44 of the patients in the AAA approach of Hansen et al. experienced arterial hypertension [33], but this refers only to the test phase. During the pinning, craniotomy and tumour resection there were only 5 patients with 10?0 increase in blood pressure. Additional analyses. The analysis of the composite outcome, order Nutlin-3a chiral including AC failure, intraoperative seizure and mortality was based on forty-one studies (S1 Fig) [10,17?6,28?0,32,34?41,43,46?2]. Of note, intraoperative seizure events, which concurrently led to an AC failure, were counted only once for this composite outcome. The total proportion was estimated to be 8 [95 CI: 6?1], with 8 [95 CI: 6?2] in the MAC group and 8 [95 CI: 5?2] in the SAS group. Logistic meta-regression did not show a difference of the event rate depending on the technique (MAC/ SAS). The OR was 0.9 [95 CI: 0.47?.76] and the residual heterogeneity I2 = 80 .PLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,32 /Anaesthesia Management for Awake MLN9708 biological activity CraniotomyFig 4. Forrest plot of intraoperative seizures. The summary value is an overall estimate from a random-effect model. The vertical dotted line shows an overall estimate of outcome proportion (based on the meta-analysis) disregarding grouping by technique. Of note, Souter et al. [60] have used both anaesthesia PD98059 cost techniques. doi:10.1371/journal.pone.0156448.gSensitivity analysis, by including only prospectively conducted trials, was performed to look at the robustness of our findings in the main summary measure analyses of the four outcomes (AC failure, conversion to GA, intraoperative seizure and new neurological dysfunction) andPLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,33 /Anaesthesia Management for Awake CraniotomyFig 5. Forrest plot of new neurological dysfunction. The summary value is an overall estimate from a random-effect model. The vertical dotted line shows an overall estimate of outcome proportion (based on the meta-analysis) disregarding grouping by technique. Neurol. dysf., neurological dysfunction. doi:10.1371/journal.pone.0156448.gthe additional analysis of the composite outcome. Sensitivity analysis referred to eighteen trials [10,17,18,21,22,25,26,28,30,32,35,36,38,47,52,55,56,61], after exclusion of one duplicate study [27]. Of note, it was not possible to predict an estimate for the outcome new neurological dysfunction in the SAS group, because only one prospective SAS study provided data for this outcome [38]. The proportions of outcomes were slightly lower in prospective studies compared to results from the main analysis, which is shown in S2 Fig. The logistic meta-regression models using the independent variables anaesthesia technique (MAC/ SAS) and prospective studies (yes/ no) showed only very small and statistically not significant differences.PLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,34 /Anaesthesia Management for Awake CraniotomyDiscussionOur systematic review has pointed out forty-seven studies addressing three main topics: SAS-, MAC- and AAA-technique of anaesthesia management for AC since 2007. We identified only two small RCTs [32,56] and one pseudo-RCT [36]. These were as well as the remaining observational studies of moderate to low methodological quality. In summary all three anaesthetic approaches were FPS-ZM1 web feasible and safe. But our results have to be seen within their limits. Nine of the identified forty-seven studies reported partially duplicate patient data, first the studies of Ouyang et al. [45,46], second the s.44 of the patients in the AAA approach of Hansen et al. experienced arterial hypertension [33], but this refers only to the test phase. During the pinning, craniotomy and tumour resection there were only 5 patients with 10?0 increase in blood pressure. Additional analyses. The analysis of the composite outcome, including AC failure, intraoperative seizure and mortality was based on forty-one studies (S1 Fig) [10,17?6,28?0,32,34?41,43,46?2]. Of note, intraoperative seizure events, which concurrently led to an AC failure, were counted only once for this composite outcome. The total proportion was estimated to be 8 [95 CI: 6?1], with 8 [95 CI: 6?2] in the MAC group and 8 [95 CI: 5?2] in the SAS group. Logistic meta-regression did not show a difference of the event rate depending on the technique (MAC/ SAS). The OR was 0.9 [95 CI: 0.47?.76] and the residual heterogeneity I2 = 80 .PLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,32 /Anaesthesia Management for Awake CraniotomyFig 4. Forrest plot of intraoperative seizures. The summary value is an overall estimate from a random-effect model. The vertical dotted line shows an overall estimate