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Eur J Cardiothorac Surg 2005;28:889-895
© 2005 Elsevier Science NL

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

Dinis Reis Miranda a , * , Diederik Gommers a , Ard Struijs b , Rien Dekker a , Joris Mekel c , Richard Feelders d , Burkhard Lachmann a , Ad J.J.C. Bogers b

a Department of Anesthesiology, Erasmus MC, Dr Molewaterplein 40, 3015 DG Rotterdam, The Netherlands
b Department of Cardio-thoracic Surgery, Erasmus MC, Rotterdam, The Netherlands
c Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
d Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

Received 4 August 2005; received in revised form 20 September 2005; accepted 3 October 2005.

* Corresponding author. Tel.: +31 10 4633713; fax: +31 10 4633722. (Email: d.dosreismiranda{at}erasmusmc.nl).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: 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. Methods: 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 PaO2/FiO2 > 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 3 h, 5 h, 24 h, 2, and 3 days after cessation of CPB. Results: 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. Conclusions: 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.

Key Words: Myocardial infarction • Postoperative care • Inflammation • Inflammatory mediators (e.g. cytokines • cytotoxins) • Ventilation, intubation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response syndrome. It has been shown that cytokine release is correlated with outcome after cardiac surgery [1]. This cytokine release is caused by contact of blood with the artificial surface of the cardiopulmonary bypass, and also by the surgical trauma and ischemia/reperfusion injury from the heart. Furthermore, mechanical ventilation with abnormal shear stress may be responsible for eliciting cytokine release from the lung [2].

In acute respiratory distress syndrome (ARDS) patients, plasma interleukin (IL)-8 and also IL-6 and tumor necrosis factor (TNF)-{alpha} concentrations increase during conventional ventilation (CV) [3,4]. The inflammatory response from the lung during mechanical ventilation originates at the alveolar membrane as a result of mechanical stress, enhanced by repetitive re-opening of atelectatic lung areas [3]. Ventilation according to the open lung concept (OLC) has been introduced to avoid atelectasis and thereby attenuating ventilator-induced lung injury [5]. This is achieved by short periods of high inspiratory pressures to open up collapsed alveoli followed by a relatively high level of positive end-expiratory pressure (PEEP) to keep the alveoli open. Using this strategy, we were able to reduce cytokine release compared to conventional ventilation in an experimental ARDS model [6,7].

As ventilation according to the OLC aims at decreasing alveolar mechanical stress, we hypothesized that OLC would attenuate pulmonary inflammation after cardiac surgery. We have previously shown that this ventilation strategy attenuates the reduction of functional residual capacity (FRC) and the occurrence of hypoxemia, at least until 3 days after extubation [8]. Especially, early application of OLC appears to be the most effective way to attenuate FRC loss after extubation. Therefore, we studied the effect of OLC on pulmonary inflammation and the influence of the timing with which OLC was initiated (before or after cardiac surgery).


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The local Human Ethics Research Committee approved this study and each patient gave written informed consent. Sixty-nine patients were enrolled in this study, the effect of OLC on FRC in this patient group was reported previously [8]. In this study, patients scheduled for coronary artery bypass graft and/or valve surgery with use of CPB were included. Patients with severe airway obstruction (defined as forced expired volume in 1 s or vital capacity more than two standard deviations below the predicted value) were not included.

After intubation, all patients were ventilated using a Siemens 900C ventilator (Siemens, Solena, Sweden) during anesthesia and during their postoperative ICU stay. Anesthesia was maintained with propofol (2–4 mg/(kg h)) and sufentanil (1 µg/kg) as needed. Antibiotic prophylaxis was given with cefazolin for 24 h. None of the patients received corticosteroids or phosphodiesterase inhibitors in the perioperative period.

Randomization by envelope occurred after induction of anesthesia. Patients were randomized to one of the three groups: Group 1 received CV. After intubation, mechanical ventilation was guided by the results of the ARDS network group [9], entailing volume control ventilation at the following settings: tidal volume of 6–8 mL/kg, PEEP of 5 cmH2O, I/E ratio of 1:2, FiO2 was set to achieve a PaO2 between 75 and 98 mmHg and respiratory rate was adjusted to achieve a PaCO2 between 34 and 49 mmHg. During CPB, the lungs were briefly disconnected from the ventilator. Thereafter, lung expansion was maintained using CPAP 3–5 cmH2O with 50% oxygen and 50% nitrogen. After CPB, ventilation was continued with the same settings as described above until the weaning procedure was started.

