Bispectral index for improving anaesthetic delivery and postoperative recovery

Yodying Punjasawadwong; Aram Phongchiewboon; Nutchanart Bunchungmongkol

doi:10.1002/14651858.CD003843.pub3

. 2014 Jun 17;2014(6):CD003843. doi: 10.1002/14651858.CD003843.pub3

Bispectral index for improving anaesthetic delivery and postoperative recovery

Yodying Punjasawadwong ^1,^✉, Aram Phongchiewboon ¹, Nutchanart Bunchungmongkol ¹

PMCID: PMC6483694 PMID: 24937564

Abstract

Background

The use of clinical signs may not be reliable in measuring the hypnotic component of anaesthesia. The use of bispectral index (BIS) to guide the dose of anaesthetic may have certain advantages over clinical signs. This is the second update of a review originally published in 2007 and updated in 2014.

Objectives

The primary objective of this review focused on whether the incorporation of BIS into the standard practice for management of anaesthesia can reduce the risk of intraoperative awareness, consumption of anaesthetic agents, recovery time and total cost of anaesthesia in surgical patients undergoing general anaesthesia.

Search methods

In this updated version, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 1), MEDLINE (1990 to 31 January 2013), Embase (1990 to 31 January 2013) and reference lists of articles. Previously, we searched to May 2009.

We reran the searches on 27 February 2017. We identified 14 potential new studies of interest which were added to a list of ‘Studies awaiting Classification' and will be incorporated into the formal review findings during the review update. In total there are 17 studies awaiting classification.

Selection criteria

We included randomized controlled trials comparing BIS with standard practice criteria for titration of anaesthetic agents.

Data collection and analysis

Two authors independently assessed trial quality, extracted data and analysed the data. We contacted study authors for further details.

Main results

We included 36 trials. In studies using clinical signs as standard practice, the results demonstrated a significant effect of the BIS‐guided anaesthesia in reducing the risk of intraoperative awareness among surgical patients at high risk for awareness (7761 participants; odds ratio (OR) 0.24, 95% confidence interval (CI) 0.12 to 0.48). This effect was not demonstrated in studies using end tidal anaesthetic gas (ETAG) monitoring as standard practice (26,530 participants; OR 1.13, 95% CI 0.56 to 2.26). BIS‐guided anaesthesia reduced the requirement for propofol by 1.32 mg/kg/hr (672 participants; 95% CI ‐1.91 to ‐0.73) and for volatile anaesthetics (desflurane, sevoflurane, isoflurane) by 0.65 standardized mean difference of minimal alveolar concentration equivalents (MAC SMD equivalences) (95% CI ‐1.01 to ‐0.28) in 985 participants. Irrespective of the anaesthetics used, BIS reduced the following recovery times: time for eye opening (2557 participants; by 1.93 min, 95% CI ‐2.70 to ‐1.16), response to verbal command (777 participants; by 2.73 min, 95% CI ‐3.92 to ‐1.54), time to extubation (1501 participants; by 2.62 min, 95% CI ‐3.46 to ‐1.78), and time to orientation (373 participants; by 3.06 min, 95% CI ‐3.63 to ‐2.50). BIS shortened the duration of postanaesthesia care unit stay by 6.75 min (1953 participants; 95% CI ‐11.20 to ‐2.31) but did not significantly reduce the time to home readiness (329 participants; ‐7.01 min, 95% CI ‐30.11 to 16.09).

Authors' conclusions

BIS‐guided anaesthesia can reduce the risk of intraoperative awareness in surgical patients at high risk for awareness in comparison to using clinical signs as a guide for anaesthetic depth. BIS‐guided anaesthesia and ETAG‐guided anaesthesia may be equivalent in protection against intraoperative awareness but the evidence for this is inconclusive. In addition, anaesthesia guided by BIS kept within the recommended range improves anaesthetic delivery and postoperative recovery from relatively deep anaesthesia.

Keywords: Humans; Anesthesia Recovery Period; Electroencephalography; Anesthesia; Anesthesia/methods; Anesthesiology; Anesthesiology/methods; Anesthesiology/organization & administration; Anesthetics; Anesthetics/administration & dosage; Intraoperative Awareness; Intraoperative Awareness/prevention & control; Monitoring, Intraoperative; Monitoring, Intraoperative/methods; Randomized Controlled Trials as Topic

Monitoring the bispectral index (BIS) to improve anaesthetic delivery and patient recovery from anaesthesia

The results from this updated review indicate that BIS can be useful in guiding the anaesthetic dose to avoid the risk of intraoperative awareness in surgical patients at high risk for awareness. Furthermore, anaesthesia guided by BIS improves anaesthetic delivery and recovery from anaesthesia.

General anaesthesia requires multiple agent administration to achieve unconsciousness (hypnotics), muscle relaxation, analgesia and haemodynamic control. Many anaesthesiologists rely on clinical signs alone to guide anaesthetic management. BIS is a scale derived from the measurement of cerebral electrical activity in anaesthetized patients so that the level of anaesthesia and drug delivery can be optimized. We systematically reviewed 36 randomized controlled studies to find out whether BIS could reduce the risk of intraoperative awareness and reduce anaesthetic use and recovery times in adult surgical patients. The risk of intraoperative awareness was determined in selected patients who were at potentially high risk for awareness. Four studies (7761 patients) that used clinical signs as a guide to anaesthetic administration in standard practice, as the control group, demonstrated a significant reduction in the risk of awareness with BIS monitoring. Four studies (26,530 patients) compared BIS monitoring with end tidal anaesthetic gas (ETAG) monitoring as a guide to management of anaesthesia and they did not demonstrate any difference in terms of intraoperative awareness. There was an overall reduction in volatile anaesthetic dose and the dose of propofol in the BIS group. Recovery from anaesthesia was quicker and postanaesthesia recovery care unit stay was shorter. The limitations of some of the clinical trials on BIS are discussed.

We reran the searches in February 2017. Fourteen potential new studies of interest were added to a list of ‘Studies awaiting Classification'. In total there are now 17 studies awaiting classification. We will deal with studies of interest when we update the review.

Summary of findings

Summary of findings for the main comparison.

Bispectral index versus standard practice (risk of awareness in surgical patients with high risk of awareness) for improving anaesthetic delivery and postoperative recovery

