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Base de datos Cochrane de Revisiones Sistemáticas Protocolo - Intervención

Paravertebral anaesthesia with or without sedation versus general anaesthesia for women undergoing breast cancer surgery

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Versión publicada: 24 febrero 2018 Historial de versiones

https://doi.org/10.1002/14651858.CD012968

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of paravertebral block with or without sedation compared to general anaesthesia in women undergoing breast cancer surgery.

Background

Description of the condition

According to worldwide public health data, breast cancer is one of the most common cancers among women. Over one million women are diagnosed with the disease globally per year (Ban 2014; Coughlin 2009; Ferlay 2015; Youlden 2012). Prior to the global surveys of cancer, breast cancer was considered to be a disease of high‐income countries, however since then the incidence has increased in low‐ and middle‐income countries (Ferlay 2015).

Women living in low‐ and middle‐income countries have a higher mortality than those living in high‐income countries (Ferlay 2015). This is because they reach hospital at later stages of the disease due to the lack of facilities for screening and early diagnosis (Coughlin 2009;Ferlay 2015; Youlden 2012). Cancer that has spread to distant organs of the body (i.e. metastases) is the main cause of death in women with breast cancer (Weigelt 2005).

Surgery is the mainstay of breast cancer treatment (Niwa 2013;Sessler 2008). However, despite the apparent complete surgical removal of a tumour, some residual disease may remain. Handling of the tumour during surgery may release cancer cells into the circulation, which results in cancer spreading to other parts of the body (Coffey 2003). The suppression of a woman's immune system during surgery and under general anaesthesia may also contribute to cancer spreading and recurrence at a later date (Coffey 2003; Niwa 2013;Sessler 2008;Tedore 2015).

Description of the intervention

Paravertebral block is a regional anaesthesia technique. It involves injecting local anaesthetic into the space alongside the vertebral column (i.e. paravertebral space) where the spinal nerves emerge from the intervertebral foramina (Karmakar 2001; Richardson 1998). A paravertebral block results in a sympathetic and sensory nerve block only on the side where the local anaesthetic is deposited. This technique can be performed as a single injection or multiple injections. In either case, as the block is only on the side where the anaesthetic is injected (i.e. unilateral), it may produce minimal physiological changes in haemodynamic and respiratory variables, and temperature changes (Karmakar 2001; Richardson 1998).

A single injection paravertebral block as an adjunct to general anaesthesia has been used to provide pain relief (Boughey 2009; Kairaluoma 2004; Moller 2007). The number of nerve segments blocked by a single injection can vary and depends on the volume of local anaesthetic injected. On average, eight sympathetic and five sensory nerve segments are estimated to be blocked with 15 mL of local anaesthetic (Cheema 1995). Only one study has used a single paravertebral injection at the fourth thoracic level to provide surgical anaesthesia for breast surgery (Pusch 1999).

In contrast, multiple (multi‐level) paravertebral block involves injecting 3 mL to 5 mL of local anaesthetic at each level from the first to the sixth thoracic paravertebral space; this can provide reliable surgical anaesthesia (Abdallah 2014; Dabbagh 2007; Greengrass 1996; Naja 2003; Weltz 1995; Wu 2015), and excellent perioperative analgesia following breast surgery (Wu 2015). Multiple or single injection paravertebral block may discourage the perioperative use of long‐acting opioids such as morphine that promote angiogenesis (i.e. the growth of new blood vessels) and survival of circulating tumour cells (Ecimovic 2011; Kairaluoma 2004; Moller 2007; Wu 2015).

Therefore, paravertebral block with or without sedation can be used as a stand‐alone technique to provide anaesthesia for breast surgery without the need for administering general anaesthesia (Abdallah 2014; Dabbagh 2007; Greengrass 1996; Naja 2003; Pusch 1999; Weltz 1995; Wu 2015).

How the intervention might work

General anaesthesia for breast cancer surgery can be provided using inhaled anaesthetic drugs or intravenous infusion of propofol [(propofol‐based total intravenous anaesthesia (TIVA)] (Tedore 2015; Vaghari 2014). Regardless of whether an inhalational or intravenous technique is used, opioid medication is used for providing pain relief unless a local anaesthetic block is administered. The use of inhaled anaesthetic drugs and opioids, such as morphine, is the more common method of providing general anaesthesia for women undergoing breast cancer surgery as compared to propofol‐based TIVA (Tedore 2015; Vaghari 2014).

