Introduction

One-lung ventilation (OLV) is a challenging situation during thoracic surgery, when gas exchange has to be provided entirely via one side of the lung system. An acceptable balance needs to be found between achieving adequate gas exchange and protective ventilation of the ventilated lung, in order to reduce postoperative pulmonary complications resulting from lung injury. An important aspect is the risk of hypoxia during OLV, so high oxygen concentrations are often required. Another frequently encountered issue during OLV is hypercapnia. Although hypercapnia can have adverse effects on patients with pre-existing pulmonary hypertension, and may trigger right heart decompensation,^1–4 it is usually better tolerated than hypoxia, and may also provide beneficial effects on lung tissue inflammation.⁵ For protective lung ventilation, a tidal volume of 4 to 6 ml kg⁻¹ predicted body weight during OLV compared to 7 ml kg⁻¹ during total lung ventilation (TLV) is recommended, together with the use of an appropriate positive end-expiratory pressure (PEEP) level (compliance-titrated) and recruitment manoeuvres.^1–6

In contrast to conventional positive pressure ventilation with intracyclic alteration between static and dynamic phases, flow-controlled ventilation (FCV) is an entirely dynamic ventilation mode capable of significantly reducing applied as well as dissipated energy.^7,8 It has been shown to improve ventilation efficiency and oxygenation in animal models^9–11 and clinical studies.^12,13 In FCV the flow is continuous, and typically identical during both inspiration and expiration. This, coupled with direct intratracheal pressure measurement, facilitates accurate evaluation of dynamic lung mechanics, and titration of the optimal PEEP and peak pressure during ventilation to achieve the highest dynamic compliance, enabling an individualised approach to artificial ventilation.¹¹ Accordingly, the applied tidal volume reflects the current environmental situation within lung-mechanical limits, which, when lung mechanics are changing due to different conditions, may lead to a higher variation and individual alteration of applied tidal volumes.

The aim of this study was to determine whether an individualised FCV approach during OLV in an animal model with lung-healthy pigs provides better gas exchange efficiency in term of oxygenation and minute volume for CO₂ removal, than best clinical practice PCV.

Methods

Ethics

This study was approved by the Institutional Animal Care and Use Committee of the Medical University of Innsbruck, Innsbruck, Austria on 13th May 2019 and the Austrian Ministry of Science, Research and Economy, Vienna, Austria on 17th June 2019 (Protocol No.: BMBWF-66.011/0098-V/3b/2019). The study was carried out at the Experimental Research Unit of the Department of Anaesthesia and Intensive Care Medicine at the Medical University of Innsbruck from September to December 2019 and was performed in accordance with EU regulations for animal experimentation (EU-Directive 2010/63 of the European Parliament and the European Council). Reporting is in accordance with current ARRIVE guidelines.¹⁴

Animal preparation

Experiments were performed on domestic pigs, 12 to 16 weeks old of either gender, with a body weight of 35 to 45 kg. Animals were prepared according to a standard protocol (see Supplemental Digital Content, https://links.lww.com/EJA/A762), with total intravenous relaxant anaesthesia, a regimen that has been proven to guarantee an appropriate depth of anaesthesia without haemodynamic disturbances.^11,15,16

In order to prepare for OLV, a left-sided mini-thoracotomy was performed in approximately the sixth intercostal space and a thoracic catheter (24 F; Covidien, Dublin, Ireland) was inserted. A bronchus blocker (7 F; Rüsch, Kernen, Germany) was introduced through the tracheal tube and positioned under bronchoscopic view, but not inflated at that time.

Ventilation was performed with either FCV (Evone®; Ventinova Medical B.V., Eindhoven, The Netherlands) or PCV (Evita XL®; Dräger, Lübeck, Germany).

Experimental protocol

After animal preparation, a recruitment manoeuvre with an inspiratory hold at 30 cm H₂O for 20 s was performed. Subsequently baseline measurements were obtained, and the experimental protocol was started with preoxygenation using 100% oxygen for 4 min, followed by blocking the left main bronchus and establishing OLV, which was checked bronchoscopically. After initiating OLV an additional recruitment manoeuvre (RM) was performed with an inspiratory hold at 20 cm H₂O for 20 s. Complete collapse of the left lung was verified by videothoracoscopy via the chest tube.

