体外循环后肺损伤机制研究

本文从补体激活、细胞因子释放、白细胞隔离激活并释放自由基、缺血再灌注损伤，血小板激活及微栓形成等方面阐述了体外循环后肺损伤的机制，认为体外循环后肺损伤主要涉及全身炎症反应综合征和缺血再灌注损伤两个病理生理过程。     

体外循环后炎症反应与肺损伤及其防治

０年代早期，Ｋｉｒｋｌｉｎ等〔１〕首次提出体外循环诱发全身炎症反应。体外循环导致补体激活、细胞因子释放、白细胞激活及其释放产物、内皮素、一氧化氮、花生四烯酸代谢产物以及血小板激活等病理生理变化。这些炎症物质的释放与术后多器官衰竭的发生有密切的联系，尤其对呼吸功能有较大影响。长时间体外循环可以产生不同程度的呼吸功能不全，在生理方面主要表现为动脉氧合不足，肺间质水肿，肺顺应性下降；在病理方面常为肺组织充血，肺血管周围出血及肺泡萎陷，肺泡上皮及血管内皮细胞肿胀坏死，白细胞浸润聚集，这种改变在肺动脉高压…     

联合使用白细胞滤器和抑肽酶对机体的保护作用

体外循环中，炎性反应和凝血反应同时被激活，这可能是导致灌注后炎性反应综合征的主要原因。白细胞滤器能够减少循环中自细胞，抑制炎性反应，但由于炎性反应和凝血反应存在密切关系，其对血液的保护作用受到限制。抑肽酶是一种丝氨酸蛋白抑制剂，能抑制纤溶酶活性，保护血小板功能，但其抗炎作用弱，对器官的保护作用仍不肯定。体外循环中联合使用白细胞滤器和抑肽酶能够同时抑制炎性反应和凝血反应，可能对机体发挥更好的保护作用。     

L-选择素在体外循环中的表达及其拮抗剂的肺保护作用

目的研究体外循环术后L-选择素的表达以及应用其拮抗剂进行肺灌注，探讨肺损伤发生的机制和阻断L-选择素表达所起的肺保护作用。方法采用大鼠体外循环及术中肺灌注模型，观察手术前、后及应用拮抗剂后L-选择素的表达，组织超氧化物歧化酶(SOD)、丙二醛(MDA)、髓过氧化物酶(MPO)含量变化，氧指数(PaO2／FiO2)及组织学改变。结果体外循环术后L-选择素的表达增加，应用其拮抗剂进行肺灌注后其表达明显降低，肺损伤相应减轻。结论L-选择素参与了体外循环中肺损伤的发生，阻断其表达可以减轻体外循环肺损伤，改善术后肺功能。     

体外循环后肺损伤机制研究

本文从补体激活、细胞因子释放、白细胞隔离激活并释放自由基、缺血再灌注损伤、血小板激活及微栓形成等方 面阐述了体外循环后肺损伤的机制。认为体外循环后肺损伤主要涉及全身炎症反应综合征和缺血再灌注损伤两个病理生理 过程。     

体外循环后肺损害

体外循环后肺损害主要表现为肺泡－动脉血氧分压差、肺内分流、肺血管阻力、静态和动态响应性增加，肺通气／血灌流失调，严重者引起ARDS。其主要机制是通过激活的白细胞与肺血管内皮细胞及肺上皮细胞粘附并分泌炎性介质；同时补体、炎性介质和缺血再灌注也可激活内皮细胞。这一过程最终导致内皮细胞和上皮细胞的完整性破坏，使血浆、白蛋白和激活的白细胞进入肺组织间隙和肺泡腔，从而造成肺损害。目前主张通过调控炎性反应过程来进行预防和治疗。     

肺保护液对肺动脉高压患儿体外循环后炎性反应的影响

肺损伤是先天性心脏病患儿体外循环后常见的并发症,在合并肺血管病变如肺动脉高压时肺损伤较为严重,导致动脉氧合不足、肺间质水肿和肺顺应性下降等[1].研究表明,经肺动脉灌注低温肺保护液可明显改善肺动脉高压患儿体外循环后的肺功能[2].本研究拟评价肺保护液对肺动脉高压息儿体外循环后炎性反应的影响,探讨其肺保护作用的可能机制.     