The second group (late open lung, LOL) was ventilated in the same way as the CV group after intubation. During CPB, the lungs were briefly disconnected from the ventilator. Thereafter, lung expansion was maintained using CPAP 3–5 cmH2O with 50% oxygen and 50% nitrogen, similar to the CV group. After CPB, ventilation was continued with the same settings. Thirty minutes after arrival on the ICU, CV was switched to OLC and this was continued until extubation. Ventilation according to the OLC was started by switching the ventilator to a pressure controlled mode with a respiratory frequency of 40 min–1. FiO2 was set to achieve a PaO2 between 75 and 98 mmHg, PEEP of 10 cmH2O, I/E ratio of 1:1 and a driving pressure to obtain a tidal volume of 4–6 mL/kg aiming at a PaCO2 of 34 and 49 mmHg. A lung recruitment maneuver was applied by increasing peak inspiratory pressure (PIP) to 40 cmH2O during 15 s to increase the PaO2/FiO2 ratio to a value greater than 375. If not reaching this value, a recruitment maneuver was repeated by increasing PIP 5 cmH2O greater than before, up to a maximum PIP of 60 cmH2O until the PaO2/FiO2 ratio became greater than 375. If the PaO2/FiO2 ratio decreased slowly below 375 after recruitment, PEEP was increased by 2 cmH2O and a recruitment maneuver (beginning at 40 cmH2O) was repeated. If PaO2/FiO2 ratio decreased below 375 after a (accidental) disconnection, a new recruitment maneuver was performed.

The third group (early open lung, EOL) received pressure controlled ventilation using the OLC strategy as described in the previous paragraph, which started directly after intubation. Ventilation was maintained during cardiac surgery and on the ICU. During CPB, patients were pressure controlled ventilated with a frequency of 40 min–1, tidal volume of 1 mL/kg, 50% oxygen and 50% nitrogen, I/E ratio of 1:1 and PEEP of 10 cmH2O. If the lungs obstructed the surgical exposure, CPAP was applied at 10 cmH2O. If inadequate vision remained, the endotracheal tube was briefly disconnected and a CPAP level of 3–5 cmH2O was applied. Ventilation settings as used before the lung deflation were restored as soon as possible. After CPB, ventilation was according to the OLC until the weaning procedure was started.

If body temperature and cardiovascular measurements were satisfactory, sedation was stopped. When the patient triggered the ventilator, ventilator mode was switched to pressure support. A support level was chosen to obtain a tidal volume of 6–8 mL/kg. PEEP was reduced to 10 cmH2O in both OLC groups and was not changed during weaning. PEEP levels in the CV group were not changed. Approachable patients with pressure support levels lower 15 cmH2O were extubated

Before initiating CPB, heparin 3 mg/kg was administered. For CPB, a non-pulsatile roller-pump was used for all patients, containing a flat sheet membrane oxygenator. The use of aprotinin (1.5 x 106 KIU) in the pump priming was left to the discretion of the surgeon. Surgery was performed with a core temperature of 28–32 °C. Heparin was reversed with 4–5 mg/kg protamine, immediately after separation of CPB in all patients. Packed red cells were administered if the hemoglobin concentration was lower than 6.0 mmol/L. To correct coagulation, fresh frozen plasma and platelet concentrates were given as indicated.

Blood samples were drawn preoperatively (before induction of anesthesia), after cessation of CPB (T = 0) and 3 h, 5 h, 24 h, 2, and 3 days after cessation of CPB. After the blood sample was taken, blood was immediately centrifuged at a speed of 3500 rpm and at a temperature of 4 °C. After centrifugation, plasma was frozen at a temperature of –20 °C. A commercially available Pelikine Compact enzyme-linked immunosorbent assay kit (Central laboratory of the Netherlands Red Cross, Amsterdam, The Netherlands) was used to determine plasma IL-6, IL-8, IL-10, TNF-{alpha}, and interferon (IFN)-{gamma} concentrations in one batch.

To determine perioperative myocardial infarction, creatine kinase subfraction MB (CK-MB) was determined directly after arrival on the ICU, and 8, 12, and 24 h after arrival on the ICU. A 12-lead electrocardiogram (ECG) was recorded 4, 16, and 24 h after admission on the ICU. CK-MB and the ECGs were evaluated by an experienced cardiologist (J.M.) who was blinded to the applied ventilation strategy. Perioperative myocardial infarction was diagnosed if: (a) the CK-MB fraction increased to more than five times the upper normal limit or (b) new Q waves appeared in a postoperative ECG [10]. New Q waves were defined as a 2-grade worsening on the Minnesota code or a 1-grade Q wave worsening with major ST segment elevation or depression.

