The Role of Protective Ventilation in Cardiac Surgery Patients D. Gommers and D. dos Reis Miranda

Introduction Cardiac surgery is associated with a pulmonary and systemic inflammatory response. The pulmonary effects of this inflammatory reaction are often modest: decreased lung compliance, pulmonary edema, increased intrapulmonary shunt fraction and decreased functional residual capacity (FRC) [1]. Less than 2 % of patients undergoing cardiac surgery develop full blown respiratory failure, the acute respiratory distress syndrome (ARDS) [1]. For example, after cardiac surgery, FRC is reduced up to 40 – 50 % during the first 24 hours after extubation [2]. However, after general anesthesia, FRC is only decreased by 20 – 30 % [3]. This exaggerated disturbance of pulmonary function is not yet fully understood. It has been suggested that this impaired pulmonary function is the result of pulmonary inflammation, triggered by cardiopulmonary bypass (CPB), ischemia-reperfusion injury, the surgical procedure itself, or by mechanical ventilation. The ARDS network trial has shown that mechanical ventilation with smaller tidal volumes leads to a reduction in mortality in patients with ARDS [4]. This result was somewhat surprising because the most common cause of death in ARDS is not pulmonary failure but rather multiple organ failure (MOF). There is increasing evidence that conventional mechanical ventilation itself can cause damage to the lung in critically ill patients, also known as ventilator-induced lung injury (VILI) [5]. Recent studies suggest that this could also be possible in cardiac surgery patients in whom CPB provides sufficient inflammation to sensitize the lungs to the harmful effects of conventional mechanical ventilation [6 – 8]. This may indicate that the exaggerated pulmonary dysfunction, as seen after cardiac surgery, is the result of two noxious hits on the lung: 1) The cardiac surgical procedure, with or without the use of CPB, and 2) mechanical ventilation of the lungs in an inflammatory environment. In this chapter, we will first discuss the two-hit model in cardiac surgery patients. Secondly, the beneficial effects of a lung protective ventilation strategy (i.e., the open lung concept) in cardiac surgery patients are discussed.

Two-hit Model First Hit: Cardiac Surgery The activation of the inflammatory response during cardiac surgery is an extremely complex process and has various triggers such as CPB, ischemia, and surgical trauma [9]. Although CPB does not seem to have a significant effect on pulmonary dysfunction, it triggers an important degree of cytokine and mediator release [10,

The Role of Protective Ventilation In Cardiac Surgery Patients

11]. Furthermore, ischemia-reperfusion injury contributes to the inflammation mainly from the myocardium, and less from the lung, as the bronchial circulation seems to meet pulmonary oxygen demands [12]. Finally, the surgical procedure itself causes a significant inflammatory response. A median sternotomy elicited greater complement release and interleukin (IL) release compared to an anterolateral thoracotomy in patients undergoing coronary artery bypass grafting (CABG) without the use of CPB [13].

Second Hit: Mechanical Ventilation Pulmonary inflammation induced by mechanical ventilation is the result of mechanical trauma and biotrauma [5]. Mechanical trauma reflects lung injury because of atelectasis, volume or pressure; biotrauma reflects pulmonary and systemic inflammation caused by mediators airborne from the ventilated lung. Atelectasis causes repetitive opening and closure of alveoli, and is therefore a major source of pulmonary inflammation [14, 15]. Roughly three zones can be identified (Fig. 1): A) alveoli that do not open even during inspiration; B) alveoli which remain open; C) alveoli that open during inspiration and collapse during expiration. Alveoli in zone C (Fig. 1) will be subjected to repetitive opening and closure, which is known to be a major cause of pulmonary inflammation [16]. As alveoli in zone A (Fig. 1) do not participate in tidal volume ventilation, tidal volume is distributed over alveoli in the other two zones. This may increase the risk of regional overdistention. Finally, co-existence of atelectatic and open alveoli may result in shear forces that exceed transpulmonary pressures, as predicted by Mead and colleagues [17]. Shear forces act on the fragile alveolar membrane in alveoli undergoing cyclic opening and closure. In a mathematical model, transpulmonary pressures of 30 cmH2O will result in shear forces between atelectatic and aerated lung areas of 140 cmH2O [17]. These shear forces, rather than end-inspiratory overstretching, may be of more importance for epithelial disruption and the loss of barrier function of the alveolar epithelium. To further explore the role of tidal volume and pressure on mechanical trauma in the lung, Dreyfuss and colleagues [18] applied high inspiratory pressures in combination with high volumes in an experimental model. These authors concluded that: 1) High pressures together with high tidal volume resulted in increased alveolar per-

Fig. 1. CT slice of the lung with atelectasis on the dorsal side. Roughly three zones can be identified: A) alveoli that do not open even during inspiration, B) alveoli which remain open, C) alveoli that open during inspiration and collapse during expiration.