In the PCV arm of the study, after the recruitment manoeuvre aiming to guarantee a PEEP trial with a fully open lung, PEEP was titrated with compliance-guidance and subsequent peak pressure (P_peak) was adjusted to achieve a tidal volume (V_T) of 6 ml kg⁻¹ and the respiratory rate was adjusted to maintain normocapnia. Intrinsic PEEP (PEEPi), or auto PEEP, occurs in alveoli with increased expiratory resistance and leads to increase alveolar end expiratory volume and overdistension. We checked that PEEP_i was not occurring at every measurement timepoint using the PEEP_i measurement manoeuvre available with the Evita XL. If it was, we then reduced the respiratory rate to a level where permissive hypercapnia occurred. The I:E ratio was kept at 1 : 1.5. The FIO₂ was then decreased in a stepwise fashion from 100% to maintain an arterial partial pressure of O₂ (PaO₂) of 10.7 to 16.0 kPa.

In the FCV arm, compliance-guided settings were applied for both the PEEP and P_peak.¹¹ First, PEEP was set by increasing or decreasing the PEEP while maintaining the same driving pressure (ΔP) and checking for the highest V_T (and dynamic compliance). P_peak was then adjusted by increasing P_peak and checking V_T and dynamic compliance. Initially, each increase of P_peak typically resulted in an increase in V_T which was proportionately greater than could be expected by the measured dynamic compliance. P_peak was then increased until there was no further disproportional increase in V_T and measured dynamic compliance. Following this, FIO₂ was reduced in a stepwise fashion from 100% as before.

OLV was maintained for three hours in the supine position, followed by deflation and removal of the bronchus blocker and re-inflating the left lung in both groups with the help of a RM (inspiratory hold at 30 cm H₂O for 20 s).

Measurement time points were defined as baseline (T1), time points T2 to T14 every 15 min during OLV and T15 to T18 every 15 min during subsequent TLV for one hour.

Respiratory and cardiovascular measurements

Respiratory and cardiovascular measurements were taken at each time point (T1 to T18). PEEP, P_peak and ΔP were directly recorded in PCV and FCV. In PCV animals a regular check for PEEP_i was performed. Respiratory rate, V_T, minute volume, compliance (C) and resistance (R) were directly recorded from the ventilator. Arterial blood gas samples were obtained and pH, PaCO₂ and PaO₂ measured (ABL800 Flex; Radiometer, Brønshøj, Denmark). To allow comparison of oxygenation at different FIO₂ level the Horowitz index was calculated (= PaO₂/FIO₂).

Cardiovascular monitoring included heart rate (HR), mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP). Cardiac output, systemic and pulmonary vascular resistance (SVR, PVR) were measured via the pulmonary artery catheter after three-fold injection of 10 ml of saline. Indices of cardiac output, SVR and PVR were calculated using the predicted body surface area for pigs.¹⁷

Statistical analysis

A mathematician (T.H.) not involved in the study procedures performed the statistical analyses using R, (R Foundation for Statistical Computing, Vienna, Austria, https://www.r-project.org, version 3.5.3). For the characteristics of laboratory animals before the start of the experiment, continuous data were presented as median (interquartile range) and categorical variables as frequencies (%). Effect size and precision were shown with estimated median differences between groups for continuous data and odds ratios for binary variables with 95% confidence interval. The Wilcoxon rank sum test and Fisher's exact test were applied to assess differences between the groups.

The course of respiratory and haemodynamic measurements during the OLV and TLV periods was illustrated per group using the median course with corresponding 95% confidence interval. Differences between groups were assessed using linear mixed-effects models with random intercepts for time points and subjects as well as the group as fixed effect.

All statistical assessments were two-sided. A significance level of 5% was applied.

