Introduction

General anesthesia is defined as "a drug-induced reversible depression of the central nervous system resulting in the loss of response to, and perception of, all external stimuli".1^(p.108) Crowder et al. further describe "unconsciousness, amnesia, analgesia, immobility, and attenuation of autonomic responses to noxious stimulation" as characteristics of the anesthetic state.1^(p.108) The anesthetic state can be achieved through the use of intravenous or inhalational anesthetic agents. Punjasawadwong et al. posit that many anesthesia providers rely on somatic signs (e.g. motor responses, changes in respiratory pattern) and autonomic signs (e.g. tachycardia, hypertension, lacrimation, sweating) to guide anesthetic dosing.2 Not only are these clinical signs unreliable measures of the conscious state of anesthetized patients, but the utilization of these signs to adjust dosing of anesthetic agents can lead to either underdosage or overdosage of anesthetic medications.2

The bispectral index (BIS) monitor is the first quantitative electroencephalography (EEG) index used in clinical practice.3 The purpose of this device is to quantitatively measure the depth of general anesthesia. Based on the evidence from numerous clinical trials, the United States (US) Food and Drug Administration approved the use of BIS monitoring in 1996 by practitioners to assess the effectiveness of general anesthetics and sedatives in achieving adequate anesthetic depth. The BIS value can range from 0-100, with 0 indicating no detectable brain activity and 100 reflecting a fully awake state.2 During general anesthesia, maintaining a BIS value of 45-60 is the standard depth expected to provide adequate hypnotic effect without the risk for patient memory/recall of events that occurred during surgery.2,4 Deep general anesthesia, as measured by BIS technology, is defined as values of less than 45.5-8 In addition to BIS, another validated method used to quantifiably measure depth of anesthesia via EEG is that of spectral edge frequency (SEF);9 an SEF value of 8-12 Hz shows deep general anesthesia.10

Acute postoperative pain is a common physiological side effect of surgery that should be alleviated as soon as possible to reduce suffering, promote the healing process and rehabilitation, and prevent complications.11 Acute postoperative pain is most commonly defined as pain occurring 0-48 hours following a surgical procedure.5-9,12 Fear of postoperative pain is one of the primary concerns among surgical patients. More than 80% of patients who undergo surgical procedures experience acute postoperative pain, and approximately 75% of those with postoperative pain report the severity as moderate, severe or extreme.13

Inadequate pain management can have serious implications.14 Delays in patient mobility, increases in the duration of hospitalization and interference with rehabilitation are just a few complications of inadequate postoperative pain control.5 These complications have both economic and medical implications that must be considered. The economic burden of treating chronic pain that develops from acute pain in a 30-year-old individual over a lifetime is estimated to be as much as $1 million USD.15 Pain prevention and effective pain treatment may improve clinical outcomes, avoid clinical complications, save healthcare resources and improve quality of life.15

To accurately quantify and treat the subjective clinical condition of a patient's level of pain, scoring systems were developed. The visual analogue scale (VAS) was created in 1923 and has been used in healthcare settings during the time period of this review.16 The VAS allows patients to score their pain by using a straight line continuum that defines extremes of pain on each end with an associated numeric value.17 The patient is asked to rate their level of pain between the two extremes: 0 being no pain and 10 being the worst pain imaginable. A second tool often used to quantify pain is the verbal rating scale (VRS). Like the VAS, the VRS uses two endpoints such as "no pain" to "extremely intense pain"; however, the VRS also incorporates adjectives to further describe different levels of pain between the endpoints (i.e. mild, moderate and severe). Both of these tools have been shown to correlate strongly with other pain assessment tools, and when compared to other assessments, patient compliance may be better.17 In clinical practice, pain scoring systems are commonly designed to incorporate both the VAS and VRS.

To date, opioid therapy has been considered a foundation of modern perioperative pain management.18 Patients in the US consume a staggering 80% of the global supply of opioids.19 Due to misuse and their addictive properties, more than 115 people die each day in the US as a result of opioid overdose.20 In 2016, opioid overdoses accounted for more than 42,000 deaths, exceeding any previous year on record; an estimated 40% of these opioid overdose deaths involved a prescription opioid.21 While researchers continue to investigate multi-modal non-opioid drug therapies and alternative strategies to attenuate the human physiologic response to pain, some existing studies suggest that deepening general anesthesia for surgical patients may decrease acute postoperative pain.5-7 Such evidence could lead to practice change; anesthesia providers and patients may benefit from decreased postoperative pain scores, increased patient satisfaction and a decreased need for and exposure to opioids in the perioperative period.

