Original Cardiovascular
677
Low Tidal Volume Ventilation during Cardiopulmonary Bypass Reduces Postoperative Chemokine Serum Concentrations
1 Department of Thoracic Surgery, Medical University Vienna,
Vienna, Austria 2 Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria 3 Department of Cardiac Surgery, Institute of Cardiology, Medical and Health Science Centre of University of Debrecen, Hungary 4 Department of Anesthesiology, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria These authors contributed equally to this work.
Tamás Maros3
Address for correspondence Hendrik Jan Ankersmit, MD, Department of Thoracic Surgery , Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria (e-mail: [email protected]).
Thorac Cardiovasc Surg 2014;62:677–682.
Abstract
Keywords
► cardiopulmonary bypass ► CCL2 ► CCL4 ► CCL20 ► systemic inflammatory response syndrome ► ventilation
Background Open-heart surgery with cardiopulmonary bypass (CPB) is associated with a generalized immune response and postoperative lung dysfunction. Chemokines are involved in the pathogenesis of postoperative lung dysfunction. We investigated whether continued mechanical ventilation during CPB has an impact on chemokine serum concentrations. Methods A total of 30 patients undergoing coronary artery bypass graft operation were randomized to either continuous ventilated group (n ¼ 15) or nonventilated group (n ¼ 15). Blood samples were drawn at the beginning and at the end of surgery and on the 5 consecutive days. Serum CCL2, CCL4, and CCL20 concentrations were measured and given as mean standard deviation. Results Chemokine concentrations were elevated at the end of surgery in both groups. CCL2 and CCL4 levels returned to baseline on postoperative day (POD)-1 in the ventilation group and stayed elevated in the nonventilation group. CCL4 serum levels were significantly lower in ventilated-group patients on POD-1 (10.9 [39.0] vs. 153.2 [168.1]; p ¼ 0.005), POD-2 (16.8 [36.8] vs. 147.9 [165.4]; p ¼ 0.019), POD-3 (14.2 [24.0] vs. 97.9 [87.1]; p ¼ 0.005), and POD-5 (6.5 [25.0] vs. 33.6 [38.4]; p ¼ 0.045). Conclusion Continued mechanical ventilation during CPB results in reduced CCL4 concentrations on POD-1 to -5.
Introduction Open heart surgery with cardiopulmonary bypass (CPB) is known to induce a strong pro- and anti-inflammatory re-
received April 21, 2014 accepted after revision June 23, 2014 published online September 10, 2014
sponse that may affect outcome. Postoperative respiratory failure following CPB ranges from 5 to 20% of patients depending on patients’ preoperative characteristics and on the definition of this complication.1,2
© 2014 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1393703. ISSN 0171-6425.
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Lucian Beer1,2, Tamás Szerafin3, Andreas Mitterbauer1,2 Tamás Debreceni3 Martin Dworschak4 Georg A. Roth4 Hendrik Jan Ankersmit1,2
Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations Pathologically activated leukocytes are thought to play a pivotal role in producing inflammatory cytokines and amplifying the inflammatory reaction that consecutively affects respiratory function.3 Strategies to attenuate the inflammatory response are therefore desired and might improve patients’ outcome. We and others have demonstrated that continued mechanical ventilation during CPB is able to reduce systemic levels of pro- and anti-inflammatory mediators4–6 and improves clinical parameters such as extravascular lung water or time to extubation.7 Systemic immune response following CPB is of multiplefactorial origin. It has been discussed that alveolar hypoxia, endotoxemia, and ischemia-reperfusion (I/R) injury of the lungs are involved in the pathogenesis of CPB-induced pulmonary dysfunction.8 Chemokines are a family of small (8–10 kDa) proteins that can be categorized into four groups on the basis of the position of the N-terminal cysteine in the protein conformation (CC, CXC, C, and CX3C) which regulate leucocyte trafficking9 and are released systemically upon open-heart surgery.10,11 Especially, CCL2 and CCL4 have emerged attention lately because both chemokines are released mainly from alveolar macrophages upon alveolar hypoxia or endotoxemia.12,13 These proteins play a key role in the trafficking of neutrophils into the injured lung. Together with proinflammatory cytokines (TNF-α [tumor necrosis factor alpha]; IL-1β [interleukin-1 beta]; CXCL8 [interleukin-8]) and adhesion molecules, these chemokines aggravate development of lipopolysaccharide (LPS)-induced acute lung injury.12 Alveolar macrophage-derived CCL2 has further been shown to initiate a systemic inflammation response following alveolar hypoxia13 and neutralization of CCL2-attenuated LPS-induced acute lung injury.14 We hypothesized that maintaining lung ventilation during CPB reduces alveolar hypoxia and subsequently attenuates activation of alveolar macrophages. Therefore, we conducted this trial to compare the effects of continued mechanical ventilation on the expression of proinflammatory chemokines (CCL2, CCL4, and CCL20).
Materials and Methods Patients and Clinical Features The study was approved by the institutional ethics committee (No. 2894–2008, DEOEC RKEB/IKEB-nél: 3849–2013, 021096–2014-OTIG) and was in accordance with the Helsinki Declaration of 1975 and the guidelines for Good Scientific Practice of the Medical University of Vienna. The study is registered at Clinical Trials gov (ClinicalTrials.gov Identifier: NCT01627756). It has to be stated that serum samples of these patients have been used in two former publications discussing the role continued mechanical ventilation during CPB in the release of immunosuppressive soluble ST25 and the systemic heat shock protein response.6 With the exception of demographic and intraoperative characteristics, no data used in this article has been shown in a prior publication. All patients signed a written consent form. A total of 30 consecutive patients undergoing coronary artery bypass surgery were recruited into the study. Patients had the following Thoracic and Cardiovascular Surgeon
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characteristics: two- or three-vessel diseases without valvular pathology suitable for coronary artery bypass graft (CABG), aged between 45 and 80 years, and elective or urgent surgery. Exclusion criteria were infections, emergency operation, acute myocardial infarction less than 3 months ago, any autoimmune disease, any immunosuppressive disease, organ failure or medication with immune-modulating drugs, as well as a left ventricular ejection fraction less than 35%. A total of 30 patients were prospectively randomized into two groups. Of the 30 patients, 15 patients received continued mechanical ventilation during CPB (ventilated group [VG]), whereas in the nonventilated group (NVG) mechanical ventilation was stopped (open to atmospheric pressure) after aortic cross-clamp.
