SIESTA 2016.

Study characteristics
Methods	Setting: single‐centre, Germany Design: RCT, parallel‐group, open‐label, blind endpoint Start date: April 2014 Completion date: February 2016
Participants	152 men and women randomised: experimental GA = 73, comparator CSA = 77; 2 excluded (missing informed consent); 150 analysed Mean age: 71.5 years Gender (men/women): 90/60 Mean NIHSS score: 17 Mean ASPECTS: 8 1 lost to 24‐hour follow‐up in CSA arm IV r‐tPA before EVT: GA = 46 (63%) and CSA = 50 (65%) 1 participant who was randomised to GA was mistakenly treated under CSA representing the only major protocol violation 11 (9.2%) participants were intubated at time of evaluation of NIHSS due to: midline shift, additional cerebral haemorrhage, or both (n = 7) pneumonia (n = 3) severe fluctuations of blood pressure including the necessity of high‐dose vasopressors (n = 1) 1 of these participants converted from CSA to GA during intervention because of respiratory insufficiency, and 10 were primarily randomised to the GA group Diagnostic: AIS with LVO in anterior cerebral circulation Inclusion criteria Aged ≥ 18 years Men or women (reported only in protocol) Severe ischaemic stroke defined by an NIHSS score > 10 (range 0–42 with higher scores indicating more severe neurological deficits (a difference of 4 points considered clinically relevant)) (not reported in protocol) Isolated or combined occlusion at any level of internal carotid artery or middle cerebral artery Decision for thrombectomy according to internal protocol for acute recanalising stroke treatment of the Heidelberg University Hospital and at discretion of physician in charge Exclusion criteria Diagnostic imaging results not clearly depicting site of vessel occlusion Clinical or imaging findings suggested occlusion of a cerebral vessel that was not an internal carotid artery or a middle cerebral artery Imaging showed intracerebral haemorrhage coma at admission (GCS score < 8 (range 3–15 points with 3 being the worst and 15 the best, composed of 3 parameters: best eye response, best verbal response, and best motor response)) Severe agitation at admission (making groin and vascular access impossible) Loss of airway‐protective reflexes of at least absence of gag reflex, insufficient saliva handling, observed aspiration, vomiting, or a combination at admission Obvious or known difficult airway Known intolerance of certain medications for sedation, analgesia, or both (not reported in protocol)
Interventions	Comparator: GA Intubation and invasive mechanical ventilation + endovascular recanalisation (drug used not reported) Experimental: CSA CS and non‐invasive ventilatory support + endovascular recanalisation (drug used not reported) Peri‐interventional management followed in‐house protocols for GA or CSA (drugs and dose used not specified in protocol). All randomised participants were non‐invasively monitored for the same haemodynamic and respiratory targets. Participants in the CSA group received IV, low‐dose, short‐acting analgesics and sedatives. Participants in the GA group received the same medication at higher doses or alternative or additional medications if necessary. In cases of interventional emergency or intolerable difficulty, respiratory failure, coma, or loss of airway protective reflexes, participants receiving CSA were immediately converted to GA Excluded medications: not reported
Outcomes	Primary outcome (specified) Early neurological improvement indicated by a change of NIHSS score 24 hours after admission (NIHSS on admission – NIHSS after 24 hours) (25–30) Primary outcome (collected) Early neurological improvement on the NIHSS after 24 hours Secondary outcomes (specified) Functional outcome 90 days after admission (mRS assessed 90 days ± 2 weeks after admission, dichotomised by 0–2 (favourable outcome) to 3–6 (unfavourable outcome); shift from 1 mRS group to another) Intrahospital mortality (yes/no, cause of death) Mortality 3 months after onset (yes/no, cause of death) Length of hospital stay (days from admission to discharge) Length of ICU stay (half‐days from ICU admission to transfer from ICU) Duration of ventilation (hours from start of ventilation to extubation and subsequent spontaneous breathing for ≥ 48 hours) Length of stay on SU (half‐days from admission to SU until transfer from SU) Final stroke size (volumetric assessment of the final infarction size on the last control imaging modality before discharge) Penumbra fate (volumetric comparison of initial DWI or cerebral blood volume lesion with final infarct size) Door‐to‐EST time (minutes) Door‐to‐recanalisation time (minutes) Duration of EST (from groin puncture to transfer from angiosuite, minutes) Degree of recanalisation (TICI) Feasibility of EST Technical and logistical problems during EST such as: substantial participant movement (yes/no) difficult groin puncture (yes/no) difficult road map (yes/no) difficult vascular approach (yes/no) poor imaging quality (yes/no) other Complications before EST impaired monitor installation (yes/no) difficulties of IV puncture (yes/no) disturbed medication application (yes/no) delay due to effect of sedative medication (yes/no) aspiration (yes/no) complications during intubation (yes/no) hypotension (< 20% of baseline SBP) (yes/no) other Complications during EST Assessment of peri‐interventional complications such as: critical hypertension or hypotension (SBP > 180 or < 120 mmHg) (yes/no) critical ventilation or oxygenation disturbance (SpO2 < 90%; ETCO2 < 35 or > 45 mmHg) (yes/no) aspiration (yes/no) intervention‐associated complications (yes/no) and specification of complications: a. femoral injury (yes/no) b. perforation with intracerebral haemorrhage or subarachnoid haemorrhage, or both (yes/no) c. other