British Journal of Anaesthesia 103 (5): 626–36 (2009)

doi:10.1093/bja/aep272

REVIEW ARTICLES
Efficacy and safety of different techniques of paravertebral block
for analgesia after thoracotomy: a systematic
review and metaregression
A. Kotzé1*, A. Scally2 and S. Howell3
1
Airedale NHS Trust, Steeton, Keighley BD20 6TD, UK. 2School of Health Studies, Bradford University, UK.
3
Academic Unit of Anaesthesia, University of Leeds, UK
*Corresponding author. E-mail: alwynkotze@doctors.net.uk
Various techniques and drug regimes for thoracic paravertebral block (PVB) have been evalu-
ated 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 (P¼0.006 at 8 h, P¼0.001 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%, P¼0.029).
Continuous infusions of LA predicted lower pain scores compared with intermittent boluses
(P¼0.04 at 8 h, P¼0.003 at 24 h, and P,0.001 at 48 h). The use of adjuvant clonidine or fenta-
nyl, 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.
Br J Anaesth 2009; 103: 626–36
Keywords: anaesthetic techniques, regional, thoracic; analgesia, postoperative; pain, acute,
regional techniques; surgery, thoracic; thoracic anaesthesia

Thoracotomy frequently causes severe postoperative pain
and significant morbidity.10 27 Atelectasis, pneumonia, pul-
monary embolism, and emergency intensive care admission
have all been found to be related to poor analgesia and con-
sequent immobility.27 66 Postoperative pain is thought to be
the single most important factor leading to ineffective venti-
lation 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 col-
leagues27 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 pul-
monary 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 inci-
dence of pulmonary complications compared with sys-
temic analgesia, whereas TEA did not.45 PVB may

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 Efficacy and safety of different techniques of PVB
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:
(i) LA dose;
(ii) administration technique, that is, continuous infusion
or intermittent boluses;
(iii) choice of LA agent;
(iv) the addition of fentanyl or clonidine to LA;
(v) pre-emptive PVB;
(vi) the addition of patient-controlled opioids to PVB.
Methods
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:
(i) randomized controlled trials (RCTs) in which at least
one trial group received paravertebral LA with or
without additives, and
(ii) postoperative pain control, pulmonary function, or
both reported as outcome measure.
Only trials involving adult patients were considered. The
keywords ‘paravertebral block’, ‘nerve block’, ‘paraverte-
bral’, ‘extrapleural’, ‘subpleural’, ‘retropleural’, ‘intercos-
tal nerve block’, ‘thoracotomy’, ‘pneumonectomy’,
‘oesophagectomy’, and the corresponding Medical Subject
Headings (MeSH) were used alone and combined with
Boolean operators.
The electronic search identified 66 papers for consider-
ation. 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 Excelw and analysed
using STATAw (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
627
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 percen-
tage 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 dose¼
loading doseþ24(infusion dose h21). Dosages were cal-
culated 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 devi-
ation (SD) was reported, the SE was calculated
p using the
formula for a normal distribution (SE¼SD/ 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 dichoto-
mous data, using Fisher’s exact test.
Results
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 under-
going 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 com-
pared repeated paravertebral boluses of bupivacaine
against systemic analgesia. Both the stated dose (0.1 mg
kg21) 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.
 Kotzé et al.

Papers identified
The trial was therefore excluded from meta-analysis.
Not randomized trials: n = 10
n = 68 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
Randomized controlled trials
No PVB group: n = 27 PVB and reported no data on pain or pulmonary function
n = 58
(Fig. 1).
The 25 trials included had recruited 763 patients to 31
RCTs with at least one PVB
PVB treatment arms (Table 1). Obtaining original patient
Not published in English: n = 2
group
No pain measurements: n = 1 data for all the included trials proved impossible.
n = 31
Seven trials conducted comparisons of different paraver-
tebral drug regimes.4 8 15 36 62 71 83 However, these trials
RCTs included in review Not an RCT in thoracotomy: n = 1 evaluated a total of nine different drug and dosage
n = 28 Unexplained patient drop-outs: n = 1 regimes. Four trials were placebo-controlled, with all
PVB dosage unclear: n = 1
patients having access to rescue medication and regular
simple analgesics.5 29 33 75 Two different PVB regimes
RCTs included in meta- were evaluated against control groups who, in turn,
analysis
n = 25 received two different analgesic regimens. One of these29
also had a control group receiving only systemic analgesia
Fig 1 QUORUM flowchart showing included and excluded studies. without a sham PVB. Three trials evaluated the addition

