Efficacy and safety of different techniques of paravertebral block for analgesia after thoracotomy: a systematic review and metaregression
1 Airedale NHS Trust, Steeton, Keighley BD20 6TD, UK
2 School of Health Studies, Bradford University, UK
3 Academic Unit of Anaesthesia, University of Leeds, UK
* Corresponding author. E-mail: alwynkotze{at}doctors.net.uk
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Abstract |
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Various techniques and drug regimes for thoracic paravertebral block (PVB) have been evaluated for post-thoracotomy analgesia, but there is no consensus on which technique or drug regime is best. We have systematically reviewed the efficacy and safety of different techniques for PVB. Our primary aim was to determine whether local anaesthetic (LA) dose influences the quality of analgesia from PVB. Secondary aims were to determine whether choice of LA agent, continuous infusion, adjuvants, pre-emptive PVB, or addition of patient-controlled opioids improve analgesia. Indirect comparisons between treatment arms of different trials were made using metaregression. Twenty-five trials suitable for metaregression were identified, with a total of 763 patients. The use of higher doses of bupivacaine (890–990 mg per 24 h compared with 325–472.5 mg per 24 h) was found to predict lower pain scores at all time points up to 48 h after operation (P=0.006 at 8 h, P=0.001 at 24 h, and P<0.001 at 48 h). The effect-size estimates amount to around a 50% decrease in postoperative pain scores. Higher dose bupivacaine PVB was also predictive of faster recovery of pulmonary function by 72 h (effect-size estimate 20.1% more improvement in FEV1, 95% CI 2.08%–38.07%, P=0.029). Continuous infusions of LA predicted lower pain scores compared with intermittent boluses (P=0.04 at 8 h, P=0.003 at 24 h, and P<0.001 at 48 h). The use of adjuvant clonidine or fentanyl, pre-emptive PVB, and the addition of patient-controlled opioids to PVB did not improve analgesia. Further well-designed trials of different PVB dosage and drug regimes are needed.
Keywords: anaesthetic techniques, regional, thoracic; analgesia, postoperative; pain, acute, regional techniques; surgery, thoracic; thoracic anaesthesia
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Introduction |
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Thoracotomy frequently causes severe postoperative pain and significant morbidity.10 27 Atelectasis, pneumonia, pulmonary embolism, and emergency intensive care admission have all been found to be related to poor analgesia and consequent immobility.27 66 Postoperative pain is thought to be the single most important factor leading to ineffective ventilation and impaired secretion clearance after thoracotomy.71 Severe or inadequately treated acute pain after thoracotomy also predicts conversion to chronic post-thoracotomy pain27 66 and long-term post-surgical fatigue.73
Thoracic paravertebral block (PVB) has been shown to provide superior post-thoracotomy analgesia and lung function, compared with systemic opioids or intrapleural local anaesthetics (LA).30 73 Three systematic reviews have compared the efficacy of PVB and thoracic epidural analgesia (TEA) after thoracotomy.27 30 45 Detterbeck30 found that PVB provided equivalent pain relief to TEA, but did not quantitatively compare complications between the two techniques. A meta-analysis by Davies and colleagues27 showed that PVB provides pain relief as good as TEA, using LA with or without opioid, but with fewer side-effects, technical problems, and failed blocks. Perhaps more importantly, PVB reduced postoperative pulmonary complications by 64% compared with epidural analgesia.27 Recently,45 it was found that PVB provided analgesia after thoracotomy that was comparable with TEA using LA only, but possibly less effective than TEA using LA with opioid. However, PVB reduced the incidence of pulmonary complications compared with systemic analgesia, whereas TEA did not.45 PVB may theoretically be a safer technique than TEA, at least in terms of the chances of serious spinal cord injury from epidural space infection41 or spinal canal haematoma.67
The systematic reviews to date27 30 45 studied PVB as a single generic technique, regardless of drug choice, dose, or administration technique. The optimal drug(s) for PVB have to date not been reviewed. We therefore undertook a systematic review with the aim of determining how the following variables influence the quality of post-thoracotomy analgesia with PVB:
- LA dose;
- administration technique, that is, continuous infusion or intermittent boluses;
- choice of LA agent;
- the addition of fentanyl or clonidine to LA;
- pre-emptive PVB;
- the addition of patient-controlled opioids to PVB.
