Effect of cardiopulmonary bypass on myocardial function, damage and inflammation after cardiac surgery in newborns and children.

Postoperative measurement of cardiac troponin I, creatine kinase and procalcitonin reflects myocardial damage and systemic inflammatory response after cardiac surgery with cardiopulmonary bypass in children. Pulse-contour cardiac output technique is a less invasive tool for determining postoperative cardiac function. OBJECTIVE: The aim of our study was to investigate myocardial lesions and systemic inflammatory response after cardiac surgery with cardiopulmonary bypass in children suffering from congenital heart defects. METHODS: The elevation of cardiac troponin I (cTnI), creatine kinase (CK) and procalcitonin (PCT) was evaluated in relationship to duration of aortic cross-clamping, incisional trauma and cardiac bypass temperature in 37 paediatric patients. To assess postoperative cardiac function, the cardiac index was measured in 7 children using the PiCCO (pulse contour cardiac output) technique. RESULTS: CTnI and PCT both peaked on the day of surgery and slowly decreased postoperatively in case of an uncomplicated course. The median values of both parameters differed significantly from the day of surgery until the fourth postoperative day in children with an aortic cross-clamping time (CCT) longer than 80 minutes or after ventriculotomy in comparison to patients with shorter clamping times or atriotomy only. CK values showed similar results, but were less significant than cTnI. A relationship between cTnI, CK or PCT and the body temperature during cardiopulmonary bypass was not found. The cardiac indices (CI) measured by the PiCCO technique in the first 48 hours after surgery showed normal values. CONCLUSION: In summary, perioperative measurement of cTnI, CK and PCT reflects myocardial damage and systemic inflammatory response and allows an improved peri- and postoperative management. PiCCO technique is an excellent, less invasive tool to determine postoperative cardiac function.     

Inflammatory response to cardiac surgery and strategies to overcome it

A general activation of the immune system is observed during any operative procedure as a physiological response to the surgical trauma. Cardiopulmonary bypass may directly activate the inflammatory response by three distinct mechanisms: direct 'contact activation' of the immune system following exposure of blood to the foreign surfaces, ischaemia-reperfusion injury to vital organs and systemic endotoxaemia resulting from gut translocation of endotoxin. The inflammatory response depends upon recruitment and activation of inflammatory cells. The cellular immune response, in particular polymorphonuclear cell-endothelial adhesion, leads to widespread endothelial damage and dysfunction. Increased oxygen derived free radical activity represents a risk for myocardial and pulmonary complications. The clinical consequences of the stress response vary from a mild generalised transient response, termed the 'systemic inflammatory response syndrome,' to life threatening organ dysfunction. The introduction of the 'off-pump' coronary artery bypass graft surgery has now made it possible to differentiate the influence of cardiopulmonary bypass and surgical access on different modalities of the immune response. 'Off-pump' cardiac surgery has been found to trigger inflammatory response, lesser than 'on-pump' cardiac surgery. Researches are directed towards understanding this complex interplay of humoral and cellular mediators and develop strategies to limit the resultant organ dysfunction. Current literature on the various mediators of this inflammatory response, the role of surgical stress, the pathogenesis of the organ damage and strategies to limit / overcome this response are reviewed.     

Antithrombin and protein C in systemic inflammatory response syndrome

Coronary artery bypass grafting with cardiopulmonary bypass can induce systemic inflammatory response syndrome. To assess the prevalence of preoperative antithrombin and protein C deficiencies in relation to the incidence of this syndrome, antithrombin and protein C levels were measured in 130 patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Systemic inflammatory response syndrome developed in 36 (27.7%) patients who were predominantly male, had a lower EuroSCORE, longer cardiopulmonary bypass time, higher pre-bypass temperature, and shorter activated coagulation time. Logistic regression showed that predictive factors included bypass duration and pre-bypass temperature; however, low antithrombin levels appeared to be a negative predictive factor. Antithrombin levels were < 80% in 33.8% of patients, and 11.6% had protein C levels < 80%. Postoperative antithrombin and protein C deficiencies are not uncommon in adults undergoing cardiac surgery with cardiopulmonary bypass, but detection of these deficits did not identify patients at increased risk of systemic inflammatory response syndrome.     