Bispectral index versus standard practice (risk of awareness in surgical patients with high risk of awareness) for improving anaesthetic delivery and postoperative recovery
Patient or population: patients for improving anaesthetic delivery and postoperative recovery Settings: Intervention: Bispectral index versus standard practice (risk of awareness in surgical patients with high risk of awareness)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Bispectral index versus standard practice (risk of awareness in surgical patients with high risk of awareness)
Awareness in surgical patients with high risk of recall awareness ‐ using clinical signs as the guide in standard practice	Study population		OR 0.24 (0.12 to 0.48)	7761 (4 studies)	⊕⊕⊕⊝ moderate^1,2
	8 per 1000	2 per 1000 (1 to 4)
	Moderate
	8 per 1000	2 per 1000 (1 to 4)
Awareness in surgical patients with high risk of recall awareness ‐ using end tidal anaesthetic gas as the guide	Study population		OR 1.13 (0.56 to 2.26)	26530 (4 studies)	⊕⊕⊝⊝ low^1,3
	1 per 1000	1 per 1000 (1 to 3)
	Moderate
	1 per 1000	1 per 1000 (1 to 2)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Study	Anaesthetic technique	Titrating strategies
Ahmad 2003	Endotracheal GA. Induction: sevoflurane Maintenance: sevoflurane‐sufentanil‐nitrous oxide‐a relaxant	Sevoflurane/sufentanil titrated for increased blood pressure/heart rate > 20%, despite a BIS value of 50‐60 or end tidal sevoflurane concentration 2%
Aime 2006	Endotracheal GA, Induction: propofol‐sufentanil Intubation: atracurium Maintenance: sevoflurane and nitrous oxide in oxygen, sufentanil, atracurium	BIS group: intermittent bolus dose of sufentanil despite BIS or Entropy values within the recommended range Control group (CS group): increased sevoflurane concentration or intermittent bolus doses of intravenous sufentanil for signs of inadequate anaesthesia, i.e. hypertension and bradycardia
Anez 2001	LMA GA. Induction: propofol‐alfentanil Maintenance: propofol‐rocuronium	NA
Assare 2002	LMA GA. Induction: propofol‐fentanyl Lidocaine infiltration prior to incision Maintenance: sevoflurane‐nitrous oxide (no muscle relaxant)	NA
Basar 2003	Endotracheal GA. Induction: fentanyl‐thiopentone Intubation: rocuronium Maintenance: sevoflurane‐nitrous oxide	Inadequate analgesia in both groups managed by increased concentration of sevoflurane (no supplemental fentanyl)
Boztug 2006	Endotracheal GA. Induction: fentanyl‐thiopentone Intubation: cis‐atracurium Maintenance: 50% O₂/air mixture and 0.8%–1.5% sevoflurane, fentanyl, and cis‐atracurium	BIS group: additional fentanyl was administered in 0.1mg doses when the BIS value rose to 55. With inadequate decreases in the haemodynamic values, sevoflurane concentration was increased by 20% Control (CS) group: fentanyl was also administered in 0.1‐mg doses if MAP increased by 20% from baseline values, and in the event of inadequate decreases in the haemodynamic values, the sevoflurane concentration was increased by 20%
Bruhn 2005	Endotracheal GA. Induction: remifentanil‐propofol Intubation: cis‐atracurium Maintenance: desflurane in O₂/air mixture and remifentanil (no more neuromuscular blocking agents)	BIS group: desflurane during maintenance was continuously adjusted according to a target value of ‘50’. In case anaesthesia was judged inadequate despite the BIS target value, the infusion rate of remifentanil could be increased. Control (CS) group: if anaesthesia was inadequate, the desflurane concentration was increased in steps of 0.5 vol%. If this was judged insufficient, the infusion rate of remifentanil could be increased
Chiu 2007	Endotracheal GA. Induction: fentanyl‐propofol Intubation:rocuronium Maintenance: before cardiopulmonary bypass ‐sevoflurane (end tidal concentration 0.5‐1.5%) with oxygen in air + infusion atracurium: during cardiopulmonary bypass ‐propofol starting TCI from 2 µG/ml in both arms	BIS group: adjustment of the propofol infusion to achieve BIS 40 to 50 Control (CS) group: titrating of TCI propofol according to perfusion pressure (70 to 90 mmHg)
Ellerkmann 2010	Endotracheal GA plus regional anaesthesia for intraoperative and postoperative pain control Induction: remifentanil, propofol Intubation:cis‐atracurium Maintenance: propofol infusion, remifentanil infusion	During maintenance of anaesthesia, all patients were assessed for signs of inadequate anaesthesia, hypotension or bradycardia. Inadequate anaesthesia was defined as hypertension, tachycardia or patient movement, eye‐opening, swallowing, grimacing, lacrimation or sweating. The definition of adverse haemodynamic responses was adapted from Garrioch et al¹⁵: responses were classified as ‘hypertension’ (SAP >40 mmHg from baseline), ‘hypotension’ (SAP <40 mmHg from baseline), ‘tachycardia’ (HR >100 beats/minute^‐1) and ‘bradycardia’ (HR <45 beats/minute^‐1). In the standard practice group, if anaesthesia was judged inadequate the propofol concentration was increased in steps of 1 mg/kg/hour as necessary
Gan 1997	Endotracheal/LMA anaesthesia Induction: propofol alfentanil Maintenance: 50%nitrous in oxygen‐propofol‐alfentanil‐relaxants	BIS group: increasing alfentanil if BIS was within the recommended range (45‐60) SP group: increasing doses of either propofol, alfentanil or antihypertensive agents
Hachero 2001	Endotracheal GA. Induction: propofol Intubation: mivacurium Maintenance: propofol‐fentanyl‐mivacurium	Signs of inadequate anaesthesia managed in both groups by fentanyl
Ibraheim 2008	Endotracheal GA. Induction: fentanyl‐propofol Intubation: succinylcholine. Maintenance: sevoflurane, nitrous oxide in oxygen, fentanyl, and atracurium	Any instances of inadequate anaesthesia were managed by increasing the concentration of sevoflurane
Kamal 2009	Endotracheal GA. Induction : propofol, Intubation:atracurium Maintenance: sevoflurane, 50% nitrous oxide in oxygen, atracurium by TOF, fentanyl	BIS group:If the patient in that group, exhibited hypertension or tachycardia the mode of treatment was dependent on the BIS index. If the BIS index was >60, anaesthesia was deepened by increasing sevoflurane concentration until BIS index was between 50 and 60. If BIS index was already in the targeted range and the patient exhibited hypertension or tachycardia, fentanyl 25‐50 μg IV was given. If BIS index was <50, sevoflurane was decreased and patient was checked for signs of lack of analgesia (i.e., lacrimation, grimacing, movement). In case of lack of analgesia, fentanyl 25‐50 μg IV was administered. But if no signs of lack of analgesia, labetalol 5‐10 mg IV was administered Standard practice group: If the patient in this group exhibited hypertension (mean arterial blood pressure >25% above baseline) (MBP) and tachycardia (heart rate (HR) >90 beats min^‐1), anaesthesia was deepened either by increasing inspired sevoflurane concentration, or administering fentanyl 25‐50 μg or labetalol 5‐10 mg IV. The mode of treatment was left to anaesthesiologist’s discretion
Kreuer 2003	Endotracheal GA. Induction: propofol‐remifentanil Intubation: cisatracurium. Maintenance: propofol (TCI)‐ remifentanil (constant infusion)	Remifentanil infusion was given in both groups for signs of inadequate anaesthesia despite achieving propofol target concentration or a target value of 50 for BIS
Kreuer 2005	Endotracheal GA, Induction: propofol‐remifentanil Intubation: cis‐atracurium Maintenance: desflurane in O₂/air mixture and remifentanil ( no more neuromuscular blocking agents)	BIS group: desflurane during maintenance was continuously adjusted according to a target value of ‘50’. In case anaesthesia was judged inadequate despite the BIS target value, the infusion rate of remifentanil could be increased. Control (CS) group: if anaesthesia was inadequate, the desflurane concentration was increased in steps of 0.5 vol%. If this was judged insufficient, the infusion rate of remifentanil could be increased
Leslie 2005a	Relaxant general anaesthesia. Induction: midazolam‐propofol or thiopentone Intubation: nondepolarizing muscle relaxants. Maintenance: propofol or volatiles‐nitrous oxide‐opioids. Hypnotic drugs. Combined general and regional anaesthesia	Narcotic analgesics on the discretion of the attending anaesthesiologists
Luginbuhl 2003	Endotracheal GA Induction: propofol and fentanyl. Intubation: vecuronium Maintenance: propofol‐fentanyl or desflurane‐fentanyl	BIS group: propofol or desflurane to keep BIS 45‐55 and opioids according clinical criteria CS group: propofol or desflurane and opioids according to haemodynamic and vital sign criteria (within 20% of the baseline value)
Masuda 2002	Endotracheal GA Induction: propofol‐fentanyl Intubation: vecuronium Maintenance: propofol‐nitrous oxide ‐ fentanyl‐vecuronium	NA

Morimoto 2002	Endotracheal GA Induction:thiopentone, Intubation: vecuronium Maintenance: sevoflurane‐nitrous oxide‐ fentanyl‐vecuronium	Managed by fentanyl 50‐100 µg, despite 2% in sevoflurane in both groups
Myles 2004	Relaxant general anaesthesia. Induction: midazolam‐propofol or thiopentone Intubation: nondepolarizing muscle relaxants. Maintenance: Propofol or volatiles‐nitrous oxide‐opioids. Hypnotic drugs. Combined general and regional anaesthesia	Narcotic analgesics on the discretion of the attending anaesthesiologists
Nelskyla 2001	Endotracheal GA. Induction:propofol Intubation: rocuronium Maintenance: Sevoflurane (0.94%‐1.4%)‐nitrous oxide‐rocuronium	Supplemental alfentanil given for haemodynamic variables >25% of the preanaesthetic value, despite BIS of 50‐60 in BIS group or sevoflurane concentration of 1.4% in CP group
Paventi 2001	Endotracheal GA. Induction: remifentanil ‐ thiopentone Intubation: vecuronium Maintenance: sevoflurane‐nitrous oxide‐remifentanil‐vecuronium	Remifentanil infusion (0.4 µG/kg/min) for both groups
Puri 2003	Endotracheal GA. Induction: midazolam‐morphine‐thiopentone Intubation:vecuronium. Maintenance: isoflurane‐nitrous oxide‐morphine	Signs of inadequate analgesia (tachycardia, hypertension, sweating, lacrimation etc) in both groups managed by morphine before vasodilators or beta‐blocker
Recart 2003	Endotracheal GA Premedication: Induction: propofol‐fentanyl Intubation: rocuronium Maintenance: desflurane‐fentanyl	Intermittent intravenous fentanyl 0.5 mg/kg as needed to maintain haemodynamic variables within 15% of the baseline value Labetalol to control sympathetic responses as needed (in the presence of adequate hypnotic and analgesic states) Intermittent intravenous fentanyl 0.5 mg/kg as needed to maintain haemodynamic variables within 15% of the baseline value Labetalol to control sympathetic responses as needed (in the presence of adequate hypnotic and analgesic states)
Song 1997	Endotracheal GA. Induction: fentanyl‐propofol. Intubation:succinylcholine Maintenance: desflurane or sevoflurane‐nitrous‐fentanyl‐mivacurium (at least 1‐2 TOF)	Inadequate analgesia (haemodynamic variables >20%of baseline) managed by supplemental doses of fentanyl (25‐30 µg)
Struys 2001	Endotracheal GA. Induction: remifentanil, propofol .Intubation: rocuronium. Maintenance: remifentanil infusion (0.5 µg/kg/min)‐propofol infusion	Remifentanil infusion
Tufano 2000	Endotracheal GA. Induction: Propofol. Intubation: Cis‐atracurium. Maintenance: propofol infusion or sevoflurane‐nitrous oxide‐cisatracurium‐fentanyl	NA
White 2004	Endotracheal GA. Induction: propofol and fentanyl Intubation: succinylcholine. Maintenance: desflurane‐nitrous‐cisatracurium	Esmolol to treat sustained increased heart rate
Wong 2002	Endotracheal GA. Induction: propofol‐fentanyl‐midazolam Intubation: rocuronium. Maintenance: isoflurane‐nitrous oxide‐fentanyl‐rocuronium‐fentanyl	BIS group: BIS > 60 increasing isoflurane concentration; BIS = 50‐60 giving supplemental fentanyl; BIS < 50 decreasing isoflurane concentration and supplementing fentanyl (signs of inadequate anaesthesia) or labetalol (no sign of inadequate anaesthesia) Control(CS) group: increasing isoflurane concentration or supplemental fentanyl or labetalol for management of hypertension (>25%) or tachycardia (>90 beats per minute)
Zohar 2006	LMA GA. Induction: propofol‐fentanyl Maintenance: sevoflurane‐nitrous oxide (no muscle relaxant)	In both groups, the sevoflurane concentration was increased in response to signs of an inadequate “depth of anaesthesia” (e.g. movement in response to surgical stimulation)

