One-lung Ventilation:Lung isolation is frequently used during thoracic surgery to improve surgical access; however this can present several challenges for anaesthetists in terms of ventilating the patient perioperatively. During lung isolation, only one lung is ventilated but both lungs are perfused – which can precipitate ventilation-perfusion mismatch, hypoxia and hypercapnia. Strategies for one-lung ventilation (OLV) are used to overcome the intrinsic ventilation-perfusion mismatch associated with lung isolation procedures. However, these strategies can sometimes induce volutrauma and barotrauma in the ventilator dependent lung, leading to Acute Lung Injury (ALI), atelectasis and Adult Respiratory Distress Syndrome (ARDS). Different ventilator settings, such as the use of high or low tidal volumes (VT) have been suggested as a way to improve the safety and efficacy of OLV. However, currently there is no consensus among the medical profession as to what method provides the safest and most efficacious method of OLV.

Aims:The aim of this project was to systematically review the safety and efficacy of high and low VT in OLV during thoracic surgery.

The objectives, in relation to OLV during thoracic surgery, were to identify:• Indicators of safety• Measurements of efficacy• Optimal strategies with regards to safety and efficacy• Current limitations of research in this field

Methodology:A broad systematic search strategy was established that focused on sensitivity rather than specificity. This was then applied to EMBASE, Web of Science and MEDLINE databases. A standard data extraction was applied to the acquired papers which was then followed up by a detailed critical appraisal. The varying outcomes of the papers were then analysed.

Results:Our search strategy provided 12 papers. Data were extracted from these papers, synthesised and critically appraised.

Conclusions:Overall, the evidence suggested a high VT strategy may be associated with an increased risk of the development of ALI/ARDS, and an increase in pro-inflammatory cytokine release. However, due to the limited research in all subject areas, definite conclusions cannot be drawn.

Acknowledgements:We would like to thank out tutor, Dr. Alston who provided us with guidance throughout the duration of the project. Additionally we would like to thank Ms Fisken for providing an expert opinion on how to best conduct our search strategy.

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Introduction>

One-Lung VentilationIn 2011-2012, there were 6928 lung resections performed in the UK and a significant majority of these operations required lung isolation.1 There are surgical advantages of isolating one lung during thoracic surgery including facilitating surgical access to the side of the chest being operated on (side of collapsed lung) and reducing the risk of contamination with pus or blood between the two lungs.2 However isolating one lung necessitates mechanically ventilating the remaining lung: a process known as one-lung ventilation (OLV).

During OLV, the ventilated (dependent) lung essentially has to function as two, to ensure adequate oxygen levels are maintained within the systemic arterial circulation, as it simultaneously attempts to maintain adequate excretion of carbon dioxide.

Ventilation-Perfusion MismatchAn important physiological concept in OLV is ventilation-perfusion (V/Q) mismatch. Ventilation (V) is the quantity of air within the alveoli of the lungs that can diffuse into general circulation; whilst perfusion (Q) is the flow of blood into the lungs available for gas exchange in the alveoli. If either of these are affected, V/Q mismatch occurs.

However, V/Q mismatch occurs normally in the body. Due to varying pressure differences within the lungs (in relation to the heart), various areas of each lung are perfused at different rates. For example, the most superior area of the lung (the apex) receives the lowest amount of blood and therefore has low (or in some alveoli - absent) perfusion. This creates dead space - lack of blood to accommodate the air flow.3 During OLV, the non-ventilated (collapsed) lung still has ongoing perfusion. Therefore, there is a large V/Q mismatch. In this instance, as there is an adequate blood supply but no air-flow, this mismatch is known as an obligate shunt. The body compensates for this through hypoxic pulmonary vasoconstriction (HPV).4 Blood flow is redistributed from the non-dependant lung to the ventilated lung to reduce V/Q mismatch.3