Perioperative Management All patients were premedicated 7.5 mg of oral midazolam and received 50 mg ranitidine and 1,500 mg cefuroxime 1 hour before anesthesia. Anesthesia was induced with 0.1 to 0.2 mg/ kg midazolam, 0.005 to 0.03 mg/kg fentanyl, and 0.15 mg/kg cis-atracurium IV; 1 to 3 Vol% sevoflurane and recurrent boli of 5 mg midazolam and 250 µg fentanyl every 30 to 60 min were administered during surgery. In both groups, a standard CABG procedure was performed using a roller pump (Stöckert, Munich, Germany) and a membrane oxygenator (SorinPumox, Modena, Italy). The CPB circuit was primed with approximately 1,500 mL crystalloid solution with a balanced electrolyte solution and 1,000 units NA heparin. Systemic heparinization to achieve an activated clotting time greater than 480 seconds was maintained during CPB. The pump flow was set at 2.4 to 2.5 L/min/m2 and patients were cooled to 31 to 33°C during CPB. After termination of CPB, heparin effect was neutralized with protamine (3 mg/kg).
Ventilation Strategy After intubation, before and after CPB, the following ventilation settings were used: tidal volume: 7 mL/kg, respiratory rate: 10 to 12/min, fraction of inspired oxygen (Fio2) between 50 and 70% and a PEEP of 5 mm Hg to obtain a PaO2 approximately 150 mm Hg. During CPB, the patients in ventilation group (n ¼ 15) underwent low tidal volume ventilation (i.e., 3–4 mL/kg) with the same FiO2, respiratory rate, and positive end-expiratory pressure (PEEP) as before going on CPB. This FiO2 as well as the chosen tidal volumes was already used in previous published trials.4,7 NVG patients (n ¼ 15) underwent typical procedure with lung ventilation during CPB.
Blood Samples Venous blood was obtained from each patient at the beginning and end of the operation, and the following 5 postoperative days (PODs). Serum samples were achieved via centrifugation of serum tubes (2.300 g for 15 min at 4°C) and aliquots were kept frozen at 80°C until specific tests were performed.
Measurement of Serum CCL2, CCL4, and CCL20 Levels Commercial ELISA kits were used to determine chemokine serum levels (R&D Systems, Minneapolis, Minnesota, United States) according to the manufacturer’s instructions.
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Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations
Beer et al.
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Gender (male/female)
Ventilated group (n ¼ 15)
Nonventilated group (n ¼ 15)
p-Value
12/3
13/2
ns
Age (y)
65 (46–80)
66 (47–76)
ns
BMI (kg/m2)
29.0 0.7
28.9 0.9
ns
COPD (n)
6
6
ns
Arterial hypertension (n)
14
10
ns
Ejection fraction (%)
50 5
53 9
ns
Euro Score
5 (2–8)
4 (1–12)
ns
Indication (elective/urgent)
11 / 4
9/6
ns
Creatinine (µmol/L)
84 (67–113)
75 (60–1,132)
ns
Instable angina pectoris (n)
0
1
ns
NYHA II (n)
15
15
ns
Preoperative stroke (n)
2
1
ns
Status post AMI (n)
7
8
ns
Preoperative PCI (n)
5
4
ns
Abbreviations: AMI, acute myocardial infarction; BMI, body mass index; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ns, nonsignificant; NYHA, New York Heart Association; PCI, percutaneous coronary intervention. Note: Data are given as mean SD, median (range), or absolute numbers, respectively.
Statistical Analysis Statistical analysis was performed with SPSS software (SPSS, Chicago, Illinois, United States). Normal distribution was verified using the Kolmogorov–Smirnov test and Shapiro– Wilks W test. Serum parameters between the two groups over time were analyzed by repeated measures one-way ANOVA. Different time points were compared by Mann–Whitney U test for nonparametric variables. Due to the explorative character of this study, no correction for multiple testing was applied. p values of 0.05 or lower were considered statistically significant. Data are given as mean (standard deviation) or median (range). For those data, which were not normally distributed, results are displayed as box plots. Dichotomous variables were analyzed using chi-square test. Based on a power analysis, detection of group differences with an 80% power and an α-level (two sided) of 0.05 would require several 15 patients per group.15
Results The demographic data and perioperative characteristics are given in ►Tables 1 and 2, respectively. The groups were comparable in all evaluated parameters. There were no perioperative deaths. Three patients were readmitted to the intensive care unit (ICU): two NVG patients because of renal failure or severe dyspnea of unknown origin. One patients of the VG was readmitted to ICU due to disorientation.
CCL2 ►Fig. 1 demonstrates a significant increase in serum CCL2 concentrations at the end of surgery as compared with
baseline in both study groups. The VG group showed an approximately 7-fold increase, whereas NVG patient showed a roughly 10-fold increase in CCL2 levels. On POD-1, no significant differences in CCL2 serum levels compared with baseline could be detected. NVG patients had significantly elevated CCL2 concentrations at POD-4 compared with VG patients. VG patients showed a trend toward lower CCL2 concentrations during the study period (p ¼ 0.069) in comparison with NVG patients.
CCL4 CCL4 serum concentrations increased in VG and NVG patients at the end of surgery compared with preoperative levels (►Fig. 2). In VG patients, CCL4 levels returned to baseline on POD-1, whereas NVG patients showed elevated CCL4 levels over an extended period of time with significant intergroup differences at POD-1, POD-2, POD-3, and POD-5. There was a statistically significant difference in serum concentrations of CCL4 between the groups over the time of the study period (p ¼ 0.009).
CCL20 Similarly, peak CCL20 concentrations were detected at the end of surgery (►Fig. 3) followed by a decrease on the 5 consecutive days. CCL20 levels rose significantly in both groups at the end of surgery (p ¼ 0.001) and were still elevated on POD-1 compared with baseline concentrations. On POD-2 and POD-3, only NVG patients showed significantly elevated concentrations, while VG patients did not show elevated CCL20 concentrations in comparison to baseline values at these time points. Thoracic and Cardiovascular Surgeon
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Table 1 Patient characteristics
Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations
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Table 2 Intraoperative data and 28-day mortality Ventilated group (n ¼ 15)
Nonventilated group (n ¼ 15)
p-Value
Number of grafts (n)
4 (2–5)
4 (2–5)
ns
AoX duration (min)
55 11
58 17
ns
CPB duration (min)
95 19
100 25
ns
ICU stay (h)
22 (17–45)
23 (17–172)
ns
Hospital stay (d)
6 (6–12)
7 (6–19)
ns
Ventilation support (h)
9 (4.5–20)
8 (4.5–85)
ns
Blood loss (mL)
700 378
600 466
ns
Autotransfusion (mL)
350 332
400 377
ns
Transfusions units (n)
1 (0–5)
2 (0–6)
ns
Hb preoperative (g/dL)
13.6 1.5
13.6 1.6
ns
Hb after surgery (g/dL)
9.8 0.9
10.1 1.2
ns
Hb POD-1 (g/dL)
10.9 0.9
10.7 1.2
ns
Reoperation because of bleeding (n)
0
0
ns
Atrial fibrillation postoperative (n)
4
2
ns
Perioperative AMI (n)
1
0
ns
Pericardial tamponade (n)
0
0
ns
28-day mortality (n)
0
0
ns
Abbreviations: AMI, acute myocardial infarction; AoX, aortic cross-clamp; CPB, cardiopulmonary bypass; Hb, hemoglobin; ICU, intensive care unit; ns, nonsignificant; PCI, percutaneous coronary intervention; POD, postoperative day. Note: Data are given as mean SD, median (range), or absolute numbers, respectively.