Interleukin-6 and procalcitonin in serum of children undergoing cardiac surgery with cardiopulmonary bypass

OBJECTIVE: The aim of our study was to investigate the systemic inflammatory response in children with congenital heart disease undergoing surgical correction with cardiopulmonary bypass. We wanted to discuss interleukin 6 and procalcitonin as components of the systemic inflammatory response syndrome to cardiopulmonary bypass and evaluate postoperative kinetics of these parameters in case of an uncomplicated course. METHODS: Procalcitonin and interleukin 6 were determined before and after cardiopulmonary bypass surgery in 37 children on the day of surgery, the first and fourth postoperative day.The increased procalcitonin and interleukin 6 levels were evaluated in relationship to intraoperative variables such as duration of aortic cross clamping, incisional trauma and cardiac bypass temperature. RESULTS: Peak levels of procalcitonin were detected on the first postoperative day, while interleukin 6 reached its highest values on the day of surgery. In contrast to interleukin 6 the median values of procalcitonin differed significantly between short versus long aortic clamping time and atriotomy versus ventriculotomy. Interleukin 6 reached normal levels on the fourth postoperative day, while procalcitonin was still clearly above normal. CONCLUSIONS: Serum concentrations of procalcitonin and interleukin 6 were influenced by systemic inflammatory response syndrome following cardiac surgery with cardiopulmonary bypass. Even in case of an uncomplicated course both parameters were elevated for at least four days.While procalcitonin serum concentrations were dependent on aortic clamping time or incisional trauma, interleukin 6 showed no significant relation with these intraoperative variables.     

Ketamine has no effect on oxygenation indices following elective coronary artery bypass grafting under cardiopulmonary bypass

Cardiopulmonary bypass is known to elicit systemic inflammatory response syndrome and organ dysfunction. This can result in pulmonary dysfunction and deterioration of oxygenation after cardiac surgery and cardiopulmonary bypass. Previous studies have reported varying results on anti-inflammatory strategies and oxygenation after cardiopulmonary bypass. Ketamine administered as a single dose at induction has been shown to reduce the pro-inflammatory serum markers in patients undergoing cardiopulmonary bypass. Therefore we investigated if ketamine can result in better oxygenation in these patients. This was a prospective randomized blinded study. Eighty consecutive adult patients undergoing elective coronary artery bypass grafting under cardiopulmonary bypass were included in the study. Patients were divided into two groups. Patients in ketamine group received 1mg/kg of ketamine intravenously at induction of anesthesia. Control group patients received an equal volume of saline. All patients received standard anesthesia, operative and postoperative care.Paired t test and independent sample t test were used to compare the inter-group and between group oxygenation indices respectively. Oxygenation index and duration of ventilation were analyzed. Deterioration of oxygenation index was noted in both the groups after cardiopulmonary bypass. However, there was no significant difference in the oxygenation index at various time points after cardiopulmonary bypass or the duration of ventilation between the two groups. This study shows that the administered as a single dose at induction does not result in better oxygenation after cardiopulmonary bypass.     

Corticosteroids and cardiopulmonary bypass : a review of clinical investigations

Traditionally, corticosteroids have been administered to patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) to ward off detrimental physiologic alterations associated with activation of the systemic inflammatory response, yet few well-controlled investigations exist, and use of these drugs in this setting remains controversial. This review article critically examines the results of clinical investigations in this area, and certain conclusions are suggested. The constellation of findings indicate that corticosteroids offer no clinical benefits to patients undergoing cardiac surgery with CPB and in fact may be detrimental. Further directions for clinical research in this area are also suggested.     

