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Original Articles: Cardiovascular

Ventilation During Cardiopulmonary Bypass: Impact on Cytokine Response and Cardiopulmonary Function

^a Department of Cardiothoracic Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
^b Department of Anesthesia, The Chinese University of Hong Kong, Shatin, Hong Kong
^c Centre of Epidemiology and Biostatistics, The Chinese University of Hong Kong, Shatin, Hong Kong

Accepted for publication July 24, 2007.

^_* Address correspondence to Dr Ng, Division of Cardiothoracic Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China (Email: calvinng{at}surgery.cuhk.edu.hk).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background: A complex inflammatory response associated with the use of cardiopulmonary bypass may ultimately lead to organ dysfunction. We investigate the effect of continuing ventilation during cardiopulmonary bypass on inflammatory reactions and cardiopulmonary function.

Methods: Fifty patients undergoing cardiopulmonary bypass were prospectively randomized to continuous ventilation and nonventilation groups. Plasma interleukin-8, interleukin-10, matrix metalloproteinase-9, tissue inhibitor metalloproteinase-1, and thromboxane B₂ levels were measured preoperatively, at 1, 4, and 6 hours after aortic declamping. Levels of these mediators were also determined in bronchoalveolar lavage preoperatively and four hours after declamping. Seven parameters of cardiopulmonary function, including dynamic compliance and systemic vascular resistance, were recorded during the same time points.

Results: Plasma interleukin-10 levels were higher at 6 hours and tissue inhibitor metalloproteinase-1 levels were higher at 1 hour after aortic declamping in the continuous ventilation compared with the nonventilation group (p = 0.04 and 0.002, respectively), while bronchoalveolar lavage levels of tissue inhibitor metalloproteinase-1 were also higher in the continuous ventilation group 4 hours after declamping (p = 0.02). Plasma interleukin-8 levels were higher at 4 hours after declamping in the nonventilation group (p = 0.04). Postoperative dynamic compliance was better preserved in continuous ventilation patients than nonventilation patients at 6 hours after declamping (p = 0.0008).

Conclusions: Continued ventilation during cardiopulmonary bypass results in lesser inflammatory and proteolytic responses, and may better preserve pulmonary function than cardiopulmonary bypass without ventilation.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Cardiopulmonary bypass (CPB) can induce a complex inflammatory response involving polymorphonuclear cell activation and the release of cytokines, which may impact directly or indirectly on postoperative cardiovascular and pulmonary functions [1]. Polymorphonuclear cell activation, partly promoted by proinflammatory cytokine interleukin (IL)-8, and pulmonary neutrophil sequestration with the local release of neutrophil proteolytic enzymes, such as matrix metalloproteinase (MMP)-9, can directly lead to lung injury [2]. In contrast, antiinflammatory mediators such as IL-10 and tissue inhibitor metalloproteinase (TIMP)-1 may exhibit protective effects against organ dysfunction after CPB [3].

Apart from contact activation, many factors involved in the use of CPB may play individual roles in inducing postoperative organ dysfunction [4]. An aspect that has not been well-investigated is the effect of stopping ventilation during CPB on inflammatory response and cardiovascular-pulmonary dysfunction [2]. Some evidence suggest that hypoventilation during CPB is associated with the development of microatelectasis, hydrostatic pulmonary edema, poor compliance, and a higher incidence of postoperative infection [5, 6]. Furthermore, the lungs are dependent on three sources of oxygen delivery to maintain lung tissue viability, bronchial artery and pulmonary artery perfusion, and alveolar ventilation. Therefore, a degree of lung ischemia can occur during CPB, through lack of pulmonary artery perfusion and ventilation, and low bronchial artery perfusion [2, 7]. Lung ischemia induces an inflammatory response by the release of tumor necrosis factor and IL-8 from endothelial cells [7]. In addition, biochemical markers of lung inflammation such as thromboxane B₂ (TxB₂) is markedly increased in bronchoalveolar lavage fluid [7]. After lung ischemia reperfusion, pulmonary neutrophil activation and release of MMP cause direct injury to lung ultrastructure and pulmonary dysfunction [2, 7]. Some investigators have hypothesized that mechanical ventilation during CPB may limit postoperative lung injury by reducing microatelectasis and reducing lung ischemia-reperfusion injury. In previous animal models, ventilation during CPB did not significantly improve pulmonary vascular resistance, cardiac index, or oxygen tensions [8], and no differences in pulmonary epithelial permeability were found between ventilated and nonventilated CPB [2]. However, maintaining ventilation and pulmonary artery perfusion during CPB have shown some benefits in limiting pulmonary platelet and neutrophil sequestration, and attenuating TxB₂ response after CPB [9, 10]. Furthermore, maintaining ventilation during CPB may affect the degree of lung ischemia by altering the balance of collateral blood flow to the lungs, and bronchial mucosal blood flow.