With the present study, performed in patients undergoing open-heart surgery, we evaluated whether continued mechanical ventilation during CPB affects systemic secretion chemokines. We were able to show that VG patients had
significantly lower concentration of proinflammatory CCL4 at POD-1 to POD-5 in comparison with NVG patients. Furthermore, we found elevated CCL20 concentrations at the end of surgery in both study groups. However, in contrast to NVG patients, values in the VG group returned to baseline values after POD-1, whereas CCL20 levels stayed elevated in
Fig. 1 Serum concentrations of CCL2 are presented as box plots for each group and time point. þ denotes p < 0.05 between groups; # denotes p < 0.05 compared with baseline concentrations; • denotes outliers. POD, postoperative day.
Fig. 2 Serum concentrations of CCL4 are presented as box plots for each group and time point. þ denotes p < 0.05 between groups; # denotes p < 0.05 compared with baseline concentrations; • denotes outliers. POD, postoperative day.
Discussion
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Fig. 3 Serum concentrations of CCL20 are presented as box plots for each group and time point. þ denotes p < 0.05 between groups; # denotes p < 0.05 compared with baseline concentrations; • denotes outliers. POD, postoperative day.
the NVG patients. Absolute CCL2 concentrations were also elevated in the NVG patients in the postoperative time period, which yet did not reach statistical significance. Cardiac surgery is accompanied by an activation of the immune system, which can lead to the development of a systemic inflammatory response syndrome (SIRS).3,8 Although it is the heart that is operated on, other organs such as the lungs, the gut, or the liver have been suggested to contribute to the development of SIRS.8 Chemokines are involved in the pathogenesis of the SIRS. They can be produced by different cell types in response to contact with bacterial endotoxins16 or proinflammatory cytokines TNF-α and IL-1β17 or cell hypoxia13 and enhance mainly neutrophil recruitment.9 Endotoxemia as well as alveolar hypoxia are commonly seen in patients undergoing heart surgery3,18 and are in part responsible for chemokine release. Elevated CCL20 serum concentrations have been mainly reported in liver disease such as acute and chronic liver failure,19 while no data are available in patients undergoing CABG surgery. We were able to show that patient undergoing CABG surgery with CPB have elevated serum concentration of CCL2, CCL4, and CCL20 at the end of surgery, which is in line with previous studies.10,11,20 The main finding of the current study was the significant reduction of CCL4 concentrations in VG patients during the first five PODs. Interestingly, patients undergoing off-pump surgery have lower CCL4 levels compared with on-pump patients,21 which might indicate that use of CPB has direct effect on CCL4 expression. Previous studies in humans have shown that elevated CCL4 concentrations can predict survival in septic patients and are involved in the development of pulmonary I/R injury.22,23 Furthermore, blocking antibodies against CCL3, which attenuate signaling of CCL3/CCL4 heterodimers, have been shown to attenuate lung vascular permeability, accumulation of neutrophils in lungs, and could reduce mortality in a murine endotoxemia I/R model, respectively.23,24 Based on these studies, we assume that reduced CCL4 concentrations in
Beer et al.
VG patients may have beneficial effects and might improve patients’ recovery. Currently, we do not know the mode of action by which ventilation during CPB reduces CCL4 secretion. One possible explanation could be a reduction of I/R injury during CPB.25 I/R is characterized by the release of free radicals, endothelial damage, and increased vascular permeability with pulmonary edema. During CPB, pulmonary oxygen supply is restricted and only partially maintained via bronchial artery while pulmonary artery perfusion and alveolar ventilation are stopped.4 However, bronchial artery blood flow during CPB is insufficient to maintain normal alveolar perfusion.26 We speculate that preserving alveolar ventilation during CPB improves alveolar oxygenation and reduces subsequent I/R injury. Both CCL2 and CCL4 are released from hypoxic alveolar macrophages and promote systemic inflammatory effects. Previous studies have already shown that continuing ventilation during CPB improves oxygen supply and reduces lactate levels indicating an attenuation of hypoxic phases during bypass.27 Another potential mechanism might be mitigated development of atelectasis, which is the major cause of intrapulmonary shunting and hypoxemia after CPB.28 While atelectasis occurs early after initiation of surgery, or even after induction of anesthesia, airway management during surgery can attenuate postoperative persistence of atelectasis and improve functional residual capacity.29 Attenuation of atelectasis with consequently reduced leucocyte sequestering in the lungs might be an explanation for the reduction of CCL4 concentrations in VG patients. The idea of using continued mechanical ventilation during the entire duration of CABG surgery instead of interrupting it during CPB has been developed to avoid on-pump surgery– associated postoperative pulmonary dysfunction. A few groups have so far addressed this question showing lower extravascular lung water, a reduced time to extubation4,7 and potentially beneficial alterations in the inflammatory response after CPB.4–6 Our findings corroborate the work by Ng and colleagues who describe that mechanical ventilation during CPB attenuates plasma IL-8 levels 4 hours after aortic declamping.4 As the CC-chemokine IL-8 is deemed to be of major pathophysiological significance in the development of SIRS, organ dysfunction, as well as lung injury after open-heart surgery,3 we speculate that the sustained elevated CCL4 concentrations in the NV group might also contribute to SIRS. In spite of these interesting findings, this investigation has two limitations. We only determined few clinical parameters in a small number of patients and are therefore not able to relate chemokine release to other potentially important parameters. Fresh frozen plasma (FFP) and platelet units were not reported in this study. In conclusion, continued mechanical ventilation during CPB was able to significantly reduce CCL4 concentrations on the first five PODs and slightly mitigated CCL2 and CCL20 release postoperatively. CABG surgery with CPB apparently induces systemic release of the CC-chemokines CCL2, CCL4, and CCL20. Further clinical studies are warranted to assess potential clinical benefits of continued mechanical ventilation during CPB. Thoracic and Cardiovascular Surgeon
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Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations
Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations Conflict of Interest None declared. 16
Funding This work was supported by the Medical University of Vienna and the Christian Doppler Research Association.
