was a significantly more rapid decline in interleukin 8 concentrations in the normothermic group in the postoperative period. Eluted IgG fraction showed a much earlier peak concentration than the other markers, occurring within 30 min of the start of cardiopulmonary bypass. Levels reached a plateau, before declining soon after the end of bypass and remained higher than preoperative values at 24 h. There was no difference between the three groups. The cumulative release of all markers was calculated from the concentration-time curves, and was not statistically different between groups. CONCLUSION: Normothermic systemic perfusion was not shown to produce a more profound inflammatory response compared to hypothermic and moderately hypothermic cardiopulmonary bypass.     

The systemic inflammatory response syndrome and cardiopulmonary bypass

Cardiac surgery using cardiopulmonary bypass (CPB) provokes a systemic inflammatory response. This is mainly triggered by contact activation of blood by artificial surfaces of the extracorporeal circuit. Although often remaining sub-clinical and resolving promptly at the end of CPB, in its most extreme form this inflammatory response may be associated with the development of the systemic inflammatory response syndrome (SIRS) that can often lead to major organ dysfunction (MODs) and death. Here, we review the pathophysiology behind the development of this "whole body" inflammatory response and some of the methods currently used to minimise it.     

全身炎症反应与体外循环

体外循环（CPB）可使机体产生大量的炎症介质,引起全身炎症反应综合征（SIRS）,进一步发展导致多器官功能障碍综合征（MODS）,其发病机制目前较为公认的是“二次打击”学说。围体外循环期SIRS的预防和治疗策略很多,CPB装置的改进及减少炎症介质的生成是主要措施。随着对核转录因子NF-kB研究的不断深入,有可能从分子生物学水平调控CPB引发SIRS的程度。     

Characterizing the inflammatory response to cardiopulmonary bypass in children

Cardiopulmonary bypass is known to trigger a global inflammatory response. Age-dependent differences in the inflammatory response, the increased susceptibility to injury of immature organ systems, and the larger extracorporeal circuit to patient size ratio results in greater susceptibility of younger and smaller patients to the damaging effects of cardiopulmonary bypass. In this review the components of the inflammatory response to cardiopulmonary bypass are reviewed with special reference to the pediatric age group, including the age-specific impact on organ systems. In addition the current and evolving strategies to prevent, limit, and treat the inflammatory response to cardiopulmonary bypass in children are examined.     

Dexamethasone reduces the inflammatory response to cardiopulmonary bypass in children

BACKGROUND: A randomized, prospective, double-blind study of 29 children was performed to evaluate the hypothesis that dexamethasone administration prior to cardiopulmonary bypass would decrease the inflammatory mediator release and improve the postoperative clinical course. METHODS: Fifteen children received dexamethasone (1 mg/kg intravenously) and 14 (controls) received saline solution 1 hour prior to CPB. Serial blood analyses for interleukin-6, tumor necrosis factor-alpha, complement component C3a, and absolute neutrophil count were performed. Postoperative variables evaluated included temperature, supplemental fluids, alveolar-arterial oxygen gradient, and days of mechanical ventilation. RESULTS: Dexamethasone caused an eightfold decrease in interleukin-6 levels and a greater than threefold decrease in tumor necrosis factor-alpha levels after CPB (p < 0.05). Complement component C3a and absolute neutrophil count were not affected by dexamethasone. The mean rectal temperature for the first 24 hours postoperatively was significantly lower in the group given dexamethasone than in the controls (37.2 degrees +/- 0.4 degrees C versus 37.7 degrees +/- 4 degrees C; p = 0.007). Dexamethasone-treated patients required less supplemental fluid during the first 48 hours (22 +/- 28 mL/kg versus 47 +/- 34 mL/kg; p = 0.04). Compared with controls, dexamethasone-treated children had significantly lower alveolar-arterial oxygen gradients during the first 24 hours (144 +/- 108 mm Hg versus 214 +/- 118 mm Hg; p = 0.02) and required less mechanical ventilation (median duration, 3 days versus 5 days; p = 0.02). CONCLUSIONS: Dexamethasone administration prior to CPB in children leads to a reduction in the postbypass inflammatory response as assessed by cytokine levels and clinical course.     