We conducted a prospective randomized study to investigate the effects of maintaining lung ventilation during CPB in patients undergoing coronary artery bypass grafting (CABG) using pulmonary and systemic inflammatory cytokine responses as major endpoints. In addition, changes in cardiopulmonary function and clinical benefits will be measured as secondary endpoints.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
After ethical approval by the Research Ethics Committee of the Chinese University of Hong Kong, 50 patients undergoing CABG were recruited over a 13-month period. Informed consent was obtained from all patients individually. Patients undergoing redo or emergency procedures, with inflammatory or infective lung condition before surgery, had a history of myocardial infarction within 6 weeks, with left ventricular ejection fraction less than 0.30, with preoperative renal failure or chronic liver dysfunction, and preoperative use of steroids were excluded from the study. Aspirin and angiotensin-converting enzyme inhibitors were stopped 7 and 2 days before surgery, respectively. All patients were scheduled as the first case of the day, and were operated on by the same surgeon. Prior to surgery, a dedicated researcher randomized patients by opening a presealed envelope to the continuous ventilation or the nonventilated groups during CPB. Except for the anesthetists and surgeon, the laboratory technicians and other clinicians caring for the patients were blinded to the intraoperative ventilation status.

Anesthesia
Cefuroxime 1.5 g (GlaxoSmithKline, Research Triangle Park, NC) was given intravenously at induction of anesthesia for antimicrobial prophylaxis. A standard anesthetic regimen was used in all patients. The patient was preoxygenated with 100% O₂ and induction was achieved by using midazolam, fentanyl, propofol, rocuronium, and isoflurane. Intraoperative relaxant maintenance was with vecuronium. Analgesia and hypnosis were maintained during CPB with fentanyl and midazolam infusion, which changed to propofol infusion after CPB. Intraoperatively, hypertension was treated with isoflurane, nitroglycerin, and fentanyl boluses. Conversely, hypotensive episodes were treated with intravenous metaraminol. No patient received corticosteroids before, during, or after the operation.

CPB and Surgical Techniques
After median sternotomy, the left internal mammary artery was harvested with opening of the left pleura in both groups of patients. Normothermic CPB (permissive temperature drift to 35°C) was established with standard systemic heparinization (3 mg/kg) maintaining activated clotting time greater than 500 seconds. The extracorporeal circuit consists of a roller pump (Sarns 9000, 3M Health Care, Ann Arbor, MI) and membrane oxygenator (Turbo, 3M Health Care). Pump flow was set at 2.4 L/min/m² while maintaining the mean arterial pressure between 60 and 70 mm Hg. Myocardial protection was identical in all patients, with the administration of intermittent antegrade cold (4°C) blood cardioplegia. The aortic cross-clamp was removed after completion of all distal anastomoses. On discontinuation of CPB, heparin was neutralized with protamine sulfate. Dopamine and norepinephrine were used for hemodynamic support as required. All patients received glyceryl trinitrate infusion titrated to blood pressure. Aprotinin was not used in any study patient.

Ventilation Strategy
Before and after CPB, all patients were ventilated with a fraction of inspired oxygen (FIO ₂) of 50%. No patient required a higher FIO ₂ to sustain an adequate oxygen saturation, and no positive end expiratory pressure was used in any of the cases. Tidal volume was 5 to 7 mL/kg before and after CPB. Likewise, respiratory rate was 10 to 12 per minute. The variation in tidal volume and respiratory rate were to titrate the partial pressure of carbon dioxide, arterial, to 35–40 mm Hg. The same ventilation was used in both the continuous ventilation and nonventilation groups.

In the continuous ventilation group, mechanical ventilation was maintained at 5 cycles per minute with a tidal volume of 5 mL/kg and FIO ₂ of 50% throughout CPB, whereas ventilation was discontinued (open to atmospheric pressure) in the nonventilation group. Postoperatively, all patients had volume-controlled ventilation in the intensive care unit until normal body temperature and stable hemodynamics and respiratory functions allowed respiratory weaning.

Sampling and Measurements
Peripheral arterial blood samples were collected from the radial artery after induction of anesthesia, and at 1, 4, and 6 hours after aortic declamping. Citrated and EDTA-anticoagulated bloods were immediately centrifuged (3,000 rpm for 10 minutes) at 4°C. The plasma was separated and stored at –70°C until assay.