17
18
References 1 Filsoufi F, Rahmanian PB, Castillo JG, Chikwe J, Adams DH. Pre-
2
3 4
5
6
7
8
9 10
11
12
13
14
15
dictors and early and late outcomes of respiratory failure in contemporary cardiac surgery. Chest 2008;133(3):713–721 Reddy SL, Grayson AD, Griffiths EM, Pullan DM, Rashid A. Logistic risk model for prolonged ventilation after adult cardiac surgery. Ann Thorac Surg 2007;84(2):528–536 Apostolakis E, Filos KS, Koletsis E, Dougenis D. Lung dysfunction following cardiopulmonary bypass. J Card Surg 2010;25(1):47–55 Ng CS, Arifi AA, Wan S, et al. Ventilation during cardiopulmonary bypass: impact on cytokine response and cardiopulmonary function. Ann Thorac Surg 2008;85(1):154–162 Beer L, Szerafin T, Mitterbauer A, et al. Continued mechanical ventilation during coronary artery bypass graft operation attenuates the systemic immune response. Eur J Cardiothorac Surg 2013; 44(2):282–287 Beer L, Szerafin T, Mitterbauer A, et al. Ventilation during cardiopulmonary bypass: impact on heat shock protein release. J Cardiovasc Surg (Torino) 2013 John LC, Ervine IM. A study assessing the potential benefit of continued ventilation during cardiopulmonary bypass. Interact Cardiovasc Thorac Surg 2008;7(1):14–17 Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology 2002;97(1):215–252 Baggiolini M. Chemokines and leukocyte traffic. Nature 1998; 392(6676):565–568 Risnes I, Ueland T, Lundblad R, et al. Changes in the cytokine network and complement parameters during open heart surgery. Interact Cardiovasc Thorac Surg 2003;2(1):19–24 de Mendonça-Filho HT, Pereira KC, Fontes M, et al. Circulating inflammatory mediators and organ dysfunction after cardiovascular surgery with cardiopulmonary bypass: a prospective observational study. Crit Care 2006;10(2):R46 Vuichard D, Ganter MT, Schimmer RC, et al. Hypoxia aggravates lipopolysaccharide-induced lung injury. Clin Exp Immunol 2005; 141(2):248–260 Chao J, Donham P, van Rooijen N, Wood JG, Gonzalez NC. Monocyte chemoattractant protein-1 released from alveolar macrophages mediates the systemic inflammation of acute alveolar hypoxia. Am J Respir Cell Mol Biol 2011;45(1):53–61 Mercer PF, Williams AE, Scotton CJ, et al. Proteinase-activated receptor-1, CCL2, and CCL7 regulate acute neutrophilic lung inflammation. Am J Respir Cell Mol Biol 2014;50(1):144–157 Szerafin T, Hoetzenecker K, Hacker S, et al. Heat shock proteins 27, 60, 70, 90alpha, and 20S proteasome in on-pump versus off-pump
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19
20
21
22
23
24
25
26
27
28
29
Beer et al.
coronary artery bypass graft patients. Ann Thorac Surg 2008; 85(1):80–87 Guan E, Wang J, Norcross MA. Identification of human macrophage inflammatory proteins 1alpha and 1beta as a native secreted heterodimer. J Biol Chem 2001;276(15):12404–12409 Shimizu Y, Murata H, Kashii Y, et al. CC-chemokine receptor 6 and its ligand macrophage inflammatory protein 3alpha might be involved in the amplification of local necroinflammatory response in the liver. Hepatology 2001;34(2):311–319 Klein DJ, Briet F, Nisenbaum R, Romaschin AD, Mazer CD. Endotoxemia related to cardiopulmonary bypass is associated with increased risk of infection after cardiac surgery: a prospective observational study. Crit Care 2011;15(1):R69 Roth W, Reuter U, Wohlenberg C, Bruckner-Tuderman L, Magin TM. Cytokines as genetic modifiers in K5-/- mice and in human epidermolysis bullosa simplex. Hum Mutat 2009;30(5):832–841 Tomic V, Russwurm S, Möller E, et al. Transcriptomic and proteomic patterns of systemic inflammation in on-pump and off-pump coronary artery bypass grafting. Circulation 2005;112(19): 2912–2920 Ghorbel MT, Cherif M, Mokhtari A, Bruno VD, Caputo M, Angelini GD. Off-pump coronary artery bypass surgery is associated with fewer gene expression changes in the human myocardium in comparison with on-pump surgery. Physiol Genomics 2010; 42(1):67–75 Nowak JE, Wheeler DS, Harmon KK, Wong HR. Admission chemokine (C-C motif) ligand 4 levels predict survival in pediatric septic shock. Pediatr Crit Care Med 2010;11(2):213–216 Krishnadasan B, Farivar AS, Naidu BV, et al. Beta-chemokine function in experimental lung ischemia-reperfusion injury. Ann Thorac Surg 2004;77(3):1056–1062 Standiford TJ, Kunkel SL, Lukacs NW, et al. Macrophage inflammatory protein-1 alpha mediates lung leukocyte recruitment, lung capillary leak, and early mortality in murine endotoxemia. J Immunol 1995;155(3):1515–1524 Schreiber JU, Lancé MD, de Korte M, Artmann T, Aleksic I, Kranke P. The effect of different lung-protective strategies in patients during cardiopulmonary bypass: a meta-analysis and semiquantitative review of randomized trials. J Cardiothorac Vasc Anesth 2012; 26(3):448–454 Schlensak C, Doenst T, Preusser S, Wunderlich M, Kleinschmidt M, Beyersdorf F. Bronchial artery perfusion during cardiopulmonary bypass does not prevent ischemia of the lung in piglets: assessment of bronchial artery blood flow with fluorescent microspheres. Eur J Cardiothorac Surg 2001;19(3):326–331, disciussion 331–332 Durukan AB, Gurbuz HA, Salman N, Unal EU, Ucar HI, Yorgancioglu CE. Ventilation during cardiopulmonary bypass did not attenuate inflammatory response or affect postoperative outcomes. Cardiovasc J Afr 2013;24(6):224–230 Groeneveld AB, Jansen EK, Verheij J. Mechanisms of pulmonary dysfunction after on-pump and off-pump cardiac surgery: a prospective cohort study. J Cardiothorac Surg 2007;2:11 Imura H, Caputo M, Lim K, et al. Pulmonary injury after cardiopulmonary bypass: beneficial effects of low-frequency mechanical ventilation. J Thorac Cardiovasc Surg 2009;137(6): 1530–1537
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677
Low Tidal Volume Ventilation during Cardiopulmonary Bypass Reduces Postoperative Chemokine Serum Concentrations
1 Department of Thoracic Surgery, Medical University Vienna,
Vienna, Austria 2 Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria 3 Department of Cardiac Surgery, Institute of Cardiology, Medical and Health Science Centre of University of Debrecen, Hungary 4 Department of Anesthesiology, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria These authors contributed equally to this work.