自体肺氧合体外循环防止炎症反应性肺损伤

目的 探讨采用自体肺代替人工氧合器的体外循环技术是否比常规体外循环对肺组织有更好的保护作用。方法12只小猪随机分为实验组和对照组。实验组用自体肺代替人工氧合器，对照组按常规体外循环方法，分别转流135min，主动脉阻断60min，测定实验前、后肺静态顺应性、肺动-静脉氧差，检测灌注液中肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6变化，测定肺组织湿，干比和观察肺病理学改变。结果两组体外循环后的肺静态顺应性均下降、肺动-静脉氧分压差增大，灌注液中TNF-α和IL-6含量增加，但两组相比，实验组的改变显著轻于对照组。肺组织标本显示，实验组的肺湿，干比明显低于对照组，光镜和电镜观察肺损伤程度也较轻。结论自体肺能够耐受非搏动性灌注而代替人工氧合器进行体外循环且可显著减轻因肺的缺血再灌注以及因采用人工氧合器所引起的炎症反应性肺损伤，对肺组织有较好的保护作用。     

体外循环后肺损害

体外循环后肺损害主要表现为肺泡-动脉血氧分压差、肺内分流、肺血管阻力、静态和动态顺应性增加,肺通气/血灌流失调,严重者引起ARDS。其主要机制是通过激活的白细胞与肺血管内皮细胞及肺上皮细胞粘附并分泌炎性介质;同时补体、炎性介质和缺血再灌注也可激活内皮细胞。这一过程最终导致内皮细胞和上皮细胞的完整性破坏,使血浆、白蛋白和激活的白细胞进入肺组织间隙和肺泡腔,从而造成肺损害。日前主张通过调控炎性反应过程来进行预防和治疗。     

常温体外循环对肺损伤的影响

目的　探讨常温体外循环对全身炎性反应和肺损伤的影响。　方法　将 3 0例心瓣膜手术患者随机分为低温组和常温组 ,每组 15例。测定两组补体、白细胞计数、多形核白细胞跨肺差值、血浆中脂质过氧化物 ( L PO)和髓过氧化物酶 ( MPO)水平。对 9例患者进行了肺组织学检查。　结果　在体外循环中、结束后 ,两组补体明显减少 ,但组间比较差别无显著性意义。主动脉开放后两组多形核白细胞跨肺差值增大 ,但组间比较差别无显著性意义。主动脉开放后两组L PO和 MPO明显增高 ,但组间比较差别无显著性意义。肺组织形态学检查 ,低温组线粒体出现肿胀 ,常温组线粒体变形 ,内质网断裂。　结论　在低温和常温体外循环中 ,炎性反应相似 ,但肺组织形态学表明常温组肺损伤明显 ,提示常温体外循环可能不利于肺保护。     

Phosphodiesterase type 4 inhibitor rolipram inhibits activation of monocytes during extracorporeal circulation

OBJECTIVE: Cardiopulmonary bypass is associated with systemic inflammatory response syndrome and risk of multiorgan injury mediated by activated leukocytes. Phosphodiesterase type 4 is the predominant phosphodiesterase isozyme in leukocytes and plays a key role in the regulation of leukocyte activation. The aim of this study was to examine the effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on functional changes of monocytes during simulated extracorporeal circulation. METHODS AND RESULTS: Simulated extracorporeal circulation was established by recirculating heparinized human blood for 120 minutes on a membrane oxygenator with or without 10 micromol/L of rolipram. L-selectin and CD11b expression of monocytes were measured with flow cytometry. C4d fragment, Bb fragment, C5b-9, and interleukin-6 were measured with enzyme immunoassay. Rolipram reduced the increase in CD11b expression and the decrease in L-selectin expression of monocytes in response to simulated extracorporeal circulation. Rolipram inhibited the increase in C4d fragment and interleukin-6, but it did not affect the increase in Bb fragment or C5b-9. CONCLUSION: Rolipram inhibited changes in adhesion molecule expression and interleukin-6 release by activated monocytes in simulated extracorporeal circulation. This study suggests that phosphodiesterase type 4 inhibition could be feasible therapeutic strategy to prevent exaggerated inflammatory response and organ injury in patients undergoing cardiopulmonary bypass.     