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Methods |
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This review followed the Quality of Reporting of Meta-analyses (QUORUM) guidelines.57 Data were extracted and analysed in keeping with the methods used in similar meta-analyses27 as far as was appropriate.
The MEDLINE and EMBASE databases were searched without language restriction up to May 2008, using the Athens portal of the United Kingdom National Library for Health. The predetermined inclusion criteria were:
- randomized controlled trials (RCTs) in which at least one trial group received paravertebral LA with or without additives, and
- postoperative pain control, pulmonary function, or both reported as outcome measure.
The electronic search identified 66 papers for consideration. The abstracts of the identified articles were reviewed to determine if the study met the inclusion criteria of the review. In addition, the reference lists of trials included in previous reviews of analgesia for thoracotomy27 30 45 73 were checked.
Data concerning the PVB group of each randomized trial were extracted into Microsoft Excel® and analysed using STATA® (StataCorp LP, College Station, TX, USA).
Average pain scores were recorded as if on a 100 mm visual analogue scale (VAS). Where scores were reported on 0–10 long ordinal scales, these were converted to a 100 mm VAS. VAS scores obtained at times close to each other were grouped together to maximize the number of trials included for each analysis. Any VAS score obtained between 6 and 10 h after operation was included with those obtained at 8 h, and VAS scores obtained on the first postoperative day or from 20 to 24 h after operation were grouped at 24 h. Pain scores were assumed to have been obtained at rest unless otherwise stated by the authors.
Spirometric measurements were recorded as a percentage of the preoperative values. Complications and side-effects of the PVB itself were recorded where these were identified by the trial authors. A complication rate of zero was only recorded where it was specifically stated that a complication did not occur.
The total LA dose in the first 24 h was calculated as overall indicator of dosage, using the formula: total dose=loading dose+24x(infusion dose h–1). Dosages were calculated for a patient weighing 70 kg where weight-related dosages were reported. For dosages reported as a simple range, the midpoint was used.
Statistical analysis
Continuous data are presented as mean values and the standard error (SE) of the mean. Where the standard deviation (SD) was reported, the SE was calculated using the formula for a normal distribution (SE=SD/
n). When no SD was given, it was imputed with the t-test if the P-value was stated; otherwise the SD was estimated as half of the mean value. When the median and range only were reported for continuous outcomes, the mean and SD were estimated by assuming that the mean was equivalent to the median and that the SD was one-quarter of the range.44 64
For continuous data, indirect comparisons between groups of trials were made by means of metaregression, using univariate analysis, and a random effects model. This was necessary because of great heterogeneity between the original randomized comparisons, described below. Two-tailed P-values were calculated for dichotomous data, using Fisher's exact test.
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Results |
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Of the 31 RCTs identified,1 4 7–10 13–15 26 28 29 31 33 36 38 46 52–54 62 63 65 68–70 72 75 80 83 84 six were excluded from meta-analysis. One31 was conducted in patients undergoing minimally invasive coronary artery surgery, rather than thoracotomy. One small trial54 had an unexplained drop-out rate of 30% (three of 10) in the PVB group within 24 h and none in the control group. Another9 compared repeated paravertebral boluses of bupivacaine against systemic analgesia. Both the stated dose (0.1 mg kg–1) and bolus size (1–2 ml) of bupivacaine was 10–20-fold lower than every other trial, or the recommended dose. It is therefore probable that the dose quoted in the paper was simply a misprint. No correction was found in the following year's issues of the journal, and the author did not reply to communications to confirm the dose used. The trial was therefore excluded from meta-analysis. Two small trials (with a total of 20 patients in the PVB groups between them) were published in French.1 80 One trial38 investigated specifically the haemodynamics of PVB and reported no data on pain or pulmonary function (Fig. 1).
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The 25 trials included had recruited 763 patients to 31 PVB treatment arms (Table 1). Obtaining original patient data for all the included trials proved impossible.