Tamás Maros3
Address for correspondence Hendrik Jan Ankersmit, MD, Department of Thoracic Surgery , Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria (e-mail: [email protected]).
Thorac Cardiovasc Surg 2014;62:677–682.
Abstract
Keywords
► cardiopulmonary bypass ► CCL2 ► CCL4 ► CCL20 ► systemic inflammatory response syndrome ► ventilation
Background Open-heart surgery with cardiopulmonary bypass (CPB) is associated with a generalized immune response and postoperative lung dysfunction. Chemokines are involved in the pathogenesis of postoperative lung dysfunction. We investigated whether continued mechanical ventilation during CPB has an impact on chemokine serum concentrations. Methods A total of 30 patients undergoing coronary artery bypass graft operation were randomized to either continuous ventilated group (n ¼ 15) or nonventilated group (n ¼ 15). Blood samples were drawn at the beginning and at the end of surgery and on the 5 consecutive days. Serum CCL2, CCL4, and CCL20 concentrations were measured and given as mean standard deviation. Results Chemokine concentrations were elevated at the end of surgery in both groups. CCL2 and CCL4 levels returned to baseline on postoperative day (POD)-1 in the ventilation group and stayed elevated in the nonventilation group. CCL4 serum levels were significantly lower in ventilated-group patients on POD-1 (10.9 [39.0] vs. 153.2 [168.1]; p ¼ 0.005), POD-2 (16.8 [36.8] vs. 147.9 [165.4]; p ¼ 0.019), POD-3 (14.2 [24.0] vs. 97.9 [87.1]; p ¼ 0.005), and POD-5 (6.5 [25.0] vs. 33.6 [38.4]; p ¼ 0.045). Conclusion Continued mechanical ventilation during CPB results in reduced CCL4 concentrations on POD-1 to -5.
Introduction Open heart surgery with cardiopulmonary bypass (CPB) is known to induce a strong pro- and anti-inflammatory re-
received April 21, 2014 accepted after revision June 23, 2014 published online September 10, 2014
sponse that may affect outcome. Postoperative respiratory failure following CPB ranges from 5 to 20% of patients depending on patients’ preoperative characteristics and on the definition of this complication.1,2
© 2014 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1393703. ISSN 0171-6425.
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Lucian Beer1,2, Tamás Szerafin3, Andreas Mitterbauer1,2 Tamás Debreceni3 Martin Dworschak4 Georg A. Roth4 Hendrik Jan Ankersmit1,2
Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations Pathologically activated leukocytes are thought to play a pivotal role in producing inflammatory cytokines and amplifying the inflammatory reaction that consecutively affects respiratory function.3 Strategies to attenuate the inflammatory response are therefore desired and might improve patients’ outcome. We and others have demonstrated that continued mechanical ventilation during CPB is able to reduce systemic levels of pro- and anti-inflammatory mediators4–6 and improves clinical parameters such as extravascular lung water or time to extubation.7 Systemic immune response following CPB is of multiplefactorial origin. It has been discussed that alveolar hypoxia, endotoxemia, and ischemia-reperfusion (I/R) injury of the lungs are involved in the pathogenesis of CPB-induced pulmonary dysfunction.8 Chemokines are a family of small (8–10 kDa) proteins that can be categorized into four groups on the basis of the position of the N-terminal cysteine in the protein conformation (CC, CXC, C, and CX3C) which regulate leucocyte trafficking9 and are released systemically upon open-heart surgery.10,11 Especially, CCL2 and CCL4 have emerged attention lately because both chemokines are released mainly from alveolar macrophages upon alveolar hypoxia or endotoxemia.12,13 These proteins play a key role in the trafficking of neutrophils into the injured lung. Together with proinflammatory cytokines (TNF-α [tumor necrosis factor alpha]; IL-1β [interleukin-1 beta]; CXCL8 [interleukin-8]) and adhesion molecules, these chemokines aggravate development of lipopolysaccharide (LPS)-induced acute lung injury.12 Alveolar macrophage-derived CCL2 has further been shown to initiate a systemic inflammation response following alveolar hypoxia13 and neutralization of CCL2-attenuated LPS-induced acute lung injury.14 We hypothesized that maintaining lung ventilation during CPB reduces alveolar hypoxia and subsequently attenuates activation of alveolar macrophages. Therefore, we conducted this trial to compare the effects of continued mechanical ventilation on the expression of proinflammatory chemokines (CCL2, CCL4, and CCL20).
Materials and Methods Patients and Clinical Features The study was approved by the institutional ethics committee (No. 2894–2008, DEOEC RKEB/IKEB-nél: 3849–2013, 021096–2014-OTIG) and was in accordance with the Helsinki Declaration of 1975 and the guidelines for Good Scientific Practice of the Medical University of Vienna. The study is registered at Clinical Trials gov (ClinicalTrials.gov Identifier: NCT01627756). It has to be stated that serum samples of these patients have been used in two former publications discussing the role continued mechanical ventilation during CPB in the release of immunosuppressive soluble ST25 and the systemic heat shock protein response.6 With the exception of demographic and intraoperative characteristics, no data used in this article has been shown in a prior publication. All patients signed a written consent form. A total of 30 consecutive patients undergoing coronary artery bypass surgery were recruited into the study. Patients had the following Thoracic and Cardiovascular Surgeon
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characteristics: two- or three-vessel diseases without valvular pathology suitable for coronary artery bypass graft (CABG), aged between 45 and 80 years, and elective or urgent surgery. Exclusion criteria were infections, emergency operation, acute myocardial infarction less than 3 months ago, any autoimmune disease, any immunosuppressive disease, organ failure or medication with immune-modulating drugs, as well as a left ventricular ejection fraction less than 35%. A total of 30 patients were prospectively randomized into two groups. Of the 30 patients, 15 patients received continued mechanical ventilation during CPB (ventilated group [VG]), whereas in the nonventilated group (NVG) mechanical ventilation was stopped (open to atmospheric pressure) after aortic cross-clamp.