Retrospective reviews and in vitro studies have shown that inhaled anaesthetic drugs and opioids suppress the body’s immune response and therefore may promote tumour spread and recurrence following surgery (Buckley 2014; Deegan 2009; Deegan 2010; Ecimovic 2011; Ecimovic 2013; Exadaktylos 2006; Jaura 2014). In contrast, retrospective evidence indicates that intravenous propofol‐based TIVA may have a protective effect against tumour spread (Gottschalk 2010; Vaghari 2014). Irrespective of the general anaesthesia technique used (inhalational or intravenous), the body responds to the pain and trauma of surgery by releasing hormones and mediators that suppress the body's immunity (surgical stress response) (Gottschalk 2010; Tedore 2015; Vaghari 2014).

Regional anaesthesia techniques produce a dense sensory block that is more effective in blunting this surgical stress response than general anaesthesia using opioids (Cata 2011; Tedore 2015). Paravertebral block has been shown to obtund the stress response to surgery (O'Riain 2005). In addition, factors such as perioperative hypothermia, hypoglycaemia, nausea‐ vomiting following surgery and the resulting delayed oral intake that can contribute to immunosuppression are more likely to occur in unconscious patients under general anaesthesia than in lightly sedated patients under regional anaesthesia who can communicate and maintain patent airway without the need for supralaryngeal airway devices (Gottschalk 2010; Tedore 2015; Vaghari 2014).

The use of regional anaesthesia could result in better‐preserved immune functions and lymphocyte (white blood cell) activity with a reduced chance of tumour spread and recurrence than that observed in women undergoing surgery under general anaesthesia (O'Riain 2005;Wu 2015). Local anaesthetic drugs used during the regional anaesthesia have also been shown to cause direct inhibition of tumour cell multiplication and migration, and increased tumour cell breakdown (Cassinello 2015; Ramirez 2015;Votta‐Velis 2015). Surgery under paravertebral anaesthesia (with or without sedation) could result in awake, pain‐free, comfortable patients with normal body temperature and minimal postoperative nausea and vomiting. Some studies have shown that paravertebral anaesthesia is likely to result in a better quality of recovery (Abdallah 2014; Buckenmaier 2010), better quality of life (Karmakar 2014), and decreased chronic pain (at six months; Chiu 2014).

An ongoing multicentre trial is investigating whether the use of regional anaesthesia (paravertebral or epidural) for breast cancer surgery results in reduced mortality compared to general anaesthesia (Sessler 2008).

Why it is important to do this review

Several systematic reviews have assessed the use of paravertebral block during surgery, but these reviews have included mixed populations (i.e. not specifically in women with breast cancer) and included non‐randomized, retrospective, and case series studies (Schnabel 2010; Tahiri 2011; Wu 2015). These reviews have included studies that compared paravertebral block and general anaesthesia to conventional general anaesthesia alone (Schnabel 2010; Tahiri 2011; Wu 2015).

This Cochrane Review will assess whether the use of paravertebral block as the main anaesthetic technique with or without sedation improves quality of recovery in the initial postoperative period (one to three days), and decreases acute pain (first postoperative day) and chronic pain (three to 12 months). It will also assess whether paravertebral anaesthesia compared to general anaesthesia is associated with improved quality of life (one to two weeks, and three to 12 months) as well‐improved disease‐free survival in women undergoing breast cancer surgery.

Objectives

To assess the effects of paravertebral block with or without sedation compared to general anaesthesia in women undergoing breast cancer surgery.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) that examine paravertebral anaesthesia with or without sedation compared to general anaesthesia for breast cancer surgery.

Types of participants

We will include women (over 18 years of age) with early or locally advanced breast cancer scheduled for breast cancer surgery irrespective of whether or not they received chemotherapy in the past.

Types of interventions

Intervention

Paravertebral anaesthesia with or without sedation.

Comparator

General anaesthesia (including opioids, and inhaled anaesthetic drugs or propofol‐based TIVA).

We will include studies that use truncal regional anaesthesia blocks in addition to the paravertebral block.

We will exclude studies where the paravertebral block is used as an adjunct to general anaesthesia and compared to general anaesthesia alone.

Types of outcome measures

Primary outcomes

  • Quality of recovery during the initial postoperative period (one to three days) using validated questionnaires.

  • Postoperative pain at rest on the first postoperative day using either a visual analogue scale (VAS) with a range of 0 to 10, or 0 to 100, or a numerical rating scale (NRS) with a similar range.