Bronchoalveolar lavage was performed after induction of anesthesia, and repeated 4 hours after aortic declamping, according to Technical Recommendations and Guidelines for Bronchoalveolar Lavage (Report of the European Society of Pneumology Task Group on Bronchoalveolar Lavage 1989). The right middle lobe was wedged by the bronchoscope while two separate aliquots of 20 mL pyrogen-free sterile saline at 37°C (isotonic 0.9% NaCl, suitable for intravenous use) were instilled, and recovered by controlled suction (negative pressures of 25 to 40 mm Hg) into sterile vessels. The bronchoalveolar lavage fluid was immediately filtered with 70 µm nylon cell strainer (Falcon, Becton Dickinson, San Jose, CA) and centrifuged at 1,500 rpm for 3 minutes. The supernatant was collected and stored at –80°C.

Plasma and bronchoalveolar lavage concentrations of IL-8, IL-10, MMP-9, TIMP-1, and TxB₂ were determined by commercially available enzyme-linked immunosorbent assays (Human Quantikine ELISA kit, R&D Systems Inc, Minneapolis, MN).

Cardiopulmonary parameters were measured after induction of anesthesia, and at 1, 4, and 6 hours after aortic declamping. Using the CO₂SMO Plus monitor (Novametrix Medical Systems Inc, Wallingford, CT) data on alveolar-arterial partial pressure of oxygen (PO ₂) gradient, alveolar dead space, and inspiratory volume-pressure curves reflecting dynamic compliance were collected. Hemodynamic parameters, including cardiac index, stroke volume, systemic vascular resistance, extravascular lung water, and global end diastolic volume were measured at the same time points by the PiCCO monitor (Pulsion Medical Systems, München, Germany) utilizing the thermodilution Fick’s principle through the central venous and femoral arterial catheter transducer, and temperature housing set.

Statistical Analysis
Power analysis suggested that, to detect a minimum difference of 15% [11] with 80% power and level (2-sided) of 0.05, 25 patients per group were required. All data were stored and analyzed using a standard computer statistical software program (Statistical Package for the Social Sciences 11.0; SPSS Inc, Chicago, IL) and MIXREG computer software (Discerning Systems Inc, Burnaby, BC, Canada). Clinical data were shown as mean ± standard deviation. The unpaired t test and ² or Fisher exact tests were used for comparing clinical variables between the two groups. Mixed-effects models (multilevel models) were used for analyzing longitudinal data by comparing the cytokine levels and pulmonary hemodynamic parameters between the two groups at each of the four time points [12]. The mixed-effects model is considered to be an extension of the ordinary least-squares regression model but also takes into account subject heterogeneity. The statistical analysis was performed on raw data and logarithmically transformed results where appropriate to correct the skewness of data. A 2-sided p value of less than 0.05 was considered significant.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The two groups were comparable clinically and in their demographics (Table 1). Complete revascularization was achieved in all patients. In two patients from the continuous ventilation CPB group, ventilation was suspended for several minutes to facilitate anastomoses to the distal left circumflex artery in the large hypertrophic heart. One patient in the nonventilation group required reexploration for bleeding. The number of patients requiring blood product transfusions was similar between the two groups. Six patients from the nonventilation group and two from the continuous ventilation group have radiologic evidence of postoperative focal atelectasis. Pneumonia, confirmed by microbial culture from sputum, developed in three from the nonventilation and one from the continuous ventilation group. There was no death or major complication in either group.

Pulmonary Function
There were significant reductions of dynamic compliance in nonventilation patients at 4 and 6 hours after aortic declamping compared with baseline. By 6 hours after declamping, continuous ventilation patients have significantly higher dynamic compliance compared with nonventilation patients (Table 4). Alveolar dead space was significantly lower at 6 hours after declamping in both nonventilation and continuous ventilation patients compared with their baselines. Alveolar-arterial PO ₂ gradient rose significantly at 1 hour after aortic declamping in both nonventilation and ventilation patients compared with their baselines (Table 4). No intergroup or intragroup differences were found for extravascular lung water.

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The study indicate that, compared with conventional CPB, continued ventilation throughout CPB is associated with lower inflammatory cytokine IL-8, but higher antiinflammatory cytokine IL-10 and proteolytic enzyme inhibitor TIMP-1 levels in the early postoperative period. Benefits in pulmonary function as reflected by better dynamic compliance was also detected in patients undergoing ventilated CPB.