Drew-Anderson technique attenuates systemic inflammatory response syndrome and improves respiratory function after coronary artery bypass grafting

BACKGROUND: Cardiopulmonary bypass causes inflammatory reactions leading to organ dysfunction postoperatively. This study was undertaken to determine whether using patients' own lungs as oxygenator in a bilateral circuit (Drew-Anderson Technique) could reduce systemic inflammatory response to cardiopulmonary bypass, improving patients clinical outcome following coronary artery bypass grafting. METHODS: A prospective randomized controlled trial involving 30 patients, divided in two groups of 15 patients each, undergoing elective coronary artery bypass grafting, was undertaken. In the Drew-group bilateral extracorporeal circulation using patient's lung as oxygenator was performed. The other patients served as control group, where standard cardiopulmonary bypass procedure was used. RESULTS: Pro-inflammatory and anti-inflammatory mediators were measured. Peak concentrations of proinflammatory interleukin-6, interleukin-8, were significantly lower in 15 patients undergoing Drew-Anderson Technique compared with the concentrations measured in 15 patients treated with standard cardiopulmonary bypass technique. Differences in patient recovery were analyzed with respect to time of intubation, blood loss, intrapulmonary shunting, oxygenation, and respiratory index. In patients undergoing uncomplicated coronary artery bypass grafting procedures bilateral extracorporeal circulation using the patients' own lung as oxygenator provided significant biochemical and clinical benefit in comparison to the standard cardiopulmonary bypass procedure. CONCLUSIONS: This prospective randomized clinical study has demonstrated that exclusion of an artificial oxygenator from cardiopulmonary bypass circuit significantly decreases the activation of inflammatory reaction, and that interventions that attenuate this response may result in more favorable clinical outcome.     

腺苷对犬体外循环后肺缺血—再灌注损伤的作用

目的　研究腺苷是否能减轻体外循环后肺组织损伤。　方法　12条犬随机分为实验组和对照组。建立体外循环模型,实验组使用腺苷(50μg/kg     

Exhaled carbon monoxide and inducible heme oxygenase expression in a rat model of postperfusion acute lung injury

OBJECTIVE: Expression of inducible heme oxygenase has been shown to be increased in various visceral inflammatory disorders, which may confer a protective role. The purpose of our study was to determine whether the expression of inducible heme oxygenase was up-regulated within lungs in a rat model of extracorporeal circulation. METHODS: Wistar rats underwent either a partial femoro-femoral extracorporeal circulation in normothermia for 3 hours (n = 5) or a sham procedure (n = 5). Exhaled carbon monoxide concentration was monitored with an infrared analyzer. After the rats were killed, lungs were harvested for determination of heme oxygenase activity and inducible heme oxygenase expression (by Western blot and immunohistochemistry). Lung injury was also assessed by arterial blood gas analysis and microscopic study. RESULTS: Extracorporeal circulation was responsible for a lung injury characterized by decreased arterial blood oxygen saturation and typical morphologic findings (marked alveolar neutrophil infiltration; interstitial edema). Exhaled carbon monoxide concentration remained stable throughout the experiment in all sham rats, whereas it increased after extracorporeal circulation (from 0.16 +/- 0.05 ppm at baseline to 0.7 +/- 0.2 ppm at end of experiment; P =.0001). Pulmonary heme oxygenase activity and inducible heme oxygenase content (assessed by Western blot) were increased within lungs of rats that underwent extracorporeal circulation. Immunohistochemistry revealed that the expression of inducible heme oxygenase was mainly localized to inflammatory cells. CONCLUSIONS: Post-extracorporeal circulation acute lung injury in rats was associated with an increased expression of inducible heme oxygenase, the functional significance of which remains to be determined.     