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Seven trials conducted comparisons of different paravertebral drug regimes.4 8 15 36 62 71 83 However, these trials evaluated a total of nine different drug and dosage regimes. Four trials were placebo-controlled, with all patients having access to rescue medication and regular simple analgesics.5 29 33 75 Two different PVB regimes were evaluated against control groups who, in turn, received two different analgesic regimens. One of these29 also had a control group receiving only systemic analgesia without a sham PVB. Three trials evaluated the addition of PVB to various systemic analgesics without including a placebo PVB group.9 13 53 Two trials72 74 compared PVB with interpleural analgesia.
Nine trials compared PVB with TEA, again using different paravertebral drug and dosage regimes.10 14 16 26 28 46 52 65 70 84
The outcomes reported consistently enough to make meta-analysis reliable were: VAS at 8, 24, and 48 h, maximal expired volume in 1 s (FEV1) at 24, 48, and 72 h after surgery, and LA toxicity (defined as confusion which resolves after cessation of the LA infusion, the occurrence of convulsions, or cardiac arrhythmias).
LA dosage
No trial making a direct comparison between different doses of a given LA was identified. An indirect comparison was possible.
The trials that used bupivacaine infusions for PVB were clearly divisible into two groups. In 12 studies patients received bupivacaine 890–990 mg in the first 24 h after operation (the ‘higher dose LA group’).4 6 8 15 25 33 46 70–72 75 83 In seven, patients received 325–472.5 mg per 24 h (the ‘lower dose group’).4 13 15 29 52 65 84 Only four of the 19 trials used less than the manufacturer's recommended maximum dose of bupivacaine 400 mg82 per 24 h.13 15 65 84 No trial used bupivacaine in the dose range of 473–889 mg. Bupivacaine boluses were not considered for dosage meta-analysis, as the time interval between bolus administration and assessment of pain scores could also influence VAS. Scatter plots of LA dosage vs VAS scores revealed a possible inverse relationship at all time points up to 48 h after surgery (Fig. 2).
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Metaregression confirmed that this apparent relationship is significant. Higher dose paravertebral bupivacaine was strongly predictive of lower VAS scores at rest, when compared with lower dose regimes at 8 h after operation (P=0.006), 24 h (P=0.001), and 48 h (P<0.001). Although there was a trend to improved analgesia on coughing at all time points, the difference did not reach statistical significance. Far fewer trials reported VAS scores on coughing than at rest: there were only two trials in each dosage group for dynamic analgesia at 8 h,8 15 65 70 and a further one at 24 and 48 h.46
The effect-size estimate for VAS improvement with higher dose bupivacaine was 26.9 mm (95% CI 7.5–46.3 mm) at 8 h after operation, 21.1 mm (95% CI 8.5–33.6 mm) at 24 h, and 17.4 mm (95% CI 8–26 mm) at 48 h. This represents about a 50% decrease in postoperative pain at rest (Tables 2 and 3).
There were no statistically significant differences in FEV1 at 24 and 48 h between higher and lower dose bupivacaine trials. Pulmonary function recovered faster in the higher dose bupivacaine group; by 72 h after surgery, the difference reached significance (20.1% better improvement in FEV1, 95% CI 2.08–38.07%, P=0.029) (Table 4).
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Three trial arms evaluated PVB with ropivacaine.14 28 53 Only one53 evaluated postoperative pain at all three time points (8, 24, and 48 h), and no trial evaluated postoperative spirometry. No meta-analysis for the effect of ropivacaine dose was therefore performed. However, scatter plots of perceived pain against dosage appear similar to those for bupivacaine (Fig. 3).
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No meta-analysis for the effect of lidocaine dose was attempted, as the two trial arms of PVB with lidocaine used virtually identical dosage regimes: 1890 mg and 1780 mg per 24 h, respectively.4 83
Continuous infusion vs intermittent bolus technique
One direct comparison between bolus and infusion technique for maintenance of PVB was found.15 This showed a slight improvement in VAS at 24 h after operation when an infusion regime was used. The difference was 15 mm at rest and 23 mm upon coughing (P=0.003 in both cases). The LA dosages used were identical but low. This study did not report on postoperative lung function.