Various adverse effects can occur during OLV. Hypoxaemia is an outcome that signifies low oxygen levels within the arterial blood and often occurs as a result of V/Q mismatch. The amount of oxygen in arterial blood is most commonly assessed using pulse oximetry (SpO2), but can also be measured by using the partial pressure of oxygen (PaO2) or oxygen saturation (SaO2) levels. Hypercapnia - high carbon dioxide levels in blood - can also result from V/Q mismatch. These two blood gas disturbances can cause important adverse events and effect the normal functioning of the human body.4

Adverse OutcomesInfrequent but severe pulmonary adverse outcomes of OLV are ALI and its more severe continuation, ARDS. These are classified by an oxygenation ratio of partial pressure of oxygen / fraction of inspired oxygen (PaO2/FiO2). ALI is defined as a ratio of <300, whereas ARDS is a more serious form defined as <200. These are associated with higher post-operative mortality rates.3

Injury to the lungs through, for example, mechanical ventilation, often causes an inflammatory response and hence the release of biological inflammatory mediators

called cytokines. A subsequent systemic response is produced. Cytokine production is a characteristic of Ventilator Induced Lung Injury (VILI). Therefore post-operative cytokine levels, including IL-6, IL-8, IL-10 and TNF-alpha can be markers of any lung injury sustained.4 This allows for a quantifiable measurement and assessment of the effects of various VT strategies during OLV.

The use of mechanical ventilation carries the risk of the development of ALI/ARDS. This risk in OLV is thought to be due to the higher VT used to maintain adequate oxygenation, therefore lower VT strategies may be used by anaesthetists in order to reduce the probability of development of such complications. This is the theoretical rationale behind  'protective' lung ventilatory strategies during OLV in thoracic surgery. This approach has been adopted from the use of low VT ventilation in other settings, in particular the treatment of ARDS.5 Overall some controversy exists in terms of OLV during thoracic surgery. Some anesthetists use high VTs while others advocate the use of low VTs during OLV, with no overall consensus in practice.

Aims and ObjectivesThe aim of this project was to systematically review the safety and efficacy of high and low VT in OLV during thoracic surgery.

The objectives, in relation to OLV during thoracic surgery, were to identify:• Indicators of safety• Measurements of efficacy• Optimal strategies with regards to safety and efficacy• Current limitations of research in this field

It was initially planned to conduct a meta-analysis if adequate comparable data from randomized controlled trials were accessible. Ultimately due to time constraints and difficulty in obtaining comparable data this was not possible.

 <Home                                                                           Methods>

The project began with an in-depth review into the background of OLV and physiology during thoracic surgery. We used textbooks produced by recommended authors, primary and secondary literature, discussions with experts in the field and observation of current OLV practice in thoracic surgery.

To establish a systematic search strategy, a general scope of current literature was performed and this highlighted the limited and specific nature of current research with inconsistencies in the terms used - making it difficult to identify all the available resources in a single reproducible search. Therefore, we consulted an academic support librarian to gain some insight on the best approach. As a result it was decided that a broad search focusing on sensitivity rather than specificity was most favourable. This involved the use of multiple keywords and Boolean operators to overcome the limitations of MESH terms in this field.  Our search was applied to EMBASE, Web of Science and MEDLINE (Ovid platform) as a means of identifying literature. (Search Information Search Report Appendix)

Our systematic approach entailed a four stage process of identification, screening, assessing eligibility and inclusion as detailed in PRISMA checklist.6

Screening was achieved by evaluating the title and abstract of all results to assess relevance. This was conducted by two separate group members for each article and discrepancies were resolved at a group level. Relevant papers were then accessed and reviewed to ensure relevance. These were also hand searched for any further relevant references.

A standardised data extraction form was devised, utilising guidelines established by both PRISMA and the Cochrane Library.7,8 This was applied to all articles by a member of the group and reviewed by another with discrepancies being resolved at a group level. Each article was then critically appraised by a member of the group and presented or discussed at meetings.

