Efficacy and safety of paravertebral blocks in breast surgery: a meta-analysis of randomized controlled trials

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1 British Journal of Anaesthesia 105 (6): (2010) Advance Access publication 14 October doi: /bja/aeq265 REGIONAL ANAESTHESIA Efficacy and safety of paravertebral blocks in breast surgery: a meta-analysis of randomized controlled trials A. Schnabel 1 *, S. U. Reichl 1, P. Kranke 2, E. M. Pogatzki-Zahn 1 and P. K. Zahn 1 1 Department of Anaesthesiology and Intensive Care, University Hospital of Münster, Albert-Schweitzer-Str. 33, Münster, Germany 2 Department of Anaesthesiology and Intensive Care, University Hospital of Würzburg, Oberdürrbacher Straße 6, Würzburg, Germany * Corresponding author. alexander_schnabel@gmx.de Key points This meta-analysis found evidence on the efficacy and safety of paravertebral block (PVB) to provide anaesthesia and postoperative analgesia during breast surgery. PVB in addition to general anaesthesia or alone provide a better postoperative pain control with little adverse effects compared with other analgesic treatment strategies during breast surgery. PVB is a feasible and effective method for an improved postoperative pain treatment after breast surgery. Background. Thoracic paravertebral blocks (PVBs) are successfully performed for pain management after breast surgery. The aim of the present quantitative systematic review was to assess the efficacy and adverse events of PVB in women undergoing breast surgery. Methods. The systematic search, data extraction, critical appraisal, and pooled analysis were performed according to the PRISMA statement. The relative risk (RR), mean difference (MD), and their corresponding 95% confidence intervals (CIs) were calculated using the RevMan w statistical software for dichotomous and continuous outcomes, respectively. Pain scores were converted to a scale ranging from 0 (no pain) to 10 (worst pain). Results. Fifteen randomized controlled trials (published between 1999 and 2009) including 877 patients met the inclusion criteria. There was a significant difference in worst postoperative pain scores between PVB and general anaesthesia (GA) at,2 h (MD: 22.68; 95% CI: to 22.02; P, ), 2 24 h (MD: 22.34; 95% CI: to 21.12; P, ), and h (MD: 21.75; 95% CI: to 0.31; P¼0.02). Accordingly, lower pain scores were observed for combined PVB with GA compared with GA alone for,2 h (MD: 21.87; 95% CI: to 21.21; P, ), 2 24 h (MD: 22.21; 95% CI: to 21.35; P, ), and h (MD: 21.80; 95% CI: to 0.68; P¼0.002). The RR for the reported adverse events (e.g. pneumothorax) was low. Conclusions. There is considerable evidence that PVB in addition to GA or alone provide a better postoperative pain control with little adverse effects compared with other analgesic treatment strategies. Keywords: breast surgery; paravertebral block; postoperative pain Accepted for publication: 9 August 2010 According to the European network of cancer registries, breast cancer is still the most common cancer among women, and most of these women require breast surgery to remove the primary tumour and axillary staging or dissection. 1 2 About 40% of these patients experience clinically meaningful acute postoperative pain, indicating that similar to other surgical interventions postoperative pain treatment is not sufficient. 3 Furthermore, acute postoperative pain is an important risk factor for the development of persistent chronic postoperative pain in women after breast surgery. 3 5 Chronic postoperative pain occurs in almost 50% of patients after breast surgery. 5 Owing to earlier diagnosis and better therapy protocols, there will be an increasing number of breast cancer survivors in Europe within the next few years 1 and chronic postoperative pain significantly impaired quality of life in more than 25% of patients after chemotherapy and surgery. 6 Thus, a more effective postoperative pain treatment of patients after breast cancer surgery is necessary. A recently published narrative review pointed out that paravertebral block (PVB) can be considered a well established option to provide anaesthesia and postoperative analgesia during breast surgery. 7 In the literature, thoracic PVBs are described as technically easy to learn with a high success rate and a relatively low rate of serious complications like pneumothorax (0.5%) The first studies investigating PVB in breast surgery, respectively, and thoracic surgery have been published in 1995 and a systematic review comparing postoperative analgesia provided by PVB or wound infiltration showed better analgesic effects of PVB in breast surgery. 12 Despite the growing number of published trials with small number of patients focused on acute and & The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oxfordjournal.org