Trial	Outcome	Value	BIS group	CS group	Note
Ahmad 2003	Bispectral index (BIS) during operation	Mean	Not applicable	Not applicable	Data not available
Basar 2003	BIS during operation	Mean	Cn = 30; mean = 44.9; SD (standard deviation) = 5.15	Cn = 30; mean = 40.5; SD = 4.53
Boztug 2006	BIS index during maintenance	Mean	Cn = 24; mean = 54 ; SD = 4	Cn = 23; mean = 46; SD = 5
Bruhn 2005	BIS index during maintenance	Mean			Data presented as a graph showing comparable BIS values between BIS and control (CS) groups at various point of anaesthesia
Chiu 2007	BIS index during cardiopulmonary by pass	Mean
Ellerkmann 2010	Intraoperative BIS	Mean	mean = 44.35 SD = 5.25	mean = 45.89 SD = 5.98
Gan 1997	BIS index during maintenance	Mean	Not applicable	Not applicable	Data presented as a graph showing BIS values at various points of anaesthesia in BIS group > in SP group
Hachero 2001	BIS index during maintenance	Median	Cn = 20; mean = 46.4; 95% confidence interval (CI ) = 44.4 to 44.8	Cn = 20; mean = 42.2; 95% CI = 40.1 to 44.2	Data presented as a graph showing BIS values at various points during cardiopulmonary bypass in BIS group > in SP group
Ibraheim 2008	BIS index during maintenance	Mean	Not applicable	Not applicable	Data: not available
Kamal 2009	BIS index during maintenance After discontinuation of anaesthesia	Mean	mean = 52.4 , SD = 3.4 mean = 70.1 SD = 11.2	Mean = 41.2 SD = 7.3 mean = 66.5 SD = 14.3	None of patients reported awareness
Kreuer 2003	BIS index during maintenance	Mean	Not applicable	Not applicable	Data presented as a graph showing BIS values at various points of anaesthesia in BIS group >in SP group
Kreuer 2005	BIS index during maintenance and at the end of surgery	Mean			Data presented as a graph showing comparable BIS values between BIS and control (CS) groups at various point during operation. At the end of surgery, BIS values were significantly higher in the BIS group
Masuda 2002	BIS index during skin incision	Mean	Cn = 20; mean = 46; SD = 6	Cn = 19; mean = 47; SD = 10
	BIS 10 minutes before end of surgery	Mean	Cn = 20; mean = 59; SD = 6	Cn =19; mean = 52; SD = 9
	BIS at end of surgery	Mean	Cn = 20; mean = 69; SD = 12	Cn = 19; mean = 60; SD = 9
	BIS at end of anaesthesia	Mean	Cn = 20; mean = 92; SD = 6	Cn = 19; mean = 88; SD = 6
Morimoto 2002	BIS index during maintenance	Mean	Not applicable	Not applicable	Data presented as graph showed BIS values at various points of anaesthesia in BIS group < in SP group
Nelskyla 2001	BIS during surgery	Median	Cn = 32; median = 54; min‐max = 49‐61	Cn = 30; median = 55; min‐max = 30‐65
Paventi 2001	BIS during surgery	Median	Cn = 45; median = 46; min‐max = 36‐67	Cn = 45; median = 42; min‐max = 39‐61
Paventi 2001	BIS after skin closure	Median	Cn = 45; median = 62; min‐max = 43‐98	Cn = 45; median = 54; min‐max = 34‐99
Recart 2003	BIS index during maintenance	Mean	Cn = 30; mean = 49; SD = 13	Cn = 30; mean = 40; SD = 11
Recart 2003	BIS during emergence from anaesthesia	Mean	Cn = 30; mean = 88; SD =11	Cn = 30; mean = 88; SD = 12	At the time of eye opening before removal of endotracheal tube
Song 1997	BIS index during operation	Mean	Cn = 15; mean = 60; SD = 4	Cn = 15; mean = 44; SD = 11
Song 1997	BIS during operation	Mean	Cn = 15; mean = 62; SD =3	Cn = 15; mean = 42; SD = 8
White 2004	BIS index during maintenance	Mean	Cn = 20; mean = 57; SD = 12	Cn = 20; mean = 41; SD = 10
Wong 2002	BIS index during operation	Mean	Cn = 29; mean = 51; SD = 4.9	Cn = 31; mean = 44.3; SD = 8.8
Wong 2002	BIS index at discontinuation of anaesthesia	Mean	Cn = 29; mean = 68; SD =13	Cn = 31; mean = 64; SD = 13
Zohar 2006	BIS index during operation	Mean	Cn = 25, mean= 57; SD = 10	Cn = 25, mean = 59; SD =10
	BIS index upon discontinuation of sevoflurane	Mean	Cn = 25, mean= 57; SD = 17	Cn = 25, mean = 58; SD = 18
	BIS index upon removal of airway device	Mean	Cn = 25, mean = 78; SD = 13	Cn = 25, mean = 81; SD = 14

Study ID
Reviewer
Study Title
Source of data base	MEDLINE EMBASE CENTRAL Handsearch
The study is published Not published Is the topic relevant? Is the study randomized /quasi‐ randomized? Are the participant adults (> 18 years)?	Yes/No Yes/NO Yes/No/Unclear Yes/No/Unclear Yes/No/Unclear
Is the surgery under general anaesthesia?	Yes/No/Unclear
Did the study group use BIS monitoring guiding the dose of anaesthetics?	Yes/No/Unclear
Did the control group use clinical signs guiding the dose of anaesthetics?	Yes/No/Unclear
Does the study fulfil the inclusion criteria? If no, state why?	Yes/No/Unclear

Study ID
Authors
MEDLINE Journal ID
Year of Publication
Language
Type of study	RCT Quasi‐RCT Non‐ RCT
Comments on study design
Does the study compare the use BIS (BIS group) and the use of clinical signs (SP group) in guiding doses of anaesthetics?
Was the assignment of subjects to treatment groups randomized?
Was there blinding? If so, who was blinded	Subject ‐Blinded? Yes/No/Unclear Anaesthesiologist Blinded? Yes/No/Unclear Outcome accessor blinded? Yes/No/Unclear
Were the BIS and SP groups similar at the start of the trial?
Apart from the treatment under investigation, were the groups treated equally?
Are all relevant outcomes measured in a standard, valid and reliable way?
What percentage of the individuals or clusters recruited into the study are included in the analysis?
Were all the subjects analysed in the groups to which they were randomly allocated?

Was an adequate concealment method used?	A = (adequate) if the allocation concealment was described as central randomization; serially numbered; opaque; or sealed envelopes B = (uncertain) if there was no mention about the allocation concealment C = (inadequate) if the allocation concealment was not used D = the randomization was not used
PARTICIPANTS How many patients participated in the study? Overall number, and in each arm of the study.	Total number: Number in each arm of study: Withdrawals: Yes/No/Unclear Number of withdrawals in each arm:
What are the characteristics of the study population? E.g. age range, sex, and disease characteristics of the population, disease prevalence.	BIS group SP group Age Sex ASA Operation
What are the characteristics of the study setting? E.g. rural, urban, hospital inpatient or outpatient, general practice, community.
How many groups/sites are there in the study? If the study is carried out on more than one group of patients, or at more than one site, indicate how many are involved.
Are there any specific issues raised by this study? Make any general comments on the study results and their implications
INTERVENTION: What interventions are evaluated in this study?