A heparin-coated circuit reduces complement activation and the release of leukocyte inflammatory mediators during extracorporeal circulation in a rabbit

Heparin coating modifies complement activation during extracorporeal circulation much more effectively than systemically administered heparin. This rabbit study was undertaken to address possible mechanisms responsible for this difference. We evaluated the effect of heparin coating on complement activation and subsequently the release of leukocyte inflammatory mediators during extracorporeal circulation through a simplified circuit. We found in the heparin-coated group a significantly reduced complement hemolytic activity (CH50), remaining higher leukocyte numbers, significantly decreased release of beta-glucuronidase, and most strikingly a complete prevention of tumor necrosis factor (TNF) formation. The significantly reduced CH50 activity in the heparin-coated groups indicates the reduction of one or more native classical complement products. This could be explained by the absorption of complement components by the circuit, which results in reduced activity of the complement cascade. We conclude therefore that heparin coating reduces complement activation and consequently reduces the release of leukocyte inflammatory mediators.     

Corticosteroids during operations using cardiopulmonary bypass

Although corticosteroids have been used for more than 30 years in the context of extracorporeal circulation, there is an ongoing debate about the benefits of their routine application. Methylprednisolone was given as early as 1966 to reduce vasoconstriction during cardiopulmonary bypass (CPB) and to prevent low output syndrome thereafter. An explanation for these findings was recently published. Lipid mediators lead to vasoconstriction and inflammatory cytokine production during CPB. There is no doubt about the potential of corticosteroids to reduce inflammatory and enhance anti-inflammatory mediators, while their possible influence on clinical parameters and their side effects are controversial, as discussed in the literature. There have been contradictory results with respect to pulmonary oxygenation, while an increase in the patient's blood glucose levels, however clinically unimportant, could be demonstrated. The influence of other drugs affecting the inflammatory response has to be taken into account, leading to a patient-specific recommendation for the use of corticosteroids during operations requiring CPB.     

Regulation of inflammatory responses by endothelial cells--understanding the molecular mechanism(s) and its therapeutic application to sepsis

Endothelial cells are activated by shear-stress and inflammatory mediators that are capable of activating sensory neurons. Activated endothelial cells increase the production of nitric oxide and prostaglandins, thereby regulating inflammatory responses induced by various insults. Dysfunction of sensory neurons and excess inflammatory mediators released from activated neutrophils damage endothelial cells, thereby increasing inflammatory responses such as an increase in tumor necrosis factor production. Pulmonary endothelial dysfunction plays a critical role in the development of acute lung injury and shock, leading to multi-organ failure. Determination of soluble E-selectin in serum samples of patients with sepsis predicts the future development of acute lung injury. Therapeutic agents that are capable of stimulating sensory neurons or inhibiting leukocyte activation might be useful in the treatment of severe sepsis especially when these agents are administered in the early stage of severe sepsis.     