2 Paravertebral blocks in breast surgery BJA chronic postoperative pain treatment, a quantitative systematic review of randomized controlled trial without any language restriction providing comprehensive up-to-date evidence in a bigger population is lacking so far. It was the aim of this quantitative systematic review to assess the efficacy and safety of PVB in comparison with other analgesic and anaesthetic regimes in women undergoing breast surgery. Methods This quantitative systematic review was performed according to the criteria of the PRISMA statement. 13 Search strategy The systematic search was conducted in the Central register of controlled trials of the Cochrane Library (to present), MEDLINE (1966 to present), and EMBASE (1980 to present) according to the current recommendations of the Cochrane Collaboration. 14 The search strategy consisted of a combination of free text words and MeSH terms: paravertebral and breast surgery. There were no restrictions concerning the language of the article or publication type. Reference lists of retrieved articles were checked again for relevant publications. Research groups working on the covered topic were contacted to retrieve information about ongoing trials. Selection of included studies Three authors (A.S., S.R., and P.K.) scanned the articles retrieved by the initial search to exclude obvious irrelevant studies. Study eligibility was determined by reading the title and abstracts and obviously irrelevant trials were excluded at this stage. Inclusion and exclusion criteria were established a priori. Inclusion and exclusion criteria All randomized controlled trials investigating the efficacy and safety of PVB compared with sham or any other analgesic modality as control in women undergoing breast surgery were included in this review. The data of all participants irrespective of their age and type of breast surgery were considered. Data extraction Two authors (A.S. and S.R.) read the full-text articles and they independently decided whether the retrieved trials met the inclusion criteria or not. Two authors (A.S. and S.R.) performed the data extraction using special standardized forms developed for this review. These included title, contact information of the authors, type of surgery, description of the techniques applied for performing the PVB [single injection (SPVB), multiple injection (MPVB), continuous catheter (CPVB)], the local anaesthetic used, the algorithm for postoperative pain management serving as control, the use of a fixed postoperative pain medication in both study groups, and the administration of a standardized postoperative nausea and vomiting (PONV) prophylaxis. The primary and secondary outcome data were entered into RevMan w provided by the Cochrane Collaboration for further statistical analysis. All differences resulting from discrepant assessments during data extraction and analysis were resolved by consulting a third author (P.K.) or discussion among the authors. Definition of relevant outcome data It was decided to allocate the outcome worst acute postoperative pain to the primary outcome acute postoperative pain in order to include as many studies as possible for this clinically important endpoint. When pain scores for pain at rest and movement were given, the worst pain score was extracted for the relevant time period. The visual analogue scale (VAS) and numeric rating scale (NRS) were considered equivalent. Where separate data on PONV were given, only the number of patients vomiting was extracted, because the authors assumed that all patients, who vomited, had also nausea. The amount of postoperative opioids was only calculated for postoperative morphine. If any other opioids were given as postoperative pain rescue, the equianalgesic doses of morphine were estimated and used for further analyses. Primary outcome (i) Acute postoperative pain scores (VAS/NRS) (,2, 2 24, and h) Worst acute postoperative pain score (VAS/NRS) Acute postoperative pain scores (VAS/NRS) at rest Acute postoperative pain scores (VAS/NRS) at movement (ii) Chronic postoperative pain (6 and 12 months) Chronic postoperative pain scores (VAS/NRS) Number of patients with chronic postoperative pain (iii) Need for rescue analgesics Number of patients who needed postoperative opioids Amount of opioids required in the postoperative period (,24 and h) Secondary outcome (i) Time to need for rescue analgesics (ii) Number of patients with PONV (iii) Number of patients with a technique failure of the PVB (iv) Number of patients with adverse events (accidental vascular puncture, accidental pneumothorax, nerve damage, and Horner s/harlequin s syndrome) Critical appraisal Two authors (A.S. and S.R.) independently performed the critical appraisal of included studies using special standardized forms. The following items of the Oxford scale were evaluated: 15 random allocation, concealment of allocation, blinding 843

3 BJA Schnabel et al. technique, and the description of drop-outs. According to the result of the Oxford scale, the studies were rated as high (Oxford scale 3) or low (Oxford scale,3) quality studies. Statistical methods The relative risk (RR), mean difference (MD), and their corresponding 95% confidence intervals (95% CIs) were calculated for the dichotomous and continuous outcome data, respectively, using a fixed-effect model. Statistical heterogeneity was assessed with the I 2 -test and assumed, if an I 2 -value.% was observed. If significant heterogeneity was detected, it was assumed that there is no single true effect underlying the data, which was constant across different populations, and therefore, a random-effects model was used. 16 Asignificant effect of an intervention was assumed if 95% CI did not include the value 1.0. If continuous data were only reported as median and range, the mean was estimated as equivalent to the median. The standard deviation (SD) was calculated, assuming that the width of the inter-quartile range would be approximately 1.35 SDs in case of a normal distribution of outcome. 