Subgroups were established to address the varying outcomes of the included articles and to qualitatively synthesis the research findings. These outcomes were all included under three headings: ALI/ARDS, Inflammation and lung ventilation and perfusion. Constant liaison and communication between subgroups was maintained to ensure quality and consistency of work.

 <Introduction                                                                Results>

A total of 12 papers were found to be eligible after review and were included in this study. The process of identifying these papers is detailed in Fig1.

Our initial search turned up 1681 studies, which we subsequently reduced to 12.

Results of the data extractions are included in the appendices linked below.

ALI/ARDSFive papers considered the outcome of ALI/ARDS. Three papers16,17,19 found that low VT led to a statistically significant reduction in atelectasis.ALI/ARDS Appendix

InflammationFour papers used cytokines as a measurement of inflammation; bronchoalveolar lavage (BAL) was used in 2 papers21,22, and arterial blood in the others, considering local and systemic inflammation respectively.Inflammation Appendix

Lung Ventilation and PerfusionFive papers looked at lung ventilation and perfusion. Comparison yielded conflicting data with regards to oxygenation.Ventilation and Perfusion Appendix

<Methods                                 Discussion:Safety and Efficacy>

Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI)

With a mortality rate of 40-50% ARDS and ALI are devastating clinical manifestations of lung injury.9 Reduced quality of life, disability and cognitive impairment are all common consequences.10 The prevalence of these conditions is reported to be much higher in those that undergo mechanical ventilation (39.6%) compared to other intensive care patients (9%).11 As mentioned in a review by Kilpatrick and colleagues12, trauma to the lung can be reduced by using particular VT strategies. In this regard, the incidence of ALI/ARDS during any mechanical ventilation strategy is an integral assessment of its safety.

InflammationDifferent VT strategies during OLV result in different quantitative changes of inflammatory cytokines. This means there are many different cytokines used as surrogate markers of VILI. Lin and colleagues13 found that alveolar macrophages and airway endothelial cells release IL-6 when an inflammatory response is stimulated. Significant increase in IL-6 was associated with an acute phase response to pulmonary complications and injuries, leading to activation of pro-inflammatory cytokines. IL-8 is one of the major cytokines that play a role in the recruitment of inflammatory mediators into the alveoli.14 Furthermore, a study conducted by Boutten15 found that an increase in levels of IL-8 corresponded to the extent of pulmonary dysfunction. Moreover, Schutte14 suggested that IL-10 is expressed in response to epithelial call activation with the purpose of decreasing the extent of lung injury by regulating the expression of pro-inflammatory cytokines, TH1, MHC class II. Therefore the literature suggests that an increase in cytokine levels is indicative of the development of lung injury. These cytokines may not be limited to the lungs as they can enter the systemic circulation and are measured in arterial samples. Therefore, an inflammatory response can be used as an outcome in the comparison of safety of different VT

strategies during OLV.

Lung Ventilation and PerfusionThe purpose of mechanical ventilation is to maintain adequate arterial oxygenation and excretion of carbon dioxide. Considering this, the measurement of lung ventilation and perfusion can directly reflect and compare the efficacy of each VT

strategy during OLV. Additionally, lung ventilation and perfusion will help compare safety in OLV by considering conditions such as hypoxaemia or hypercapnia, as these can have severe systemic and potentially life-threatening consequences.

<Results                                                                    ALI/ARDS>