Interleukin-8 is known to attract and activate neutrophils and T-lymphocytes, as well as control their trafficking [3, 10]. Clinical studies have documented that the myocardium can be a major source of IL-8 after significant ischemia [13]. Circulating IL-8 levels correlate with the degree of myocardial injury and development of left ventricular wall dyskinesia in the postoperative period [14, 15]. Furthermore, reperfusion can enhance IL-8 release by alveolar macrophage, contributing to increased IL-8 levels [10]. Interestingly, bronchoalveolar lavage and circulating levels of IL-8 can also be significantly influenced by their consumption and clearance by the lung [16, 17]. We observed no difference between the groups in ischemic time, CPB duration, or cardiac function (cardiac index, stroke volume), which suggests that the lower IL-8 levels found in the blood in continuous ventilated patients may be related to less lung ischemia-reperfusion injury and improved metabolism and clearance of IL-8 by the lung, rather than reduced IL-8 production from myocardium. By maintaining ventilation throughout CPB, we speculate that there was less ischemia-reperfusion lung injury and activation of alveolar macrophage, thereby attenuating release of IL-8 into the circulation [10]. The attenuated IL-8 response in the continuous ventilated group also supports the previous findings of a lesser systemic inflammatory cytokine (IL-6, IL-8) response following the Drew-Anderson technique of bilateral extracorporeal bypass without oxygenator, where lung ventilation and pulmonary artery perfusion is maintained during bypass [2]. Furthermore, higher IL-8 levels in the nonventilated group may also partly be attributable to IL-8 release from reexpansion of atelectatic lungs. We were careful in choosing a protective ventilation strategy, thereby limiting the up-regulation of cytokine release as the response to alveolar stretch injury [10, 18]. The lower levels of IL-8 associated with continuous ventilation CPB may also explain the previously observed attenuation of pulmonary polymorphonuclear cell activation and sequestration in these patients [19].

Interleukin-10 can directly inhibit the release of proinflammatory cytokines, or indirectly exert antiinflammatory effects by triggering the release of IL-1 receptor antagonist and tumor necrosis factor soluble receptors 1 and 2 [14]. Previous studies found the release of IL-10 to be proportional to the levels of IL-8 during either on-pump [20] or off-pump CABG [3], thereby maintaining the balance between pro- and antiinflammatory responses. Greater release of IL-10 after CPB has been associated with improved postoperative cardiac index and pulmonary gas exchange [21], although the exact mechanism is unclear. In part, IL-10 protects the lungs from pulmonary microvascular fibrin deposition and thrombosis after pulmonary ischemia-reperfusion by reducing the imbalance between plasma plasminogen activator inhibitor and tissue-type plasminogen activator activities [22]. Increased pulmonary IL-10 by gene transfection of transplanted lungs shifted the mode of cell death from necrosis to apoptosis with associated improvement of lung function [23]. Our data suggest that continued ventilation during CPB tips the balance in favor of anti-inflammatory IL-10 response with reduction in IL-8 compared with conventional CPB. The mechanism of how lung ventilation may influence IL-10 production remains unclear. Recent evidence indicated that the lungs can release IL-10 in the early post-CPB period [24], although the liver can also be a source of IL-10 during CPB [14, 25].

Activation of neutrophils by CPB can cause the release of MMP-9 into the systemic circulation and locally into the lung tissue. Significant increases in plasma MMP-9 has been associated with the use of CPB [26, 27], consistent with our findings. The MMP-9 contributes to the development of post-CPB lung injury by breaking down the pulmonary ultrastructure, particularly type IV collagen at the lung basement membrane, facilitating neutrophil sequestration, increase microvascular permeability and endothelial damage, pulmonary edema, and protein accumulation of the lung [2, 28]. The MMP-9 is also at least in part responsible for the release of, and has a positive-feedback relationship with neutrophil elastase from activated neutrophils, which contribute to the pulmonary ultrastructure injury [2]. Furthermore, MMPs may be involved in cardiac dysfunction through breakdown of the myocardial extracellular matrix [26]. Tissue inhibitor of metalloproteinase-1, the natural inhibitor to MMP-9, is produced in several organs including the lung to help maintain pulmonary structural integrity. In contrast to our results showing higher bronchoalveolar lavage and blood TIMP-1 levels after CPB, a previous study observed that TIMP-1 decreased during CPB [27]. The observed discrepancy may be the result of different sampling times. In fact, there may be a trend toward lower bronchoalveolar lavage MMP-9 levels in patients from the continuous ventilation CPB group, which may be a reflection of the lesser neutrophil activation from the attenuated IL-8 response from the continued ventilation strategy. The less proteolytic environment in the lung of continued ventilation patients may attenuate the development of postoperative lung injury and cardiac dysfunction.