Role of Platelets in Acute Lung Injury After Extracorporeal Circulation in Cardiac Surgery Patients: A Systemic Review

In vitro circulation (cardiopulmonary bypass, CPB) has been widely used in heart surgery. In the past, it was believed that the reduction of platelet count and impaired platelet function during cardiac surgery were the main causes of acute lung injury (ALI). ALI is a life-threatening clinical syndrome in critically ill patients due to an uncontrolled systemic inflammatory response resulting from direct injury to the lung or indirect injury in the setting of a systemic process. Platelets have an emerging and incompletely understood role in a myriad of ALI after extracorporeal circulation in cardiac surgery patients. An electronic literature search was performed using Pubmed, Scopus and Cinahl investigating ALI, pathogenesis, and role of platelets, treatment and management for ALI patients. Many studies have shown that in vitro circulation is a nonphysiological process that can lead to a decrease in the number of platelets and impaired platelet function, as well as varying degrees of lung damage. The relationship between the effects of in vitro circulation on platelets and acute lung injury is still controversial. This review article discusses the role of platelets in lung injury after cardiopulmonary bypass and resent development in the management of ALI.     

The organ effects of systemic inflammation response activated during open heart surgery and current treatment methods]

Multi-organ failure may occur due to activation of systemic inflammatory process with many other factors in open-heart procedures when cardiopulmonary bypass is used. Activation of systemic inflammatory process may cause postoperative complications. Surgical trauma, contact of blood with foreign surface, endotoxemia and ischemia-reperfusion injury are major factors that contribute to activation of inflammatory response. In this review we purposed to investigate the factors which contribute to the systemic inflammatory process, multiorgan dysfunction and the therapeutic modalities during open heart surgery.     

Capillary leakage in cardiac surgery with cardiopulmonary bypass

Cardiopulmonary bypass causes a systemic inflammatory response, which can lead to capillary leak syndrome. In 15 adults undergoing elective cardiac surgery with cardiopulmonary bypass, we determined the volume and peak time of capillary leakage from the measurements of extracellular fluid volume and circulating blood volume taken preoperatively, at various intervals up to 24 hours after surgery, and on the 7th postoperative day. Extracellular fluid volume rose from 15.5 +/- 2.7 L preoperatively to a peak 4 hours after surgery of 18.3 +/- 3.2 L and remained elevated at 24 hours. Circulating blood volume fell from 4.10 +/- 0.68 L preoperatively to 3.20 +/- 0.58 L at the end of surgery. Fluid administered intraoperatively did not raise the circulating blood volume. Intraoperative fluid balance was positive at 2.62 +/- 0.72 L but negative at all time points postoperatively. There was significant postoperative capillary leakage, increasing from 4.7% +/- 2.3% of body weight at the end of surgery to a peak 4 hours later of 5.4% +/- 2.0% and falling to 2.8% +/- 3.3% at 24 hours. This knowledge of the pattern of change in capillary leakage after cardiac surgery with cardiopulmonary bypass might serve as a valuable guide for postoperative management.     

Transfusion-related immunomodulation: a second hit in an inflammatory cascade?

Allogeneic blood transfusions are dose-dependently associated with postoperative complications. Leucocytes present in blood components may play a role in these effects, referred to as transfusion-related immunomodulation. Of 19 randomized controlled trials of the effect of allogeneic leucocytes in transfusions, 13 looked into the effect of leucocyte-containing red blood cells (RBCs) in the surgical setting on the occurrence of postoperative infections and/or mortality. In contrast to conflicting outcomes of the trials in other settings, in cardiac surgery there is evidence that leucocyte-containing RBCs increase postoperative complications associated with mortality. The studies performed in cardiac surgery show less heterogeneity than studies in other surgical interventions and had been conducted either in one or a few participating centres. In this review, we discuss possible explanations for these results in cardiac surgery (as opposed to other settings), which may relate to clinical as well as transfusional factors. We suggest that leucocyte-containing transfusions during and after cardiac surgery add a second insult to the cardiopulmonary bypass procedure-induced systemic inflammatory response.     

体外循环肺保护的研究进展

肺损伤是体外循环心内直视手术的主要并发症之一,随着心肌保护技术的日益成熟,肺保护成为近年的研究热点。肺保护的方法多种多样,如药物干预、肺动脉灌注低温保护液、白细胞滤过等,其目的在于降低全身性炎症反应,减轻或避免缺血再灌注损伤。作者回顾近年来体外循环肺保护方法的研究状况。     

Prophylactic Use of Immunoglobulins in Cardiac Surgery

Cardiopulmonary bypass is associated with an injury that may cause pathophysiological changes in form of systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and mediator induced multi organ failure (MIMOV). Systemic endotoxinaemia, release of proinflammatory cytokines, and interactions between neutrophils and endothelium have been reported to correlate with a high incidence of organ dysfunctions, infections and sepsis following cardiac surgery. This review discusses the dysregulation of immune response as a major reason for the higher susceptibility to infections following cardiac surgery, various treatment strategies to reduce CPB-induced inflammation, and especially the prophylactic use of immunoglobulins in cardiac surgery.     