17 Different analyses were planned to explore relevant statistical and clinical heterogeneity. A potential publication bias was assessed using funnel plots. Subgroup analysis investigated the influence of different types of paravertebral modalities (SPVB, MPVB, and CPVB), use of a fixed additional analgesic, or PONV prophylaxis regime. Sensitivity analysis was applied with respect to different methodical quality of the included trials (studies with low quality vs studies with high quality). Results Description of included and excluded studies Database searches yielded 50 relevant articles (Fig. 1). After screening of title and abstracts, 18 studies were identified as 50 potentially relevant references identified and screened 18 full-text articles retrieved for detailed evaluation 15 articles with usable information included in meta-analysis 32 references excluded by review of the abstract 3 references excluded - non-randomized controlled trial - other study design - full text not available Fig 1 Flow diagram of included and excluded studies according to the PRISMA statement. potentially relevant to meet the inclusion criteria. The full-text publications of these studies were examined in more detail. Finally, the data of randomized controlled trials were included in the present meta-analysis (Table 1). Three studies were excluded because either it was impossible to retrieve the full texts, the lack of group randomization, or other study design violations. A total of 877 participants with breast surgery from 15 trials were randomly assigned to intervention or control groups. The number of participants in each trial ranged from 10 to 90 per group. Seven trials investigated the analgesic efficacy of PVB alone vs general anaesthesia (GA). Seven studies compared patients receiving either GA in combination with a PVB or only GA. The final included study 31 compared the effects of an SPVB with a continuous local anaesthetic wound infusion in addition to a GA. Most studies included patients undergoing minor and major elective breast tumour resection or mastectomy with/without axillary dissection partly with reconstruction. Only one investigator demonstrated a detailed surgical statistic and operation data. 29 Terheggen and colleagues 32 included only patients with minor breast surgery (lumpectomies, breast biopsies, etc.). Main inclusion criteria entailed adults (18 yr or older) with ASA class I III. Coagulation disorders, treatment with anticoagulants, allergy to local anaesthetics, and infection at thoracic injection site were exclusion criteria in all studies. The loss-of-resistance technique described by Eason and Wyatt 33 was mostly used to establish the PVB. If an SPVB or a CPVB was applied, local anaesthetics were commonly injected into the paravertebral space of the third and fourth thoracic level. Seven trials investigated a single-shot technique, three trials used a continuous catheter, and five trials tested the multilevel injection method from C7 to Th7. Bupivacaine % was the most commonly applied local anaesthetic (seven of 15 studies). In three studies, ropivacaine 0.5% was applied using a total dose of ropivacaine 0.5% (100 mg) for SPVB and 25 mg per level for MPVB. The local anaesthetic lidocaine 2% (SPVB, 0 mg) was used in one study, 21 while another study 27 tested a mixture of lidocaine 2%, bupivacaine 0.5%, epinephrine, fentanyl, and clonidine in the applied MPVB. In contrast to the latter result, one study used both local anaesthetics, ropivacaine 0.2% and bupivacaine 0.125%, for their PVB. Patients of three studies received CPVB using bupivacaine % (2 25 mg h 21 ) up to h after operation. Patients randomized to receive PVB as a single technique were sedated with propofol, midazolam, or both during the operation. GA was induced in most trials with propofol, fentanyl, or sufentanil, while two investigators used thiopental as a hypnotic agent. In all studies, analgesia was provided by various opioids as bolus administration or patient-controlled analgesia. Different additional analgesics [acetaminophen, traditional non-steroidal anti-inflammatory drugs (NSAIDs), Coxibe] were given in seven of 12 trials. In order to prevent PONV, patients of three studies were treated with dexamethasone, ondansetron, or both before operation. 844

4 Paravertebral blocks in breast surgery BJA Table 1 Main characteristics of included studies comparing PVB vs GA (1 4, 7, 11, 12), PVB in combination with GA vs GA alone (5, 6, 8 10, 13, 15) and PVB in combination with GA vs GA in combination with a wound infusion (14). The studies were rated as high (Oxford scale 3) or low (Oxford scale,3) quality studies Reference Number of patients PVB Additional analgesics (opioid/nsaid) PONV prophylaxis 1 Pusch and colleagues SPVB Bupivacaine 0.5% +/+ 2 1/0/1 2 Klein and colleagues MPVB Bupivacaine 0.5%, epinephrine +/2 + 2/0/1 3 Terheggen and colleagues 32 SPVB Bupivacaine 0.5%, epinephrine +/+ 2 2/0/1 4 Naja and colleagues MPVB Lidocaine 1%, bupivacaine 0.5%, 2/+ 2 2/0/1 fentanyl, clonidine, epinephrine 5 Buggy and Kerin CPVB Levobupivacaine 0.25%, +/2 2 2/0/1 6 Kairaluoma and colleagues SPVB Bupivacaine 0.5% +/+ 2 1/2/1 7 Paleczny and colleagues SPVB Ropivacaine 0.5%, fentanyl, clonidine +/+ 2 1/0/1 8 Burlacu and colleagues CPVB Levobupivacaine 0.25%, fentanyl, +/+ + 2/0/1 clonidine, 9 Iohom and colleagues CPVB Bupivacaine 0.25% +/+ 2 2/0/1 10 Kairaluoma and colleagues SPVB Bupivacaine 0.5% +/+ 2 1/2/1 11 Shkol nik and colleagues 180 MPVB Bupivacaine 0.125%, ropivacaine 0.2% 2/2 2 1/0/0 12 Dabbagh and Elyasi SPVB Lidocaine 2% +/2 2 1/0/1 13 Moller and colleagues MPVB Ropivacaine 0.5% +/+ 2 2/2/1 14 Sidiropoulou and colleagues SPVB Ropivacaine 0.5% +/2 + 2/0/1 15 Boughey and colleagues MPVB Ropivacaine 0.5 1%, epinephrine +/+ + 1/0/0 Oxford scale Critical appraisal of the study quality All trials were randomized