  • Postoperative pain on movement on the first postoperative day using either a VAS with a range of 0 to 10, or 0 to 100, or a NRS with a similar range.

  • Mortality related to the anaesthetic technique, if any.

Secondary outcomes

  • Adverse events due to the paravertebral block (i.e. hypotension, bilateral block, pneumothorax, Horner's syndrome, bleeding, neurological deficit).

  • Disease‐free survival (often defined as time to first detection of local recurrence or distant metastasis, or progression‐free survival, time to progression, or time to treatment failure).

  • Chronic pain that persists beyond the immediate postoperative period i.e. at three to 12 months.

  • Quality of life at one to two weeks and three to 12 months postoperatively using a validated questionnaire.

Search methods for identification of studies

Electronic searches

We will search the following databases.

Searching other resources

Bibliographic searching

We will screen the reference lists of identified relevant trials or reviews. We will obtain a copy of the full article for each reference reporting a potentially eligible trial. Where this is not possible, we will attempt to contact study authors to provide additional information.

Data collection and analysis

Selection of studies

Two review authors (AC and AS) will independently screen all titles and abstracts for eligibility. We will obtain and assess the full articles of all potentially eligible RCTs for relevance based on the pre‐specified inclusion criteria. Each review author will independently document the reason for excluding a study. We will resolve any disagreement by discussion with a third review author (HP), who will decide on the inclusion or exclusion of the study. We will compile a list of all eligible studies and will record the study selection process in the PRISMA flow diagram. If further information is required to make a decision about trial inclusion, AC will contact the authors of the relevant trial.

We will not impose any language restrictions and will include all peer‐reviewed journals. We will obtain the articles and request translation through Cochrane TaskExchange or through our network.

We will record studies that are excluded from the review in the 'Characteristics of excluded studies' table.

Data extraction and management

Two review authors (AC and RS) will independently extract the data into a standard data extraction form. We will resolve any disagreements through consultation with a third author (HP). In the case of additional information being required, AC will contact the first author of the relevant trial.

For studies with more than one publication, the data will be extracted from all of the publications and records relating to the same study will be combined under the overall trial ID.

Assessment of risk of bias in included studies

We will minimise selection bias by including RCTs.

We will use the recommended Cochrane ʻRisk of bias' tool to assess risk of bias in the following domains (Higgins 2011).

  • Random sequence generation (selection bias).

  • Concealment of the allocated sequence (selection bias).

  • Blinding of participants and personnel (performance bias).

  • Blinding of outcome assessment (detection bias).

  • Incomplete outcome data (attrition bias).

  • Selective outcome reporting (reporting bias).

  • Other potential sources of bias, which we will assess by comparing groups at baseline with respect to staging of disease and if there was any difference in treatment administered except for the intervention.

After reviewing the methodology used, we will decide whether the risk of bias for a particular domain is ‘high’, ‘low’, or ‘unclear’ (insufficient data available to decide whether risk of bias exists). This would be done only after we contact the study authors to obtain additional information. Two review authors (AC and MKA) will assess the risk of bias. In the case of any conflict of opinion, we will resolve disagreements through consultation with a third review author (HP).

We will note the financial or logistical support of each included study.

Measures of treatment effect

For continuous data, such as difference in quality of recovery scores (at one to three days), acute postoperative pain scales on the first postoperative day and quality of life (at one to two weeks, and three to 12 months postoperatively), we will calculate the mean difference (MD; if data are on the same scale) or the standardised mean differences (SMD; if data are on different scales).

For dichotomous outcomes (where only either one of two outcomes is possible such as adverse events (hypotension, bilateral block, pneumothorax, Horner's syndrome, bleeding) or no adverse events; chronic pain at three to 12 months or no chronic pain, we will calculate the risk ratio (RR) and 95% confidence interval from a fixed‐effect or random‐effects model analysis depending on the presence of heterogeneity. We will report the ratios of treatment effects for response so that RRs less than 1.0 favour the paravertebral group and RRs greater than 1.0 favour the general anaesthesia group.

For time‐to‐event outcomes, such as mortality related to the anaesthetic technique and disease‐free survival, we will express results as hazard ratios (HRs). If we cannot obtain the HR and associated variance directly from the trial publication, we will obtain the data indirectly using methods described by Parmar 1998 or extracted from published Kaplan‐Meier curves.

Unit of analysis issues

We will include RCTs with a parallel group design.