Off-pump coronary artery bypass graft surgery: the incidence of postoperative atrial fibrillation

Atrial fibrillation (AF) occurs in one quarter to one third of patients after coronary artery bypass graft surgery (CABG). Conventional CABG uses cardiopulmonary bypass, a process that is itself associated with a systemic vascular inflammatory response that contributes to postoperative morbidity. The avoidance of cardiopulmonary bypass is associated with a significant reduction in the inflammatory response and in the release of markers of myocardial necrosis when compared with conventional CABG. There is speculation that off-pump CABG may reduce the incidence of postoperative AF through reduced trauma, ischaemia, and inflammation. Current data, however, do not emphatically answer the question of whether the incidence of post-CABG AF is reduced by off-pump surgery. The evidence from both observational and randomised studies is conflicting and many studies have weaknesses in design, conduct, or interpretation. It remains an attractive hypothesis that postoperative AF is reduced by off-pump CABG but more robust data are required.     

Cytokines and pediatric open heart surgery with cardiopulmonary bypass

It is well known that, subsequent to cardiopulmonary bypass, and particularly in children, an inflammatory response within the body can often result in a characteristic syndrome. Recently, it has been suggested that this phenomenon is due to a systemic inflammatory response, with significant involvement of cytokines. With this in mind, we investigated the behavior of tumour necrosis factor-alpha and interleukin-6 during the operative and in the immediate postoperative period in a group of children submitted to open heart surgery. We investigated any possible relation between the levels of these cytokines in the serum and the length of cardiopulmonary bypass, with the serum levels of lactate, and with the extent of use of inotropic drugs in postoperative period. The cytokines were measured in samples withdrawn after induction of anesthesia, after 10 minutes of cardiopulmonary bypass, after re-establishment of circulation, and then 2 and 24 hours after the end of cardiopulmonary bypass. The levels of tumour necrosis factor-alpha and interleukin-6 increased between the beginning and at two hours of the end of cardiopulmonary bypass. There was no correlation between the levels of these cytokines in the serum and the length of cardiopulmonary bypass, although there was a positive relation between levels of interleukin-6 and lactate in samples withdrawn at two hours of the end of bypass, and the measured levels of the cytokines correlated with the extent of inotropic drugs employed in the postoperative period.     

Preoperative Statin Therapy in Cardiac Surgery Is More Effective in Patients Who Display Preoperative Activation of the Inflammatory System