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meability; 2) combining low pressure with high volume (iron lung ventilation) resulted again in increased alveolar permeability; 3) if high pressure was associated with low tidal volume (chest wall strapping) the alveolar permeability of the study group did not differ from the control group. These investigators concluded that (high) tidal volume ventilation, not pressure, is the main determinant of lung injury. Mechanical forces such as shear forces between open and closed alveoli or alveolar overdistention cause an inflammatory response, called biotrauma. Although it is not clear how mechanical forces are converted to biochemical signals, several pathways have been suggested, such as stretch-sensitive channels, mechanoreceptors, stress-activated signaling cascade of mitogen-activated protein kinase (MAPK) [14, 19], and activation of the transcription of nuclear factor-kappa B (NF-κB) [20]. In ARDS patients, Ranieri and colleagues [21] have shown that cytokine levels (tumor necrosis factor [TNF]- [ , IL-6 and IL-8) in bronchoalveolar lavage fluid (BAL) were attenuated by a protective ventilation strategy. In the protective ventilation strategy, a tidal volume of 7 ml/kg was applied with 10 cm H2O of positive end-expiratory pressure (PEEP). In the control group, a tidal volume of 11 ml/kg was applied with 6 cmH2O of PEEP. These authors concluded that mechanical ventilation induces a cytokine response, which can be reduced by minimizing overdistention and repetitive alveolar collapse. In a large multicenter study in 861 ARDS patients (ARDS Network trial), low tidal volume ventilation (6 ml/kg) led to lower plasma IL-6 concentrations and a significant decrease in 28-day mortality in ARDS patients [4]. Stüber et al. [22] have shown that switching from a lung protective ventilation strategy of low tidal volume and high PEEP to a conventional strategy with high tidal volume and low PEEP in patients with ALI, led to an increase in plasma cytokines within one hour, which decreased to baseline after switching back to lung-protective ventilation. In addition, Imai et al. [23] showed that injurious ventilation induced apoptosis in distal organs (kidney and small intestine) in a rabbit model of ARDS. In contrast, protective ventilation in this study was associated with much lower levels of plasma cytokines, very little apoptosis, and only minimal changes in biochemical markers. These authors concluded that protective ventilation could in fact protect distal organs from ventilator-induced end organ dysfunction. They also suggested that this mechanism might explain the decrease in mortality observed in the ARDS Network trial of low tidal volume ventilation [4]. From the results of the plasma measurements of cytokines of patients enrolled in this latter trial [4], it has been shown that the highest cytokine levels are measured in patients with ARDS due to sepsis and pneumonia and that the beneficial effect of protective ventilation was better in these patients. This provides further evidence that the pre-existing inflammatory process present at diagnosis of ARDS can be modulated by the early application of low tidal volume ventilation.

Protective Ventilation in Non-ARDS From ARDS studies it has become clear that high tidal volume ventilation can induce a systemic inflammatory response and protective ventilation attenuates this response. Therefore, several investigators have studied the effect of protective ventilation on the cytokine network in patients without ALI/ARDS. Wrigge et al. [24, 25] performed two studies in patients with normal pulmonary function undergoing elective surgery and found no difference between injurious and non-injurious ventilation. These authors concluded that the protective effect of non-injurious ventila-