An indirect comparison of studies using boluses15 36 and continuous infusions8 13 15 25 29 33 46 47 52 65 70 72 75 83 84 for maintenance revealed that the use of a continuous infusion for maintenance of PVB is associated with an improvement in analgesia at rest at all time points up to 48 h. The effect size was 29.8 mm at 8 h (95% CI 0.98–58.7 mm, P=0.04), 26.7 mm at 24 h (95% CI 9.2–44.3 mm, P=0.003), and 23.3 mm at 48 h (95% CI 13.7–32.9 mm, P<0.001). As was the case for an increase in LA dosage, there was a trend towards improved dynamic analgesia in the few trials that reported on this, but it did not reach statistical significance (Table 5).
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Neither of the studies using PVB bolus regimes15 36 evaluated postoperative pulmonary mechanics. There is therefore no evidence available from indirect or direct comparisons about the effect of administration technique on pulmonary mechanics or the incidence of complications.
Choice of LA
We identified two direct comparisons between lidocaine and bupivacaine for PVB.4 83 Neither found a difference between bupivacaine and lidocaine in terms of VAS at rest, morphine requirements, or postoperative pulmonary function. Meta-analysis also found no statistically significant difference (P=0.06, Table 6). No studies directly compared bupivacaine and ropivacaine. Regression analysis revealed no difference in analgesic quality between trials that administered bupivacaine8 13 15 25 29 33 46 47 52 65 70 72 75 83 84 or ropivacaine14 28 53 (P=0.705, Table 6).
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The use of additives to LA
Clonidine
One trial directly evaluated the addition of clonidine (2 µg kg–1 h–1) to an infusion of bupivacaine for PVB. The authors8 found a modest (9 mm on a 100 mm VAS) improvement in the overall marginal mean postoperative VAS score after thoracotomy. There was no difference in lung function between the groups.
When an indirect comparison was made between the results achieved in the clonidine group of the above trial and the trial arms using plain bupivacaine,8 13 15 25 29 33 46 47 52 65 70 72 75 83 84 no difference was found in pain scores (P=0.7, Table 6).
Fentanyl
No direct comparisons between LA-only PVB and PVB with adjuvant opioid were identified. Eighty-nine patients in three trial arms10 62 received LAs with fentanyl during the course of trials comparing PVB with bupivacaine and ropivacaine, and PVB with epidural analgesia, respectively.
There was no difference found in analgesia between the trials that added fentanyl to the LA for PVB, and those that did not8 13 15 25 29 33 36 46 47 52 65 70 72 75 83 84 (P=0.648, Table 6).
Timing of PVB
Only one study directly compared pre-emptive PVB with an identical regimen established immediately after surgery.71 In an elegant two3 factorial trial, Richardson and colleagues compared the presence or absence of opioid premedication, presence/absence of non-steroidal anti-inflammatory premedication, and presence/absence of pre-emptive PVB. Those patients who received all three components of their pre-emptive analgesia regimen had significantly better analgesia, faster recovery of pulmonary mechanics, and less stress hormone release. Although statistically significant, the magnitude of the difference in perceived pain with pre-emptive PVB was small: mean VAS scores were improved by 5.1 mm on a 100 mm scale at 24 h after surgery. The observed difference in lung function was of clinical and statistical significance.
The results of the regression analysis do not support the conclusion of the above-mentioned trial. All studies reported on timing of PVB. PVB was established before skin incision in eight.14 52 62 65 70–73 No significant difference was found between pre-emptive PVB and block established after surgery at rest or on coughing, at 8 or 24 h after operation, although there was a trend towards improved analgesia in those groups who received PVB before skin incision. The respective P-values were 0.187 and 0.294 for analgesia at rest, and P=0.07 and 0.270 for analgesia on coughing (Table 6). At 48 h after surgery, pre-emptive PVB seems statistically to be associated with an improvement in analgesia at rest of 13.6 mm on a 100 mm scale (P=0.005, 95% CI 4–23 mm), but associated with significantly higher pain scores on coughing (21.1 mm, 95% CI 13–28 mm, P<0.001).