We sought to determine whether preoperative statin treatment is more effective in reducing, after cardiac surgery with cardiopulmonary bypass, systemic inflammatory response and myocardial damage markers in patients who have elevated preoperative interleukin-6 levels than in patients who have normal preoperative interleukin-6 levels.The study involved a prospective cohort of 164 patients who underwent coronary and valvular surgery with cardiopulmonary bypass. There were 2 study groups: group A (n = 60), patients with elevated preoperative interleukin-6 levels; and group B (n = 104), patients with normal preoperative interleukin-6 levels. Each group was subdivided according to whether patients were (group 1) or were not (group 2) treated preoperatively with statins. Accordingly, the subdivided study groups were A1 (n = 40), A2 (n = 20), B1 (n = 56), and B2 (n = 48). The plasma levels of proinflammatory interleukin-6 were measured 1, 6, 24, and >72 hours after surgery.The baseline, operative, and postoperative morbidity and mortality characteristics were similar in all groups. Group A1 had significantly lower levels of interleukin-6 and troponin I than did group A2 at all postoperative time points. Group B1 had significantly lower levels of interleukin-6 than did group B2 postoperatively. There were no significant differences in troponin I levels between groups B1 and B2.We conclude that, in patients with preoperative activation of the inflammatory system, preoperative treatment with statins is associated with lower postoperative interleukin-6 and troponin I levels after cardiac surgery with cardiopulmonary bypass.Key words: Anticholesteremic agents/therapeutic use, biological markers, coronary artery bypass/adverse effects, inflammation mediators, interleukin-6/blood, postoperative complications/blood, systemic inflammatory response syndrome/prevention & control, statin treatment, troponin/bloodSome sequelae to cardiac surgery with cardiopulmonary bypass (CPB) appear to be related to an excessive systemic inflammatory response and to the cardiac biomarkers released in reaction to CPB and surgical trauma.^1,2 As a result of systemic inflammatory response, the plasma levels of some factors such as tumor necrosis factor (TNF-α), and interleukin (IL)-6 and IL-8 are elevated in patients who undergo cardiac interventions.^3,4 Further, there is a correlation between elevated IL levels (mainly elevated IL-6) and some postoperative complications.^5–10 Currently, no drugs or techniques have been shown to reduce the severity or incidence of systemic inflammatory response.Statins, which are 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors used as primary and secondary prevention measures, are effective hypolipidemic agents that have shown efficacy in reducing cardiovascular events.^11–14 The mechanism of action of statins, which act as anti-inflammatory agents, has been elucidated in several in vitro studies. The pleiotropic effects of statins might, in part, explain the clinical benefits of statins that cannot be attributed to their hypolipidemic properties.¹⁵ Statins also have reduced the morbidity and mortality rates associated with cardiovascular surgery, and their long-term use has improved bypass graft patency and long-term mortality rates in patients undergoing coronary artery bypass grafting (CABG).^16,17 The benefits of statins for reducing perioperative death and morbidity in cardiovascular surgery, mainly in valvular surgery, are more controversial, although some studies have shown the benefits of statins on perioperative death and morbidity related to atrial fibrillation and stroke rates in patients undergoing cardiovascular surgery.^11,18–22 Statins also reduce inflammatory markers. The preoperative administration of statins decreases proinflammatory cytokines, mainly IL-6, in the first hours after cardiac surgery.^23–26 It would be very helpful to determine which group of patients would benefit most from statin use.We hypothesized that the preoperative administration of statins would more strongly affect patients with preoperative activation of the inflammatory system (that is, patients with high preoperative levels of IL-6) than it would affect patients with normal preoperative levels of IL-6; and we hypothesized that this response would manifest itself as a more substantial reduction of postoperative levels of IL-6 and myocardial injury biomarkers. Before this study, there were no prospective studies that tested this hypothesis. On the basis of preoperative statin treatment and inflammation state, we prospectively analyzed the reduction of postoperative IL-6 and troponin I levels that rose as a result of systemic inflammatory response and complications after cardiac surgery with CPB.     

Effect of coronary bypass and cardiac valve surgery on systemic endothelial function

Seventeen patients scheduled for a cardiac procedure necessitating cardiopulmonary bypass underwent serial perioperative assessment of brachial artery flow-mediated dilation. Patients who underwent coronary bypass surgery had a sustained systemic endothelial dysfunction in the perioperative period, whereas those undergoing cardiac valve surgery experienced transient postoperative systemic endothelial dysfunction.     

Residual effects when chronic propranolol therapy is discontinued within 48 hours of cardiopulmonary bypass.