Outcomes	Interventions
Outcomes	BIS group	Non‐BIS (SP) group	Difference, P
Dose of anaesthetic agents	Mean SD	Mean SD
Time to recovery (please specify end point) Time to eye opening: Time to response to command: Time to extubation: Time to: Time to: Time to:	Mean SD	Mean SD
Relaxants
Narcotics
Awareness (Cn/N, %)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Risk of awareness in BIS versus CS guided anaesthesia	4	7761	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.24 [0.12, 0.48]
2 Risk of awareness in BIS versus ETAG guided anaesthesia	4	26530	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.13 [0.56, 2.26]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to eyes opening (minutes)	20	2557	Mean Difference (IV, Random, 95% CI)	‐1.93 [‐2.70, ‐1.16]
1.1 propofol	7	552	Mean Difference (IV, Random, 95% CI)	‐3.59 [‐5.15, ‐2.04]
1.2 desflurane	4	322	Mean Difference (IV, Random, 95% CI)	‐0.51 [‐1.44, 0.42]
1.3 isoflurane	1	60	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐2.32, 0.52]
1.4 sevoflurane	8	530	Mean Difference (IV, Random, 95% CI)	‐1.42 [‐2.45, ‐0.38]
1.5 propofol/volatile anaesthetics	1	1093	Mean Difference (IV, Random, 95% CI)	‐1.73 [‐1.00, ‐0.46]
2 Time to respond to verbal command (minutes)	12	777	Mean Difference (IV, Random, 95% CI)	‐2.73 [‐3.92, ‐1.54]
2.1 propofol	3	359	Mean Difference (IV, Random, 95% CI)	‐4.88 [‐7.57, ‐2.20]
2.2 desflurane	3	130	Mean Difference (IV, Random, 95% CI)	‐3.38 [‐4.68, ‐2.07]
2.3 isoflurane	2	90	Mean Difference (IV, Random, 95% CI)	‐3.86 [‐11.87, 4.15]
2.4 sevoflurane	4	198	Mean Difference (IV, Random, 95% CI)	‐1.30 [‐3.06, 0.46]
3 Time to extubation (minutes)	18	1501	Mean Difference (IV, Random, 95% CI)	‐2.62 [‐3.46, ‐1.78]
3.1 propofol	6	539	Mean Difference (IV, Random, 95% CI)	‐4.55 [‐5.36, ‐3.73]
3.2 desflurane	6	432	Mean Difference (IV, Random, 95% CI)	‐1.64 [‐2.97, ‐0.32]
3.3 isoflurane	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 sevoflurane	9	530	Mean Difference (IV, Random, 95% CI)	‐2.29 [‐3.24, ‐1.35]
4 Time to orientation (minutes)	7	373	Mean Difference (IV, Fixed, 95% CI)	‐3.06 [‐3.63, ‐2.50]
4.1 propofol	1	20	Mean Difference (IV, Fixed, 95% CI)	‐2.19 [‐8.19, 3.81]
4.2 desflurane	2	70	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐4.23, ‐0.97]
4.3 isoflurane	1	44	Mean Difference (IV, Fixed, 95% CI)	‐3.6 [‐5.92, ‐1.28]
4.4 sevoflurane	4	239	Mean Difference (IV, Fixed, 95% CI)	‐3.10 [‐3.73, ‐2.48]
5 PACU stay (minutes)	12	1953	Mean Difference (IV, Random, 95% CI)	‐6.75 [‐11.20, ‐2.31]
5.1 propofol	3	318	Mean Difference (IV, Random, 95% CI)	‐5.84 [‐10.07, ‐1.62]
5.2 desflurane	4	272	Mean Difference (IV, Random, 95% CI)	‐14.76 [‐29.61, 0.09]
5.3 isoflurane	1	60	Mean Difference (IV, Random, 95% CI)	‐14.00 [‐34.12, 6.12]
5.4 sevoflurane	4	180	Mean Difference (IV, Random, 95% CI)	‐7.56 [‐15.85, 0.72]
5.5 propofol/volatile anaesthetics	1	1123	Mean Difference (IV, Random, 95% CI)	‐3.41 [‐9.72, 2.90]
6 Time to home readiness (minutes)	6	329	Mean Difference (IV, Random, 95% CI)	‐7.01 [‐30.11, 16.09]
6.1 propofol	1	39	Mean Difference (IV, Random, 95% CI)	‐5.36 [‐33.01, 22.29]
6.2 isoflurane	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6.3 desflurane	2	70	Mean Difference (IV, Random, 95% CI)	‐30.93 [‐107.35, 45.48]
6.4 sevoflurane	4	220	Mean Difference (IV, Random, 95% CI)	8.93 [‐4.49, 22.35]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Normalized propofol infusion rate (mg/kg/hr)	10	672	Mean Difference (IV, Random, 95% CI)	‐1.32 [‐1.91, ‐0.73]
2 Volatile anaesthetic requirement, minimal alveolar concentration equivalents (MAC equivalents)	14	985	Std. Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.01, ‐0.28]
2.1 desflurane	5	352	Std. Mean Difference (IV, Random, 95% CI)	‐1.02 [‐2.03, ‐0.01]
2.2 isoflurane	1	60	Std. Mean Difference (IV, Random, 95% CI)	‐0.37 [‐0.88, 0.14]
2.3 sevoflurane	9	573	Std. Mean Difference (IV, Random, 95% CI)	‐0.52 [‐0.87, ‐0.18]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total dose of fentanyl (microgramme)	7	333	Mean Difference (IV, Random, 95% CI)	13.80 [‐19.80, 47.40]
2 average normalized remifentanil infusion rates ( microgramme/kg/min)	3	276	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.02, ‐0.00]
3 Total dose of sufentanil ( microgramme)	1	40	Mean Difference (IV, Fixed, 95% CI)	‐33.80 [‐51.03, ‐16.57]

Methods	RCT
Participants	Country: USA N = 99 ASA: I/II Gender: female Age: 31.5±8.7, 35.4±8.9 Exclusion: not mentioned Operation: gynaecologic laparoscopy Duration of anaesthesia: 67±36; 6937 min
Interventions	Sevoflurane inhalation guided by BIS, BIS value of 50‐60 (BIS group), Cn = 49 Sevoflurane inhalation guided by clinical signs (blood pressure and heart rate) (CS group) Cn = 48
Outcomes	Successful fast track rate (using modified Aldrete Score, main outcome) mean concentration of sevoflurane (%, sevoflurane requirement) mean dose of sufentanil mean dose of rocuronium mean duration of phase II recovery room stay (time to discharge) pain in phase II recovery area (Cn, %) nausea/vomiting in phase II recovery area (Cn, %)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about the sequence generation process
Allocation concealment (selection bias)	Low risk	"...99 patients...were enrolled and randomised, using a closed envelope technique with random numbers,..."
Incomplete outcome data (attrition bias) All outcomes	Low risk	"...2 patients required inpatient hospitalisation postoperatively for surgical complications and were withdrawn from the final analysis." Plausible effect size (difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size
Selective reporting (reporting bias)	Low risk	All expected outcomes have been reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to ' learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"In the BIS‐monitored group, sevoflurane was titrated to maintain the BIS value in the 50‐60 range...." This indicates no blinding of the anaesthesia provider
Blinding of outcome assessors?	Unclear risk	The study has not mentioned outcome assessor blinding

Methods	RCT
Participants	Country: USA N = 125 ASA: I/II/III 13/16/5, 14/19/4, 26/24/4 Gender: M/F 14/20, 23/14, 23/33 Age: 57±19, 58±18, 54±15 years Exclusion: a history of any disabling central nervous or cerebrovascular disease, hypersensitivity to opioids or substance abuse, treatment with opioids or any psychoactive medication, or a body weight 70% or more than 130% of ideal body weight Operation: elective abdominal, gynaecologic, urologic, or orthopedic surgery expected to last at least 1 hour Duration of anaesthesia: 182.8±85.3, 190.8±84.9, 170.8±90.6 min
Interventions	Sevoflurane guided by BIS (a Datex‐Ohmeda S/5 monitor, Helsinki, Finland), BIS value of 40‐60, Cn = 34 (BIS group) Sevoflurane guided by Entropy (Datex‐Ohmeda S/5 monitor, Helsinki, Finland), Entropy value of 40‐60, Cn = 37 Sevoflurane guided by routine clinical signs (CS group), Cn = 54
Outcomes	Sevoflurane consumption (gm/kg/hr) (primary outcome) Recovery times (min) ‐ time to spontaneous eye opening ‐ time to tracheal extubation Sufentanil consumption (µg/kg/hr) Intraoperative recall by using a standardized interview (Cn, %)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"...140 adult patients were randomly allocated to one of three groups, the standard practice group, the BIS‐guided group, or the spectral entropy‐guided group, using a randomization list performed with computer‐generated random numbers."
Allocation concealment (selection bias)	Unclear risk	No mention about allocation concealment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	"Six patients were excluded from the standard practice group (1 was not extubated at the end of surgery because of hypothermia, 3 required intraoperative propofol administration, and there were missing data in 2 cases), six patients were excluded from the BIS‐guided group (3 were not extubated at the end of surgery because of hypothermia, 2 required intraoperative propofol administration, and monitor data were lost in 1 case) and three from the spectral entropy‐guided group (all were not extubated at the end of surgery due to hypothermia, 2 required intraoperative propofol administration) (ns)." The study has not clearly stated how to deal with these excluded patients
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologists could potentially lead to 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"In both EEG‐groups, anaesthesiologists were instructed to adjust the sevoflurane concentration to keep BIS, SE, and RE values, in the respective group, in the range of 40‐60. ." It was unlikely to blind the anaesthesia providers
Blinding of outcome assessors?	Unclear risk	Insufficient information