Lung InjurySeveral publications support the association between the use of higher VTs during OLV for cardiothoracic surgery and an increased incidence of ALI/ARDS.16,17,18,21  Notably, in a cohort study, Licker and colleagues16 found a decrease in the incidence of ALI (3.7% to 0.9% in the control cohort, p<0.01) in patients ventilated with a lower VT. (<8ml/kg). This was conducted with a large sample size (n=1091) which analyses  confounding factors which can be skewed by small sized studies.17,18,19,20 These findings were echoed in a retrospective study by Jeon and colleagues18 who found a strong association between the development of ALI/ARDS and the use of higher VT during elective pneumonectomies for primary lung cancer (VT =8.2 vs 7.7 ml/ kg, p=0.016). However, the retrospective nature of this study introduces the prospect of selection bias affecting into the results. No reasons were given for the time period used to analyse data, nor why they only used one centre in the study, which limits the generalisability of the results.18 A randomised-control trial (RCT) by Yang and colleagues17 supported an association between the development of lung dysfunction and higher VTs used during cardiothoracic surgery but not necessarily the development of all aspects of ALI/ARDS as stated by the 1992 American-European consensus conference on ARDS.21 Both studies suggest that lower VTs would be beneficial in reducing the development of post-surgery ALI/ARDS, yet their results were not echoed in two smaller RCTs,19,20 finding no statistically significant association between the use of higher VTs and the development of ALI/ARDS. However, this was not the primary objective of these studies, thus there is insufficient data to establish a significant link between VT and ALI/ARDS. This could be due to their small study population (n= 34 and n=52).19,20

AtelectasisALI/ARDS are not the only clinically significant manifestation of VILI. Independent of the association between higher VT during OLV and the development of ALI/ARDS, high VT also appears to be implicated in the development of post-surgical atelectasis. Licker and colleagues16 found a statistically significant link between the incidence of atelectasis (8.8% to 5.0% in the protective cohort, p=0.018) and the use of a protective lung strategy which entailed the use of lower VTs (<8ml/kg) during cardiothoracic surgery. The study by Yang and colleagues17 further supports this argument, showing an association between the use of high VT (10ml/kg) with volume-controlled ventilation and the incidence of lung infiltration or atelectasis compared to lower VT group (10 vs 2 cases, p=0.03). The comparatively small study population, however, reduces the statistical strength of this finding (n=100) and warrants a larger study to be conducted.17 Furthermore, it is important to note that both of these studies were examining the differences between two strategies for OLV, not merely the differences between high and low VT. It is therefore possible that the association noted was not entirely due to VT, but a product of confounding.

ICU Admissions and Length of Hospital StayLicker and colleagues16 have demonstrated an association between low VT used during OLV and a reduction in the duration of hospital stay as well as a reduction in the number of patients admitted to intensive care unit (ICU) post-surgery (hospital stay: 14.5 to 10.8 days, p<0.001, and in ICU admission: 9.4% to 2.5%, p<0.001, when lower VT was used). This has implications for resource allocation within hospitals, given the high cost of maintaining an ICU, issues arising due to lack of bed-space and patient management. Conversely, several other studies failed to find any link between

length of hospital/ICU stay and VTs used during OLV17,19,20, however, no definitive conclusions could be drawn from the data collected. It must also be taken into consideration that the data provided from one centre may reflect the practice of that single centre.

LimitationsMost studies included based their definitions of ALI/ARDS on the consensus conference on ARDS21.  However, each study seems to modify this definition in its own way. In the study by Jeon18, the period for which mechanical ventilation was reintroduced post-surgery was set to one week compared to just 72 hours in the study by Yang17. The rationale behind the difference in time may have been to increase the size of those classified as having ARDS in the retrospective study, to give it more statistical weight but in doing so, the authors increased the risk of confounding and bias.

Sample sizes were frequently underpowered to identify clinically significant associations with adverse effects, resulting in Type II statistical error. A further source of potential bias lies in the statistical analysis of confounding factors. Many papers used logical regression analysis.16,18,19,20 However, this form of analysis did not allow for the consideration of each patient as a unique combination of factors,  producing a separate confounder. The combination of old age and COPD, for example, may have had a confounding effect, whereas the analysis eliminated age and COPD separately as having no confounding effect. In two of the studies 16,18 the stage of cancer was considered in the analysis of confounding variables but the type of cancer was not. 18

There is an increased chance of bias in the direct comparison of patients with different types of cancer, which the author has failed to report.