Results

The experimental protocol was conducted and completed in 16 pigs. Individual characteristics were comparable in both groups. However, due to the different ventilation methods some baseline characteristics were significantly different between groups (Table 1): V_T was higher in FCV and at the same time respiratory rate and minute volume were reduced. Despite a lower minute volume, PaCO₂ was lower in FCV compared to PCV, whereas PaO₂ was comparable in both groups. PEEP was lower in FCV compared to PCV, whereas P_peak was similar in both groups. Haemodynamic variables revealed a higher HR, lower MPAP and PCWP and a higher CI in FCV animals.

Comparing respiratory variables during OLV (Table 2), V_T was similar in both groups despite compliance-guided individualisation of ventilator settings in FCV. However, respiratory rate and minute volume were lower in FCV while maintaining normocapnia, whereas in PCV, in order to avoid air trapping and PEEP_i, hypercapnia had to be accepted. The reduced minute volume and respiratory rate in FCV led to a lower calculated mechanical power¹⁸ of artificial ventilation. In the first hour of OLV, oxygenation was significantly improved in FCV compared to PCV. After one hour, however, no difference in oxygenation could be detected between groups (Fig. 2B). Pulmonary shunt fraction doubled in both groups during OLV without any significant differences between groups.

Compliance-guided PEEP was lower in FCV compared to PCV with comparable P_peak in both groups. This resulted in an increase in ΔP in FCV compared to PCV animals. The continuous flow in FCV led to lower overall resistance.

Haemodynamic variables were comparable in both groups during OLV except for MPAP which remained lower in FCV (Table 3).

After re-inflation of the left lung, respiratory and metabolic measurements returned to baseline values in all animals (Table 2). No important differences in haemodynamic variables between FCV and PCV animals could be found (Table 3).

Discussion

The main finding of this study was that compliance-guided individualisation of FCV maintained normocapnia during OLV, whereas in PCV hypercapnia had to be accepted when ventilator settings were adjusted according to the current standard for lung-protective ventilation with no PEEP_i.

In FCV animals, normocapnia was maintained despite a substantially lower minute volume compared to PCV animals. For FCV improved CO₂ removal has been previously shown,¹⁹ but the exact mechanism responsible for this is not completely clear. It seems unlikely that improved hypoxic pulmonary vasoconstriction in FCV may have contributed to the observed effect on decarboxylation as calculated pulmonary shunt fraction was not different between groups. Furthermore, V_T was similar in both groups during the OLV phase. Thus, the observed difference in PaCO₂ during OLV cannot be related to differences in V_T. Also, the slightly reduced technical dead space of the Evone compared to the Evita XL (approx. 65 vs. 75 ml) does not provide a satisfactory explanation for the amount by which CO₂ removal was improved in FCV. Rather, we hypothesise that an improvement in the ventilation/perfusion ratio in FCV might be a contributor, since computed tomography scans in previous studies showed a more homogeneous gas distribution for FCV.^9–11 We also hypothesise that the differing flow profiles over time in the two ventilation modes make an additional contribution. The nature of PCV is a decelerating flow profile with an initially high peak flow during inspiration and expiration. In terms of flow physics, it is plausible that mainly fast(er) lung compartments will participate in ventilation in PCV and thus contribute to carbon dioxide elimination. In FCV in contrast, gas is shifted in and out of the lungs at the lowest flow, assuring normoventilation. As a consequence, inspired gas is distributed more homogenously among faster and slower lung compartments and thus contribute more efficiently to CO₂ removal. This possible physical explanation for improved CO₂ removal needs to be investigated in further studies as suggested earlier.¹⁹

In contrast to previous findings,^9–13 significantly improved oxygenation in FCV animals was limited to the first 75 min of the OLV period (Fig. 2), although the exact mechanism responsible is not clear, and a presumed more rapid hypoxic pulmonary vasoconstriction can only be speculated. The finding of similar oxygenation values during the whole OLV period (Table 2) may be due to repeated recruitment manoeuvres in both ventilation groups performed during the protocol, which may have masked a more pronounced tendency for atelectasis in PCV, as recently found in a long-term comparison.¹¹ However, during the OLV phase the pigs in the PCV group were hypercarbic. An increase in PaCO₂ causes a right shift of the oxygen dissociation curve leading to a higher PaO₂ at the same saturation (Bohr effect). Accordingly, the PaO₂ in the PCV group would have been significantly lower at a lower PaCO_2, as in the FCV group. In consequence, persisting significant differences in oxygenation between both groups during the OLV phase are likely to be masked.