体外循环炎症反应中粘附分子变化及干预性治疗的研究

目的探讨体外循环(CPB)围术期中药川芎嗪干预性治疗的作用机制及临床意义.方法选取诊断明确的先天性心脏病病人32例,随机分成川芎嗪组20例,对照组12例.前者在体外循环预充液中加入盐酸川芎嗪5 mg/kg,后者不用.分别于麻醉诱导后,转机15 min,停机2、6、12、24 h共6个时点,抽取动脉血,采用双抗体夹心法酶联免疫吸附试验测定血浆中可溶性细胞间粘附分子(sICAM-1)、可溶性P-选择素(sP-Selectin)的表达值.结果麻醉诱导后(基值)川芎嗪组和对照组sICAM-1、sP-Selectin无明显差异(P＞0.05);转机后15 min、停机2、6、12 h两组的sICAM-1、sP-Selectin表达值均明显升高,其中停机6、12 h最为明显,与基值比较 ,差异有显著性(P＜0.05);但川芎嗪组较对照组为低(P＜0.05).结论川芎嗪能减弱CPB致炎症反应中sICAM-1、sP-Selectin表达,减轻CPB所致炎症反应,从而减少CPB下心脏直视手术并发症的发生.     

Systemic inflammatory response during cardiopulmonary bypass and strategies

Organ dysfunction after cardiopulmonary bypass (CPB) still is a major problem in patients undergoing cardiovascular surgery. Studies have demonstrated that systemic inflammatory response (SIR) remains one of the major causes of CPB-associated organ injury. The mechanism of SIR during CPB includes the interaction of blood and artificial surface and endotoxemia. The interaction of blood and artificial surface is initiated by protein adsorption. As a result of series of chain reactions, the numerous powerful inflammatory mediators, including hormones and autacoids, are formed and released. Subsequently, the contact system, coagulation system, complement system, fibrinolysis system, and leukocytes, platelets, and endothelial cells, are all activated to participate in the interaction of blood and artificial materials. These activations of different systems and blood cells can interact and magnify each other. CPB-associated endotoxemia has been demonstrated to intensify and deteriorate SIR during CPB. SIR leads to organ injury. In clinical setting, the most common SIR-related organ damage is pulmonary dysfunction, which often is manifested by decreasing of lung compliance, rise in shunt fraction, work of breathing, and likelihood of atelectasis and pneumonia. Strategies to control CPB-related SIR have been developed, such as improvement of biocompatibility of artificial surface (new biomaterials), temporary inhibition of blood cells activation ("blood anesthesia") during CPB, and blockage of the bioactivities and effects of inflammatory mediators.     

两种氧合器对心肺转流炎症反应的影响

目的动态监测室间隔缺损修补术患者在心肺转流(CPB)各时段血清可溶性细胞间粘附分子(sICAM-1)、可溶性E-选择素(sE-selection)及肿瘤坏死因子α(TNF-α)的变化规律,并比较西京-90鼓泡式氧合器和希健-Ⅱ膜式氧合器对其的影响。方法选择择期行室间隔缺损修补术的患者30例,随机均分为鼓泡式氧合器组(B组)和膜式氧合器组(M组)。所有患者分别在麻醉后CPB开始前(T1)、主动脉阻断开放前(T2)、CPB结束时(T3)、术后2h(T4)、6h(T5)、24h(T6)及48h(T7)取静脉血5ml用ELISA法测定sICAM-1、sE-selection及TNF-α的浓度。结果两组患者血清中的TNF-α于T2时开始显著升高,T4时达到峰值(P<0·01)。sICAM-1于T5时开始升高,T6时达峰值。sE-selection于T4时开始升高,T5时达峰值(P<0·01)。M组大部分时点TNF-α、sICAM-1、sE-selection的浓度均低于B组。结论希健-Ⅱ膜式氧合器引起的炎症反应较轻。     