Patient-controlled analgesia in addition to PVB
This review found no direct comparisons on whether opioid administered via patient-controlled analgesia (PCA) is superior to intermittent administration for post-thoracotomy analgesia, when added to PVB.
Nine trial regimes included the use of a morphine PCA.26 52 53 65 69–72 74 83 Regression analysis revealed that the use of a morphine PCA did not predict an improvement in postoperative pain (P=0.21, Table 6) over the administration of intermittent opioids. There was no detectable relationship between postoperative pain scores and morphine consumption via PCA (P=0.93). Higher consumption of PCA morphine did not predict better analgesia, nor did higher pain scores predict consumption of more PCA morphine (Fig. 4).
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Complications of PVB
The occurrence of complications of the PVB or of surgery was not as well reported as pain scores and pulmonary function.
Possible LA toxicity (manifested by confusion that resolved after LA administration was stopped, convulsions or cardiac dysrhythmias) was the only complication reported in the majority of studies. Only 15 of the 19 studies using bupivacaine8 13 15 25 29 33 46 47 52 65 70 72 75 83 84 reported specifically whether this complication occurred or not. Neurological effects which may have been due to LA toxicity occurred in four of 225 patients in the higher dose bupivacaine trials, compared with two of 110 patients in the lower dose trials (P=1.0). Cardiac arrhythmias occurred in two of 173 patients who received higher dose bupivacaine, and none of the 69 patients who received lower dose bupivacaine (P=1.0) (Table 7). No lasting patient harm was reported due to possible LA toxicity.
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Discussion |
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This indirect comparison of data from 25 RCTs found that higher dose LA regimens for PVB and the use of continuous infusions for maintenance are predictive of lower VAS scores up to 48 h after thoracotomy; decreasing postoperative pain by around 50% in each case. Choice of one LA over another, the addition of clonidine or fentanyl, or the use of patient-controlled morphine over intermittent parenteral morphine were not found to be predictive of less pain.
Our meta-analysis is different from previous ones on this topic, which were concerned with establishing the superiority of one technique over another. Because of the great heterogeneity between previous direct comparisons, we were unable to conduct a meta-analysis which preserved the randomized nature of the original trials. We therefore include indirect comparisons between the treatment arms of different trials. These are by nature not randomized, and vulnerable to confounding factors and other sources of bias. However, indirect comparisons are common in anaesthesia, for example, the Oxford Pain Relief Unit's Bandolier league table,85 and meta-analyses of postoperative nausea and vomiting42 81 and postoperative shivering.43 49 Indirect comparisons are also published in internal medicine.35 37 A systematic review of all medical meta-analyses published over a 5 yr period39 found that 9.5% (31 of 327) contained an indirect comparison.
We used metaregression to analyse any continuous data in this review to assess the association between different aspects of PVB technique (exposure) and outcome. Metaregression may partially compensate for the non-randomized nature of the comparisons where there is heterogeneity between different trials, but the differences within trials and within the groups of trials are small.39 This review deals with just such a situation. Robust indirect comparisons are graded as level II evidence by some authors, alongside direct randomized trials with surrogate outcomes, and ahead of non-randomized direct comparisons.55 56
Post-thoracotomy pain arises as a consequence of pleural and muscular damage, costovertebral joint disruption,70 and intercostal nerve damage.63 Peripheral and central sensitization as a consequence of acute tissue damage and progenitor of severe acute and chronic pain has also been demonstrated in a variety of animal models and experiments in human subjects.23 24 33 There is consensus that a multimodal analgesic regimen, incorporating a form of neural blockade, simple analgesics, and strong opioids, is optimal after thoracotomy.21 27 32 33 48 50 59 67 71 77 78
From our analyses, the strongest predictor of improved analgesia (and hence a lower failure rate) after thoracotomy is a higher dose of LA. Postoperative pain appears to be decreased by around 50% with higher dose regimens, which is both clinically and statistically significant. Perhaps even more importantly, the improved analgesia from higher dose regimes also translated into better recovery in pulmonary function. Pulmonary complications and mortality data were not reported widely enough for us to examine formally whether higher doses of LA also improve survival.