The finding of similar V_T but significantly higher ΔP in FCV during OLV may give the deceptive impression that individualised FCV resulted in worse compliance compared to PCV. However, in FCV a constant flow occurs during the whole ventilation cycle necessarily leading to a pressure difference between the trachea and the alveolar space at any time.²⁰ Based on the measured resistance and the applied constant flow, this pressure difference can be calculated (Fig. 3) and yields to a mean alveolar pressure amplitude of 12.0 cm H₂O in FCV compared to 14.0 cm H₂O in PCV, which indicates improved dynamic compliance in FCV.

Even when considering the significantly higher mean alveolar PEEP compared to tracheal PEEP in FCV (Fig. 3), PEEP in PCV was still approximately 1.5 cm H₂O higher than the mean alveolar PEEP in FCV during OLV, although in both groups the PEEP was titrated using compliance measurements. This finding may be explained by the recruiting effect of controlling the expiratory flow in FCV as described in a previous study, resulting in less atelectasis despite a lower PEEP level.¹¹ Furthermore, the end-expiratory pressure in FCV is only reached for a moment, whereas it is a plateau pressure phase in PCV. Cyclic intra-tidal alveolar recruitment and collapse is clearly a risk at low PEEP levels, but we concluded the risk to be negligible after compliance-guided PEEP titration. The titrated ‘best’ PEEP was repeatedly checked after OLV initiation. In the presence of cyclic alveolar collapse, the ‘best’ PEEP would have been found to be higher over time, which was not the case.

Interestingly, FCV animals showed significantly lower MPAP and PCWP values during baseline (Table 1) as well as significantly lower MPAP values during OLV (Table 3) compared to PCV animals. It is worth noting that there were significantly lower PEEP levels and alveolar ΔP in FCV animal; we think this may be explained by the lower intrathoracic pressure in FCV. Even though pH was significantly lower in the PCV control group during the OLV phase, due to mild hypercapnia, most probably this finding was not clinically relevant. However, all other haemodynamic variables, such as confidence interval and hazard ratio, did not show any significant differences during OLV or TLV and all values were within the normal range.

Recent studies suggest that the energy (or the rate of energy delivery, i.e. mechanical power) delivered from the ventilator to the lung tissue contributes to ventilator-induced lung injury (VILI).^21–25 The advantage of calculating applied mechanical power is that it incorporates not only tidal volume and driving pressure, but also the gas flow profile and the respiratory rate. Therefore, this measurement allows for a more comprehensive view of artificial ventilation.

Referring to the rules of thermodynamics, reduction of mechanical power and energy dissipation can only be achieved by an optimally low, continuous, and stable inspiratory and expiratory gas flow.^7,8 Any higher (peak) gas flow necessarily increases (peak) energy and results in more applied mechanical power as well as dissipated energy.^7,8,26 To be able to reduce the gas flow to a minimum in FCV, optimisation of ventilation efficiency is demanded. Plausibly, the minute volume required for adequate CO₂ removal can be further reduced by increasing V_T within lung-mechanical limits with the help of compliance-guided setting of PEEP and P_peak. This reduces both, the risk of cyclical alveolar collapse / recruitment and the likeliness of overdistension, which are otherwise accompanied by a reduction in dynamic compliance. Thereby, the amount of dead space ventilation can be minimised and thus respiratory rate and minute volume can be reduced resulting in less applied and dissipated energy over time.¹¹ Indeed, it seems to be counterintuitive (if not a retrograde step) to increase V_T above currently used limits for low tidal volume ventilation at first sight. However, individualised FCV reduces energy to physical and individual lung mechanical limits and may therefore be considered a lung-protective strategy.^7,8 Notably, the results of a recent animal trial suggest that even low amounts of applied mechanical power may not be considered safe in long-term ventilation.²⁵ Accordingly, it seems crucial to limit applied mechanical power and dissipated energy during artificial ventilation whenever possible to limit damage to the lung tissue.