Balanced Ultrafiltration: Inflammatory Mediator Removal Capacity

Ultrafiltration with a hemoconcentrator may remove excess fluid load and alleviate tissue edema and has been universally adopted in extracorporeal circulation protocols during pediatric cardiac surgery. Balanced ultrafiltration is advocated to remove inflammatory mediators generated during surgery. However, whether balanced ultrafiltration can remove all or a portion of the inflammatory mediator load remains unclear. The inflammatory mediator removal capacity of zero‐balanced ultrafiltration was measured during pediatric extracorporeal circulation in vitro. Extracorporeal circulation was composed of cardiotomy reservoir, D902 Lilliput 2 membrane oxygenator, and Capiox AF02 pediatric arterial line filter. The Hemoconcentrator BC 20 plus was placed between arterial purge line and oxygenator venous reservoir. Fresh donor human whole blood was added into the circuit and mixed with Ringer's solution to obtain a final hematocrit of 24–28%. After 2 h of extracorporeal circulation, zero‐balanced ultrafiltration was initiated and arterial line pressure was maintained at approximately 100 mm Hg with Hoffman clamp. The rate of ultrafiltration (12 mL/min) was controlled by ultrafiltrate outlet pressure. Identical volume of plasmaslyte A was dripped into the circuit to maintain stable hematocrit during the 45 min of the experiment. Plasma and ultrafiltrate samples were drawn every 5 min, and concentrations of inflammatory mediators including interleukin‐1β (IL‐1β), IL‐6, IL‐10, neutrophil elastase (NE), and tumor necrosis factor‐α (TNF‐α) were measured. All assayed inflammatory mediators were detected in the ultrafiltrate, demonstrating that the ultrafiltrator may remove inflammatory mediators. However, dynamic observations suggested that the concentration of NE was highest among the five inflammatory mediators in both plasma and ultrafiltrate (P < 0.001). IL‐1β had the lowest concentration in plasma, whereas the concentration of TNF‐α was the lowest in ultrafiltrate (P < 0.001). Concentrations of all inflammatory mediators in the ultrafiltrate did not increase linearly compared with those in plasma. The respective ultrafiltrate to plasma concentration and amount ratios indicated that the total removal effect of hemoconcentrator on the inflammatory mediators was 4.17 ± 2.68% for IL‐1β, 0.64 ± 0.69% for IL‐6, 0.24 ± 0.18% for IL‐10, 2.84 ± 1.65% for NE, and 0.51 ± 0.81% for TNF‐α, respectively. Balanced ultrafiltration may selectively remove inflammatory mediators from serum. Respective ratios of inflammatory mediators in ultrafiltrate compared with plasma, as well as total amount of inflammatory mediators in the ultrafiltrate suggest that balanced ultrafiltration removes a limited portion of the total inflammatory mediator load.     

Hemocompatibility of a Miniaturized Extracorporeal Membrane Oxygenation and a Pumpless Interventional Lung Assist in Experimental Lung Injury

Extracorporeal membrane oxygenation (ECMO) is used for most severe acute respiratory distress syndrome cases in specialized centers. Hemocompatibility of devices depends on the size and modification of blood contacting surfaces as well as blood flow rates. An interventional lung assist using arteriovenous perfusion of a low-resistance oxygenator without a blood pump (Novalung, Hechingen, Germany) or a miniaturized ECMO with reduced filling volume and a diagonal blood pump (Deltastream, Medos AG, Stolberg, Germany) could optimize hemocompatibility. The aim of the study was to compare hemocompatibility with conventional ECMO. Female pigs were connected to extracorporeal circulation for 24 h after lavage induced lung injury (eight per group). Activation of coagulation and immune system as well as blood cell damage was measured. A P value <0.05 was considered significant. Plasmatic coagulation was slightly activated in all groups demonstrated by increased thrombin-anti-thrombin III-complex. No clinical signs of bleeding or thromboembolism occurred. Thrombelastography revealed decreased clotting capacities after miniaturized ECMO, probably due to significantly reduced platelet count. These resulted in reduced dosage of intravenous heparin. Scanning electron microscopy of oxygenator fibers showed significantly increased binding and shape change of platelets after interventional lung assist. In all groups, hemolysis remained negligible, indicated by low plasma hemoglobin concentration. Interleukin 8 and tumor necrosis factor-α concentration as well as leukocyte count remained unchanged. Both devices demonstrated adequate hemocompatibility for safe clinical application, although a missing blood pump did not increase hemocompatibility. Further studies seem necessary to analyze the influence of different blood pumps on platelet drop systematically.