Response In Cardiac Surgery Research Articles

Hsp70 and cardiac surgery: molecular chaperone and inflammatory regulator with compartmentalized effects

Open heart surgery is a unique model to study the interplay between cellular injury, regulation of inflammatory responses and tissue repair. Stress-inducible heat shock protein 70-kDa (Hsp70) provides a molecular link between these events. In addition to molecular chaperoning, Hsp70 exerts modulatory effects on endothelial cells and leukocytes involved in inflammatory networks. Hsp70 residing in the intracellular compartment is part of an inhibitory feedback loop that acts on nuclear factor kappaB (NF-kappaB). In contrast, extracellular Hsp70 is recognized by multiple germline-encoded immune receptors, e.g., Toll-like receptor (TLR) 2, TLR4, LOX-1, CD91, CD94, CCR5 and CD40. Hsp70 is thereby able to enhance chemotaxis, phagocytosis and cytolytic activity of innate immune cells and stimulate antigen-specific responses. These apparent contradictory pro- and anti-inflammatory effects of endogenous Hsp70 in the context of cardiac surgery are still not fully understood. An all-embracing model of the compartmentalized effects of endogenous Hsp70 in the orchestration of inflammatory responses in cardiac surgery is proposed.

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients

IntroductionOxidative stress is involved in the development of secondary tissue damage and organ failure. Micronutrients contributing to the antioxidant (AOX) defense exhibit low plasma levels during critical illness. The aim of this study was to investigate the impact of early AOX micronutrients on clinical outcome in intensive care unit (ICU) patients with conditions characterized by oxidative stress.MethodsWe conducted a prospective, randomized, double-blind, placebo-controlled, single-center trial in patients admitted to a university hospital ICU with organ failure after complicated cardiac surgery, major trauma, or subarachnoid hemorrhage. Stratification by diagnosis was performed before randomization. The intervention was intravenous supplements for 5 days (selenium 270 μg, zinc 30 mg, vitamin C 1.1 g, and vitamin B1 100 mg) with a double-loading dose on days 1 and 2 or placebo.ResultsTwo hundred patients were included (102 AOX and 98 placebo). While age and gender did not differ, brain injury was more severe in the AOX trauma group (P = 0.019). Organ function endpoints did not differ: incidence of acute kidney failure and sequential organ failure assessment score decrease were similar (-3.2 ± 3.2 versus -4.2 ± 2.3 over the course of 5 days). Plasma concentrations of selenium, zinc, and glutathione peroxidase, low on admission, increased significantly to within normal values in the AOX group. C-reactive protein decreased faster in the AOX group (P = 0.039). Infectious complications did not differ. Length of hospital stay did not differ (16.5 versus 20 days), being shorter only in surviving AOX trauma patients (-10 days; P = 0.045).ConclusionThe AOX intervention did not reduce early organ dysfunction but significantly reduced the inflammatory response in cardiac surgery and trauma patients, which may prove beneficial in conditions with an intense inflammation.Trials RegistrationClinical Trials.gov RCT Register: NCT00515736.

The Inflammatory Response in Cardiac Surgery. An Up-to-date Overview with the Emphasis on the Role of Heat Shock Proteins (HSPs) 60 and 70

Cardiac surgical operations are associated with the development of a systemic inflammatory response syndrome (SIRS). In most cases, the inflammatory response is apparent only in its subclinical form. In some cases, however, it can become clinically manifest or even life-threatening. This review article presents some new data regarding its biological importance, along with an insight into the recently discovered role played by heat shock proteins 60 and 70.

Réponse inflammatoire et perturbations hématologiques en chirurgie cardiaque : vers une circulation extracorporelle plus physiologique

The systemic inflammatory response in cardiac surgery is closely related to the haemostasis disturbances. It is responsible of a significant morbidity and mortality that was previously suspected to be caused by cardiopulmonary bypass alone. However, it is time now to clearly identify the factors that are material-dependent from that material-independent. From this point of view, off-pump surgery allowed for better comprehension of the multiple sources of the inflammatory response. Numerous pathways are activated, involving complement, platelets, neutrophiles and monocytes. The tissue pathway of the coagulation system, through tissue factor, is of major importance and has to be surgically considered in order to reduce the whole body inflammatory response postoperatively. The quality of the extracorporeal perfusion through its consequences on organ perfusion, particularly in the splanchnic area, also participates to this pathophysiological process. Beyond the progress of technology provided by the industry, particularly the minimally extracorporeal circulation derived from off-pump surgery evolution, the surgical approach is of major importance in the control of the systemic inflammatory response and must not be ignored yet.