controlled trials, of which the study quality was high in 10 studies and low in the remaining five. Seven studies used randomly numbered sealed envelopes for the concealment of allocation. A blinding of the patients using saline as vehicle instead of local anaesthetic in the PVB was only performed in three trials The anaesthesiologist performing the PVB was only blinded in two trials Blinding to the outcomes of the tested intervention was performed in eight studies Outcome data of patients lost in the follow-up period were not described in any of the included trials. Primary and secondary outcome data Studies were analysed separately according to their different study protocols. Seven trials evaluated the efficacy of PVB vs GA, seven trials assessed the effects of PVB in addition to a GA vs GA, and one study 31 investigated the efficacy of SPVB vs a continuous wound infusion in addition to a GA. Paravertebral blocks vs GA Acute postoperative pain scores (VAS/NRS) (,2, 2 24, and h) Six trials including data of 344 patients were eligible assessing acute postoperative pain scores (VAS/NRS) in women undergoing surgery in PVB alone in comparison with GA during three different time periods. The data of one study could not be analysed, because mean or SD was not clearly stated in the article. There was a significant difference in worst postoperative pain scores between the PVB and GA groups at,2 h (Fig. 2), 2 24 h (Fig. 3), and h (Fig. 4). Heterogeneity influenced the results in all time periods. Therefore, the following tests and analyses were performed, exploring potential reasons for this heterogeneity: funnel plot testing a potential publication bias, subgroup analyses investigating the different types of PVB, and the influence of a fixed additional non-opioid analgesic regime and sensitivity analyses testing the influence of different reported outcomes in the studies (median vs mean) and different study quality. Funnel plots showed an asymmetry and it can be assumed that negative results were less reported than positive results. A subgroup analysis investigating the different types of PVB as single or multiple injection technique showed better results for the MPVB trials in all time periods, but was also influenced by a significant heterogeneity. The influence of a fixed additional non-opioid analgesic regime was assessed in another subgroup analysis showing slightly better results in the group with fixed additional analgesics. A sensitivity analysis testing the influence of one trial, 27 whose mean and SD were calculated using a statistical approach provided by the Cochrane handbook, 17 showed slightly lower analgesic effects in the treatment group. Another sensitivity analysis due to a lower study quality of three included trials showed a higher MD of postoperative pain scores in the PVB group influenced by a lower heterogeneity. Separate data on pain at rest and movement were only eligible in one trial. 27 There was a significant reduction in pain scores at rest in the 2 24 h period and in all time intervals during movement. 845

5 BJA Schnabel et al. PVB GA Study or subgroup Mean SD Total Mean SD Total Weight i.v. random, 95% CI Dabbagh and Elyasi Klein and colleagues Paleczny and colleagues Pusch and colleagues 29 1 Terheggen and colleagues % 14.6% 21.7% 34.3% 3.6% 2.20 ( 2.79, 1.61) 3.50 ( 4.68, 2.32) 2.87 ( 3.65, 2.09) 1.90 ( 2.03, 1.77) 3. ( 6.25, 0.35) i.v. random, 95% CI Total (95% CI) 142 Heterogeneity: t 2 = 0.26; c 2 = 13.98, df = 4 (P = 0.007); I 2 = 71% Test for overall effect: Z = 8.20 (P< ) % 2.47 ( 3.06, 1.88) Favours PVB Favours GA Fig 2 Pooled data analysis assessing worst pain scores (VAS/NRS) in the early (,2 h) postoperative period in study groups receiving a PVB as single technique (n¼142) compared with GA (n¼142). A random-effect model was used, because there was a significant heterogeneity (I 2 ¼71%). PVB GA Study or subgroup Mean SD Total Mean SD Total Weight i.v. random, 95% CI Dabbagh and Elyasi Klein and colleagues Naja and colleagues 27 3 Paleczny and colleagues Pusch and colleagues % 18.1% 7.0% 22.3% 28.6% 2.25 ( 2.78, 1.72) 1.20 ( 2.13, 0.27) 4.50 ( 6.63, 2.37) 1.59 ( 2.24, 0.94) 1.20 ( 1.27, 1.13) i.v. random, 95% CI Total (95% CI) 157 Heterogeneity: t 2 =0.38; c 2 =24.88; df=4 (P<0.0001); I 2 =84% Test for overall effect: Z=5.34 (P< ) % 1.77 ( 2.42, 1.12) Favours PVB Favours GA Fig 3 Pooled data analysis assessing worst postoperative pain scores (VAS/NRS) 2 24 h after a PVB as single technique (n¼157) when compared with GA (n¼157). This result was influenced by heterogeneity (I 2 ¼84%) and so the data were analysed using a random-effect model. PVB GA Study or subgroup Mean SD Total Mean SD Total Weight i.v. random, 95% CI Klein and colleagues 25 Naja and colleagues 27 Paleczny and colleagues % 26.5% 39.5% 0.90 ( 1.97, 0.17) 4.00 ( 5.70, 2.) 0.97 ( 1.52, 0.42) i.v. random, 95% CI Total (95% CI) 83 Heterogeneity: t 2 =1.29; c 2 =11.44; df=2 (P=0.003); I 2 =83% Test for overall effect: Z=2.38 (P=0.02) % 1.75 ( 3.19, 0.31) Favours PVB Favours GA Fig 4 Pooled data analysis assessing worst postoperative pain scores (VAS/NRS) h after a PVB as single technique (n¼83) compared with GA (n¼85). A random-effect model was used, because there was a significant heterogeneity (I 2 ¼83%). Chronic postoperative pain (6 and 12 months) There were no data on chronic postoperative pain available. Need for rescue analgesics Five trials reported data on the need for rescue analgesics. The number of patients requiring postoperative opioids was significantly lower in women undergoing surgery with PVB in comparison with GA at 0 24 h (RR: 0.16; 95% CI: ; P¼0.005) and h 27 (RR: 0.18; 95% CI: ; P¼0.002). The group of patients undergoing breast surgery in PVB also needed a lower total amount of morphine at 0 24 h (MD: 23.80; 95% CI: to 21.50; P¼0.001). Time to need for rescue analgesics There were no data available investigating the time to need for rescue analgesics. 846