Methods	Quasi‐randomization
Participants	Country: Spain N = 40 ASA: I/II Gender: ? Age: 40 (average) Exclusion: using psychotropic medication Operation: vascular (venous) or orthopaedic outpatient surgery
Interventions	Propofol TCI (target controlled infusion) guided by BIS (BIS A‐2000 Aspect); BIS value of 40‐60, Cn = 20 Propofol administration guided by clinical signs, Cn = 19
Outcomes	Propofol consumption Immediate and total recovery times Presence of intraoperative alertness
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	The study used sequential randomization (quasi‐randomization). The rational for this 'sequence' was to avoid any contamination or influence of the 'BIS guided anaesthesia' on the 'standard anaesthesia' administered subsequently
Allocation concealment (selection bias)	High risk	The allocation concealment was not used
Incomplete outcome data (attrition bias) All outcomes	Low risk	One in the control group was excluded from the analysis. Plausible effect size (difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	Insufficient information
Blinding of patients?	Low risk	The patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"Anesthesia administered guided by BIS monitor." (Ivan Sola, translator)
Blinding of outcome assessors?	Unclear risk	Insufficient information

Methods	RCT
Participants	Country: Sweden N = 60 (20,20,20) ASA: I/II Gender: not stated Age: 45±12, 45±12, 44±11 yr (mean±SD) Exclusion: not stated Operation: elective arthroscopy (ambulatory surgery) Duration of anaesthesia: 15±5, 15±5.5, 17±4.8 (min)
Interventions	Sevoflurane inhalation guided by BIS (Aspect 2000, BIS Algorithm 3.4), BIS value of 60 (BIS group), Cn = 20 Sevoflurane inhalation guided by auditory evoked potential (AEP, A‐Line AEP monitoring, Danmeter A/S; Odense, Denmark) (AEP group) Cn = 20 Sevoflurane inhalation guided by routine clinical signs (CS group) Cn = 20
Outcomes	Sevoflurane consumption (g/min) Emergence times: ‐time to removal of laryngeal mask (min) ‐time to state of birth and name (min) ‐time to ready for discharge (min)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No detailed information regarding the sequence generation process
Allocation concealment (selection bias)	Unclear risk	No detailed information regarding allocation concealment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information regarding withdrawals/dropouts
Selective reporting (reporting bias)	Low risk	All expected outcomes have been reported
Other bias	Unclear risk	The unblinded anaesthesiologist could lead to ' learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"...sevoflurane was titrated to maintain a target BIS of 60 during surgery." This indicates no blinding of the anaesthesia care provider
Blinding of outcome assessors?	Unclear risk	No detailed information regarding blinding of outcomes assessors

Methods	RCT, multicentre
Participants	Country: USA N = 1961 ASA: I/II/III/IV 21/ 265/ 454/ 222, 15/ 252/ 503/ 202 Gender: Male, Cn(%): 516 (53.4%), 5323(53.7%) Age: 59.5±14.8, 59.2±14.6 yr Inclusion: patients with at least one major criterion (preoperative long‐term use of anticonvulsant agents, opiates, benzodiazepines, or cocaine; a cardiac ejection fraction less than 40%; a history of anaesthesia awareness; a history of difficult intubation or anticipated difficult intubation, ASA physical status class 4 or class 5; aortic stenosis; end‐stage lung disease; marginal exercise tolerance not resulting from musculoskeletal dysfunction; pulmonary hypertension; planned open‐heart surgery; and daily alcohol consumption) or two minor criteria (preoperative use of beta‐blockers, chronic obstructive pulmonary disease, moderate exercise tolerance not resulting from musculoskeletal dysfunction, smoking two or more packs of cigarettes per day, and obesity, defined as a body‐mass index (the weight in kilograms divided by the square of the of more than 30) Exclusion: the surgical procedure or positioning of the patient prevented BIS monitoring or if the surgery required a wake‐up test Duration of anaesthesia: NA
Interventions	BIS‐guided anaesthesia (A BIS Quatro Sensor, Aspect Medical Systems), A target BIS value of 40‐60 Anaesthesia guided by end tidal anaesthetic gas (ETAG) concentrations between 0.7 MAC and 1.3 MAC (routine care group)
Outcomes	Definite intraoperative awareness (Cn, %)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	".... in which 2000 patients underwent prerandomization electronically in blocks of 100, with 50 patients assigned to a BIS‐guided protocol and 50 to an ETAG‐guided protocol." This indicates adequate sequence generation
Allocation concealment (selection bias)	Low risk	The design was a single‐centre, prospective study, in which 2000 patients underwent prerandomization electronically in blocks of 100, with 50 patients assigned to a BIS‐guided protocol and 50 to an ETAG‐guided protocol
Incomplete outcome data (attrition bias) All outcomes	Low risk	Table 7 of the study shows 33 in the BIS group and 20 in the ETAG group were excluded. Intention‐to‐treat analysis was planned
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologists could potentially lead to 'learning contamination bias'
Blinding of patients?	Low risk	"The anaesthesia practitioners were aware of the assignments of the patients, but the patients, the postoperative interviewers, the expert reviewers, and the statistician were not."
Blinding of anaesthesiologists?	High risk	"The anaesthesia practitioners were aware of the assignments of the patients, but the patients, the postoperative interviewers, the expert reviewers, and the statistician were not."
Blinding of outcome assessors?	Low risk	"The anaesthesia practitioners were aware of the assignments of the patients, but the patients, the postoperative interviewers, the expert reviewers, and the statistician were not."

Methods	RCT
Participants	Country: Turkey N = 60 ASA: I/II Gender: male/female, 17/13,18/12 Age: 42.1±3.3, 39±4.5 yrs Exclusion‐ renal, hepatic or neurological dysfunction, use of benzodiazepines, anticonvulsants, alcohol, opioids or other psychotropic drugs Operation: open abdominal surgery Duration of anaesthesia: 85±10.5, 90.4±8.7 min
Interventions	Sevoflurane guided by BIS (Aspect A‐2000 R), BIS value of 40‐60, Cn = 30 (BIS group) Sevoflurane inhalation guided by clinical signs (blood pressure and heart rate, somatic response), Cn = 30 (CS group)
Outcomes	Mean sevoflurane exposure (aged adjusted minimal alveolar concentration, main outcome) Amount of sevoflurane used (ml, main outcome) Immediate recovery times (time to open eyes on verbal command, time to motor respond to verbal command) Aldrete score at 10 min
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information regarding withdrawals/dropouts
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Unclear risk	The unblinded anaesthesiologists could lead to 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"..the anaesthesiologist had access to the monitor and adjusted the concentration of sevoflurane to achieve a target BIS in the range of 40‐60." This indicates no blinding of the anaesthesia care provider
Blinding of outcome assessors?	Unclear risk	The author did not mention about blinding of the outcome assessors

Methods	RCT
Participants	Turkey N = 50 ASA: I/II Gender: male/female 13/11, 11/12 Age: 45±11, 50±10 yrs Exclusion: any medication interaction with the central nervous system (antidepressant drugs, anti seizure drugs) or cardiopulmonary system (antihypertensive drugs, beta blockers), or a need for postoperative ventilation or other psychotropic drugs) Operation: Supratentorial craniotomy Duration of anaesthesia: 239±30, 222±32 min
Interventions	Sevoflurane guided by BIS (an A‐200 EEG monitor, Aspect Medical Systems), BIS value of 40‐60 during maintenance and of 60–70 during the last 15 minutes of surgery, Cn = 24 (BIS group) Sevoflurane inhalation guided by clinical signs (blood pressure and heart rate, somatic response), Cn = 23 (CS group)
Outcomes	Average end tidal concentrations (mean±SD) of sevoflurane Recovery times (min): ‐from end of surgery to first spontaneous breathing ‐from end of surgery to eye opening ‐from end of surgery to extubation PACU stay
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer‐generated sequence of number was used
Allocation concealment (selection bias)	Low risk	A sealed envelope technique was used
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	"Three patients were excluded from the study due to disconnection of BIS probe (2) or artefact contamination (1)." The study has not been mentioned how to deal with the missing outcome data in the analysis
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to ' learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"...sevoflurane was adjusted in an effort to achieve a target BIS of 40‐60..." This indicates no blinding of the anaesthesia provider
Blinding of outcome assessors?	Unclear risk	The study has not mentioned clearly about the blinding of outcomes assessors

Methods	RCT
Participants	Country: Malaysia N = 20 ASA: I/II/III Gender: male/female 7:3, 8:2 Age: 52±12, 51±16 yrs Exclusion: previous cardiac surgery, preoperative neurologic disease, ejection fraction of less than 30%, known allergy to one of the drugs used, and severe renal and hepatic impairment Operation: cardiac surgery requiring cardiopulmonary bypass Duration of anaesthesia during cardiopulmonary bypass: 138 (120,181), 128 (120,175) min
Interventions	Propofol guided by BIS (Aspect Medical System), BIS value of 40‐50, Cn = 10 (BIS group) Propofol guided by clinical signs (blood pressure), Cn=10(CS group)
Outcomes	‐Propofol requirement during cardiopulmonary bypass ‐Haemodynamic stability during cardiopulmonary bypass
Notes	‐Both arms were conducted during cardiopulmonary bypass
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomly allocated by computer generated random numbers in closed envelopes."
Allocation concealment (selection bias)	Low risk	Patients were randomly allocated by computer‐generated random numbers in closed envelopes
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologists could potentially introduce 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"In group B, BIS‐controlled adjustment of the propofol infusion was used to achieve a BIS value of 40 to 50." This indicates no blinding of the anaesthesia care provider
Blinding of outcome assessors?	Unclear risk	Insufficient information