Table 1 Details of included studies. B, bupivacaine

Trial n Compared against Loading dose Maintenance 24 h PCA

total

Groups receiving bupivacaine infusions

Perttunen and colleagues65 15 Epidural (local only)þsingle-injection IC 8 –12 ml 0.25% B 4– 8 ml h21 0.25% B 385 Yes
nerve blocks
Richardson and colleagues70 46 Epidural (local only) 20 ml 0.5% B 0.1 ml kg21 h21 0.5% 990 Yes
(pre-incision)þ20 ml 0.25% B
B (end of surgery)
Bhatnagar and colleagues8 14 Two paravertebral groups: plain bupivacaine B 2 mg kg21 (0.125%) 0.5 mg kg21 h21 980 No
and bupivacaineþclonidine. Plain group’s (0.125%)
data used
Barron and colleagues4 22 Two paravertebral groups: bupivacaine, B 0.3 ml kg21 0.25% 0.1 ml kg21 h21 472.5 No
lidocaine, against placebo. Bupivacaine 0.25%
group used
Sabanathan and colleagues75 29 Placebo (both had access to i.m. opioid) B 100 mg 0.1 ml kg21 h21 0.5% 940 No
B
Dauphin and colleagues 26
24 Lumbar epidural morphine infusion B with epinephrine 1:200 000 0.1 ml kg21 h21 0.5% 950 Yes
B
Catala and colleagues15 15 Two paravertebral regimes: infusion and B 0.375% 15 ml with 5 ml h21 0.25% B 6.25 No
paravertebral bupivacaine and norepinephrine epinephrine 1:200 000 with epinephrine
boluses 6-hourly 1:200 000
Richardson and colleagues72 22 Interpleural bupivacaine B 150 mg 0.1 ml kg21 h21 0.5% 990 Yes
B
Carabine and colleagues13 10 PCA morphine B 25 mg 5 ml h21 0.25% 325 Yes
bupivacaine
Eng and Sabanathan33 40 Placebo (both had access to i.m. opioid) B 100 mg 0.5 mg kg21 h21 940 No
bupivacaine
Berrisford and Sabanathan6 25 Placebo (both had access to i.m. opioid) B 100 mg 7 ml h21 0.5% 940 No
bupivacaine
Luketich and colleagues52 47 Epidural (B 0.125% and PF morphine 0.05 10 ml 0.5% B 0.1 ml kg21 h21 470 Yes
mg ml21) 0.25% B
Kaiser and colleagues46 15 Epidural (B 0.25 –0.375%þfentanyl 2 mg 20 ml 0.5%B 0.1 ml kg21 h21 0.5% 940 No
ml21) B
Watson and colleagues83 23 Two paravertebral groups: bupivacaine 0.5% 10 ml 0.5% B 0.1 ml kg21 h21 0.5% 890 Yes
and lidocaine 1% in identical volumes B
Deneuville and colleagues29 26 Placebo and regular i.m. buprenorphine 20 ml 0.5% B 3 ml h21 0.5% B 460 No
Wedad and colleagues84 20 Epidural (local only), interpleural block 10 ml 0.25% B 6 ml h21 0.25% B 385 No
Richardson and colleagues71 56 Pre-emptive PVB vs PVB after surgery 20 ml 0.5% B 0.1 ml kg21 h21 0.5% 990 No
B
Richardson and colleagues69 10 20 ml 0.5% B 0.1 ml kg21 h21 of 990 No
0.5% B
Richardson and colleagues74 6 Interpleural bupivacaine 20 ml 0.5% B 0.1 ml kg21 h21 of 990 No
0.5% B
465

628
 Efficacy and safety of different techniques of PVB

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 compari-
son 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 adminis-
tration 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).
Metaregression confirmed that this apparent relationship
is significant. Higher dose paravertebral bupivacaine was
strongly predictive of lower VAS scores at rest, when com-
pared with lower dose regimes at 8 h after operation
(P¼0.006), 24 h (P¼0.001), 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

Bupivacaine dose vs pain scores at rest: 8 h Bupivacaine dose vs pain scores on coughing: 8 h
100 100
Mean VAS score on
VAS score at rest

80 80
60
coughing

60
40
40
20
20
0
0 0 200 400 600 800 1000 1200
–20
0 200 400 600 800 1000 1200
Bupivacaine dose (mg per 24 h)
Bupivacaine dose (mg per 24 h)
Bupivacaine dose vs pain scores at rest: 24 h Bupivacaine dose vs pain scores on coughing: 24 h
100
60
Mean VAS score on

50 80
40
coughing

60
VAS at rest

30
40
20
10 20
0 0
0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200
–10
Bupivacaine dose (mg per 24 h) Bupivacaine dose (mg per 24 h)

Bupivacaine dose vs pain scores at rest: 48 h Bupivacaine dose vs pain scores on coughing: 48 h
50 70
Mean VAS scores

Mean VAS score on

40 60
50
coughing

30 40
20 30
20
10
10
0 0
0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200
Bupivacaine dose (mg per 24 h) Bupivacaine dose (mg per 24 h)

Fig 2 Scatter plots of visual analogue scores vs bupivacaine dosage. Bubble graphs depicting resting and dynamic visual analogue scores at 8, 24, and
48 h after thoracotomy. The diameter of each bubble is proportional to the number of patients in the PVB group(s) of each trial.