Calculated applied mechanical power¹⁸ showed a reduction to one third in individualised FCV compared to standard PCV during OLV (Table 2) even though a higher PaCO₂ level was accepted in PCV. Indeed, the observed mild hypercapnia may not be clinically relevant, but mechanical power above a threshold of 12 J min⁻¹ has previously been shown to cause VILI in piglets.²³ The observed mean of 18.6 J min⁻¹ during TLV creates concern for the development of VILI in PCV, whereas 6.7 J min⁻¹ in FCV seems acceptable. This difference becomes even more evident during OLV where the calculated mean mechanical power of 22.0 J min⁻¹ was applied to only one side of the lung in PCV compared to 7.5 J min⁻¹ in FCV.

Our study has several limitations. Although porcine studies are accepted for ventilation research, pigs have a lower compliance of the lung and chest wall, stronger hypoxic pulmonary vasoconstriction and a physiologically higher metabolic rate, and therefore demand a respiratory minute volume which exceeds the typical range of anaesthetised adult humans. While the use of a double lumen tube (DLT) is the most common method for lung isolation in clinical practice, a standard DLT cannot be used in pigs for anatomical reasons. Also considering the lower impact on airway resistance, we opted for a bronchus blocker. From the point of view of flow physics, a narrower airway would unfairly favour FCV with its low and continuous flow compared to the high flow peaks and decelerating flow profile in PCV. Additionally, the lung physiology of humans may be altered by age and frequent comorbidities such as chronic obstructive pulmonary disease or neo-adjuvant chemotherapy or radiation. This was not considered in this animal model where young, lung-healthy pigs were used to reduce the complexity of the trial.

A second, more important limitation of this study is that experiments were carried out in the supine position which, according to our experience, reduces the risk of dislocation of the bronchus blocker during the experiment. Moreover, we were concerned about the feasibility of an OLV study in pigs because of their higher metabolic rate that necessitates a higher respiratory minute volume, also during OLV. In fact, these concerns were found to be justified by the results of the PCV group where hypercapnia had to be accepted to avoid air trapping at a very high respiratory rate and minute volume (respiratory rate 45 min⁻¹, minute volume 11.6 l min⁻¹). In the lateral decubitus position the low compliance in pigs compared to humans, and also functional residual capacity, would have further declined, so ventilation of the pigs would have become even more challenging. However, supine positioning does not represent the situation of a patient during lung surgery, which may have influenced our results to some extent. Additionally, we maintained the same ventilation method (either FCV or PCV) throughout the protocol in each arm of the study (both prior to and after lung separation) so that we simulated as closely as possible conditions that were most likely to pertain in clinic practice.

Because the ventilation interventions were short, we did not anticipate substantial difference in inflammatory biomarkers between the different arms and, further, we wished to avoid changes in lung mechanics that might result from procedures such as lavage for biomarker investigation. We therefore did not investigate biomarkers in this study.

Additionally, a RM was performed only once after OLV initiation but not thereafter, which could have promoted atelectasis formation during the considerably long OLV period of three hours. Finally, in PCV, the PEEP level during OLV was measured periodically during a short-lasting ‘no flow’ hold at the end of expiration to allow pressure to equilibrate. However, the peak inspiratory pressure in the alveoli could not be measured as precisely as PEEP due to the high respiratory rate which impedes pressure equilibration. Thus, we described only airway P_peak pressure in PCV, being aware that alveolar peak pressure may have been slightly lower.

Conclusion

In this porcine model of simulated thoracic surgery requiring OLV, individualised FCV enabled normocapnia despite a significantly lower respiratory minute volume and thus lower mechanical exposure compared to best clinical practice PCV. Further studies are needed to fully understand the mechanisms leading to improved CO₂ removal.

Supplemental Digital Content

• EJA_2022_08_23_MARTINI_EJA-D-22-00069_SDC1.docx; [Word] (14 KB)