Conclusion of Evidence: ALI/ARDSCurrent evidence indicates that the use of higher VTs during OLV may be associated with the development of ALI/ARDS, although this association has not been conclusively established – necessitating further research in the area. Without exception, the papers analysed were partly flawed, with small study population proving to be particularly prominent, and therefore more prospective RCTs with large sample sizes are required to provide a strong clinical argument for the potential benefits of lower VTs in the development of ARDS/ALI. While evidence is currently inconclusive, the tentative association between low VT and ALI/ARDS is, however, important for patients, clinicians and policy-makers given the mortality, morbidity and financial burden associated with ALI and ARDS. A link between use of higher VT during OLV and atelectasis was also shown which has implications both for the efficacy and safety of OLV since the development of atelectasis is thought to produce an increased inflammatory response, leading to an increased risk of post-operative complications.16

<Main Discussion                          Inflammation>

Pulmonary Cytokine LevelsA link between the use of higher VT during OLV and increased localised interleukin levels has been shown in studies conducted by Shen and colleagues. 22 They found that patients undergoing oesophagectomy with a low VT during OLV had a smaller increase in IL-8 compared with the group ventilated with a high VT (258.75±188.24 vs 403.95±151.44 pg/mL; p<0.05).22 However, these results were not replicated in research conducted by Schilling and colleagues23 which found no statistical difference between IL-8 levels following high or low VT use during OLV. They did, however, find that there was an increase in sICAM-1 - a biomarker for inflammation - that was significantly greater in high VT compared to low VT immediately after OLV and 2 hours postoperatively.23

Systemic Cytokine LevelsHigher VT has been associated with an increase systemic response by Michelet and colleagues20 in a RCT which found a significantly larger increase in IL-6 and IL-8 in patients undergoing oesophagectomy with high VT during OLV (91[61–117] vs. 189[127–294] pg/ml, p<0.001 and 30[22– 45] vs. 49[29–69] pg/ml, p<0.05, in low and high VT) 24 hours post-surgery. This finding was echoed in another RCT conducted by Lin and colleagues13 which also examined changes in systemic inflammation during oesophagectomy (IL-6: 278.2±100.8 vs. 335.8±98.7 kg/ml, P<0.05 and IL-8: 124.2±40.1 vs. 178.5±18.3 ng/ml, p<0.05, in low and high VT). Both of these studies had a small study population (n=52 and n=40), hence results obtained could have been due to Type I statistical error.13,20

LimitationsAlthough there was a greater general increase in cytokine levels in patients undergoing OLV with a higher VT, studies used different cytokines, making it difficult to compare studies as only the cytokines common to all studies could be compared.

Differences in study design in all of the papers introduce bias during comparison. The patients considered by each study underwent different procedures – oesophagectomy13,20,22 and pneumonectomy or pulmonary resections. 23 This was noted in particular when comparing Shen22 and Shilling’s23 studies which differed in the length of follow up and the times at which measurements were taken. Furthermore, positive end-expiratory pressure (PEEP) was used in the study conducted by Shen22, while Schilling used zero end-expiratory pressure (ZEEP)23, making the studies arguably not comparable since the use of PEEP has been shown to improve alveolar recruitment and oxygenation20 and therefore could have impacted on the levels of inflammation. Both Schilling23 and Shen22 studies also had small sample sizes and hence it is difficult to determine which was more reliable. As the studies produced conflicting information, it is not possible to determine whether VT has an effect on local inflammation.

A further limitation across the four studies was their choice of the sampling method. Both Schilling23 and Shen22 investigated cytokine levels from a bronchoalveolar lavage (BAL), whereas Lin13 and Michelet20 took a systemic approach, by measuring transpulmonary blood gradients of cytokines in the blood by arterial and venous catheters. This further hinders any attempts to directly compare all four studies.

