Albertin 2005.

Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Nitrous oxide‐free ‐A Number randomized: NR Number analysed: 23 Age (mean): 40 (± 8) % male: 0 Type of surgery: Elective abdominal surgery requiring skin incision Nitrous oxide‐free ‐B Number randomized: NR Number analysed: 30 Age (mean): 39 (± 7) % male: 0 Type of surgery: Elective abdominal surgery requiring skin incision Nitrous oxide‐based ‐B Number randomized: NR Number analysed: 27 Age (mean): 38 (± 7) % male: 0 Type of surgery: Elective abdominal surgery requiring skin incision Nitrous oxide‐based ‐A Number randomized: NR Number analysed: 22 Age (mean): 36 (± 8) % male: 0 Type of surgery: Elective abdominal surgery requiring skin incision Included criteria: Women, aged 20 – 50 yrs, ASA I, scheduled for elective abdominal surgery requiring skin incision Excluded criteria: Patients undergoing laparoscopic procedures, obesity (BMI 30 kg/m²), history of cardiac, pulmonary or renal diseases, drug or alcohol abuse, or current use of any medications affecting the cardiovascular system or blocking the adrenergic responses to surgical incision
Interventions	Intervention Characteristics Nitrous oxide‐free ‐A Name: Nitrous oxide‐free remifentanil 3 ng/ml Induction: IV propofol (2 mg/kg) and TCI remifentanil 4 ng/ml for intubation Maintenance: Sevoflurane combined with oxygen and air FiO₂ 40%, TCI remifentanil 3 ng/ml Recovery: NR Other drugs used: NR Premedication: None used Duration of anaesthesia (min): NR Nitrous oxide‐free ‐B Name: Nitrous oxide‐free remifentanil 1 ng/ml Induction: IV propofol (2 mg/kg) and TCI remifentanil 4 ng/ml for intubation Maintenance: Sevoflurane combined with oxygen and air FiO₂ 40% TCI remifentanil 3 ng/ml Recovery: NR Other drugs used: NR Premedication: None used Duration of anaesthesia (min): NR Nitrous oxide‐based ‐B Name: Nitrous oxide‐based remifentanil 1 ng/ml Induction: IV propofol (2 mg/kg) and TCI remifentanil 4 ng/ml for intubation Maintenance: Sevoflurane combined with 60% N₂O in oxygen, TCI remifentanil 1 ng/ml Recovery: NR Other drugs used: NR Premedication: None used Duration of anaesthesia (min): NR Nitrous oxide ‐based ‐A Name: Nitrous oxide‐based remifentanil 3 ng/ml Induction: IV propofol (2mg/kg) and TCI remifentanil 4ng/ml for intubation Maintenance: Sevoflurane combined with 60% N2O in oxygen, TCI remifentanil 3ng/ml Recovery: NR Other drugs used: NR Premedication: None used Duration of anaesthesia (min): NR Monitoring The remifentanil infusion was set at the desired concentration ensuring an adequate equilibration time between plasma and effect site (based upon the very short equilibration time between plasma and effect site (KeO)). An up/down technique was then used to determine the MAC of sevoflurane. The first participant assigned to all groups received 1.5 MAC of sevoflurane adjusted for age (3%) . The subsequent participant then received a variable dose of sevoflurane (decreased or increased by 0.25 MAC (0.5%)) according to whether the preceding participant had responded (increase in heart rate of blood pressure by 15% or not after surgical incision). After 3 sequential negative deflections the change in MAC for each up/down response was reduced to 0.1 MAC (0.2%)
Outcomes	Accidental awareness On the first postoperative day visit participants were questioned about any recall of intraoperative events.
Identification	Country: Italy Setting: NR Authors name: Andrea Albertin Institution: Vita‐Salute University of Milano Email: albertin.andrea@hsr.it Address: Department of Anesthesiology, IRCCS H, San Raffaele, Vita‐Salute University of Milano, Via Olgettina 60, 20132 Milan, Italy
Aim of study	To determine the effects of adding nitrous oxide on sevoflurane requirement for blunting sympathetic responses after surgical incision combined with 2 different target‐controlled concentrations of remifentanil (1 and 3 ng/ml) in women.
Notes	Depth of anaesthesia would not be equivalent in nitrous vs nitrous‐free ‐ at induction (before MAC monitoring) Lack of clarity on numbers studied: "102 female patients..... were prospectively enrolled" but "A total of 102 female patients completed the study" and "Three patients in Group N3 and one patient in Group A1 were withdrawn from the study for hypotension requiring vasoactive agents." Sponsorship source: This study was supported by the Vita‐Salute University of Milano
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computer‐generated sequence of numbers," Comment: No further details
Allocation concealment (selection bias)	Unclear risk	Comment: No details given
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "anaesthesiologist recording cardiovascular parameters and determining the positive–negative response to surgical incision was blinded to patient grouping." Comment: Anaesthetist giving anaesthetic not blinded. Study described as double‐blind but no details of participant blinding. Anaesthetist delivering anaesthetic presumably not blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: Not reported as to whether the outcome assessor for awareness was blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: Unclear as to whether 102 participants were randomized or analysed; 3 withdrawals stated but whether they were included in the final analysis is unclear
Selective reporting (reporting bias)	Low risk	Comment: All relevant outcomes described in Methods were reported
Other bias	Low risk	Comment: None identified