Dealing with missing data

We will perform quantitative analysis on an intention‐to‐treat (ITT) basis and contact the trial authors in order to obtain any missing data. We will analyse missing data, if any, by imputation using a best‐case and worst‐case scenario method. However, some studies exclude a small number of patients who were randomized but did not start their allocated treatment (often referred to as modified ITT (mITT) analysis). We will include mITT results if ITT results are not available. We will discuss the impact of missing data and imputation methods in the 'Discussion' section of the review.

We will perform sensitivity analysis to explore the consistency of effect size measures in trials with low risk of bias versus high risk of bias, and to investigate the impact of any missing data using the imputation method described above.

Assessment of heterogeneity

We will use the Q statistic (Cochran 1954) to test the statistical heterogeneity between trials and consider P ≤ 0.05% as indicating significant heterogeneity. We will use the I2 statistic to assess the magnitude of heterogeneity (Higgins 2003) with interpretation of I2 statistic as follows.

  • 0% to 40%: might not be important.

  • 30% to 60%: may represent moderate heterogeneity.

  • 50% to 90%: may represent substantial heterogeneity.

  • 75% to 100%: considerable heterogeneity.

We will use a random‐effects model analysis if the I2 statistic value is greater than 50% (Higgins 2011).

We will use unadjusted effect estimates for the meta‐analysis of RCTs.

Assessment of reporting biases

A funnel plot will be constructed to evaluate the degree of publication or reporting bias. We will test for funnel plot asymmetry using weighted linear regression of effect estimates on their standard errors if more than 10 trials are included (Egger 1997).

Data synthesis

We will quantitatively review the included data and combine the data by intervention, outcome, and population if appropriate using Review Manager 5 (RevMan 5) (RevMan 2014).

For dichotomous outcomes, we will express pooled estimates as RRs and use a fixed‐effect model in the absence of significant statistical heterogeneity (I2 statistic value is less than 50%) (Mantel 1959). In the case of significant heterogeneity, we will use the random‐effects analysis (DerSimonian 1986).

For continuous outcomes, we will express pooled estimates of the MD and use a fixed‐effect analysis (i.e. inverse‐variance method) in the absence of significant statistical heterogeneity (I2 statistic value is less than 50%). In the case of heterogeneity we will use a random‐effects analysis (i.e. inverse variance method with the variance including the between study variation).

For time‐to‐event outcomes, such as mortality and disease‐free survival, we will use the HR and generic inverse variance depending on the data available (Parmar 1998).

ʻSummary of findings' table

Two review authors (AC and HP) will use the principles of the GRADE system to assess the overall quality of the evidence associated with specific outcomes (Schünemann 2011; Guyatt 2011).

We will construct a ʻSummary of findings' table using GRADEpro GDT software (GRADEpro GDT 2015). The GRADE approach appraises the quality of a body of evidence for each outcome based on five domains: (1) risk of bias of the included studies (methodological quality), (2) inconsistency (i.e. heterogeneity), (3) indirectness (relevance to the review question), (4) imprecision (i.e. confidence intervals), and (5) risk of publication bias.

We will list the following main outcomes in the ʻSummary of findings' table and will assess the quality of the evidence.

  • Quality of recovery at one to three days postoperatively using a validated questionnaire.

  • Postoperative pain at rest on the first postoperative day using either a VAS with a range of 0 to 10, or 0 to 100, or a NRS with a similar range.

  • Mortality related to the anaesthetic technique, if any.

  • Adverse events due to the paravertebral block (hypotension, bilateral block, pneumothorax, Horner’s syndrome, bleeding, neurological deficit).

  • Disease‐free survival.

  • Quality of life at one to two weeks and three to 12 months postoperatively using a validated questionnaire.

Subgroup analysis and investigation of heterogeneity

We will conduct subgroup analysis to assess the effect of the following.

  • Breast tumour receptor status on clinical outcome, specifically, disease‐free survival.

  • Primary surgery as compared to surgery following chemotherapy on clinical outcomes viz. quality of recovery at one to three days, disease‐free survival (often defined as time to first detection of local recurrence or distant metastasis or progression‐free survival, time to progression, or time to treatment failure) and quality of life at one to two weeks and at four to eight months.

Sensitivity analysis

We will perform sensitivity analyses to explore the consistency of effect size measures in trials with low risk of bias versus high risk of bias. We will consider studies that are at high or unclear risk of bias in three or more domains to be at high risk of bias. We will interpret absence of blinding in outcome assessment, such as incidence of mortality from medical records, as low risk of bias; however, absence of blinding in patient‐reported outcomes will be taken as high risk of bias.