2.1 Statistics
The changes from baseline (=end of CPB) measurements on cytokines were calculated and used to compare the three groups using analysis of variance for repeated measurements. The difference between the different time points and preoperative values were compared using a paired Student's t-test. The incidence of myocardial infarction in each group was compared with a {chi} 2-test. Data are presented as mean ± SEM.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The patient characteristics were comparable between the groups and are given in Table 1 . Failure to adequately collect blood samples occurred in seven patients; these patients were only excluded for the cytokine analyses (CV 1 patient, LOL 5 patients, and EOL 1 patient). Detailed cardiovascular parameters and pulmonary complication rates are described previously [8]. In summary, no differences between cardiovascular parameters were detected and occurrence of pneumonia (CV 5 patients, LOL 3 patients, and EOL 3 patients) and pneumothorax (CV 2 patients, LOL 1 patients, and EOL 2 patients) were comparable between groups.


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  		Table 1. Patient characteristics
 
The overall decrease in IL-8 after CPB was significantly greater in both OLC groups compared to the CV group (Fig. 1 ). Immediately after cessation of CPB (T = 0), IL-8 were significantly elevated compared to preoperative values, but these concentrations were comparable between the groups (Fig. 2 ). In the CV group, IL-8 concentrations remained significantly elevated until 72 h after CPB compared to the preoperative values (Fig. 2). In both OLC groups, however, IL-8 concentrations were only significantly elevated until 24 h after CPB (Fig. 2).



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  		Fig. 1. Interleukin (IL), tumor necrosis factor (TNF), and interferon (IFN) concentration at different time points minus the concentration at the cessation of cardiopulmonary bypass (CPB). Solid bars: conventional mechanical ventilation (CV), open bars: late open lung (LOL) ventilation, hatched bars: early open lung (EOL) ventilation. * p < 0.05 versus CV. Mean ± SEM.

 


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  		Fig. 2. Interleukin (IL), tumor necrosis factor (TNF), and interferon (IFN) concentrations in time (hours after cardiopulmonary bypass (CPB)). T = –1 is preoperative. Conventional mechanical ventilation (CV) is represented by closed circles, late open lung (LOL) ventilation by open circles, and early open lung (EOL) ventilation by triangles. * p < 0.05 each time point versus preoperative.

 
The overall decrease in IL-10 after CPB was only significantly greater in the EOL group (Fig. 1). At T = 0, IL-10 concentrations were significantly elevated compared to preoperative values, but were comparable between the groups (Fig. 2). After T = 0, IL-10 was comparable to preoperative values in the EOL group. In the LOL and CV group, however, IL-10 concentrations remained significantly elevated until 5 h after CPB (Fig. 2).

IL-6 concentrations were comparable between all groups (Fig. 2).

Directly after CPB (T = 0), TNF-{alpha} and IFN-{gamma} concentrations did not differ significantly between the three groups throughout the study period (Fig. 1). Postoperative C-reactive protein concentrations were comparable between the groups (Fig. 3 ).



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  		Fig. 3. C-reactive protein (CRP) concentrations following CPB. T = 0 is before CPB. Solid bars: CV group, open bars: LOL, and hatched bars: EOL group. Mean ± SEM.

 
Total PEEP values were in the CV group 5.5 ± 0.1 cmH2O, in the LOL group 14.6 ± 0.4 cmH2O, and in the EOL group 14.1 ± 0.2 cmH2O. PIP was 24 ± 1 cmH2O in the CV group, 25 ± 1 cmH2O in the LOL group, and 24 ± 1 cmH2O in the EOL group. The PaO2/FiO2 ratio in the CV group was 285 ± 8 mmHg, in the LOL group 428 ± 8 mmHg, and in the EOL group 450 ± 8 mmHg. PaCO2 concentrations were comparable between groups (CMV: 38 ± 5 mmHg, LOL: 37 ± 6 mmHg, and EOL: 38 ± 4.5 mmHg).

Myocardial infarction did not occur in the EOL group, whereas one patient in the CV group and two patients in the LOL group suffered from a perioperative myocardial infarction (p = 0.35).

Administered units of blood products were equally divided between the groups (CV: 1.8 ± 0.3, LOL: 1.7 ± 0.3, and EOL: 1.5 ± 0.1 number of products per patient).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our results show that the early application of OLC (EOL) is significantly associated with the decline in plasma concentrations of IL-8 and IL-10 after cardiopulmonary bypass compared to conventional ventilation. Late application of OLC (LOL) results in a significant decrease of IL-8, but not IL-10, after CPB.