Additionally, the periods of investigation in all four studies were relatively short, thus the actual effect on inflammatory response might not have been investigated appropriately. Follow-ups until cytokine levels resumed normal levels would have been more appropriate as this would have allowed for a more accurate analysis of data.

Conclusion of Evidence: InflammationAlthough it is difficult to compare studies directly, evidence points towards an increase in both localised and systemic cytokines released perioperatively and postoperatively with higher VT during OLV. This has impacts on the safety of mechanical OLV as a heightened inflammatory response has previously been found to be predictive of post-surgical pulmonary complications including ALI. Before inclusive recommendations can be reached, more comparable research and data are required to show the effect of VT on cytokine production.

 <ALI/ARDS                       Lung Ventilation and Perfusion>

Lung Oxygenation There is conflicting evidence regarding OLV strategies and oxygenation. Katz and colleagues24 argue that higher VT provides better oxygentation than low VT. These researchers found oxygenation to be statistically lower in those ventilated with a low VT strategy (8% of Total Lung Capacity (TLC)) compared to the high VT group (16% TLC), giving a mean PaO2 of 184±28 mmHg vs 210±30mmHg.24 This argument was supported by Kim and colleagues25 who showed that low VT (6ml/kg) strategies caused higher rates of hypoxaemia (PaO2<80 mmHg) compared to high VT strategies (10ml/kg). They argued that hypoxaemia occurred in 5% of those ventilated with high VT compared to 70% (no PEEP) and 65% (with PEEP) of the low VT group.  This study adopted strict selection criteria (ASA 1 or 2 only) thus introducing a selection bias through making it less generalisable to the majority of patients undergoing thoracic surgery who might have higher ASA scores.25

In contrast, a low VT strategy may provide comparable results to a high VT strategy. Végh and colleagues26 argued that low VT ventilation (5ml/kg) provided no significant difference in PaO2 compared to high VT ventilation (10ml/kg). Severe hypoxemia (PaO2<60 mmHg) did not feature in any of the patients. The large sample size (n=100) and cross-over design of the trial allowed strong statistical assumptions to be made as each individual essentially became their own control which gave increase confidence in the findings.26 Similarly, Maslow and colleagues19 found that the Pa02/Fi02 ratio was not significantly different when comparing a high VT strategy (10ml/kg) to a low VT strategy (5ml/kg). There was no statistical difference in PaO2 after 20 minutes of OLV (p<0.37) or PaO2/FiO2 (p<0.76). FiO2 was, however, allowed to vary in order to maintain a constant SaO2.19

Carbon Dioxide Levels Although high respiratory frequencies are combined with low VT  to compensate for low air flow, literature suggests that PaCO2 is nevertheless higher in OLV with lower VT. Evidence for this is shown by Katz and colleagues24 who found that PaCO2 was greater in lower VT (37.6mmHg) compared to higher VT (35.4mmHg, p<0.05), however, the mean difference was quite small. Caution has to be taken when considering their arterial blood gas measurements as the instruments used were not as accurate or precise as they could be today.24 Modern studies also show a trend of lower VT ventilation resulting in higher PaCO2. For example, Maslow and colleagues19 concluded that high VT (10mL/kg) resulted in less hypercapnia than low VT, (5mL/kg) (42.8mmHg vs 40.9mmHg respectively, p<0.18). While this study was underpowered with only 32 patients, a similar trend was found in a comparatively larger randomised cross-over trial. 26 Again, Végh and colleagues26 argued that low VT

was associated with higher PaCO2.  Interestingly, Végh and colleagues defined high and low VT similarly to Maslow's paper, but Végh found a more statistically significant result (p<0.001).26

Shunting, Atelectasis and Venous AdmixtureMixed opinions exist among researchers when assessing shunting and atelectasis in OLV and their effect on venous admixture - the mixing of oxygenated and deoxygenated blood. Some papers, such as Katz and colleagues24 argue that high VT

results in less shunting. Patients who received higher VT had lower venous admixture (34.5 ± 2.0 UNITS) compared to patients who received a low VT (39.3 ± 2.2 UNITS). Even with PEEP, a higher VT had lower venous admixture compared to lower VT.