Perioperative Management All patients were premedicated 7.5 mg of oral midazolam and received 50 mg ranitidine and 1,500 mg cefuroxime 1 hour before anesthesia. Anesthesia was induced with 0.1 to 0.2 mg/ kg midazolam, 0.005 to 0.03 mg/kg fentanyl, and 0.15 mg/kg cis-atracurium IV; 1 to 3 Vol% sevoflurane and recurrent boli of 5 mg midazolam and 250 µg fentanyl every 30 to 60 min were administered during surgery. In both groups, a standard CABG procedure was performed using a roller pump (Stöckert, Munich, Germany) and a membrane oxygenator (SorinPumox, Modena, Italy). The CPB circuit was primed with approximately 1,500 mL crystalloid solution with a balanced electrolyte solution and 1,000 units NA heparin. Systemic heparinization to achieve an activated clotting time greater than 480 seconds was maintained during CPB. The pump flow was set at 2.4 to 2.5 L/min/m2 and patients were cooled to 31 to 33°C during CPB. After termination of CPB, heparin effect was neutralized with protamine (3 mg/kg).
Ventilation Strategy After intubation, before and after CPB, the following ventilation settings were used: tidal volume: 7 mL/kg, respiratory rate: 10 to 12/min, fraction of inspired oxygen (Fio2) between 50 and 70% and a PEEP of 5 mm Hg to obtain a PaO2 approximately 150 mm Hg. During CPB, the patients in ventilation group (n ¼ 15) underwent low tidal volume ventilation (i.e., 3–4 mL/kg) with the same FiO2, respiratory rate, and positive end-expiratory pressure (PEEP) as before going on CPB. This FiO2 as well as the chosen tidal volumes was already used in previous published trials.4,7 NVG patients (n ¼ 15) underwent typical procedure with lung ventilation during CPB.
Blood Samples Venous blood was obtained from each patient at the beginning and end of the operation, and the following 5 postoperative days (PODs). Serum samples were achieved via centrifugation of serum tubes (2.300 g for 15 min at 4°C) and aliquots were kept frozen at 80°C until specific tests were performed.
Measurement of Serum CCL2, CCL4, and CCL20 Levels Commercial ELISA kits were used to determine chemokine serum levels (R&D Systems, Minneapolis, Minnesota, United States) according to the manufacturer’s instructions.
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Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations
Beer et al.
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Gender (male/female)
Ventilated group (n ¼ 15)
Nonventilated group (n ¼ 15)
p-Value
12/3
13/2
ns
Age (y)
65 (46–80)
66 (47–76)
ns
BMI (kg/m2)
29.0 0.7
28.9 0.9
ns
COPD (n)
6
6
ns
Arterial hypertension (n)
14
10
ns
Ejection fraction (%)
50 5
53 9
ns
Euro Score
5 (2–8)
4 (1–12)
ns
Indication (elective/urgent)
11 / 4
9/6
ns
Creatinine (µmol/L)
84 (67–113)
75 (60–1,132)
ns
Instable angina pectoris (n)
0
1
ns
NYHA II (n)
15
15
ns
Preoperative stroke (n)
2
1
ns
Status post AMI (n)
7
8
ns
Preoperative PCI (n)
5
4
ns
Abbreviations: AMI, acute myocardial infarction; BMI, body mass index; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ns, nonsignificant; NYHA, New York Heart Association; PCI, percutaneous coronary intervention. Note: Data are given as mean SD, median (range), or absolute numbers, respectively.
Statistical Analysis Statistical analysis was performed with SPSS software (SPSS, Chicago, Illinois, United States). Normal distribution was verified using the Kolmogorov–Smirnov test and Shapiro– Wilks W test. Serum parameters between the two groups over time were analyzed by repeated measures one-way ANOVA. Different time points were compared by Mann–Whitney U test for nonparametric variables. Due to the explorative character of this study, no correction for multiple testing was applied. p values of 0.05 or lower were considered statistically significant. Data are given as mean (standard deviation) or median (range). For those data, which were not normally distributed, results are displayed as box plots. Dichotomous variables were analyzed using chi-square test. Based on a power analysis, detection of group differences with an 80% power and an α-level (two sided) of 0.05 would require several 15 patients per group.15
Results The demographic data and perioperative characteristics are given in ►Tables 1 and 2, respectively. The groups were comparable in all evaluated parameters. There were no perioperative deaths. Three patients were readmitted to the intensive care unit (ICU): two NVG patients because of renal failure or severe dyspnea of unknown origin. One patients of the VG was readmitted to ICU due to disorientation.
CCL2 ►Fig. 1 demonstrates a significant increase in serum CCL2 concentrations at the end of surgery as compared with
baseline in both study groups. The VG group showed an approximately 7-fold increase, whereas NVG patient showed a roughly 10-fold increase in CCL2 levels. On POD-1, no significant differences in CCL2 serum levels compared with baseline could be detected. NVG patients had significantly elevated CCL2 concentrations at POD-4 compared with VG patients. VG patients showed a trend toward lower CCL2 concentrations during the study period (p ¼ 0.069) in comparison with NVG patients.
CCL4 CCL4 serum concentrations increased in VG and NVG patients at the end of surgery compared with preoperative levels (►Fig. 2). In VG patients, CCL4 levels returned to baseline on POD-1, whereas NVG patients showed elevated CCL4 levels over an extended period of time with significant intergroup differences at POD-1, POD-2, POD-3, and POD-5. There was a statistically significant difference in serum concentrations of CCL4 between the groups over the time of the study period (p ¼ 0.009).
CCL20 Similarly, peak CCL20 concentrations were detected at the end of surgery (►Fig. 3) followed by a decrease on the 5 consecutive days. CCL20 levels rose significantly in both groups at the end of surgery (p ¼ 0.001) and were still elevated on POD-1 compared with baseline concentrations. On POD-2 and POD-3, only NVG patients showed significantly elevated concentrations, while VG patients did not show elevated CCL20 concentrations in comparison to baseline values at these time points. Thoracic and Cardiovascular Surgeon
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Table 1 Patient characteristics
Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations
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Table 2 Intraoperative data and 28-day mortality Ventilated group (n ¼ 15)
Nonventilated group (n ¼ 15)
p-Value
Number of grafts (n)
4 (2–5)
4 (2–5)
ns
AoX duration (min)
55 11
58 17
ns
CPB duration (min)
95 19
100 25
ns
ICU stay (h)
22 (17–45)
23 (17–172)
ns
Hospital stay (d)
6 (6–12)
7 (6–19)
ns
Ventilation support (h)
9 (4.5–20)
8 (4.5–85)
ns
Blood loss (mL)
700 378
600 466
ns
Autotransfusion (mL)
350 332
400 377
ns
Transfusions units (n)
1 (0–5)
2 (0–6)
ns
Hb preoperative (g/dL)
13.6 1.5
13.6 1.6
ns
Hb after surgery (g/dL)
9.8 0.9
10.1 1.2
ns
Hb POD-1 (g/dL)
10.9 0.9
10.7 1.2
ns
Reoperation because of bleeding (n)
0
0
ns
Atrial fibrillation postoperative (n)
4
2
ns
Perioperative AMI (n)
1
0
ns
Pericardial tamponade (n)
0
0
ns
28-day mortality (n)
0
0
ns
Abbreviations: AMI, acute myocardial infarction; AoX, aortic cross-clamp; CPB, cardiopulmonary bypass; Hb, hemoglobin; ICU, intensive care unit; ns, nonsignificant; PCI, percutaneous coronary intervention; POD, postoperative day. Note: Data are given as mean SD, median (range), or absolute numbers, respectively.