of outcome proportion (based on the meta-analysis) disregarding grouping by technique. Of note, Souter et al. [60] have used both anaesthesia techniques. doi:10.1371/journal.pone.0156448.gSensitivity analysis, by including only prospectively conducted trials, was performed to look at the robustness of our findings in the main summary measure analyses of the four outcomes (AC failure, conversion to GA, intraoperative seizure and new neurological dysfunction) andPLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,33 /Anaesthesia Management for Awake CraniotomyFig 5. Forrest plot of new neurological dysfunction. The summary value is an overall estimate from a random-effect model. The vertical dotted line shows an overall estimate of outcome proportion (based on the meta-analysis) disregarding grouping by technique. Neurol. dysf., neurological dysfunction. doi:10.1371/journal.pone.0156448.gthe additional analysis of the composite outcome. Sensitivity analysis referred to eighteen trials [10,17,18,21,22,25,26,28,30,32,35,36,38,47,52,55,56,61], after exclusion of one duplicate study [27]. Of note, it was not possible to predict an estimate for the outcome new neurological dysfunction in the SAS group, because only one prospective SAS study provided data for this outcome [38]. The proportions of outcomes were slightly lower in prospective studies compared to results from the main analysis, which is shown in S2 Fig. The logistic meta-regression models using the independent variables anaesthesia technique (MAC/ SAS) and prospective studies (yes/ no) showed only very small and statistically not significant differences.PLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,34 /Anaesthesia Management for Awake CraniotomyDiscussionOur systematic review has pointed out forty-seven studies addressing three main topics: SAS-, MAC- and AAA-technique of anaesthesia management for AC since 2007. We identified only two small RCTs [32,56] and one pseudo-RCT [36]. These were as well as the remaining observational studies of moderate to low methodological quality. In summary all three anaesthetic approaches were feasible and safe. But our results have to be seen within their limits. Nine of the identified forty-seven studies reported partially duplicate patient data, first the studies of Ouyang et al. [45,46], second the s.44 of the patients in the AAA approach of Hansen et al. experienced arterial hypertension [33], but this refers only to the test phase. During the pinning, craniotomy and tumour resection there were only 5 patients with 10?0 increase in blood pressure. Additional analyses. The analysis of the composite outcome, including AC failure, intraoperative seizure and mortality was based on forty-one studies (S1 Fig) [10,17?6,28?0,32,34?41,43,46?2]. Of note, intraoperative seizure events, which concurrently led to an AC failure, were counted only once for this composite outcome. The total proportion was estimated to be 8 [95 CI: 6?1], with 8 [95 CI: 6?2] in the MAC group and 8 [95 CI: 5?2] in the SAS group. Logistic meta-regression did not show a difference of the event rate depending on the technique (MAC/ SAS). The OR was 0.9 [95 CI: 0.47?.76] and the residual heterogeneity I2 = 80 .PLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,32 /Anaesthesia Management for Awake CraniotomyFig 4. Forrest plot of intraoperative seizures. The summary value is an overall estimate from a random-effect model. The vertical dotted line shows an overall estimate of outcome proportion (based on the meta-analysis) disregarding grouping by technique. Of note, Souter et al. [60] have used both anaesthesia techniques. doi:10.1371/journal.pone.0156448.gSensitivity analysis, by including only prospectively conducted trials, was performed to look at the robustness of our findings in the main summary measure analyses of the four outcomes (AC failure, conversion to GA, intraoperative seizure and new neurological dysfunction) andPLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,33 /Anaesthesia Management for Awake CraniotomyFig 5. Forrest plot of new neurological dysfunction. The summary value is an overall estimate from a random-effect model. The vertical dotted line shows an overall estimate of outcome proportion (based on the meta-analysis) disregarding grouping by technique. Neurol. dysf., neurological dysfunction. doi:10.1371/journal.pone.0156448.gthe additional analysis of the composite outcome. Sensitivity analysis referred to eighteen trials [10,17,18,21,22,25,26,28,30,32,35,36,38,47,52,55,56,61], after exclusion of one duplicate study [27]. Of note, it was not possible to predict an estimate for the outcome new neurological dysfunction in the SAS group, because