Methods	RCT
Participants	Country: Germany N = 90 (20,20,20) ASA: I/II/III 10/16/1, 4/15/6, 10/10/7 Gender: male/female 9/18, 10/15, 12/15 Age: 50.6±15.7, 58±14.2, 53.6±18.4yr (mean±SD) Exclusion: history of any disabling central nervous or cerebrovascular diseases, hypersensitivity to opioids or substance abuse, or a treatment with opioids or any psychoactive medication Operation: minor surgery expected to last at least one hour (orthopaedic patients receiving regional anaesthesia for intra‐ and postoperative pain control for surgery to the upper or lower extremity in combination with general anaesthesia) Duration of anaesthesia: 100±30.7, 123.7±44.6, 119.5±50.6 (min)
Interventions	1. Propofol guided by BIS (A‐2000 BIS^® monitor (version XP, software version 4.0), Target BIS=50 2.Propofol guided by Entropy (an Entropy Module^®), Target entropy=50 3. Propofol guided by clinical parameters (blood pressure, heart rate, sweating, tear production, movement)
Outcomes	‐drug consumption ‐recovery times ‐intraoperative recall awareness
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patients were randomized by drawing lots from a closed box
Allocation concealment (selection bias)	Unclear risk	No information regarding concealed randomization
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Due to insufficient regional anaesthesia or EEG data loss, five patients in the entropy group and three patients in each of the BIS and standard practice groups had to be excluded from further investigation
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologists could potentially introduce 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"Propofol was sequentially adjusted according to the predetermined target values of BIS or Entropy (SE) or clinical parameters."
Blinding of outcome assessors?	Unclear risk	No information

Methods	RCT
Participants	Participants country: Saudi Arabia N = 30 ASA: I/II 8/7, 10/5 Morbidity obese: body‐mass index of greater than 35 Gender: male/female 9/6, 11/4 Age: 39± 4.50, 41.21± 5.07 years Exclusion: renal, hepatic or neurological dysfunction or use of benzodiazepines, anticonvulsants, alcohol, opioids or other psychotropic drugs Operation: gastric banding procedures Duration of anaesthesia: 136.6±113.7, 138.9±13.8 minutes
Interventions	1) Sevoflurane administration guided by BIS (BIS A‐2000 software 2.21, Aspect Medical Systems, Newton, and Mass), BIS value of 40‐60 during maintenance (BIS group), Cn = 15 2) Sevoflurane administration guided by signs of inadequate anaesthesia (increased blood pressure of greater than 20%, increased heart rate of greater than 90 beats per minutes and other somatic responses) (CS group), Cn = 15
Outcomes	Sevoflurane used during maintenance (ml/hr) Recovery times (min) ‐time to awakening (opening eyes on verbal command) ‐time to extubation ‐time to Aldrete score of 9
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficiet information regarding withdrawal/dropouts
Selective reporting (reporting bias)	Low risk	All expected outcome reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"Group BIS: the anaesthesiologist had access the monitor.." This indicates no blinding of the anaesthesia care provider
Blinding of outcome assessors?	Low risk	"Blinded study personnel recorded the time ...." This is blinding of outcomes assessors

Methods	RCT
Participants	Country: Egypt N = 60 ASA: I/II/III Gender: male/female 18/11, 20/8 Age: 51.6±7.4 , 52.1±5.2 years Exclusion: a history of any disabling central nervous or cerebrovascular disease, hypersensitivity to opioids, substance abuse, treatment with opioids or any psychoactive medication and a body mass index >40 Operation: elective moderate abdominal surgical procedures Anaesthesia: propofol induction, atracurium, sevoflurane, nitrous in oxygen, fentanyl Duration of anaesthesia: 111.7±14.6, 108.7±10.5 minutes
Interventions	1) Sevoflurane administration guided by BIS (Aspect Medical Systems, model A‐2000,Newton, MA, USA), Maintenance BIS :50‐60, end of surgery BIS 55‐70 2) Sevoflurane or fentanyl administration guided by clinical signs (mean arterial blood pressure > 25 above baseline >25% above baseline or heart rate > 90 beats per minutes) or labetalol based on anaesthesiologist's discretion
Outcomes	‐recovery times ‐anaesthetic drug consumption ‐amount of sevoflurane (ml) ‐end tidal sevoflurane concentration ‐incidence of awareness
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patients were randomly selected and assigned into two groups of 30 patients each
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Three patients were discarded, two from BIS‐b group and one from BIS‐g group
Selective reporting (reporting bias)	Low risk	All expected outcome reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"exhibited hypertension or tachycardia the mode of treatment was dependent on the BIS index"
Blinding of outcome assessors?	Low risk	"...Aldrete score assessment is expressed in Table 6 and performed at 15 min interval by a research assistant blinded to group assignment..."

Methods	RCT
Participants	Country: Germany N = 120 ASA: I/II/III 12/25/3, 12/24/4,13/24/3 Gender: male/female 20/20,20/20,20/20 Age: 43.8±4.2, 46.1±14.5, 44.8±15.9 years Exclusion: disabling, central nervous or cerebrovascular diseases, hypersensitivity to opioid or substance abuse, or treatment with opioids or any psychoactive medication Operation: minor orthopaedic surgery lasted at least 1 hr Duration of anaesthesia: 121.2±40.9; 108.2±44.2 min
Interventions	Target ‐ controlled infusion (TCI) of propofol guided by a BIS monitor (A‐2000, software version 3.2), target BIS value at 50, Cn = 40 Target ‐ controlled infusion (TCI) of propofol guided by a Narcotrend monitor (software version 2.0 AF), target BIS value at 50, Cn = 40 Target ‐ controlled infusion (TCI) of propofol guided by standard clinical signs, Cn = 40
Outcomes	‐Normalized propofol infusion rate (µg/kg/hr) ‐Normalized remifentanil infusion rate (µg/kg/min) ‐Time to open eyes (min, primary outcome) ‐Time to be extubated (min) ‐Time to arrive in PACU (min) ‐Awareness (Cn, %) ‐Number of patients receiving intervention to treat intraoperative hypotension
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	".. patients were randomized by drawing lots from a closed box."
Allocation concealment (selection bias)	Low risk	".. patients were randomized by drawing lots from a closed box."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The study has not mentioned about the withdrawal/dropouts
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to ' learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"..Propofol TCI during maintenance of anaesthesia was continuously adjusted according to a target value of.......50 for BIS.". This indicates no blinding of anaesthesia care providers
Blinding of outcome assessors?	Low risk	"Recovery times and propofol consumption were recorded by a blinded investigator."

Methods	RCT
Participants	Country: Germany N = 120 ASA: I/II/III 7/30/3, 13/23/4, 11/27/2 Gender: male/female 20/20, 20/20, 20/20 Age: 46.5±14.1, 44.7±15.6, 43.6±16.0 years. Exclusion: history of any disabling central nervous or cerebrovascular disease, hypersensitivity to opioids or substance abuse, or a treatment with opioids or any psychoactive medication Operation: minor orthopaedic surgery expected to last at least 1 hour Duration of anaesthesia: 113±57, 122±50, 125±51 min
Interventions	Desflurane administration guided by a BIS monitor (an A‐2000 BIS monitor version XP), a target BIS value of 50 during maintenance and of 60 during last fifteen minutes of surgery, Cn = 40 Desflurane administration guided by a Narcotrend monitor (software version 2.0 AF) at a target value of "D0" during maintenance and of "C1" during last fifteen minutes of surgery, Cn = 40 Desflurane administration guided by standard clinical signs, Cn = 40
Outcomes	Outcomes ‐ desflurane consumption (mg/min) Recovery times: ‐Time to open eyes (min, primary outcome) ‐Time to be extubated (min) ‐Time to arrive in PACU (min)
Notes	.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	".. patients were randomized by drawing lots from a closed box."
Allocation concealment (selection bias)	Low risk	".. patients were randomized by drawing lots from a closed box."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The study has not mentioned about the withdrawal/dropouts
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to ' learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"..desflurane during maintenance of anaesthesia was continuously adjusted according to a target value of.......50 for BIS ". This indicates no blinding of anaesthesia care providers
Blinding of outcome assessors?	Low risk	"Recovery times were recorded by a blinded investigator."