With the present study, performed in patients undergoing open-heart surgery, we evaluated whether continued mechanical ventilation during CPB affects systemic secretion chemokines. We were able to show that VG patients had
significantly lower concentration of proinflammatory CCL4 at POD-1 to POD-5 in comparison with NVG patients. Furthermore, we found elevated CCL20 concentrations at the end of surgery in both study groups. However, in contrast to NVG patients, values in the VG group returned to baseline values after POD-1, whereas CCL20 levels stayed elevated in
Fig. 1 Serum concentrations of CCL2 are presented as box plots for each group and time point. þ denotes p < 0.05 between groups; # denotes p < 0.05 compared with baseline concentrations; • denotes outliers. POD, postoperative day.
Fig. 2 Serum concentrations of CCL4 are presented as box plots for each group and time point. þ denotes p < 0.05 between groups; # denotes p < 0.05 compared with baseline concentrations; • denotes outliers. POD, postoperative day.
Discussion
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Fig. 3 Serum concentrations of CCL20 are presented as box plots for each group and time point. þ denotes p < 0.05 between groups; # denotes p < 0.05 compared with baseline concentrations; • denotes outliers. POD, postoperative day.
the NVG patients. Absolute CCL2 concentrations were also elevated in the NVG patients in the postoperative time period, which yet did not reach statistical significance. Cardiac surgery is accompanied by an activation of the immune system, which can lead to the development of a systemic inflammatory response syndrome (SIRS).3,8 Although it is the heart that is operated on, other organs such as the lungs, the gut, or the liver have been suggested to contribute to the development of SIRS.8 Chemokines are involved in the pathogenesis of the SIRS. They can be produced by different cell types in response to contact with bacterial endotoxins16 or proinflammatory cytokines TNF-α and IL-1β17 or cell hypoxia13 and enhance mainly neutrophil recruitment.9 Endotoxemia as well as alveolar hypoxia are commonly seen in patients undergoing heart surgery3,18 and are in part responsible for chemokine release. Elevated CCL20 serum concentrations have been mainly reported in liver disease such as acute and chronic liver failure,19 while no data are available in patients undergoing CABG surgery. We were able to show that patient undergoing CABG surgery with CPB have elevated serum concentration of CCL2, CCL4, and CCL20 at the end of surgery, which is in line with previous studies.10,11,20 The main finding of the current study was the significant reduction of CCL4 concentrations in VG patients during the first five PODs. Interestingly, patients undergoing off-pump surgery have lower CCL4 levels compared with on-pump patients,21 which might indicate that use of CPB has direct effect on CCL4 expression. Previous studies in humans have shown that elevated CCL4 concentrations can predict survival in septic patients and are involved in the development of pulmonary I/R injury.22,23 Furthermore, blocking antibodies against CCL3, which attenuate signaling of CCL3/CCL4 heterodimers, have been shown to attenuate lung vascular permeability, accumulation of neutrophils in lungs, and could reduce mortality in a murine endotoxemia I/R model, respectively.23,24 Based on these studies, we assume that reduced CCL4 concentrations in
Beer et al.
VG patients may have beneficial effects and might improve patients’ recovery. Currently, we do not know the mode of action by which ventilation during CPB reduces CCL4 secretion. One possible explanation could be a reduction of I/R injury during CPB.25 I/R is characterized by the release of free radicals, endothelial damage, and increased vascular permeability with pulmonary edema. During CPB, pulmonary oxygen supply is restricted and only partially maintained via bronchial artery while pulmonary artery perfusion and alveolar ventilation are stopped.4 However, bronchial artery blood flow during CPB is insufficient to maintain normal alveolar perfusion.26 We speculate that preserving alveolar ventilation during CPB improves alveolar oxygenation and reduces subsequent I/R injury. Both CCL2 and CCL4 are released from hypoxic alveolar macrophages and promote systemic inflammatory effects. Previous studies have already shown that continuing ventilation during CPB improves oxygen supply and reduces lactate levels indicating an attenuation of hypoxic phases during bypass.27 Another potential mechanism might be mitigated development of atelectasis, which is the major cause of intrapulmonary shunting and hypoxemia after CPB.28 While atelectasis occurs early after initiation of surgery, or even after induction of anesthesia, airway management during surgery can attenuate postoperative persistence of atelectasis and improve functional residual capacity.29 Attenuation of atelectasis with consequently reduced leucocyte sequestering in the lungs might be an explanation for the reduction of CCL4 concentrations in VG patients. The idea of using continued mechanical ventilation during the entire duration of CABG surgery instead of interrupting it during CPB has been developed to avoid on-pump surgery– associated postoperative pulmonary dysfunction. A few groups have so far addressed this question showing lower extravascular lung water, a reduced time to extubation4,7 and potentially beneficial alterations in the inflammatory response after CPB.4–6 Our findings corroborate the work by Ng and colleagues who describe that mechanical ventilation during CPB attenuates plasma IL-8 levels 4 hours after aortic declamping.4 As the CC-chemokine IL-8 is deemed to be of major pathophysiological significance in the development of SIRS, organ dysfunction, as well as lung injury after open-heart surgery,3 we speculate that the sustained elevated CCL4 concentrations in the NV group might also contribute to SIRS. In spite of these interesting findings, this investigation has two limitations. We only determined few clinical parameters in a small number of patients and are therefore not able to relate chemokine release to other potentially important parameters. Fresh frozen plasma (FFP) and platelet units were not reported in this study. In conclusion, continued mechanical ventilation during CPB was able to significantly reduce CCL4 concentrations on the first five PODs and slightly mitigated CCL2 and CCL20 release postoperatively. CABG surgery with CPB apparently induces systemic release of the CC-chemokines CCL2, CCL4, and CCL20. Further clinical studies are warranted to assess potential clinical benefits of continued mechanical ventilation during CPB. Thoracic and Cardiovascular Surgeon
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Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations
Low Tidal Volume Ventilation during CPB Reduces Postoperative Chemokine Serum Concentrations Conflict of Interest None declared. 16
Funding This work was supported by the Medical University of Vienna and the Christian Doppler Research Association.