629
 Kotzé et al.

Table 2 Bupivacaine dosage and pain at rest. Results of a meta-regression showing the effect of higher dose bupivacaine (890 –990 mg per 24 h) over lower
dose bupivacaine (325 – 472.5 mg per 24 h). VAS values are presented as mean (SE). 95% CI, 95% confidence interval for effect-size estimate; P, probability
value for effect size existing by chance

VAS lower dose Effect-size estimate for higher 95% CI (mm) P-value No. of studies
bupivacaine (mm) dose bupivacaine (mm)

8 h after operation 40 (8) 227 27 to 246 0.006 10

24 h after operation 34 (5) 221 28 to 234 0.001 12
48 h after operation 27 (3) 217 29 to 226 ,0.001 12

Table 3 Bupivacaine dosage and pain on coughing. Results of a meta-regression showing the effect of higher dose bupivacaine (890 – 990 mg per 24 h) over
lower dose bupivacaine (325 –472.5 mg per 24 h). VAS values are presented as mean (SE). 95% CI, 95% confidence interval for effect-size estimate; P,
probability value for effect size existing by chance

Pooled VAS low-dose Effect size estimate for higher 95% CI (mm) P-value No. of studies
bupivacaine (mm) dose bupivacaine (mm)

8 h after operation 29 (2) 2 215 to 20 0.804 4

24 h after operation 32 (2) 3 211 to 18 0.625 5
48 h after operation 26 (2) 4 210 to 18 0.580 5

Table 4 Bupivacaine dosage and postoperative pulmonary function. Results of a meta-regression showing the effect of higher dose bupivacaine (890 –990 mg
per 24 h) over lower dose bupivacaine (325 –472.5 mg per 24 h). Spirometry values are presented as a percentage of preoperative values, mean (SE). 95% CI,
95% confidence interval for effect-size estimate; P, probability value for effect size existing by chance

Pooled FEV1 lower Effect-size estimate for higher 95% CI (%) P-value No. of studies
dose bupivacaine (%) dose bupivacaine (%)

24 h after operation 54 (5) 10 22 to 23 0.11 19

48 h after operation 60 (7) 11 26 to 28 0.20 18
72 h after operation 46 (7) 20 2 to 38 0.02 6

The effect-size estimate for VAS improvement with Ropivacaine dose vs pain scores at rest: 24 h
higher dose bupivacaine was 26.9 mm (95% CI 7.5– 46.3 40
mm) at 8 h after operation, 21.1 mm (95% CI 8.5– 33.6 35
Mean VAS at rest

mm) at 24 h, and 17.4 mm (95% CI 8 – 26 mm) at 48 30

25
h. This represents about a 50% decrease in postoperative
20
pain at rest (Tables 2 and 3). 15
There were no statistically significant differences in 10
FEV1 at 24 and 48 h between higher and lower dose 5
bupivacaine trials. Pulmonary function recovered faster in 0
0 200 400 600 800 1000
the higher dose bupivacaine group; by 72 h after surgery,
Ropivacaine dose (mg per 24 h)
the difference reached significance (20.1% better improve-
ment in FEV1, 95% CI 2.08238.07%, P¼0.029) Fig 3 Scatter plots of visual analogue scores vs ropivacaine dosage.
Bubble graphs depicting resting and dynamic visual analogue scores at
(Table 4).
24 h after thoracotomy. The diameter of each bubble is proportional to
Three trial arms evaluated PVB with ropivacaine.14 28 53 the number of patients in the PVB group(s) of each trial.
Only one53 evaluated postoperative pain at all three time
points (8, 24, and 48 h), and no trial evaluated postopera-
tive spirometry. No meta-analysis for the effect of ropiva- Continuous infusion vs intermittent bolus technique
caine dose was therefore performed. However, scatter plots One direct comparison between bolus and infusion tech-
of perceived pain against dosage appear similar to those nique for maintenance of PVB was found.15 This showed
for bupivacaine (Fig. 3). a slight improvement in VAS at 24 h after operation when
No meta-analysis for the effect of lidocaine dose was an infusion regime was used. The difference was 15 mm
attempted, as the two trial arms of PVB with lidocaine at rest and 23 mm upon coughing (P¼0.003 in both
used virtually identical dosage regimes: 1890 mg and cases). The LA dosages used were identical but low. This
1780 mg per 24 h, respectively.4 83 study did not report on postoperative lung function.