The Role of Protective Ventilation In Cardiac Surgery Patients

tion on the release of cytokines does not occur in healthy lungs during major noncardiac surgery where the surgery-induced systemic inflammatory response is relatively small. This suggests that protective ventilation modulates the cytokine network only in the presence of a more significant primary inflammatory stimulus, such as CPB. This was shown by the group of Ranieri [6] who observed lower IL-6 and IL-8 concentrations in BAL fluid (6 hrs after CPB) in a lung protective group (tidal volume 7 ml/kg, PEEP 9 cmH2O), compared with the control group (tidal volume 11 ml/kg, PEEP 3 cmH2O). However, Koner et al. [7] and Wrigge et al. [8] found no, or only a minor, effect of protective ventilation on systemic and pulmonary inflammatory responses in patients with healthy lungs after uncomplicated CPB surgery. The open lung concept is also a protective ventilation strategy that combines low tidal volume ventilation with high levels of PEEP [26]. To open up collapsed alveoli, a recruitment maneuver is performed and a sufficient level of PEEP is used to keep the lung open. The smallest possible pressure amplitude is used in order to prevent lung overdistention and this results in low tidal volume (4 – 6 ml/kg) ventilation. We applied this open lung concept in cardiac surgery patients and found that open lung concept ventilation (tidal volume 6 ml/kg, PEEP 14 cmH2O), applied immediately after intubation, significantly decreased plasma IL-8 and IL-10 compared to conventional ventilation (tidal volume 8 ml/kg, PEEP 5 cmH2O) [27]. The application of an open lung concept was accompanied by a significantly higher PaO2/FiO2 ratio during mechanical ventilation, suggesting a significant reduction of atelectasis [28]. We could also demonstrate that ventilation according to the open lung concept led to a significantly better preservation of FRC and better oxygenation several days after extubation when compared to conventional ventilation [29]. A decreased FRC is associated with post-operative pulmonary dysfunction. After cardiac surgery, respiratory dysfunction accounts for 40 % of the readmissions on the ICU [30, 31]. Chung et al. [32] have shown that each percent increase in FiO2 on discharge from the ICU, significantly increases the risk of readmission. Several other attempts to preserve FRC after extubation in cardiac patients have been without success. When considering the two-hit model, one should start the open lung concept immediately after CPB and continue this ventilation strategy until extubation. When the open lung concept is initiated immediately after CPB, this approach seems to have great beneficial effects, such as decreased interleukin release [27], increased PaO2/FiO2 ratio during mechanical ventilation [28], an attenuated FRC decrease after extubation, and fewer episodes of hypoxemia [29]. Three days after extubation, patients were not in need of additional oxygen when ventilated according to the open lung concept peri-operatively [29]. This may indicate earlier hospital discharge.

Effect of PEEP Ventilation on Cardiac Performance It has been shown that PEEP affects right ventricular (RV) afterload. Biondi et al. [33] have shown that the use of PEEP levels above 15 cmH2O increased RV volume and decreased elastance, indicating an increase in RV afterload and a decline in RV contractility. Spackman and colleagues [34] have shown that during high frequency ventilation, mean airway pressure above 12 cmH2O resulted in a decrease in the RV ejection fraction (RVEF) and was associated with an increase in the RV end-systolic

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volume. The authors attributed these findings to an increase in the RV afterload due to increased mean airway pressure. Dambrosio et al. [35] found that the RVEF and the RV stroke work/RV end-diastolic volume ratio started to decrease at PEEP levels higher than 10 cmH2O in patients with acute respiratory failure. Schmitt et al. [36] used echo Doppler data obtained by transesophageal echocardiography (TEE) to assess the effect of PEEP on RV outflow impedance. In their study, use of PEEP levels (13 „ 4 cmH2O) caused an increased RV afterload. These studies show clearly that RV afterload is elevated during mechanical ventilation with moderate to high levels of PEEP. Use of large tidal volumes increased RV outflow impedance as assessed by echoDoppler of the pulmonary artery [37]. Moreover, large tidal volume ventilation is more likely to occur in the presence of atelectasis because of the so-called baby-lung effect: If one imagines a lung with 50 % atelectasis, then a pre-set tidal volume of 10 ml/kg would result in a tidal volume of 20 ml/kg in aerated lung areas. Therefore, atelectasis may cause an increase in the RV afterload due to: a) an increase in the tidal volume in aerated lung areas (baby-lung effect); b) hypoxic pulmonary vasoconstriction in non-aerated lung areas. This atelectasis cannot be reversed with the use of high PEEP ventilation; only by the application of recruitment maneuvers. In volume loaded patients after cardiac surgery, Dyhr et al. [38] found no decrease in cardiac output when applying recruitment maneuvers followed by a mean of 15 cmH2O PEEP. This was confirmed by our results in which RV afterload, as assessed by echo-Doppler of the pulmonary artery (Fig. 2), was comparable between open lung concept ventilation with a PEEP of 15 cmH2O compared to con-

Fig. 2. Echo-Doppler of the pulmonary artery. Bottom line represents airway pressure. Dotted line in the second beat indicates the acceleration of the pulmonary flow during inspiration.