only one prospective SAS study provided data for this outcome [38]. The proportions of outcomes were slightly lower in prospective studies compared to results from the main analysis, which is shown in S2 Fig. The logistic meta-regression models using the independent variables anaesthesia technique (MAC/ SAS) and prospective studies (yes/ no) showed only very small and statistically not significant differences.PLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,34 /Anaesthesia Management for Awake CraniotomyDiscussionOur systematic review has pointed out forty-seven studies addressing three main topics: SAS-, MAC- and AAA-technique of anaesthesia management for AC since 2007. We identified only two small RCTs [32,56] and one pseudo-RCT [36]. These were as well as the remaining observational studies of moderate to low methodological quality. In summary all three anaesthetic approaches were feasible and safe. But our results have to be seen within their limits. Nine of the identified forty-seven studies reported partially duplicate patient data, first the studies of Ouyang et al. [45,46], second the s.44 of the patients in the AAA approach of Hansen et al. experienced arterial hypertension [33], but this refers only to the test phase. During the pinning, craniotomy and tumour resection there were only 5 patients with 10?0 increase in blood pressure. Additional analyses. The analysis of the composite outcome, including AC failure, intraoperative seizure and mortality was based on forty-one studies (S1 Fig) [10,17?6,28?0,32,34?41,43,46?2]. Of note, intraoperative seizure events, which concurrently led to an AC failure, were counted only once for this composite outcome. The total proportion was estimated to be 8 [95 CI: 6?1], with 8 [95 CI: 6?2] in the MAC group and 8 [95 CI: 5?2] in the SAS group. Logistic meta-regression did not show a difference of the event rate depending on the technique (MAC/ SAS). The OR was 0.9 [95 CI: 0.47?.76] and the residual heterogeneity I2 = 80 .PLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,32 /Anaesthesia Management for Awake CraniotomyFig 4. Forrest plot of intraoperative seizures. The summary value is an overall estimate from a random-effect model. The vertical dotted line shows an overall estimate of outcome proportion (based on the meta-analysis) disregarding grouping by technique. Of note, Souter et al. [60] have used both anaesthesia techniques. doi:10.1371/journal.pone.0156448.gSensitivity analysis, by including only prospectively conducted trials, was performed to look at the robustness of our findings in the main summary measure analyses of the four outcomes (AC failure, conversion to GA, intraoperative seizure and new neurological dysfunction) andPLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,33 /Anaesthesia Management for Awake CraniotomyFig 5. Forrest plot of new neurological dysfunction. The summary value is an overall estimate from a random-effect model. The vertical dotted line shows an overall estimate of outcome proportion (based on the meta-analysis) disregarding grouping by technique. Neurol. dysf., neurological dysfunction. doi:10.1371/journal.pone.0156448.gthe additional analysis of the composite outcome. Sensitivity analysis referred to eighteen trials [10,17,18,21,22,25,26,28,30,32,35,36,38,47,52,55,56,61], after exclusion of one duplicate study [27]. Of note, it was not possible to predict an estimate for the outcome new neurological dysfunction in the SAS group, because only one prospective SAS study provided data for this outcome [38]. The proportions of outcomes were slightly lower in prospective studies compared to results from the main analysis, which is shown in S2 Fig. The logistic meta-regression models using the independent variables anaesthesia technique (MAC/ SAS) and prospective studies (yes/ no) showed only very small and statistically not significant differences.PLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,34 /Anaesthesia Management for Awake CraniotomyDiscussionOur systematic review has pointed out forty-seven studies addressing three main topics: SAS-, MAC- and AAA-technique of anaesthesia management for AC since 2007. We identified only two small RCTs [32,56] and one pseudo-RCT [36]. These were as well as the remaining observational studies of moderate to low methodological quality. In summary all three anaesthetic approaches were feasible and safe. But our results have to be seen within their limits. Nine of the identified forty-seven studies reported partially duplicate patient data, first the studies of Ouyang et al. [45,46], second the s.

## 44 of the patients in the AAA approach of Hansen et al.

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