The inflammatory response after CPB is known to be mediated by several mechanisms including mechanical ventilation, extracorporeal circulation, and tissue damage [11]. Cytokines initiate and coordinate the inflammatory response and act in a complex cascade. TNF-{alpha} is a proximal mediator within this cascade and induces a second wave of cytokines such as IL-6, an important regulator of the hepatic acute phase response, and IL-8. IL-8 is a cytokine with important neutrophil-activating and chemoattractant properties and can be produced by alveolar macrophages. Other mediators of the cytokine network are the so-called T helper (Th) 1 and Th2 cytokines. Uncommitted T cells can differentiate into either the Th1 phenotype which produces cytokines like IL-2 and IFN-{gamma}, or the Th2 phenotype which produces IL-4 and IL-10. Th1 cytokines have pro-inflammatory effects and are involved in cellular immunity, whereas Th2 cytokines have anti-inflammatory properties and are regulators of the humoral immune response [12]. There is to some extent a reciprocal cross-regulation between Th1 and Th2 cytokines.

The decrease of IL-8 after CPB as seen in the OLC groups suggests that mechanical ventilation promotes the systemic inflammatory response after cardiac surgery [13]. It has repeatedly been shown that mechanical ventilation leads to IL-8 production in the lung due to cyclic alveolar stress [14,15]. OLC, however, aims at avoiding this cyclic alveolar stress by minimizing atelectasis, and should therefore lead to a reduction of pulmonary inflammation. Our group [6] has previously shown that this ventilation strategy reduces the influx of polymorphonuclear neutrophils, IL-8 and thrombin activity in broncho-alveolar lavage (BAL) fluid in newborn piglets [6]. Ranieri et al. [4] measured IL-8 in BAL fluid in ARDS patients and showed a reduction of IL-8 when using a protective ventilation strategy. In contrast to the present study, Ranieri et al. [4] did not find any effect of this protective ventilation strategy on plasma IL-8 levels.

Furthermore, IL-8 probably plays an important role in the pathophysiology of myocardial ischemia and infarction. In patients with acute myocardial infarction, IL-8 concentration appeared to be correlated to complications after myocardial infarction [16]. In addition, myocardial injury could be prevented by administration of antibodies of IL-8 in an experimental model [17]. This suggests that IL-8 participates in the pathogenesis of myocardial infarction. As OLC ventilation is accompanied by a more rapid normalization of IL-8 levels, it might be speculated that this ventilation modality could have beneficial effects on the perioperative myocardial infarction rate. In the present study, the incidence of myocardial infarction was comparable between the groups; however, it is fortunately a relatively infrequent complication and this study was not powered to show any difference in the myocardial infarction rate.

In the present study the decrease in IL-10 after CPB was only significantly greater in the EOL group compared to the CV group. During inflammation, IL-10 levels increase, suppressing pro-inflammatory cytokine production. When the primary injury is attenuated, both pro- and anti-inflammatory cytokine responses decrease after cardiac surgery [18,19]. As stated above, ventilation according to the OLC aims at reducing shear stress in atelectatic lung areas, thus avoiding ventilator-induced lung injury [7]. Lower IL-10 levels in combination with lower IL-8 levels suggest attenuated primary injury in the lung during early application of OLC. In neither the CV group nor both OLC groups did we find an increase in plasma IFN-{gamma} concentrations. This may indicate an absence of Th1 activation after CPB, although effects on tissue IFN-{gamma} production cannot be excluded, nor can inhibition of the Th1 pathway by elevated IL-10 levels.

Based on these results we conclude that ventilation according to the OLC may actually protect the lung against injury and therefore is best applied early. Late application of OLC also reduced IL-8 release, but did not affect IL-10 concentrations. The greater decreases in IL-10 concentration in only the EOL group suggest that the LOL group may initially have developed a greater degree of pulmonary inflammation compared to the EOL group. That IL-8 after CPB also decreases significantly in the LOL group suggests that further development of pulmonary inflammation on the ICU is attenuated by using OLC in the ICU. The findings of the ARDS network group [20] support the suggestion that IL-10 indicates the degree of primary pulmonary inflammation [18] and IL-8 indicates the development of further pulmonary inflammation related to mechanical ventilation. This group showed in 703 patients with acute lung injury that IL-6 and IL-8, but not IL-10 decreased when a protective ventilation strategy was initiated [20]. We therefore assume that the LOL group suffered from greater primary pulmonary inflammation than the EOL group.