Xenon and the inflammatory response to cardiopulmonary bypass in the rat

OBJECTIVE: The purpose of this study was to investigate the effect of xenon on the inflammatory response to cardiopulmonary bypass. DESIGN: Prospective, randomized experimental study. SETTING: University research laboratory. PARTICIPANTS: Sprague-Dawley rats. INTERVENTIONS: After surgical preparation, rats were randomly divided into 4 groups: (1) SHAM rats were cannulated but did not undergo cardiopulmonary bypass; (2) cardiopulmonary bypass rats were subjected to 60 minutes of cardiopulmonary bypass using an oxygenator receiving a 30% O(2), 65% N(2), and 5% CO(2) gas mixture; (3) MK801 rats received MK801 (0.15 mg/kg intravenous) 15 minutes before 60 minutes of cardiopulmonary bypass with the same gas mixture; and (4) xenon rats underwent 60 minutes of cardiopulmonary bypass receiving a 30% O(2), 60% xenon, 5% N(2), and 5% CO(2) gas mixture. MEASUREMENTS AND MAIN RESULTS: All bypass groups showed elevations in both cytokines compared with the SHAM-operated group. However, the inflammatory response to cardiopulmonary bypass in the group receiving xenon was no different from the other bypass groups. CONCLUSIONS: Xenon appears to have no effect on the inflammatory response to cardiopulmonary bypass, making its previously described neuroprotective effect during cardiopulmonary bypass likely independent of any inflammation modulation.     

核因子kappa B与体外循环炎性反应

核因子κB(NF κB)是近年发现的一种重要转录因子 ,参与多种细胞因子及免疫基因表达的转录、调节。一般情况下 ,NF κB与抑制蛋白IκB结合呈非活性状态 ,受刺激激活后与其抑制蛋白解离 ,移位到核内 ,参与细胞因子、粘附分子、生长因子和急性期蛋白等因子的转录、调控 ,在炎性疾病的启动中起重要作用 ,并在体外循环中诱发炎性反应。现就NF κB在体外循环炎性反应发生机制中所起的作用 ,并对现有NF κB激活的抑制药物和措施作一综述。     

The inflammatory response to colloids and crystalloids used for pump priming during cardiopulmonary bypass

Background: Systemic inflammatory response frequently occurs after coronary artery bypass surgery and is strongly correlated with the risk of postoperative morbidity and mortality. This study tests the hypothesis that the priming of the extracorporeal circuit with colloid solutions results in less inflammation in patients undergoing cardiac surgery than priming with crystalloid solutions. Methods: A prospective, randomized study was designed. Forty‐four patients undergoing elective coronary artery bypass grafting were randomly allocated to one of two groups: 22 patients primed with Ringer's lactate (RL) solution and 22 patients primed with gelatin‐containing solution during the surgery. Plasma levels of interleukin (IL)‐6, IL‐8, tumor necrosis factor (TNF)‐α, C‐reactive protein (CRP) and, complement 4 were measured during the surgical intervention and over the following 48 postoperative hours. Cytokine levels were measured by enzyme‐linked assays from plasma samples obtained at specific time points pre‐ and post‐operatively. Results: In both groups the serum levels of the pro‐inflammatory cytokines (IL‐6, IL‐8, TNF‐α), CRP, complement 4, and leukocytes increased significantly over the baseline, although no significant differences were observed between the two groups. The operation time, blood loss, need for inotropic support, extubation time, and length of intensive care unit stay did not differ significantly between the two groups. Conclusion: Priming with gelatin vs. RL produces no significant differences in the inflammatory response in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.     