6 Paravertebral blocks in breast surgery BJA Number of patients with PONV Four trials providing no PONV prophylaxis reported the number of patients with PONV (Table 2). Patients receiving only PVB had a lower RR of 0.26 (95% CI: ; P,0.0001) for PONV than women undergoing surgery in GA. Number of patients with a failed anaesthetic technique The pooled analysis of four included trials showed a higher RR for a failed anaesthetic technique (RR: 4.34; 95% CI: ; P¼0.1) in the women undergoing surgery only in PVB in comparison with women receiving GA (Table 2). Three trials performed the PVB using loss-of-resistance technique, while one trial 27 identified the paravertebral space with a nerve stimulator. Number of patients with adverse events (accidental vascular puncture, accidental pneumothorax, nerve damage, and Horner s/harlequin s syndrome) All trials reported the number of patients with adverse events following a PVB (Table 2). No study reported any patients with vascular puncture or nerve damage. There was one patient suffering Horner s syndrome in a trial 29 investigating SPVB, while another trial testing MPVB reported 11 patients with Horner s syndrome. A patient with an accidental pneumothorax was reported only in one study 32 investigating the efficacy and safety of SPVB. Paravertebral blocks combined with GA vs GA Acute postoperative pain scores (VAS/NRS) (,2, 2 24, and h) Five trials including data of 215 patients investigated acute postoperative pain scores (VAS/NRS) in women undergoing surgery with PVB combined with a GA in comparison with GA alone in the acute postoperative pain management. One trial 18 could not be analysed, because the investigators did not report the SD. There was a significant difference in worst postoperative pain scores between the PVB group and control at,2 h (Fig. 5). The pooled data analysis showed a significant analgesic effect in the PVB group at 2 24 h (Fig. 6). At h, only one trial was available reporting a difference of MD: (95% CI: to 0.68; P¼0.002) concerning worst acute postoperative pain. All analyses were not influenced by heterogeneity (I 2 ¼2%, respectively, I 2 ¼0%). A potential publication bias was investigated using a funnel plot, which showed no asymmetry. A subgroup analysis investigating the different types of PVB as single, multiple injection, or continuous catheter technique showed better results for the CPVB trials at,2 h. At 2 24 h, the SPVB trial 23 scored a slightly better result than the CPVB studies. The influence of a fixed additional non-opioid analgesic regime was assessed in another subgroup analysis showing heterogeneous results. At,2 and 2 24 h, trials with additional non-opioid medication had slightly lower pain scores. A sensitivity analysis due to the influence of a calculation of mean and corresponding SD in three trials showed slightly better results for the PVB group in the first time interval. Separate data on pain scores at rest were eligible in two studies and there was only a slightly better pain score during all time intervals in the PVB group that failed to reach statistical significance. In contrast to the latter results, there was a significant reduction in pain at movement scores in all time intervals in women having a PVB in addition to a GA. Chronic postoperative pain (6 and 12 months) Three trials including the data of 167 patients investigated the influence of PVB combined with GA compared with GA alone on the development of chronic postoperative pain. The RR for chronic pain was slightly lower in the PVB group 6 months after surgery (RR: 0.16; 95% CI: ; P¼0.07). Twelve months after surgery, two trials reported a lower number of patients with chronic pain, when they had a PVB in addition to their GA (RR: 0.61; 95% CI: ; P¼0.64). Both analyses were influenced by heterogeneity (I 2 ¼53%, respectively, I 2 ¼83%). The worst postoperative chronic pain score (VAS/NRS) was reported only in one trial 24 showing a trend for a better outcome 12 months after surgery (MD: 22.00; 95% CI: to 0.68; P¼0.14). Need for rescue analgesics Data on the need for rescue analgesics were investigated by four trials There was a lower number of patients requiring postoperative opioids at 0 24 h undergoing surgery with a PVB combined with GA in comparison with GA alone (RR: 0.46; 95% CI: ; P¼0.18). The PVB group also needed a lower total amount of morphine at 0 24 h (MD: 22.81; 95% CI: to 5.07; P¼0.48). Table 2 RRs and consecutive 95% CIs of adverse events in women undergoing surgery in PVB alone in comparison with GA Outcome Number of trials References Patients RR 95% CI P-value Failed anaesthetic technique 4 24, PONV , , Nerve damage 4 20,24,26, Pneumothorax 5 20,24,26,29, to Vascular puncture 4 20,24,26, Horner s/harlequin s syndrome 5 20,24,26,28,