A preliminary search of Ovid MEDLINE, CINAHL, PROSPERO, the Cochrane Database of Systematic Reviews, and JBI Database of Systematic Reviews and Implementation Reports was conducted using the keywords anesthesia, bispectral index monitor, consciousness monitor and postoperative pain. No systematic reviews were identified regarding the effect of general anesthesia depth on acute postoperative pain. This preliminary search yielded four individual studies conducted on adult surgical patients, which assessed the effect of intraoperative depth of anesthesia on postoperative pain. Three of these studies demonstrated a reduction in acute postoperative pain, as well as a reduction in opioid consumption.5-6,8 The fourth study, a randomized controlled trial conducted by Law et al.,7 failed to find a statistically significant difference in pain scores between groups on differing depths of anesthesia.

Evidence-based clinical practice recommendations are needed to reduce the use of opioids in the treatment of acute postoperative pain. The objective of this systematic review therefore is to synthesize the best available evidence related to the effect of the depth of general anesthesia on acute postoperative pain in adult patients.

Review question

What is the effect of deep general anesthesia compared to standard depth of general anesthesia on acute postoperative pain and patient safety in adult surgical patients?

Inclusion criteria

Participants

This review will consider studies that include adult patients who are18 years or over and undergoing elective surgical procedures under general anesthesia. General anesthesia will refer to both a total intravenous anesthetic approach (TIVA), as well as the use of inhalational agents. Patients receiving regional anesthesia techniques, including neuraxial anesthesia or peripheral nerve blocks, will be excluded, as these techniques may affect acute postoperative pain scores. Given differences in general anesthetic dosing requirements for children, as compared to adults, only studies including adult patients will be included in this review. Studies on both adults and children will be included if the results for adults are disaggregated and available separately. In such studies, only the data and/or results related to adult patients will be included in this review.

Intervention

This review will consider studies that incorporate the intervention of deep general anesthesia (BIS values of 45 or less), with anesthetic depth measured using a valid and reliable quantitative EEG index monitor (i.e. BIS Monitor, Medtronic/Covidien, US; SEDline monitor, Masimo Medical, US; GE Datex-Ohmeda Entropy, GE Healthcare, US).

Comparator

This review will consider studies that compare the intervention to the standard depth of general anesthesia (BIS values 45-60), with anesthetic depth measured using a valid and reliable quantitative EEG index monitor.

Outcomes

This review will consider studies that include acute postoperative pain scores (within the first 48 hours) as a primary outcome variable. This outcome will be measured using the VAS or VRS pain scoring tool. A secondary outcome of interest is the reported measures of opioid consumption in the first 48 hours postoperatively, including morphine-equivalents (i.e. amount of any opioid consumed by a patient reported in terms of the equivalent amount of morphine). Adverse outcomes reported in any study that meets inclusion criteria, including postoperative nausea or vomiting, delayed emergence from anesthesia, or postoperative cognitive dysfunction, will also be included as secondary outcomes. Postoperative nausea or vomiting is generally reported as an incidence (i.e. raw number or percentage in each comparison group). Delayed emergence results involve a comparison of the number of minutes required for patients in each group to regain consciousness. Assessment of postoperative cognitive dysfunction involves both pre- and postoperative psychometric testing.

Types of studies

This review will consider both experimental and quasi-experimental study designs including randomized controlled trials, non-randomized controlled trials, before and after studies and interrupted time-series studies. In addition, analytical observational studies including prospective and retrospective cohort studies, case-control studies and analytical cross-sectional studies will be considered for inclusion. This review will also consider descriptive observational study designs including case series, individual case reports and descriptive cross-sectional studies for inclusion. Studies published in English will be included. Studies published from 1992 to the present will be included, as this time period correlates with the advent of BIS EEG monitoring technology in anesthesia practice.4

Methods

This systematic review will be conducted in accordance with JBI methodology for systematic reviews of effectiveness evidence.22,23

Search strategy

The search strategy will aim to find both published and unpublished literature. Based on JBI methodology for systematic reviews, a three-step search strategy will be used for this review.22,23 An initial limited search of Ovid MEDLINE, and CINAHL has been undertaken followed by the analysis of text words contained in the title and abstract, and of the index terms used to describe the article. A full secondary search will be performed across all included databases, using the keywords and index terms identified from the initial limited search. A full search strategy for Ovid MEDLINE is included in Appendix I. To help identify any additional studies, a tertiary literature search will be performed by examining the reference lists of all studies included in the review.