However, this data should be considered with caution, as the small sample size (n=17) could put the results down to chance.24

The results of this study mirror the more robust, prospective, randomised trial conducted by Maslow and colleagues19 in 2013. The fact that Katz and colleagues24

results were replicated by a modern study adds significant weight to them. Maslow and colleagues19 found that atelectasis scores, derived from the assessment of chest x-rays by a blinded physician, were significantly higher for the low VT group on postoperative days 1 and 2 (p<0.05 and 0.04 respectively). The low VT group had an atelectasis score of 1.37 compared to the high VT group’s score of 0.87 on postoperative day 2. Despite the small sample size, the trial still achieves a strong statistical power of 80% and demonstrates a robust and reliable method.19

However, not all modern papers are in agreement- Végh and colleagues26 concluded that high and low VT were comparable in terms of perioperative venous admixture. These researchers found that even lower VT provided similar intrapulmonary shunt values to the higher VT (25±9% versus 24±8%, p<0.14). All patients received both high and low VT at different stages of the surgery, so perhaps this may explain why there is no significant difference in atelectasis between the study groups. The washout time may not have been sufficient to remove the residual effects of the first stage of the experiment. Végh and colleagues26 believe that their study design was sufficient to remove this effect, but it is still a possible source of bias and their results should be taken with caution.

LimitationsOur ability to extract any meaningful, valid conclusions from the data is limited due to the different definitions used by different authors. Each author defines high and low VT differently with varying parameters for hypoxemia and hypercapnia. We are also restricted by the co-interventions employed by the different research papers. For example, does the 'protective' effect associated with a certain ventilatory strategy come from the set VT, PEEP or other factor? Interestingly, Katz and colleagues24 also compared a low VT strategy with 10cmH20 PEEP to a high VT with 10cmH2O PEEP and this showed no significant differentiation between oxygen levels. While this may suggest that PEEP has minimal, if any, effect on oxygenation, further research is needed to make significant conclusions. Other studies have not separated the co-intervention of PEEP from differing VT highlighting a possible confounding effect on their results, in particular Maslow and colleagues19 who included 5cm of H2O PEEP only for their low VT group.

We are also aware that the same haemodynamic and pulmonary function indicators were measured at different stages - preoperatively, perioperatively and postoperatively. This could have confounded the results and we were cautious not to link data from different studies if the outcomes were measured at different stages. For example, we cannot combine Végh’s26 and Maslow’s19 research of atelectasis and shunting as Végh26 looks at shunting perioperatively, whereas Maslow19 assesses atelectasis (related to shunting) postoperatively. Both these studies employed similar high and low VT, but Végh26 suggests that there is no difference between the ventilation modalities, while Maslow19 implies that high VT provides a better postoperative outcome in terms of atelectasis. Perhaps, the impact of VT is only seen postoperatively and this may explain why Végh26 failed to observe any notable

difference. Whether high VT is protective postoperatively remains unclear and should be explored in further research.

Furthermore, selection bias could have affected the results. Importantly, the studies had different inclusion and exclusion criteria which makes collecting data and generalising results more challenging due to possible effects of confounding. For example, Végh and colleagues26 excluded patients who had severe alteration of pulmonary function (set at FEV1<70%) whereas Maslow and colleagues19 excluded patients who needed supplementary oxygen support preoperatively. Some of the included patients may respond differently to treatment than the standard patient profile, making the results no longer representative of the average patient for such procedures.