7 BJA Schnabel et al. PVB + GA GA Study or subgroup Mean SD Total Mean SD Total Weight i.v. fixed, 95% CI Buggy and Kerin Burlacu and colleagues 20 0 Iohom and colleagues Kairaluoma and colleagues 23 3 Moller and colleagues % 23.2% 12.2%.2% 11.8% 2.60 ( 3.99, 1.21) 1.00 ( 2.37, 0.37) 2.90 ( 4.79, 1.01) 1.80 ( 3.00, 0.60) 1. ( 3.22, 0.62) i.v. fixed, 95% CI Total (95% CI) 105 Heterogeneity: c 2 =4.10; df=4 (P=0.39); I 2 =2% Test for overall effect: Z=5.55 (P< ) % 1.87 ( 2.53, 1.21) Favours PVB + GA Favours GA Fig 5 Pooled data analysis assessing worst pain scores in the early (,2 h) postoperative period in study groups undergoing surgery in a PVB combined with GA (n¼105) compared with GA alone (n¼110). This result was not influenced by heterogeneity (I 2 ¼2%) and so the meta-analysis was performed using a fixed-effect model. PVB + GA GA Study or subgroup Mean SD Total Mean SD Total Weight i.v. fixed, 95% CI Buggy and Kerin 19 2 Burlacu and Colleagues 20 2 Iohom and Colleagues Kairaluoma and Colleagues % 19.2% 22.0% 20.3% 2.10 ( 3.49, 0.71) 2.00 ( 3.96, 0.04) 2. ( 4.13, 0.47) 2.50 ( 4.41, 0.59) i.v. fixed, 95% CI Total (95% CI) 67 Heterogeneity: c 2 =0.17; df=3 (P=0.98); I 2 =0% Test for overall effect: Z=5.03 (P< ) % 2.21 ( 3.07, 1.35) Favours PVB + GA Favours GA Fig 6 Pooled data analysis assessing worst postoperative pain scores (VAS/NRS) 2 24 h after a PVB combined with GA (n¼67) compared with GA alone (n¼69). A fixed-effect model was used due to the fact that there was no heterogeneity (I 2 ¼0). Table 3 RRs and consecutive 95% CI of adverse events in women receiving a PVB combined with GA in comparison with GA alone Outcome Number of trials References Patients RR 95% CI P-value Failed anaesthetic technique PONV 2 22, Nerve damage 3 17,22, Pneumothorax 3 17,22, Vascular puncture 3 17,22, Horner s/harlequin s syndrome 4 17,21,22, Time to need for rescue analgesics Only Kairaluoma and colleagues investigated the time to need for rescue analgesics. The duration of the postoperative analgesic effect in the group receiving PVB combined with a GA was twice as long as in the control group receiving only GA (MD: min; 95% CI: to 23.64; P¼0.15). Number of patients with PONV Only two trials reported the number of patients with PONV. The group undergoing surgery in PVB combined with GA had a lower risk for PONV than the GA group (RR: 0.69; 95% CI: ; P¼0.20) (Table 3). Number of patients with a failed anaesthetic technique One trial 19 showed a higher risk for a failed anaesthetic technique (RR: 3.00; 95% CI: ; P¼0.49) in women undergoing breast surgery receiving a PVB combined with GA (Table 3). Number of patients with adverse events (accidental vascular puncture, accidental pneumothorax, nerve damage, and Horner s/harlequin s syndrome) There were four trials including the data of 248 patients available reporting explicitly the number of patients with adverse events after surgery in PVB combined with GA in 848

8 Paravertebral blocks in breast surgery BJA comparison with GA (Table 3). There were no patients suffering from clinical signs of a nerve damage or an accidental pneumothorax. One trial 22 testing the efficacy of CPVB mentioned a patient with a Horner s syndrome, while another study 23 investigating SPVB reported a patient with convulsions after a paravertebral injection of bupivacaine 0.5%. Paravertebral analgesia vs continuous wound infiltration There was only one trial 31 available including the data of 48 women investigating the efficacy of an SPVB vs a continuous wound catheter in addition to a GA in postoperative care after breast surgery. There was a minimal difference in worst postoperative pain ratings in favour of the wound catheter group at 2 24 h (MD: 1.00; 95% CI: to 2.26; P¼0.12). The wound catheter group needed a lower total amount of postoperative opioids in comparison with the SPVB group (MD: 3.9; 95% CI: to 10.12; P¼0.22), but the RR for PONV was lower in the SPVB group (RR: 0.38; 95% CI: ; P¼0.03). Discussion In the present quantitative systematic review, we included 15 randomized controlled trials (published ) and analysed data of 877 patients. In conclusion, we observed for patients receiving a PVB alone or in combination with GA significant lower resting, evoked and worst pain scores compared with other analgesic treatment strategies indicating that a PVB provides improved postoperative pain control in patients undergoing breast surgery. Furthermore, there might be a reduced need for postoperative opioid requirements and consecutively a decrease in opioid-induced adverse effects in patients receiving a PVB. Implications for practice Several surveys in Europe 34 and the USA 35 demonstrated that postoperative pain management is still inadequate. Accordingly, 40% of women after breast cancer surgery complain about clinically meaningful acute pain with pain scores above five. 3 Insufficiently controlled postoperative pain may delay recovery, lead to a prolonged hospital stay, extend medical costs, is a major concern of surgical patients, and cause persistent-chronic pain. Several studies investigated the feasibility of a PVB in order to improve postoperative pain after breast surgery (as an effective postoperative pain treatment strategy for breast cancer surgery). By analysing the included studies, we observed considerable evidence that a PVB in addition to GA or alone provides better postoperative analgesia with little adverse effects compared with other analgesic treatment strategies, indicating that a perioperative PVB is a feasible and effective method for an improved postoperative pain treatment after breast surgery. Accordingly, several studies demonstrated the analgesic efficacy of a PVB for thoracotomy, multiple fractured ribs, and hernia repair. For instance, two recent meta-analyses reported that a PVB provided similar pain relief compared with thoracic epidural analgesia after thoracotomy but with fewer side-effects, technical problems, and failed blocks. An appropriate risk