There is good evidence that the addition of PVB improves analgesia, when compared with systemic opioid only.30 45 73 Our meta-analysis found that giving patients free access to opioid via PCA in addition to PVB appears not to improve analgesia greatly. This confirms that some form of neural block may be valuable for post-thoracotomy analgesia. There was no clear relationship between opioid requirement and the mean pain scores achieved in the reviewed trials. Higher opioid consumption did not predict better analgesia, and patients did not appear to use more PCA morphine in those studies with higher pain scores. This suggests that patients limited their use of PCA morphine because of other factors than achieving good analgesia; a finding which is supported by literature specific to PCA.11 18 19 34 76 79
Pre-emptive PVB51 58 and the use of an additive to LA were the subject of only one direct comparison each.8 71 In each case, the authors found a modest improvement in perceived pain. Their conclusions are not supported by our findings. Adjuvant clonidine increased the risk of sedation.8
We were unable to find any procedure-specific evidence to recommend any one technique of establishing PVB. Of note is that most researchers in this field have taken steps to ensure that LA spreads longitudinally along the vertebral column and thus covers a number of spinal segments. A single-injection technique has been shown to produce a block that is safe but unpredictable in spread,16 20 22 40 and multiple injections have been shown to produce superior results in patients undergoing breast, thoracic, and upper abdominal surgery.60 61
The improvement in analgesia and pulmonary mechanics with the use of higher doses of paravertebral LA shown above must be balanced against the risk of possible LA toxicity. The absorption of bupivacaine from the paravertebral space has been shown to be rapid, with accumulation to toxic levels shown after prolonged infusion at 0.5 mg kg–1 h–1, 6 12 17 25 but not when dosage is reduced to 0.25 mg kg–1 h–1 after 24 h.46 The incidence of possible LA toxicity was not significantly different between lower and higher dose trials, even though one65 used doses less than the manufacturer's recommendation. No patient in any of the trials in this review suffered convulsions. One of the two cases of cardiac arrhythmia (atrial fibrillation) in the higher dose trials26 was reported by the authors as being related to intrinsic cardiac disease. It was successfully treated without stopping the LA infusion. The other was not commented on.70 A previous systematic review found an incidence of 0.8% for LA toxicity after PVB with bupivacaine. All cases presented as transient confusion only.30 The incidence of serious LA toxicity with higher dose regimes is likely to be low regardless of agent, especially where high doses are administered for 24 h or less. The incidence of such rare events may best be established through a collaborative audit project rather than a research study.
Ropivacaine does not appear to accumulate in the same linear manner as bupivacaine, and is seen by some authors as a safer choice for PVB.16 28 53 The trials that evaluated the use of ropivacaine for PVB14 28 53 did not explicitly report on LA toxicity, and this review can therefore present no safety data to compare bupivacaine with other LAs. Ropivacaine appears equipotent with bupivacaine, despite being given in doses far closer to the recommended maximum.2
This review does have weaknesses. As already stated, our comparisons were non-randomized and therefore essentially observational in nature, although the statistical technique of meta-regression partially compensates for this.39 55 The data on postoperative complications should be interpreted cautiously, as the quality of complication reporting in the original studies was variable. There was no consistent reporting of a preoperative risk assessment, and therefore no reliable way of comparing data on mortality or pulmonary morbidity across trials. The exclusion of two small trials not published in English is unlikely materially to affect our results.
In conclusion, we present evidence on optimizing PVBs after thoracotomy, from both direct and indirect comparisons (Table 8). Prospective and specific research on the effect of LA dosage on post-thoracotomy pain is needed before definitive conclusions may be drawn on what the optimal dosage may be. Safety data are also urgently required. The question of whether PVB or TEA is best after thoracotomy is yet unanswered. Ultimately, a direct comparison between optimized TEA and PVB regimes is necessary. The definitive answer on how best to manage pain, rehabilitation, and risk in this difficult group of patients is still not clear.
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