Platelet–monocyte pro-coagulant interactions in on-pump coronary surgery

Platelets and monocytes possess haemostatic properties, but the clinical effect of platelet-monocyte interactions on haemostasis following coronary surgery is not known. The study characterises the platelet and monocyte responses in cardiac surgery and its impact on haemostasis. In 1342 patients, changes in white blood cell counts (WBC), monocyte counts and platelet counts were measured. PMC formation was analysed by flow-cytometry using monoclonal antibodies against pan-leucocyte marker CD45, monocyte marker CD14 and platelet marker CD42. TF expression was determined using monoclonal antibodies against, CD45, CD14 and human-TF. Continuous variables were expressed as mean+/-SD. Changes in monocyte and platelet counts over time were considered as repeated measures data, and analysed using Generalised Estimating Equations (GEE). Multivariate regression analysis was used to evaluate the effect of several factors on blood loss. A monocytosis occurs with on-pump coronary surgery, but is less pronounced than with off-pump surgery. No difference was seen in patients having redo-surgery or more complex cardiac surgery. Factors associated with monocytosis on multivariate analysis were higher body mass index (p=0.02), diabetes (p=0.035) and smoking (p=0.01). Older patients manifested a lower response (p<0.001). Cross-clamp fibrillation was associated with a lower (p=0.048) monocytic response than was cardioplegia. PMC formation dropped following administration of heparin, peaked at 5 min of CPB, and declined by 2h of CPB (p=0.04). A return towards preoperative levels was found during postoperative days 1-5. No significant change in monocyte TF expression occurred. The mean postoperative blood loss was 581.2+/-292.8 ml, and inversely related to increasing preoperative platelet counts (p<0.001), and to higher monocyte % counts (p=0.012). Patients, who were female (p<0.001), had higher body mass indices (p<0.001), and higher core body temperatures during surgery (p=0.013), as well as patients having perioperative aprotinin (p<0.001) related to less blood loss. A higher postoperative platelet count as well as monocyte% significantly and independently decreases postoperative blood loss following cardiac surgery.

Ventilation according to the open lung concept attenuates pulmonary inflammatory response in cardiac surgery☆

Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response, which is correlated with outcome. We hypothesized that ventilation according to the open lung concept (OLC) attenuates cytokine release. A prospective, single center randomized controlled clinical study containing 62 patients scheduled for elective coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass. Before surgery, patients were randomly assigned to three groups: (1) conventional mechanical ventilation (CV), (2) OLC started after arrival on the ICU (late open lung, LOL), and (3) OLC started directly after intubation (early open lung, EOL). In both OLC groups, recruitment maneuvers were applied until PaO(2)/FiO(2)>50. The CV group received no recruitment maneuvers. Interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured preoperatively, immediately after cessation of CPB, and 3h, 5h, 24h, 2, and 3 days after cessation of CPB. CPB caused a significant increase of IL-6, IL-8, and IL-10 in all groups. Thereafter, IL-8 decreased significantly more rapidly in both OLC groups compared to CV. IL-10 decreased significantly more rapidly after CPB only in the EOL group, compared with CV. Three hours after cessation of the CPB, IL-10 was already comparable with preoperative levels in the EOL group, but not in the LOL or CV group. IL-6, TNF-alpha, and IFN-gamma did not differ significantly between groups. OLC ventilation leads to an attenuated inflammatory response, presumably by reducing additional lung injury after cardiac surgery. Studies on cytokines after cardiac surgery should take these findings into account.