Recommendations regarding the safe waiting period between discontinuing chronic oral propranolol therapy and beginning cardiopulmonary bypass have varied from a few hours to 2 weeks. In the present study, utilizing adult dogs, propranolol was discontinued 8 or 48 hours prior to surgery. A reduction in cardiac output and elevations of left ventricular end-diastolic pressure, peak systolic pressure, and systemic resistance were noted when cardiac function was evaluated following the induction of anesthesia and prior to undertaking cardiopulmonary bypass. The magnitude of these differences was directly related to the degree of volume loading and inversely related to the interval between the last dose of propranol and the determination of cardiac function. Reduction of heart rate was the most evanescent of propranolol's hemodynamic effects as the marked bradycardia which persisted throughout the course of propranolol therapy was no longer evident 8 hours after the last oral dose of the drug. Following total cardiopulmonary bypass of 1 hour's duration, undertaken 8 hours after the last oral dose of propranolol, cardiac output and left ventricular end-diastolic pressure had returned to normal but peak systolic pressure and systemic resistance remained significantly elevated, When 48 hours had elapsed between discontinuing propranolol and beginning cardiopulmonary bypass, postbypass cardiac function was essentially normal with only slight persistent elevations of peak systolic pressure and systemic resistance detected. When the combined effects of ischemic heart disease and propranolol therapy, the altered metabolic and hemodynamic effects of different routes of drug administration, and the varying durations of cardiopulmonary bypass are taken into consideration, some of the discrepancies between previously reported clinical and experimental findings regarding the duration of persistent propranolol effects can be understood. The clinical course is usually benign in patients who have received propranolol to within a few hours of surgery without specific indication. However, it is often complicated when the drug is continued until just prior to surgery in patients dependant on propranolol for pain or arrhythmia control. In patients demonstrating propranolol dependence, control of symptoms with intra-aortic balloon counterpulsation is recommended followed by the gradual withdrawal of propranolol and elective aortocoronary bypass surgery.     

The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication?

BACKGROUND: It has been suggested that inflammation can have a role in the development of atrial arrhythmias after cardiac surgery and that a genetic predisposition to develop postoperative complications exists. This study was conceived to verify if a potential genetic modulator of the systemic inflammatory reaction to cardiopulmonary bypass (the -174 G/C polymorphism of the promoter of the Interleukin-6 gene) has a role in the pathogenesis of postoperative atrial fibrillation (AF). Patients and Results- In 110 primary isolated coronary artery bypass patients the -174G/C Interleukin-6 promoter gene variant was determined. Interleukin-6, fibrinogen and C-reactive protein plasma levels were determined preoperatively, 24, 48, and 72 hours after surgery and at discharge. Heart rate and rhythm were continuously monitored for the first 36 to 48 hours; daily 12-lead electrocardiograms were performed thereafter until discharge. GG, CT, and CC genotypes were found in 62, 38, and 10 patients, respectively. Multivariate analysis (which included genotype, age, sex, and classical risk factors for AF) identified the GG genotype as the only independent predictor of postoperative AF. The latter occurred in 33.9% of GG versus 10.4% of non-GG patients (hazard ratio 3.25, 95%CI 1.23 to 8.62). AF patients had higher blood levels of Interleukin-6 and fibrinogen after surgery (P<0.001 for difference between the area under the curve). CONCLUSIONS: The -174G/C Interleukin-6 promoter gene variant appears to modulate the inflammatory response to surgery and to influence the development of postoperative AF. These data suggest an inflammatory component of postoperative atrial arrhythmias and a genetic predisposition to this complication.     

体外循环心脏术后消化系统并发症的防治进展

体外循环心脏术后消化系统并发症虽然发生率不高,但病死率却极高.体外循环期间多种因素导致消化系统血液供应减少、组织损伤、炎性介质大量释放,从而引起包括胃肠道出血、消化性溃疡、缺血性肠炎、胰腺炎、胆囊炎、肝衰竭等在内的消化系统并发症.严密观察患者临床表现并早期诊断予以干预,对患者的预后有重要帮助.本文就近年来体外循环心脏术后消化系统并发症的机制、危险因素及诊断治疗的进展予以综述.     

Current State of Anticoagulants to Treat Deep Venous Thrombosis

Coronary artery bypass grafting (CABG) remains the preferred treatment in patients with complex coronary artery disease. However, whether the procedure should be performed with or without the use of cardiopulmonary bypass, referred to as off-pump and on-pump CABG, is still up for debate. Intuitively, avoidance of cardiopulmonary bypass seems beneficial as the systemic inflammatory response from extracorporeal circulation is omitted, but no single randomized trial has been able to prove off-pump CABG superior to on-pump CABG as regards the hard outcomes death, stroke or myocardial infarction. In contrast, off-pump CABG is technically more challenging and may be associated with increased risk of incomplete revascularization. The purpose of the review is to summarize the current literature comparing outcomes of off-pump versus on-pump coronary artery bypass surgery.