Methods	RCT
Participants	Country: Switzerland N = 160 Sex: female Exclusion:central nervous system disease (i.e. history of cerebrovascular disease or epilepsy) or taking EEG‐affecting drug ans ASA > 3 Operation: gynaecological surgery lasted >15 min Desflurane subgroups ‐ASA: I/II/III 22/15/3, 15/22/3 ‐Gender: female ‐Age: 45.2±17.5, 47.1±17.8 years ‐Duration of anaesthesia: 100.5±58.2; 90.9±53.6 min Propofol subgroup (N = 80) ‐ASA: III/III 21/18/1, 22/16/2 ‐Gender: female ‐Age: 46.3±15.4, 48.7±15.7 years ‐Duration of anaesthesia: 100.5±58.2; 90.9±53.6 min
Interventions	Propofol guided by BIS (Aspect A‐2000‐2000 monitor, BIS version 3.3 , Aspect Medical Systems, Natick, MA), BIS target value between 45 and 55 during surgery, Cn = 40 Propofol using standard clinical guide (haemodynamic and vital signs criteria), Cn = 40 Desflurane guided by BIS (Aspect A‐2000 monitor, BIS version 3.3 , Aspect Medical Systems, Natick, MA), BIS target value between 45 and 55 during surgery, Cn = 40 Desflurane using standard clinical guide (haemodynamic vital signs criteria), Cn = 40
Outcomes	Mean propofol infusion rate (mg/kg/hr) Desflurane usage (age‐adjusted MAC‐hours) ‐Recovery profiles ‐Aldrete score ‐Global clinical impression score ‐Extubation time ‐Duration of PACU stay
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"...the patients were randomized into four groups by drawing lots from sealed envelopes."
Allocation concealment (selection bias)	Low risk	"...the patients were randomized into four groups by drawing lots from sealed envelopes."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information regarding withdrawal or dropouts
Selective reporting (reporting bias)	Low risk	All expected outcome reported
Other bias	Unclear risk	The unblinded anaesthesiologists could potentially lead to 'learning contamination bias'
Blinding of patients?	Low risk	"The patients, the PACU nurses and the nurses on the ward were blinded to the allocation of the patients"
Blinding of anaesthesiologists?	High risk	"In the BIS group, the hypnotic drug concentration... was adjusted to keep the BIS between 45 and 55 during surgery" This indicates no blinding of the anaesthesia care providers
Blinding of outcome assessors?	Low risk	"The patients, the PACU nurses and the nurses on the ward were blinded to the allocation of the patients."

PERMALINK

Bispectral index for improving anaesthetic delivery and postoperative recovery

Yodying Punjasawadwong

Aram Phongchiewboon

Nutchanart Bunchungmongkol

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Monitoring the bispectral index (BIS) to improve anaesthetic delivery and patient recovery from anaesthesia

Summary of findings

Summary of findings for the main comparison.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Figure 1.

Included studies

Table 1.

Table 2.

Excluded studies

Studies awaiting classification

Ongoings studies

Risk of bias in included studies

Figure 2.

Figure 3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Figure 4.

Figure 5.

Effects of interventions

Risk of intraoperative recall awareness

Analysis 1.1.

Analysis 1.2.

Recovery profiles

Analysis 2.1.

Analysis 2.2.

Analysis 2.3.

Analysis 2.4.

Postanaesthetic care unit (PACU) stay

Analysis 2.5.

Time to home readiness (discharge time)

Analysis 2.6.

Requirement of anaesthetics

Analysis 3.1.

Methods	RCT
Participants	Country: USA N = 18836 9460, 9376 Inclusion criteria ‐Age more than 18 yr, ‐Anaesthesia using inhalational or intravenous technique ‐Surgery any surgical case that did not involve the forehead ‐Availability for follow‐up interviews Exclusion criteria ‐intracranial procedures ‐adhesive allergy ‐psychosis, or history of traumatic brain injury
Interventions	1. BIS group: electronic alerts in the event of median BIS values more than 60 2. ETAG group: electronic alerts for median age‐adjusted MAC level of less than 0.5
Outcomes	The incidence of definite intraoperative awareness (using modified intention‐to‐treat analysis)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was performed using a random‐number, computer‐generated block scheme based on even or odd operating room number"
Allocation concealment (selection bias)	Low risk	"...practitioners were not made aware of the randomization scheme or dates for randomization change during the study."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	"Of the 9,460 patients randomized to the BIS intervention and successfully interviewed, 3,384 or 36% did not have BIS data recorded because of technical issues described in Materials and Methods.This population was used for secondary analysis only as a post hoc control group because it had neither intervention;"
Selective reporting (reporting bias)	Low risk	Selective reporting (reporting bias)
Blinding of patients?	Low risk	"Patients, postoperative interviewers, and all case reviewers were blinded to group assignment"
Blinding of anaesthesiologists?	High risk	"Practitioners receiving pages regarding BIS or MAC values were not blinded to group assignment."
Blinding of outcome assessors?	Low risk	"Patients, postoperative interviewers, and all case reviewers were blinded to group assignment"

Methods	RCT
Participants	Country: Japan N = 46 ASA: I/II Gender: Female/male 15/5, 15/4 Age: 33±9, 37±14 years. Exclusion ‐ not mentioned Operation: laparotomy (6;4), laparoscopy (7;3), surgery on extremities (5;5), arthroscopy (1;2), surface (1;1), head and neck (0;3) Duration of anaesthesia: 190±45, 191±57
Interventions	Propofol infusion guided by BIS (A‐1050), target BIS value at 40‐60, Cn =20 Propofol guided by standard clinical signs, Cn =19
Outcomes	‐Propofol infusion rate ‐Total amount of propofol used ‐Recovery profiles ‐Patients with undesirable responses
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information
Allocation concealment (selection bias)	Unclear risk	Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	Insufficient information
Blinding of patients?	Low risk	Patients were anaesthetized
Blinding of anaesthesiologists?	High risk	It was unlikely to blind the anaesthesia provider from the assigned groups
Blinding of outcome assessors?	Unclear risk	Insufficient information

Methods	RCT
Participants	Country: Japan N = 60 (enrolled) ASA: I/II Gender: Male/Female 21/25 Age: 18‐70 yr Operation: not specified Duration of anaesthesia: 284±85; 256±172
Interventions	Sevoflurane guided by BIS (A 1050, version 3.4), BIS value of 40‐60 during maintenance and 60‐75 at the end, Cn = 21 Sevoflurane guided by clinical signs (heart rate and blood pressure), Cn = 25
Outcomes	‐Anaesthetic ‐ sevoflurane consumption (ml‐1) ‐Fentanyl required ‐Vecuronium required ‐Time to open eyes on verbal command ‐Time to extubate ‐Time to discharge from the recovery room
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information
Allocation concealment (selection bias)	Unclear risk	Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	14 subjects were excluded: 11 subjects excluded because surgery was either longer than 6 hrs or shorter than 2 hours, and 3 patients excluded because of mechanical dysfunction of BIS.How these missing data affect on the result is unclear
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to 'learning contamination bias'
Blinding of patients?	Low risk	Patients were anaesthetized
Blinding of anaesthesiologists?	High risk	It was unlikely to blind the anaesthesiologists from the assignment groups because they had to adjust the anaesthetic according to the target BIS values in the BIS group
Blinding of outcome assessors?	Unclear risk	Insufficient information

Methods	RCT
Participants	Country: India N = 40 (enrolled) (20 isoflurane, 20 propofol) Operation: elective off‐pump coronary artery bypass grafting (CABG) Exclusion: Patients with poor ventricular function of lesser than 40%; left ventricular aneurysms; and renal/hepatic dysfunction, requiring extra corporeal circulation; preoperative or intraoperative intraaortic balloon pump, presence of unstable angina, carotid stenosis, cerebrovascular accident; excessive alcohol intake and drug abuse Isoflurane Gender: male/female 9/1, 8/2 Age: 50±6, 50±4 years Weight: 71±5, 71±6 kg Propofol Gender: male/female 8/2, 10/0 Age: 52±7, 47±5 years Weight: 71±6, 71±4 kg
Interventions	BIS‐guided isoflurane administration, target BIS (Zipprep, Aspect Medical System, Natick, MA, USA) value = 50±5); Cn = 10 No BIS‐guided isoflurane anaesthesia, maintaining end tidal isoflurane 1‐2%, Cn=10 BIS‐guided propofol administration, target BIS (Zipprep, Aspect Medical System, Natick, MA, USA) value = 50±5); Cn = 10 No BIS‐guided propofol anaesthesia, propofol 6‐8 mg/kg/hr during sternotomy and 4‐6 mg/kg/hr during maintenance; Cn=10
Outcomes	‐Amount of isoflurane (ml) or propofol (ml) ‐Time to extubation ‐Intraoperative recall awareness
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information regarding the sequence generation process
Allocation concealment (selection bias)	Low risk	"Patients were randomly divided into four groups by a sealed envelope technique.."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information regarding withdrawal/dropouts
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologists could potentially lead to ' learning contamination bias" during administration of the anaesthetics
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	It is unlikely to blind the anaesthesia providers who delivery the anaesthetics
Blinding of outcome assessors?	Unclear risk	insufficient information. The study has not stated clearly whether the intensive care unit research fellow, who was an interviewer, blinded to the group assignment or not