17
18
References 1 Filsoufi F, Rahmanian PB, Castillo JG, Chikwe J, Adams DH. Pre-
2
3 4
5
6
7
8
9 10
11
12
13
14
15
dictors and early and late outcomes of respiratory failure in contemporary cardiac surgery. Chest 2008;133(3):713–721 Reddy SL, Grayson AD, Griffiths EM, Pullan DM, Rashid A. Logistic risk model for prolonged ventilation after adult cardiac surgery. Ann Thorac Surg 2007;84(2):528–536 Apostolakis E, Filos KS, Koletsis E, Dougenis D. Lung dysfunction following cardiopulmonary bypass. J Card Surg 2010;25(1):47–55 Ng CS, Arifi AA, Wan S, et al. Ventilation during cardiopulmonary bypass: impact on cytokine response and cardiopulmonary function. Ann Thorac Surg 2008;85(1):154–162 Beer L, Szerafin T, Mitterbauer A, et al. Continued mechanical ventilation during coronary artery bypass graft operation attenuates the systemic immune response. Eur J Cardiothorac Surg 2013; 44(2):282–287 Beer L, Szerafin T, Mitterbauer A, et al. Ventilation during cardiopulmonary bypass: impact on heat shock protein release. J Cardiovasc Surg (Torino) 2013 John LC, Ervine IM. A study assessing the potential benefit of continued ventilation during cardiopulmonary bypass. Interact Cardiovasc Thorac Surg 2008;7(1):14–17 Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology 2002;97(1):215–252 Baggiolini M. Chemokines and leukocyte traffic. Nature 1998; 392(6676):565–568 Risnes I, Ueland T, Lundblad R, et al. Changes in the cytokine network and complement parameters during open heart surgery. Interact Cardiovasc Thorac Surg 2003;2(1):19–24 de Mendonça-Filho HT, Pereira KC, Fontes M, et al. Circulating inflammatory mediators and organ dysfunction after cardiovascular surgery with cardiopulmonary bypass: a prospective observational study. Crit Care 2006;10(2):R46 Vuichard D, Ganter MT, Schimmer RC, et al. Hypoxia aggravates lipopolysaccharide-induced lung injury. Clin Exp Immunol 2005; 141(2):248–260 Chao J, Donham P, van Rooijen N, Wood JG, Gonzalez NC. Monocyte chemoattractant protein-1 released from alveolar macrophages mediates the systemic inflammation of acute alveolar hypoxia. Am J Respir Cell Mol Biol 2011;45(1):53–61 Mercer PF, Williams AE, Scotton CJ, et al. Proteinase-activated receptor-1, CCL2, and CCL7 regulate acute neutrophilic lung inflammation. Am J Respir Cell Mol Biol 2014;50(1):144–157 Szerafin T, Hoetzenecker K, Hacker S, et al. Heat shock proteins 27, 60, 70, 90alpha, and 20S proteasome in on-pump versus off-pump
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19
20
21
22
23
24
25
26
27
28
29
Beer et al.
coronary artery bypass graft patients. Ann Thorac Surg 2008; 85(1):80–87 Guan E, Wang J, Norcross MA. Identification of human macrophage inflammatory proteins 1alpha and 1beta as a native secreted heterodimer. J Biol Chem 2001;276(15):12404–12409 Shimizu Y, Murata H, Kashii Y, et al. CC-chemokine receptor 6 and its ligand macrophage inflammatory protein 3alpha might be involved in the amplification of local necroinflammatory response in the liver. Hepatology 2001;34(2):311–319 Klein DJ, Briet F, Nisenbaum R, Romaschin AD, Mazer CD. Endotoxemia related to cardiopulmonary bypass is associated with increased risk of infection after cardiac surgery: a prospective observational study. Crit Care 2011;15(1):R69 Roth W, Reuter U, Wohlenberg C, Bruckner-Tuderman L, Magin TM. Cytokines as genetic modifiers in K5-/- mice and in human epidermolysis bullosa simplex. Hum Mutat 2009;30(5):832–841 Tomic V, Russwurm S, Möller E, et al. Transcriptomic and proteomic patterns of systemic inflammation in on-pump and off-pump coronary artery bypass grafting. Circulation 2005;112(19): 2912–2920 Ghorbel MT, Cherif M, Mokhtari A, Bruno VD, Caputo M, Angelini GD. Off-pump coronary artery bypass surgery is associated with fewer gene expression changes in the human myocardium in comparison with on-pump surgery. Physiol Genomics 2010; 42(1):67–75 Nowak JE, Wheeler DS, Harmon KK, Wong HR. Admission chemokine (C-C motif) ligand 4 levels predict survival in pediatric septic shock. Pediatr Crit Care Med 2010;11(2):213–216 Krishnadasan B, Farivar AS, Naidu BV, et al. Beta-chemokine function in experimental lung ischemia-reperfusion injury. Ann Thorac Surg 2004;77(3):1056–1062 Standiford TJ, Kunkel SL, Lukacs NW, et al. Macrophage inflammatory protein-1 alpha mediates lung leukocyte recruitment, lung capillary leak, and early mortality in murine endotoxemia. J Immunol 1995;155(3):1515–1524 Schreiber JU, Lancé MD, de Korte M, Artmann T, Aleksic I, Kranke P. The effect of different lung-protective strategies in patients during cardiopulmonary bypass: a meta-analysis and semiquantitative review of randomized trials. J Cardiothorac Vasc Anesth 2012; 26(3):448–454 Schlensak C, Doenst T, Preusser S, Wunderlich M, Kleinschmidt M, Beyersdorf F. Bronchial artery perfusion during cardiopulmonary bypass does not prevent ischemia of the lung in piglets: assessment of bronchial artery blood flow with fluorescent microspheres. Eur J Cardiothorac Surg 2001;19(3):326–331, disciussion 331–332 Durukan AB, Gurbuz HA, Salman N, Unal EU, Ucar HI, Yorgancioglu CE. Ventilation during cardiopulmonary bypass did not attenuate inflammatory response or affect postoperative outcomes. Cardiovasc J Afr 2013;24(6):224–230 Groeneveld AB, Jansen EK, Verheij J. Mechanisms of pulmonary dysfunction after on-pump and off-pump cardiac surgery: a prospective cohort study. J Cardiothorac Surg 2007;2:11 Imura H, Caputo M, Lim K, et al. Pulmonary injury after cardiopulmonary bypass: beneficial effects of low-frequency mechanical ventilation. J Thorac Cardiovasc Surg 2009;137(6): 1530–1537
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