other Complications after EST Assessment of postinterventional complications such as: hypertension or hypotension (SBP > 180 mmHg or < 120 mmHg) (yes/no) hyperthermia or hypothermia (temperature < 36.0 °C or > 37.2 °C) (yes/no) delayed (> 2 hours after cessation of sedation and analgesia) extubation (yes/no) ventilation‐associated complications (yes/no) and specification tube‐related injury (yes/no) ventilation‐associated pneumonia (yes/no) pneumothorax (yes/no) other Other Reasons for conversion from CSA to intubation and GA during EST agitation or movement, or both (yes/no) vomiting (yes/no) aspiration (yes/no) respiratory failure (ETCO2 or SpO2 outside protocol range for > 5 minutes (yes/no) other Circulatory and respiratory stability (percentage of EST duration within predefined parameter target range (SBP, DBP, ETCO2, SpO2) according to EST SOP)) Cerebral and systemic physiology monitor parameters (means, minimal, maximal values of SBP (mmHg), DBP (mmHg), heart rate (beats/minute), SpO2 (%), ETCO2 (mmHg)) Relevant medication (type and dose of sedatives, analgesics, and vasopressors during EST) Treatment costs (per participant for stay in total according to the diagnosis‐related groups case points) Secondary outcomes (collected) Functional outcome 90 days after admission mRS ≤ 2 (mRS assessed 90 days ± 2 weeks after admission, dichotomised by 0–2 (favourable outcome) to 3–6 (unfavourable outcome); shift from 1 mRS group to another) Intrahospital mortality Mortality 3 months after onset Length of hospital stay Length of ICU stay Length of ventilation Length of SU stay Door‐to‐arterial puncture time, minutes Door‐to‐reperfusion, minutes Duration of EST Feasibility of EST Reperfusion grade (TICI) Substantial reperfusion grade 2b–3 (TICI) Substantial participant movement Difficult vascular approach other Complications before EST Incomplete cardiovascular monitoring Difficulties of arterial puncture Other complications Complications during EST Critical hypertension or hypotension (> 180 mmHg or < 120 mmHg) Critical ventilation or oxygenation disturbance Intervention‐associated complications and specification of complications Vessel perforation with intracerebral haemorrhage or subarachnoid haemorrhage, or both Allergic reaction after application of contrast agent Complications after EST Hypertension or hypotension (> 180 mmHg or < 120 mmHg) Hyperthermia or hypothermia (> 37.2 °C or < 36.0 °C) Delayed extubation Ventilation‐associated complications Time points reported: at discharge and 90 days after the procedure
Notes	Conflicts of interest: (quote) "There is no external steering committee for this monocentric trial". Funding: quote: "There is no funding of the trial". Protocol: NCT02126085
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomly divided into two groups GA and CS … computer‐generated list".
Allocation concealment (selection bias)	Low risk	Quote: "Patients selected for thrombectomy were preliminarily randomised 1:1 (using sealed, opaque envelopes based on a computer‐generated list not allowing for sequence guessing) to receive either conscious sedation or general anaesthesia, standardised according to institutional treatment protocols".
Blinding of participants and personnel (performance bias)	High risk	Not described, but due to the nature of the interventions, we assumed that blinding of personnel was not possible.
Blinding of outcome assessment (detection bias)	Low risk	Quote: "Investigators evaluating the primary (early neurological improvement) and certain secondary outcomes (long‐term functional outcome and causes of mortality) were blinded to allocation".
Incomplete outcome data (attrition bias)	Low risk	Quote: "1 lost to 24‐hour follow‐up (primary endpoint)". There was 1 loss to 24‐hour follow‐up (primary outcome). Crossover occurred in 1 participant from CSA to GA group during the intervention because of respiratory insufficiency but was analysed as ITT. 1 participant who was randomised to the GA group was mistakenly treated under CSA representing the only major protocol violation. 11 (9.2%) participants were intubated at time of evaluation of NIHSS due to several clinical statuses and were primarily randomised to the GA group.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported.
Other bias	Low risk	No evidence of other bias related to this study.

AIS: acute ischaemic stroke; ASA: American Society of Anaesthesiologists; ASPECT: Alberta Stroke Program Early Computed Tomography Score; BIS: Bispectral Index; BMI: body mass index; CAM: Confusion Assessment Method; CS: conscious sedation; CSA: conscious sedation anaesthesia; CT: computed tomography; CTA: computed tomographic angiogram; DBP: diastolic blood pressure; DSA: digital subtraction angiography; DWI: diffusion‐weighted imaging; EEG: electroencephalography; EST: endovascular stroke therapy; ETCO₂: end‐tidal carbon dioxide; EVT: endovascular treatment; GA: general anaesthesia; GCS: Glasgow Coma Scale; GFAP: glial fibrillary acidic protein; ICU: intensive care unit; IQR: interquartile range; ITT: intention‐to‐treat; IV: intravenous; LA: local anaesthesia; LVO: large vessel occlusion; MAP: mean arterial pressure; MMSE: Mini‐Mental State Examination; MOCA: Montreal Cognitive Assessment; MRA: magnetic resonance angiography; MRI: magnetic resonance image; mRS: modified Rankin Scale; mTICI: modified Thrombolysis in Cerebral Infarction; NIHSS: National Institutes of Health Stroke Scale; PROBE: prospective, randomized, open, blinded endpoint; RCT: randomised clinical trial; r‐tPA: recombinant tissue plasminogen activator; SBP: systolic blood pressure; SD: standard deviation; SOP: standard operating procedure; SpO₂: saturation of peripheral oxygen; SU: stroke unit; TICI: Thrombolysis In Cerebral Infarction.