Methods	RCT
Participants	Country: Finland N = 62 ASA :I/II Gender: Female Age: 32±6 Operation: gynaecologic laparoscopy (tubal ligation excluded) Duration of anaesthesia: 59±39; 55±50 min
Interventions	Sevoflurane guided by BIS (Aspect version 3.21), BIS value of 50‐60, Cn = 32 Sevoflurane guided by clinical signs (blood pressure and heart rate), Cn = 30
Outcomes	‐Nausea and vomiting (N/V) in PACU (main outcome) (Cn, %) ‐Anaesthetic exposure (sevoflurane exposure; sevoflurane end tidal concentration, %.h) ‐Number of patients required alfentanil ‐Time to open eyes spontaneously (min) ‐Time to follow command (squeezing hand) (min) ‐Time to be extubated (min) ‐Time to be eligible to discharge/home readiness
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No detailed information regarding adequate sequence generation process
Allocation concealment (selection bias)	Unclear risk	No detailed information regarding allocation concealment
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data Table 6
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Unclear risk	The unblinded anaesthesiologist could lead to 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"In the BIS group, sevoflurane was titrated to maintain a BIS value of 50‐60...." This indicates no blinding of the anaesthesia provider
Blinding of outcome assessors?	Unclear risk	The authors did not mention about the outcome assessors blinding

Methods	RCT
Participants	Country: Italy N = 90 ASA: no information Gender: no information Age: mean 42‐48 years Exclusion: history of neurologic disease, medication affecting central nervous system (CNS) and alcohol and drug abuse Operation: general abdominal surgery >30 min Duration of anaesthesia 74‐102 min
Interventions	1) Sevoflurane and remifentanil administration guided by BIS (Version 3.22) of 40‐60 during maintenance, Cn = 45 2) Anaesthetic administration without BIS information, Cn = 45
Outcomes	‐Direct cost of anaesthesia management (total drug cost/min versus cost of BIS electrodes and monitor) (main outcome) ‐% sevoflurane required (median and range) ‐Remifentanil required, µg/kg/hr) (median and range) ‐Recovery times 1. Time to breath spontaneously (min) 2. Time to be extubated (min) 3. Time to eye opening (min) 4. Time to orientation (min) ‐Cost 1. total drug cost/min 2. Cost of BIS electrodes (EUR/patient) ‐Sevoflurane requirement (median, range)
Notes	Withdrawals ‐ not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information
Allocation concealment (selection bias)	Unclear risk	Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information regarding withdrawal or dropouts of the participants
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologist could probably lead to 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"In group 1 the anaesthetics were given according to the BIS value rate between 40 to 60." This indicates no blinding of the anaesthesia providers
Blinding of outcome assessors?	Low risk	"All recovery parameters were assessed by the same research coordinator not involved in treatment of the patient." This indicates blinding of the outcome assessors

Methods	RCT
Participants	Country: India N = 30, ASA: III or greater Gender: no information Age: 38.25±14.02, 32.08±13.84 Inclusion: undergoing either coronary artery grafting (CAGB) or valve replacement under cardiopulmonary bypass (CP) Exclusion: neurological disorders, poor ventricular function, New York Heart Association grade IV, diabetes mellitus, and impaired renal or hepatic function Operation: coronary artery grafting (CAGB) or valve replacement under cardiopulmonary bypass (CP) Duration of surgery: 295±45, 285±40 minutes
Interventions	Isoflurane administration guided by BIS (Aspect A‐1000, version 3.1) of 45 to 55 Isoflurane administration guided by clinical signs
Outcomes	Number of haemodynamic disturbances: hypertension, tachycardia, hypotension, bradycardia Recovery endpoint ‐ time from switching off anaesthetic vaporizer to opening eyes or response to verbal commands Time to tracheal extubation Awareness*
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"......were randomized into ......using computer‐generated numbers." This indicate adequate sequence generation
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment
Incomplete outcome data (attrition bias) All outcomes	Low risk	From table 1 of the study, it is likely that all patients were included in the analysis
Selective reporting (reporting bias)	Low risk	All expected outcomes are reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"In the study group, the anaesthesiologist was allowed to see and use the monitor.." This indicates no blinding of anaesthesia care providers
Blinding of outcome assessors?	Unclear risk	Insufficient information regarding blinding of outcome assessors

Methods	RCT
Participants	Country: USA N = 90 ASA: NA Gender: Male/Female 21/9, 20/10, 24/6 Age: 47±17,46±15,42±14 Exclusion: history of CNS disease, chronic use of psychoactive medication, and clinical significant cardiovascular, renal, hepatic or endocrinology disorders Operation: laparoscopic general surgery procedures (cholecystectomy, gastric bypass/banding, hernia repair) Duration of anaesthesia: 125±52; 127±38 min
Interventions	Desflurane guided by BIS (BIS TM sensor XP, Aspect Medical Systems, Newton, MA) for maintaining BIS values of 45‐55 Desflurane guided by clinical signs Desflurane guided by auditory evoked potential index (AAI)
Outcomes	‐End tidal concentrations of desflurane (%) (main outcome) ‐Total fentanyl used ‐Total rocuronium used (mg) ‐ Requirement of labetalol (Cn,%) ‐Time to open eyes ‐Time to obey simple verbal commands ‐Time to orientation ‐Time to be extubated ‐Time to achieve White fast‐track score ≥12 ‐Time to achieve Aldrete discharge score of 10 ‐Length of stay in the postanaesthesia care unit (PACU) ‐Patients with recall of intraoperative awareness (Cn, %)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to ' learning information bias'
Blinding of patients?	Low risk	Patients were anaesthetized
Blinding of anaesthesiologists?	High risk	".... , the real time AAI and BIS values were only made available during the procedure to those anaesthesiologists caring for patients in the AEP or BIS‐guided groups,..." This indicates no blinding of anaesthesia care providers
Blinding of outcome assessors?	Low risk	" Emergence times were determined .......by a blinded observer." This indicates blinding of outcome assessors

Methods	RCT
Participants	Country: Saudi Arabia N =40; 20, 20 ASA: not specified Age: mean (SD) 55.3 (10.4), 60.8 (10.2) yr sex: not specified Operation: cardiac revascularization procedure by the off‐pump technique Anaesthesia: intravenous (midazolam, and sufentanil), relaxant (rocuronium), and supplemented sevoflurane Duration: of anaesthesia, mean (SD) min 239.8 (20); 230 (24.5)
Interventions	1. BIS‐guided anaesthetics for maintaining BIS values of 40‐60 2. No BIS monitoring
Outcomes	1. Anaesthetic requirements 2. The need for circulatory support (dosage of phenylephrine) 3. Extubation time 4. Intraoperative recall awareness (Cn, %)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	"Randomization was performed using patient's medical record number, being odds related to group I and evens related to group II"
Allocation concealment (selection bias)	High risk	"Randomization was performed using patient's medical record number, being odds related to group I and evens related to group II"
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing data reported
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	High risk
Blinding of patients?	Low risk	All patients were anaesthetised
Blinding of anaesthesiologists?	High risk	It was not possible to blind the anaesthesiologists
Blinding of outcome assessors?	Low risk	"Postoperatively, patients were visited on the second postoperative day by one of the medical staff about the grouping

Methods	RCT
Participants	Country: USA N = 60 (30 sevoflurane, 30 desflurane) Sex: female Exclusion: neurologic disease, CVS or metabolic diseases, impaired renal or hepatic function, BW > 100% above the ideal or history of alcohol or drug abuse Operation: laparoscopic tubal ligation Desflurane subgroup (treatment, control) ‐ASA: I/II; 10/5, 11/4 ‐Age: 28±4, 27±6 ‐Duration of anaesthesia:76±20;78±22 min Sevoflurane subgroup (treatment, control) ‐ASA: I/II; 11/4, 10/5 ‐Age: 26±6, 26±7 ‐Duration of anaesthesia: 74±21, 75±21 min
Interventions	Desflurane guided by BIS (Rev 3.12U; Model A ‐1050, Aspect Medical Systems, Natick, MA) at value of 60 Desflurane using standard clinical guide Sevoflurane guided by BIS BIS (Rev3.12U; Model A ‐1050, Aspect Medical Systems, Natick, MA) at value of 60 Sevoflurane using standard clinical guide
Outcomes	‐End tidal concentration (%) ‐Exposure to desflurane (MAC. hrs) ‐Consumption of desflurane (ml) ‐Consumption of mivacurium (mg) ‐Consumption of fentanyl (µg) ‐Time to verbal response (min) ‐Time to extubation (min) ‐Time to orientation (min) ‐Time to PACU stay (min) ‐Time to oral intake (min) ‐Time to home readiness (min) ‐Patients with recall awareness ‐Patients with increased airway pressure ‐Patient with coughing and bucking
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	" Patients were randomly assigned to one of four study groups according to a computer‐generated random numbers table."
Allocation concealment (selection bias)	Unclear risk	The study has not mentioned about the allocation concealment
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Unclear risk	The unblinded anaesthesiologist could potentially lead to 'learning contamination bias'
Blinding of patients?	Low risk	All patients were anaesthetized
Blinding of anaesthesiologists?	High risk	"In the BIS‐titrated groups, the volatile anaesthetics were titrated to maintain a BIS index of 60." This indicates no blinding of anaesthesia care providers
Blinding of outcome assessors?	Unclear risk	The study has not mentioned about outcome assessor blinding