Increased plasma and bronchoalveolar lavage levels of TxB₂ after CPB is associated with more severe lung dysfunction due to pulmonary hypertension, increase pulmonary capillary permeability, and neutrophil sequestration [2, 9], which can be eliminated by TxB₂ inhibition in the animal model. Previously, the lung has been suggested to be a major source of TxB₂ [2, 9]. We found higher TxB₂ levels in the circulation 6 hours after declamping and in the postoperative bronchoalveolar lavage, although differences between groups were not significant. One possible explanation is that pulmonary artery perfusion and other aspects of the CPB circuit may be more important than maintaining continuous ventilation during CPB on TxB₂ production [9]. The clinical implication of higher plasma and bronchoalveolar lavage TxB₂ levels after CPB warrants further investigation.

In our study, a higher dynamic compliance at 6 hours after declamping was detected in the continuous ventilated group. It is known that hypoventilation during CPB is associated with development of microatelectasis, hydrostatic pulmonary edema, poor compliance, and a higher incidence of postoperative infection [5, 6]. Various ventilation strategies after CPB, including vital capacity maneuver, continuous positive airway pressure, and continuous ventilation during CPB, have been investigated. In experimental models, vital capacity maneuver at the end of CPB improved pulmonary gas exchange and atelectasis [5, 6]. Meanwhile, better postoperative gas exchange and less pulmonary shunting were observed in patients who received continuous positive airway pressure during CPB, although such benefits were not always reproducible [2]. To date, the evidence favoring continuous ventilation alone during CPB on cardiopulmonary function is inconsistent, with most studies showing no benefit [2]. The exact mechanism behind the better preserved dynamic compliance that we observed in ventilated patients 6 hours after declamping remains unknown. Similar extravascular lung water between the groups suggests pulmonary edema is unlikely to be a major factor influencing dynamic compliance in this setting. Reducing pulmonary microatelectasis, better alveolar recruitment, and lower airway resistance by continued ventilation during CPB as well as the attenuated inflammatory cytokine responses may be more important factors in improved dynamic compliance [2, 5, 6]. In some centers where positive end expiratory pressure is applied during CPB, such benefits may be less pronounced.

This study has limited patient numbers and therefore is prone to bias. Although we have measured many important cytokines, inevitably many others were omitted. It is likely that the balance between pro- and antiinflammatory cytokines is more important than individual cytokines. Furthermore, clinical factors such as transfusion may have influenced outcome. A more prolonged measure of dynamic compliance beyond 6 hours may have provided more information on the trend. However, many of our patients undergoing routine CABG would be weaning from or weaned off their ventilator by that time. In addition, patient tolerance to pain, their psychosocial status, and compliance to physiotherapy exercises, can easily mask clinical benefits derived from the ventilation strategy in the current study. The study is underpowered for detecting differences in clinical outcome measures such as incidence of postoperative pneumonia. The power analysis base on these data suggests that 115 patients per group are required to detect significant differences in clinical outcome. Future studies should focus on the source of the pulmonary chemokines and investigate pulmonary neutrophil and macrophage sequestration and activation during continuous ventilation CPB.

In summary, CABG surgery patients undergoing conventional nonventilation CPB produced a more profound systemic and local inflammatory proteolytic response. Postoperative cardiopulmonary dysfunction may in part be related to ischemia-reperfusion to the lung and mechanical atelectasis after nonventilation CPB. We propose that continued ventilation throughout CPB can partially lessen the degree of lung dysfunction, as reflected by the shift toward a more antiinflammatory and less proteolytic environment, and better dynamic compliance. Although we were unable to demonstrate improved oxygenation, ventilator time, intensive care unit stay, and incidence of postoperative atelectasis or pneumonia in continuous ventilation patients due to limited sample size, the observed biochemical advantages and potential clinical benefits warrant further investigation.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We would like to thank perfusionists Carmen Chan and Jack So for their kind assistance.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Calvin S.H. Ng Ahmed A. Arifi Song Wan Innes Y.P. Wan Anthony P.C. Yim Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ng, C. S.H. Articles by Yim, A. P.C. Search for Related Content PubMed PubMed Citation Articles by Ng, C. S.H. Articles by Yim, A. P.C. Related Collections Extracorporeal circulation