Alpha‐Gal on bioprostheses: xenograft immune response in cardiac surgery

The alpha-Gal (Galalpha1,3-Galbeta1-4GlcNAc-R) epitope is the major xenoantigen causing hyperacute rejection of pig organs transplanted into primates. Porcine bioprostheses are utilized in cardiac surgery. However, premature degeneration of bioprostheses has limited utilization in younger patients and the immune response remains elusive. We sought to investigate whether a specific alpha-Gal immune response may play a role in this clinical scenario. We investigated the presence of alpha-Gal-epitope on native and fixed porcine valves by means of confocal laser scanning microscope (CLSM). ELISA was utilized to evidence whether implantation of bioprostheses elicits augmentation of pre-existing cytotoxic anti alpha-Gal IgM antibodies within 10 days of surgery. Patients who underwent coronary artery bypass grafting (CABG) or mechanical valve replacement served as controls (each group, n = 12). To corroborate the clinical relevance of the alpha-Gal immune response in vivo, we studied serum obtained before and after implantation of bioprostheses and its potency to lyse porcine alpha-Gal-bearing PK15 cells. We found the immunogenic alpha-Gal-epitope on fibrocytes interspersed in the connective tissue of porcine valves as determined by vimentin/IB4 lectin binding. Moreover, patients who were provided with a bioprostheses had developed a significant increase of naturally occurring cytotoxic IgM antibodies directed towards alpha-Gal after surgical intervention as compared with control patients (P < 0.0001, respectively). Sera obtained from the patients after the implantation of bioprostheses demonstrated an increased cytotoxicity against alpha-Gal-bearing PK-15 cells as compared with preoperative sera (P < 0.001). The specificity of the cytotoxic effects was proven as soluble Galalpha1-3Galbeta1-4GlcNAc markedly inhibited cell death of alpha-Gal-bearing PK15 cells (P < 0.001). Our data suggest that implantation of bioprostheses in cardiac surgery induces a xenograft-specific immune response. Procedures diminishing the presence of alpha-Gal on bioprostheses, such as utilization of genetically manipulated alpha-Gal-deficient xenograft or pretreatment with alpha-Galactosidase, might diminuate the immune response against bioprostheses and extend durability.

New strategies to control the inflammatory response in cardiac surgery

To present and interpret data from recent clinical studies (July 2002-August 2003) of strategies to control the inflammatory response after cardiac surgery. Off-pump coronary artery bypass techniques, which avoid the need for extracorporeal circulation, attenuate the inflammatory response and appear to confer clinical benefit. Concerns regarding the quality of the revascularization after off-pump coronary artery bypass appear to have been allayed. At present, ventricular assist devices do not enhance the efficacy of off-pump coronary artery bypass. In patients undergoing cardiopulmonary bypass, heparin-coated circuits, hypothermic pulmonary perfusion, normoxic reperfusion after aortic unclamping, and modified ultrafiltration hold promise. Strategies to maintain perioperative haemodynamic stability, such as enoximone therapy, may be beneficial, particularly in elderly patients. Aprotinin may have important beneficial anti-inflammatory actions in higher-risk adult and paediatric patients. The therapeutic potential of corticosteroids, particularly when administered in multiple dosages is increasingly clear. Direct anti-mediator therapies that focus upon key effector molecules and pathways of the inflammatory response offer future therapeutic options. The potential for strategies that inhibit the inflammatory response to improve outcome after cardiac surgery is clear. Large-scale multicentre trials investigating the most promising strategies, including off-pump coronary artery bypass, heparin-coated circuits, and perioperative corticosteroid and aprotinin therapy, are urgently needed. These trials need to be restricted to the high-risk patient groups most likely to experience benefit. In the interim, the optimal strategy to minimize the inflammatory response to cardiac surgery will remain elusive.