Conclusion of Evidence: Lung Ventilation and PerfusionThere appears to be mixed evidence on the level of oxygenation achieved by the use of either high or low VT during OLV - oxygenation was either similar or lower in groups who received OLV at a lower VT. Similarly there were significant disparities between studies when comparing venous admixture. Some found that the use of a higher VT reduced venous admixture whilst others reported it to be similar for both high and low VT groups. Perhaps, the lack of conclusive evidence can be explained by the heterogeneity of interventions between authors. With regard to hypercapnia, however, low VT almost universally lead to higher levels of PaCO2. <Inflammation               Optimal Ventilatory Strategy>

Is there an optimal strategy for OLV?Whether any of these indicators of safety and efficacy are significant to justify an optimal VT for use during OLV has yet to be concluded. Deciding on an OLV strategy centres around maintaining adequate oxygenation levels while reducing the risk of adverse outcomes. Considering current evidence, there appears to be no clearly defined effect of VT on efficacy, therefore any current rationale for advocating one VT over another is dependent on the safety of the procedure.

Since ALI/ARDS is a clinically significant outcome, its prevention should be prioritised over surrogate outcomes of safety including cytokine release and pulmonary function. These may contributing factors to the development of ALI/ARDS, which further emphasises the critical role of ALI/ARDS in determining which OLV strategy should be employed. Therefore, there appears to be a benefit in using a lower VT during OLV to improve post-operative outcomes, such as ALI/ARDS, in thoracic surgery.

Use of a low VT may lead to an increased level of hypercapnia although transient increases in PaCO2. This may not be a significant justification to increase VT  which may dispose patients to an increased risk of more serious adverse outcomes.  Whether higher levels of hypercapnia associated with low VT are permissible clearly depends on each patient’s individual circumstances.

LimitationsMaking recommendations for OLV strategies is fraught with difficulties due to the inherent limitations of current literature. The studies analysed had a number of weaknesses: small sample size, short follow up times, different data collection methods and varying definitions for high and low VT. In addition, many papers referred to a strategy consisting of a lower VT as ‘protective’ which introduced the concept of an in-built source of bias towards the strategy’s beneficial effect over others. Furthermore, the use of PEEP during OLV reduced the comparability of results and may act as a potential confounding factor. These limitations affected the reliability of individual study results as well as any comparisons that we could draw since there was no uniform intervention used. This systematic review was further limited by other factors. We were forced to exclude studies which were not written in English and those to which we could not gain access; hence we discarded potentially relevant data.

Recommendations for Future ResearchAlthough this systematic review suggests a possible benefit of low VT in terms of development of ALI/ARDS, the various limitations of the review do not allow any significant conclusions to be drawn. Further research is required to allow a rigid comparison of the two strategies in order to advocate for one strategy to be considered over the other. Multicentre, randomised-controlled trials are required to reach a definitive conclusion on which VT provides the best patient outcome for safety and efficacy. In particular we suggest that definitions of what constitutes high and low VT are universally agreed, co-interventions, such as PEEP, are standardised and the relative merits of volume versus pressure-controlled ventilation are assessed.

<Lung Ventilation and Perfusion                            Conclusion>

• By synthesising the available literature, it is clear that the general consensus for indicators of safety are the development of ALI/ARDS, lung ventilation and perfusion, and inflammatory mediators such as IL8 and IL10.

• In terms of efficacy, literature focused on haemodynamics, in particular lung ventilation and perfusion mismatch.

• There is tentative evidence to suggest that lower VT in OLV during thoracic surgery are safer for patients due to a decreased incidence of ALI/ARDS. Inflammatory markers also demonstrate this trend. A low VT strategy could lead to increased levels of PaCO2, but this may be permissible in some patients.

• There is no definite evidence to currently advocate for an optimal VT for OLV based on efficacy, as measured by oxygenation.

• Current decisions can only be based on clinical indicators of safety, such as ALI/ARDS, but ultimately, decision makers need to take into account each patient’s individual circumstances along with current evidence for OLV strategies.

• It is difficult to come to any conclusion as to which VT provides optimum ventilation during thoracic surgery in terms of both safety and efficacy. Current literature on the use of different VT during OLV is limited and flawed, and further research is required to resolve this clinical conundrum.

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