benefit analysis was not possible to perform in the present meta-analyses with the available data, because adverse events of a PVB were only reported by 11 included studies (771 patients) (Tables 2 and 3). The most common adverse event after a PVB for breast surgery was a temporary Horner s syndrome, which resolved within 8 10 h spontaneously. One patient had convulsions after an SPVB without losing consciousness, which was aborted by a small dose of a benzodiazepine; this adverse event was most likely caused by an accidental intravascular injection of part of the local anaesthetic. Interestingly, only one case of an accidental pneumothorax after a SPVB was reported. Other side-effects including nerve injuries were not mentioned in the available data. The most extensive database published in the literature concerning adverse effects and failure rates after multiple lumbar and thoracic PVB in 620 adults and 42 children reported an incidence for an overall failure rate of 6.1%, for vascular puncture of 6.8%, and for hypotension of 4%. 8 Besides these minor sideeffects, major complications including extensive epidural or intrathecal spread (1%), accidental pleural puncture (0.8%), and pneumothorax (0.5%) were observed rarely after a PVB. Severe neurological complications associated with a PVB have been reported only on rare occasions. Besides few historical reports, there is only one case of segmental thoracic pain after cholecystectomy that lasted for 3 months after surgery and was presumably secondary to intercostal nerve trauma caused by a PVB. 38 Another important issue for a successful PVB may be the appropriate drug choice, dose, and administration technique. By analysing the included data of the present meta-analysis, there was variability in drug concentrations, combinations with different additives, and type of local anaesthetics administered into the paravertebral space. Bupivacaine and ropivacaine 0.5% were most commonly administered for MPVB or SPVB, while levobupivacaine or ropivacaine 0.25% was administered as bolus and continuous infusion via a paravertebral catheter. In agreement with other systematic reviews for thoracotomy, ml of bupivacaine or ropivacaine % was used for the blockade of a single thoracic segment. A CPVB was started with a ml bolus followed by a continuous infusion of 8 15 ml h 21 depending on the concentration of local anaesthetic. However, sufficient randomized controlled trials investigating the optimal dose and type of local anaesthetic and additives used in thoracic PVB for breast surgery are still missing. One randomized controlled trial investigating ropivacaine 0.5% vs bupivacaine 0.5% in 70 women undergoing modified radical mastectomy showed that ropivacaine provided a more rapid onset and a wider and longer lasting sensory block (. 9 segments) than bupivacaine, but the analgesic efficacy of both local anaesthetics was equipotent. 40 Similarly, Kotze and colleagues 39 demonstrated in their meta-analysis for post-thoracotomy pain that higher doses of local anaesthetics but neither the 849

9 BJA Schnabel et al. choice of local anaesthetic nor the administration of additives like clonidine or fentanyl improved the analgesic efficacy of the PVB. Furthermore, the authors concluded that the incidence of serious local anaesthetic toxicity with higher doses of bupivacaine (,0.25 mg kg 21 h 21 ) or ropivacaine is likely to be low. The optimal technique (SPVB, MPVB, and CPVB) to establish a sufficient and reliable PVB for breast surgery has not been clarified yet. In the present meta-analysis, we observed in a subgroup analysis that MPVB vs SPVB provided better analgesia compared with GA. If PVB were combined with GA, analgesia offered by a CPVB was slightly better than after multiple or single injection of local anaesthetics. Accordingly, Greengrass and Buckenmaier 41 concluded in their review that MPVB are the technique of choice in establishing a PVB for mastectomy. Furthermore, Kotze and colleagues 39 demonstrated in their recent meta-regression analysis for post-thoracotomy pain that a CPVB combined with GA reduced postoperative non-evoked and evoked pain scores more effectively than an intermittent bolus technique. Thus, we suggest that a CPVB in combination with GA may provide the most effective perioperative analgesia for breast surgery. However, further studies are necessary to assess the optimal risk benefit ratio for the different techniques of PVB (SPVB, MPVB, and CPVB). Implications for clinical research Chronic postoperative pain including paraesthesia, intercostobrachial neuralgia, and phantom breast pain occurs in 25 50% of patients after breast cancer surgery. Predictive risk factors for the development of persistent postoperative pain after breast cancer surgery are adjuvant radiotherapy, axillary lymph node dissection, psychosocial factors, younger age (,40 yr), and severe postoperative pain. 5 Furthermore, current evidence demonstrated that an appropriate postoperative pain treatment may reduce the incidence for the development of chronic postoperative pain after breast surgery. Accordingly, our meta-analysis demonstrated a moderate decrease in chronic postoperative pain 6 12 months after breast surgery for patients with a GA in combination with PVB compared with GA alone, but due to the limited number of included trials and the observed heterogeneity, this finding has to be interpreted with caution. Therefore, larger studies are necessary to investigate a possible preventive role of a PVB on the incidence of chronic postoperative pain for patients after breast surgery. A retrospective analysis of 129 patients undergoing mastectomy and axillary lymph node dissection showed a lower risk for cancer recurrence in patients having surgery with a PVB combined with a GA compared with patients with GA alone. 