Aprotinin and the systemic inflammatory response after cardiopulmonary bypass

Cardiopulmonary bypass is associated with a systemic inflammatory response, a spectrum of pathophysiologic changes ranging from mild organ dysfunction to multisystem organ failure. Complications include coagulation disorders (bleeding diathesis, hyperfibrinolysis) from platelet defects and plasmin activation, as well as pulmonary dysfunction from neutrophil sequestration and degranulation. Diverse injuries are a consequence of multiple inflammatory mediators (complement, kinins, kallikrein, cytokines). Both plasmin and kallikrein amplify the inflammatory response by activating components of the contact activation system. The full-Hammersmith (high dose) of aprotinin, a serine protease inhibitor approved for reducing blood loss and transfusion requirements in cardiopulmonary bypass, inhibits kallikrein and plasmin, resulting in suppression of multiple systems involved in the inflammatory response. Specifically, inhibition of factor XII, bradykinin, C5a, neutrophil integrin expression, elastase activity, and airway nitric oxide production are observed. Clinical correlates include reduced capillary leak, preserved systemic vascular resistance and blood pressure, and improved myocardial recovery following ischemia. Overall, evidence indicates that aprotinin attenuates the systemic inflammatory response associated with cardiopulmonary bypass.     

Inflammatory response to cardiopulmonary bypass

Inflammation in cardiac surgical patients is produced by complex humoral and cellular interactions with numerous pathways including activation, generation, or expression of thrombin, complement, cytokines, neutrophils, adhesion molecules, mast cells, and multiple inflammatory mediators. Because of the redundancy of the inflammatory cascades, profound amplification occurs to produce multiorgan system dysfunction that can manifest as coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive defects. Coagulation and inflammation are also closely linked through networks of both humoral and cellular components including proteases of the clotting and fibrinolytic cascades, including tissue factor. Vascular endothelial cells also mediate inflammation and the cross talk between coagulation and inflammation. Novel antiinflammatory agents inhibit these processes by several mechanisms such as preventing proteolysis of the protease-activated receptor (aprotinin), inhibiting complement-mediated injury (pexelizumab), or inhibiting contact activation (kallikrein inhibitors). Surgery alone also activates specific hemostatic responses, activation of immune mechanisms, and inflammatory response mediated by the release of various cytokines and chemokines. Novel agents are under investigation to further improve outcomes in cardiac surgical patients.     

The systemic inflammatory response after cardiac surgery with cardiopulmonary bypass in children

Paediatric cardiac surgery often requires cardiopulmonary bypass (CPB) during the surgical intervention. CPB is known to elicit a systemic inflammatory response with activation of the complement and coagulation systems, stimulation of cytokine production, cellular entrapment in organs, neutrophil activation with degranulation, platelet activation, and endothelial dysfunction. These changes are associated with a risk of postoperative organ dysfunction and increased morbidity and mortality in the postoperative period. Clinical studies have concentrated on measurement of inflammatory markers and mediators in peripheral blood, where the systemic inflammatory response in the paediatric cardiac patient seems to be different from the adult case. Looking at the organ level, experimental studies have the advantage of providing information contributing to a better understanding of the pathological events that may lead to the deteriorated organ function. This review focuses on the systemic inflammatory response after cardiac surgery with CPB in children and experimental CPB models.     

白细胞滤除对犬体外循环诱发全身炎性反应的影响

目的探讨白细胞滤除对犬体外循环（CPB）诱发全身炎性反应的影响。方法蒙古犬12只，体重25—30kg，随机分为2组（n=6）：对照组（C组）和白细胞滤除组（LD组），C组不使用白细胞滤器，LD组将滤器安装于CPB的静脉回流端，在CPB2min时打开滤器5min。分别于CPB前即刻（T0）、阻断升主动脉后即刻（T1）、阻断升主动脉30min（T2）、开放升主动脉后5min（T3）、停CPB即刻（T4）、停CPB2h（T5）自股静脉抽血，测定白细胞计数和血浆L-选择素、白细胞介紊（IL）-6、IL-8、髓过氧化物酶（MPO）水平。于过滤后30、60、90min时测定滤器内IL-6、IL-8浓度，并在过滤后90min时取滤膜行病理学检查。结果LD组T1时白细胞计数低于C组；两组CPB期间血浆L-选择素、IL-6、IL-8浓度均高于T0，T5时LD组血浆L-选择素、IL-6、IL-8、MPO水平均低于C组。过滤后60、90min时滤器中IL-6、IL-8浓度高过滤后30min；滤器内白细胞滤膜全层布满白细胞，人血面白细胞多于出血面。结论白细胞滤除能抑制犬CPB所引起的全身炎性反应。     