Information sources

The databases to be searched include: Ovid MEDLINE, Embase, and CINAHL. Sources of unpublished studies and gray literature to be searched include: OpenGrey (gray literature database from Europe), Networked Digital Library of Theses and Dissertations (NDLTD), Google Scholar, and ClinicalTrials.gov.

Study selection

Following the search, all identified citations will be collated and uploaded into RefWorks (ProQuest, LLC, Ann Arbor, USA) and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. Potentially relevant studies will be retrieved in full and their citation details imported into the JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; Joanna Briggs Institute, Adelaide, Australia). The full text of selected citations will be retrieved and assessed in detail against the inclusion criteria by two independent reviewers. Full-text studies that do not meet inclusion criteria will be excluded, and reasons for exclusion will be recorded and reported in an appendix in the final systematic review report. Any disagreements that arise between the reviewers at each stage of the study selection process will be resolved through discussion or with a third reviewer. The results of the search will be reported in full in the final report and presented in a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram.24

Assessment of methodological quality

Eligible studies will be critically appraised by two independent reviewers for methodological quality using standardized critical appraisal instruments from JBI;23 the appraisal instrument used will be based on the type of study to be appraised. Authors of papers will be contacted to request missing or additional data for clarification, where required. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. The results of critical appraisal will be reported in narrative form and in a table. Following critical appraisal, studies that do not meet an established quality threshold (70% of quality indicators answered in the affirmative) will be excluded. This decision will be based on the reviewers' overall assessment of quality and risk of bias.

Data extraction

Data will be extracted from studies included in the review by two independent reviewers using the standardized data extraction tool available in JBI SUMARI. The data extracted will include specific details about the population, study methods, interventions, and outcomes of significance to the review question. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. Authors of papers will be contacted to request missing or additional data, where required.

Data synthesis

Studies will, where possible, be pooled with statistical meta-analysis using JBI SUMARI. Effect sizes will be expressed as either odds ratios (for dichotomous data) and weighted (or standardized) final post-intervention mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-squared and I-squared tests. Tufanaru et al.22 will guide the reviewers' choice of model (random or fixed effects) and method for meta-analysis. Subgroup analysis will be conducted where there is sufficient data to investigate differences between groups (standard versus deep general anesthesia) in acute postoperative pain scores, opioid consumption, postoperative nausea or vomiting, delayed emergence, postoperative cognitive dysfunction, or other reported adverse outcome.

Sensitivity analyses will be conducted to test decisions made regarding whether confounding variables contributed to the effect. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. A funnel plot will be generated to assess publication bias if there are 10 or more studies included in a meta-analysis. Statistical tests for funnel plot asymmetry (Egger test, Begg test, Harbord test) will be performed, where appropriate.

Assessing certainty in the findings

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the certainty of evidence will be followed and a Summary of Findings (SoF) will be created using GRADEpro software (McMaster University, ON, Canada). The SoF will present the following information where appropriate: absolute risks for treatment and control; estimates of relative risk; and a ranking of the quality of the evidence based on the risk of bias, directness, heterogeneity, precision, and risk of publication bias of the review results. The outcomes reported in the SoF will be: acute postoperative pain scores, opioid consumption in the acute postoperative period, and the incidence of adverse outcomes of interest (postoperative nausea or vomiting, delayed emergence from anesthesia, postoperative cognitive dysfunction, or other reported adverse outcome).

Acknowledgments

This systematic review has been developed as part of the requirements toward completion of a doctoral degree in nurse anesthesia for authors HF and EA.

Appendix I: Search strategy for MEDLINE (Ovid)

Search conducted: 25 March 2019

References