42 Considerable evidence indicates that surgery, which releases tumour cells directly into circulation, volatile anaesthetics, which impairs the immune function, and the use of postoperative opioids, which aggravate the postoperative immune depression and promotes proangiogenic factors and pain by itself are associated with cancer recurrence. 43 Our meta-analysis showed a reduced need for postoperative morphine in the group of patients undergoing surgery with PVB indicating a potential pathophysiological mechanism for a lower incidence of breast cancer recurrence. However, due to the limited number of included studies and a significant heterogeneity, this outcome has to be interpreted with caution. After Eason and Wyatt 33 reintroduced the PVB to the clinics, several approaches for establishing a PVB have been described including neurostimulation, loss-of-resistance technique, and recently the use of ultrasound. In a lately published small clinical study, O Riain and colleagues 44 demonstrated the effective ultrasound-guided establishment of a unilateral PVB for 10 patients undergoing breast surgery. Although ultrasound-guided regional anaesthesia has become increasingly popular and may increase safety, current evidence does not suggest that the use of ultrasound improves success of regional anaesthesia vs most other techniques. 45 Therefore, further studies are needed to compare the rate of failure and the incidence of adverse events of an ultrasound-guided PVB with other approaches, including nerve stimulation and loss-of-resistance technique. The efficacy of a continuous local anaesthetic wound infusion for postoperative pain control has already been demonstrated for several types of surgery In the last few years, two randomized controlled studies investigating the analgesic properties provided by a continuous local anaesthetic wound infusion vs a standard opioid-based analgesic regime in 44 patients undergoing major breast surgery showed significant lower pain scores and a lower need for postoperative opioids for the wound infusion group. Our meta-analysis included the only randomized controlled trial comparing the analgesic effects of an SPVB vs a continuous ropivacaine wound infusion in addition to GA and showed that SPVB and a continuous wound infusion are comparably effective. Although there is currently sparse evidence for the analgesic efficacy of continuous wound infusion after breast surgery, further studies should investigate whether the combination of GA with a continuous local anaesthetic wound infusion provide comparable effects in the postoperative period (acute and chronic postoperative pain control) compared with a CPVB. Limitations The results of the present meta-analysis are limited due to clinical heterogeneity of several included studies. First, pain scores were rated either on a visual analogue scale (VAS) or on an NRS and due to the limited number of included trials, we decided to rate the different 10 point scales as equivalent. Furthermore, only three trials explicitly described, whether pain was evaluated during rest or movement. Secondly, pain scores depended on the extent of breast surgery, indicating that less invasive operations like segment resections will produce lower postoperative pain scores than mastectomy with axillary lymph node dissection. Thirdly, the type of local anaesthetics and additives including 850

10 Paravertebral blocks in breast surgery BJA clonidine or opioids varies between the studies and may bias postoperative pain assessment. However, there is some evidence that ropivacaine, bupivacaine, levobupivacaine, and lidocaine produce similar analgesia and that the administration of additives did not enhance pain therapy. 39 Nevertheless, there is a lack of data for the appropriate local anaesthetic dosing used for PVB in breast surgery. Fourthly, different techniques of establishing a PVB (SPVB, MPVB, and CPVB) may play a role in the efficacy of analgesia. In the present meta-analysis, we observed a trend for superior and longer analgesia after the combination of GA with a CPVB. Finally, as in many meta-analyses, results of the present review may be influenced by a positive publication bias, because in general negative study results are less likely to be submitted and published. Conclusions There is considerable evidence that PVB in addition to GA or alone provide better postoperative pain control with little adverse effects compared with other analgesic treatment strategies, indicating that a perioperative PVB is a feasible and effective method for an improved postoperative pain treatment after breast surgery. However, these results were limited by clinical heterogeneity due to the application of different surgical procedures and the use of diverse types and doses of local anaesthetics. Conflict of interest None declared. Funding This work was only supported by departmental funding. References 1 Tyczynski JE, Bray F, Parkin DM. ENCR Cancer Fact Sheets: Breast Cancer in Europe (June 2, 2010); 4 2 American Cancer Society. Overview: Breast Cancer Poleshuck EL, Katz J, Andrus CH, et al. Risk factors for chronic pain following breast cancer surgery: a prospective study. J Pain 2006; 7: Shapiro FE. Anesthesia for outpatient cosmetic surgery. 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