While early application of OLC seems to attenuate pulmonary inflammation, the optimal timing of this early initiation of OLC is unclear. In the present study it is unlikely that the protective effect of the EOL on pulmonary inflammation occurred during induction of anesthesia, before initiation of CPB. Major surgery in patients without pulmonary dysfunction does not seem to elicit significant interleukin release [21]. It is also doubtful whether this primary pulmonary dysfunction in the LOL group occurred during CPB. It could be argued that pulmonary tissue hypoxia (followed by ischemia/reperfusion injury) occurred in the LOL group, as this group was not ventilated during CPB, in contrast to the EOL group. However, non-ventilation during CPB is not expected to cause pulmonary tissue hypoxia, as the bronchial circulation seems to meet pulmonary oxygen demands [2]. In addition, it is unlikely that mechanical ventilation with a tidal volume of 1 mL/kg would cause sufficient alveolar ventilation to avoid pulmonary tissue hypoxia. Furthermore, application of only CPAP during CPB does not cause cyclic re-opening of alveolar units and thus no additional cytokine release [22]. Therefore, it is also unlikely that the primary pulmonary inflammation in the LOL group is caused by 3–5 cmH2O CPAP during CPB compared to the 10 cmH2O CPAP with small tidal volume ventilation in the EOL group. The most likely cause of the accentuated primary pulmonary inflammation in the LOL group is the application of conventional ventilation immediately after CPB. Immediately after release of the aortic crossclamp, cytokine concentrations are significantly elevated, as shown in Fig. 1. Cytokine release induced by conventional mechanical ventilation is in part dependent on the pro-inflammatory condition induced by CPB [23]. Therefore, the accentuated primary pulmonary inflammation in the LOL group compared to the EOL group is probably caused by the application of conventional ventilation immediately after CPB. This suggests that OLC should at the latest be initiated immediately after cessation of CPB.

IL-6 is a pro-inflammatory cytokine and is probably more influenced by the degree of surgical trauma than by specific myocardial or lung injury after cardiac surgery [24]. In several studies no reduction of IL-6 levels were found with on-pump cardiac surgery compared to off-pump surgery [18,19]. Also in the present study, no effect of OLC on IL-6 levels was observed. This might be explained by the major release of IL-6 due to surgical trauma, masking the possible effects of OLC on IL-6 production.

In this study, the influence of EOL on pulmonary inflammation is mainly based on the decrease of IL-8 and IL-10 concentrations after CPB. CPB is known to cause a firm inflammatory response and before initiation of CPB, lungs are relatively healthy. Ventilator induced lung injury does not occur in healthy lungs [21], as described above. However, ventilator induced lung injury is likely to occur when mechanical ventilation occurs in an inflammatory environment. Therefore, increment or attenuation of interleukin release after CPB could theoretically reveal the effect of ventilatory strategy on pulmonary inflammation.

A possible drawback of this study is that aprotinin was used at the discretion of the surgeon. High dose aprotinin (2 x 106 KIU loading dose + 2 x 106 KIU priming dose + infusion 5 x 105 KIU/h) significantly reduces IL-8 and IL-10 plasma levels [25]. However, the effect of aprotinin on interleukin release is dose dependent: low dose (0.5 x 105 KIU/kg or 2.0 x 106 KIU at pump priming) does not significantly affect interleukin release [26]. In this study, low dose aprotinin was used at pump priming and was equally distributed over the three groups (Table 1). We therefore think that the influence of aprotinin on interleukin concentrations in this study is negligible.

Another possible drawback is that cytokine concentrations in broncho-alveolar fluid were not obtained. Cytokines obtained from a BAL are specifically produced by the lung and may reflect the intrapulmonary inflammation more accurately. However, a BAL has the potential to transiently aggravate pulmonary dysfunction. In addition, a BAL reflects a local pulmonary inflammation status of one pulmonary lobe. To avoid a possible bias of a BAL on the effect of mechanical ventilation on pulmonary inflammation, we did not perform a BAL.

We conclude that in cardiac patients, OLC ventilation leads to an attenuated inflammatory response, presumably by reducing additional lung injury. In addition, early application of the OLC has a more pronounced effect on pulmonary inflammation compared to late application of this ventilation strategy. Studies on cytokines after cardiac surgery should take these findings into account.


   Footnotes
 
{star} Presented at the joint 18th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 12th Annual Meeting of the European Society of Thoracic Surgeons, Leipzig, Germany, September 12–15, 2004.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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