Cardiopulmonary bypass and the systemic inflammatory response: Effects on drug action

GOAL-DIRECTED PHARMACOTHERAPY is an essential component of cardiac surgery. 1 Hall RI Anaesthesia for coronary artery surgery—a plea for a goal-directed approach. Can J Anaesth. 1993; 40: 1178-1194 Crossref PubMed Google Scholar The emphasis on rapid recovery from anesthesia to permit earlier tracheal extubation with shortened intensive care unit and hospital length of stay 2 Cheng DC Karski J Peniston C et al. Early tracheal extubation after coronary artery bypass graft surgery reduces costs and improves resource use: A prospective, randomized, controlled trial. Anesthesiology. 1996; 85: 1300-1310 Crossref PubMed Scopus (248) Google Scholar , 3 Cheng DC Karski J Peniston C et al. Morbidity outcome in early versus conventional tracheal extubation after coronary artery bypass grafting: A prospective randomized controlled trial. J Thorac Cardiovasc Surg. 1996; 112: 755-764 Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar and the conduct of surgery without the use of cardiopulmonary bypass (CPB) 4 Gamoso MG Phillips-Bute B Landolfo KP et al. Off-pump versus on-pump coronary artery bypass surgery and postoperative renal dysfunction. Anesth Analg. 2000; 91: 1080-1084 PubMed Google Scholar , 5 Lloyd CT Ascione R Underwood MJ et al. Serum S-100 protein release and neuropsychologic outcome during coronary revascularization on the beating heart: A prospective randomized study. J Thorac Cardiovasc Surg. 2000; 119: 148-154 Abstract Full Text Full Text PDF PubMed Google Scholar , 6 Cox CM Ascione R Cohen AM et al. Effect of cardiopulmonary bypass on pulmonary gas exchange: A prospective randomized study. Ann Thorac Surg. 2000; 69: 140-145 Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar , 7 Ascione R Caputo M Calori G et al. Predictors of atrial fibrillation after conventional and beating heart coronary surgery: A prospective, randomized study. Circulation. 2000; 102: 1530-1535 Crossref PubMed Google Scholar , 8 Ascione R Lloyd CT Gomes WJ et al. Beating versus arrested heart revascularization: Evaluation of myocardial function in a prospective randomized study. Eur J Cardiothorac Surg. 1999; 15: 685-690 Crossref PubMed Scopus (200) Google Scholar , 9 Ascione R Lloyd CT Underwood MJ et al. On-pump versus off-pump coronary revascularization: Evaluation of renal function. Ann Thorac Surg. 1999; 68: 493-498 Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar , 10 Ascione R Lloyd CT Underwood MJ et al. Inflammatory response after coronary revascularization with or without cardiopulmonary bypass. Ann Thorac Surg. 2000; 69: 1198-1204 Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar , 11 Wan S Izzat MB Lee TW et al. Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg. 1999; 68: 52-56 Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar makes the provision of appropriate anesthesia a challenge. A thorough understanding of the influence of CPB and hypothermia on drug disposition and action and the interplay of the systemic inflammatory response in cardiac surgery on these processes is necessary for the cardiac anesthesiologist to meet this challenge. This review updates the practitioner in this area, incorporating and building on information provided in previous reviews of the subject. 12 Holley FO Ponganis KV Stanski DR Effect of cardiopulmonary bypass on the pharmacokinetics of drugs. Clin Pharmacokinet. 1982; 7: 234-251 Crossref PubMed Google Scholar , 13 Buylaert WA Herregods LL Mortier EP et al. Cardiopulmonary bypass and the pharmacokinetics of drugs: An update. Clin Pharmacokinet. 1989; 17: 10-26 Crossref PubMed Google Scholar , 14 Hall R The pharmacokinetic behaviour of opioids administered during cardiac surgery. Can J Anaesth. 1991; 38: 747-756 Crossref PubMed Google Scholar , 15 Mets B The pharmacokinetics of anesthetic drugs and adjuvants during cardiopulmonary bypass. Acta Anaesthesiol Scand. 2000; 44: 261-273 Crossref PubMed Scopus (31) Google Scholar , 16 Hall RI Changes in the pharmacokinetics and pharmacodynamics of drugs administered during cardiopulmonary bypass. in: ed 2. Cardiopulmonary Bypass: Principles and Practice. Lippincott Williams & Wilkins, Baltimore, MD2000: 265-303 Google Scholar , 17 Gedney JA Ghosh S Pharmacokinetics of analgesics, sedatives and anaesthetic agents during cardiopulmonary bypass. Br J Anaesth. 1995; 75: 344-351 Crossref PubMed Google Scholar