The Role of Protective Ventilation In Cardiac Surgery Patients

ventional ventilation using 5 cmH2O of PEEP in cardiac surgery patients [39]. This suggests that when atelectasis is avoided, RV afterload is not increased by open lung concept ventilation. This could explain the results of Huemer et al. [40], who found no increased RV afterload using 12 cmH2O of continuous positive airway pressure (CPAP) in healthy volunteers (without atelectasis), assessed by echo-Doppler. The separate effects of PEEP and tidal volume on RV impedance during open lung concept ventilation remain, however, unknown. RV afterload is not only increased by high PEEP levels; also during inspiration RV afterload increment is observed. Poelaert et al. [41] showed that inspiration rather than expiration with high levels of PEEP caused RV afterload increment in cardiac surgery patients. Vieillard-Baron et al. [37] also showed that RV afterload is mainly increased during inspiration in patients with ARDS. These authors separated the effects of peak inspiratory pressure (PIP) and tidal volume by chest trapping and application of PEEP. They found that tidal volume, and not PIP or PEEP increased RV afterload. Although these results were very clear, theoretically this is hard to explain. Only intrathoracic pressure, but not volume, generates a force that could compress pulmonary capillaries, increasing RV afterload. In addition, of course, volume changes require pressure changes. The physiological explanation for the finding that tidal volume, not PIP, increases RV afterload is not known yet. However, this is more than a semantic discussion: If PIP and not tidal volume is to increase RV afterload, then elevated PEEP levels should increase RV afterload because of the increased PIP. This phenomenon did not occur during open lung concept ventilation as assessed by echo-Doppler of the pulmonary artery. In cardiac surgery patients, mean acceleration time decreased during inspiration during conventional ventilation but not during open lung concept ventilation [39]. Ventilation according to the open lung concept was accompanied by a lower tidal volume (4 ml/kg vs. 8 ml/kg) but a higher inspiratory pressure (25 vs. 17 cmH2O) compared to conventional ventilation [39]. The low tidal volume used during open lung concept ventilation may explain the lack of increase in RV afterload during inspiration. Also alveolar overdistention during inspiration could be reduced by application of open lung concept ventilation, despite the use of high PEEP levels. Namely, De Matos et al. [42] demonstrated, using a computed tomography (CT) scan, that tidal recruitment and degree of overdistention during inspiration in ARDS patients decreased when a recruitment maneuver was performed compared with pre-recruitment with 25 cmH2O PEEP. This implies that during open lung concept ventilation RV afterload is not increased during inspiration due to: 1) the reduction in tidal volume ventilation in aerated lung areas due to homogenization of pulmonary gas distribution; and 2) the use of lower tidal volumes, set on the ventilator. Furthermore, these two effects of open lung concept ventilation act in synergy: Homogenization of pulmonary gas distribution reduces tidal volume ventilation of aerated lung areas which is reduced even further by the lower tidal volume ventilation set on the ventilator. In addition, in patients who have undergone cardiac surgery, the pericardium has been opened. Therefore, the effect of open lung concept ventilation on RV outflow afterload with an intact pericardium (such as in ARDS patients) still remains unknown. However, Schmitt et al. [36] have shown that the mean acceleration time did decrease significantly during inspiration using a protective ventilation strategy in patients with ARDS. This strategy used a PEEP level above the lower inflection point and a low tidal volume in order to prevent overdistention but this strategy is without a recruitment maneuver and, thus, in the presence of atelectasis.

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Conclusion Pulmonary dysfunction after cardiac surgery is probably a two-hit process: The first hit is due to the surgical procedure, the second hit due to mechanical ventilation of the lung in an inflammatory environment. Pulmonary inflammation is aggravated by non-optimal mechanical ventilation of the lung. The open lung concept is a lung protective ventilation strategy, reducing pulmonary dysfunction after cardiac surgery. The beneficial effect of this ventilation strategy is best when applied immediately after intubation. Furthermore, this ventilation strategy, using low tidal volume ventilation together with avoiding atelectasis, might attenuate the effect of airway pressure on RV afterload. Acknowledgement: The authors thank Laraine Visser-Isles for English-language editing.

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The Role of Protective Ventilation In Cardiac Surgery Patients

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