Modulation of the inflammatory response to cardiopulmonary bypass by dopexamine and epidural anesthesia

BACKGROUND: Cardiopulmonary bypass (CPB) induces a systemic inflammatory reaction. Microcirculation-dependent alteration of the gut mucosal barrier with subsequent translocation of endotoxins is a postulated mechanism for this inflammatory response. This study was designed to elucidate whether two different approaches to modulate splanchnic perfusion may influence systemic inflammation to CPB. METHODS: We examined 40 patients scheduled for elective coronary bypass surgery in a prospective, randomized study. One group (DPX) received dopexamine (1 micro g. kg-1. min-1) continuously after induction of anesthesia until 18 h after CPB. The control group (CON) received equal volumes of NaCl 0.9% in a time-matched fashion. In a third group (EPI) a continuous epidural infusion of bupivacaine 0.25% [(body height (cm) - 100). 10-1=ml.h-1] was administered for the whole study period. Procalcitonin (PCT), tumor necrosis factor (TNF-alpha), soluble TNF receptor, human soluble intercellular adhesion molecule-1, C-reactive protein (CRP) and leukocyte count were measured as parameters of inflammation. RESULTS: All parameters significantly increased following CPB. Increases of PCT, TNF-alpha and leukocyte count were significantly attenuated in the DPX and EPI groups at different time points. However, neither splanchnic blood flow nor oxygen delivery and consumption were different when compared with the CON-group. CONCLUSION: These results do suggest that mechanisms other than an improved splanchnic blood flow by DPX and EPI treatment have to be considered for the anti-inflammatory effects.     

Hemostatic activation and inflammatory response during cardiopulmonary bypass: impact of heparin management

BACKGROUND: Cardiac surgery involving cardiopulmonary bypass (CPB) leads to fulminant activation of the hemostatic-inflammatory system. The authors hypothesized that heparin concentration-based anticoagulation management compared with activated clotting time-based heparin management during CPB leads to more effective attenuation of hemostatic activation and inflammatory response. In a randomized prospective study, the authors compared the influence of anticoagulation with a heparin concentration-based system (Hepcon HMS; Medtronic, Minneapolis, MN) to that of activated clotting time-based management on the activation of the hemostatic-inflammatory system during CPB. METHODS: Two hundred elective patients (100 in each group) undergoing standard cardiac surgery in normothermia were enrolled. No antifibrinolytic agents or aprotinin and no heparin-coated CPB systems were used. Samples were collected after administration of the heparin bolus before initiation of CPB and after conclusion of CPB before protamine infusion. RESULTS: There were no differences in the pre-CPB values between both groups. After CPB there were significantly higher concentrations ( < 0.05) for heparin and a significant reduction in thrombin generation (25.2 +/- 21.0 SD vs. 34.6 +/- 25.1), d-dimers (1.94 +/- 1.74 SD vs. 2.58 +/- 2.1 SD), and neutrophil elastase (715.5 +/- 412 SD vs. 856.8 +/- 428 SD), and a trend toward lower beta-thromboglobulin, C5b-9, and soluble P-selectin in the Hepcon HMS group. There were no differences in the post-CPB values for platelet count, adenosine diphosphate-stimulated platelet aggregation, antithrombin III, soluble fibrin, Factor XIIa, or postoperative blood loss. CONCLUSION: Compared with heparin management with the activated clotting time, heparin concentration-based anticoagulation management during CPB leads to a significant reduction of thrombin generation, fibrinolysis, and neutrophil activation, whereas there is no difference in the effect on platelet activation. The generation of fibrin even in the presence of high heparin concentrations most likely has to be attributed to the reduced antithrombin III concentrations or reduced inhibition of clot-bound thrombin. Therefore, in addition to maintenance of higher heparin concentrations, monitoring and substitution of antithrombin III should be considered to ensure more efficient antithrombin activity during CPB.