630
 Efficacy and safety of different techniques of PVB

An indirect comparison of studies using boluses15 36 and The use of additives to LA

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 improve-
ment 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,
P¼0.04), 26.7 mm at 24 h (95% CI 9.2– 44.3 mm,
P¼0.003), 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 stat-
istical significance (Table 5).
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 signifi-
cant difference (P¼0.06, Table 6). No studies directly
compared bupivacaine and ropivacaine. Regression analy-
sis 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 (P¼0.705, Table 6).
Clonidine
One trial directly evaluated the addition of clonidine (2 mg
kg21 h21) 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
(P¼0.7, 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 (P¼0.648,
Table 6).
Timing of PVB
Only one study directly compared pre-emptive PVB with
an identical regimen established immediately after

Table 5 Effect of continuous infusion techniques. Results of a meta-regression showing the effect of continuous infusion techniques for maintenance,
compared with intermittent boluses. VAS values are presented as mean (SE). 95% CI, 95% confidence interval for effect-size estimate; P, probability value for
effect size existing by chance

VAS at rest with bolus Effect size estimate for 95% CI (mm) P-value No. of studies
regimes (mm) infusion regimes (mm)

8 h after operation 54 (14) 224 21 to 258 0.04 16

24 h after operation 49 (8) 223 216 to 230 0.003 22
48 h after operation 40 (4) 216 213 to 232 ,0.001 21
VAS on coughing with Effect-size estimate for 95% CI (mm) P-value No. of studies
bolus regimes (mm) infusion regimes (mm)

8 h after operation 35 (5) 214 26.65 to 35.18 0.18 7

48 h after operation 26 (5) 10 218 to 40 0.47 10

Table 6 Postoperative pain and PVB maintenance regimes. Results of regression analyses showing the effects of different PVB regimes at rest 24 h after
operation. VAS values are presented as mean (SE). 95% CI, 95% confidence interval for effect-size estimate; P, probability value for effect size existing by
chance

Pooled VAS at rest, 24 Effect-size estimate (mm) 95% CI (mm) P-value No. of studies
h after operation (mm)

Lidocaine vs bupivacaine 20 (4) 222 246 to 1 0.063 14

Ropivacaine vs bupivacaine 20 (4) 23 221 to 14 0.705 15
Clonidine added to local anaesthetic 28 (4) 8 234 to 51 0.705 21
Fentanyl added to local anaesthetic 28 (4) 5 219 to 31 0.648 21
Pre-emptive PVB 30 (5) 11 29 to 32 0.294 22
Morphine via PCA added to PVB 30 (5) 13 27 to 35 0.211 22

631
 Kotzé et al.
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 stat-
istically significant, the magnitude of the difference in per-
ceived 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 differ-
ence 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 P¼0.07 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 (P¼0.005, 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 improve-
ment in postoperative pain (P¼0.21, Table 6) over the
administration of intermittent opioids. There was no
detectable relationship between postoperative pain scores
and morphine consumption via PCA (P¼0.93). Higher
consumption of PCA morphine did not predict better
analgesia, nor did higher pain scores predict consumption
of more PCA morphine (Fig. 4).
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
632
PCA morphine consumption and pain scores
60 at rest: 24 h
Mean VAS score
50
40
30
20
10
0
0 20 40 60 80 100
Amount of PCA morphine in first 24 h (mg)
Fig 4 PCA morphine consumption and pain scores. Bubble graphs
depicting resting and dynamic visual analogue scores at 24 h after
thoracotomy. The diameter of each bubble is proportional to the number
of patients in the PVB group(s) of each trial.
Table 7 Bupivacaine dose and complication incidence
Lower dose trials Higher dose trials P-value
Neurology 2/110 4/225 1.0
Cardiac arrhythmias 0/69 2/173 1.0
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 (P¼1.0). Cardiac arrhythmias
occurred in two of 173 patients who received higher dose
bupivacaine, and none of the 69 patients who received
lower dose bupivacaine (P¼1.0) (Table 7). No lasting
patient harm was reported due to possible LA toxicity.
Discussion
This indirect comparison of data from 25 RCTs found that
higher dose LA regimens for PVB and the use of continu-
ous infusions for maintenance are predictive of lower VAS
scores up to 48 h after thoracotomy; decreasing postopera-
tive 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 par-
enteral 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 superior-
ity 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
 Efficacy and safety of different techniques of PVB
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 hetero-
geneity 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 exper-
iments 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 pulmon-
ary function. Pulmonary complications and mortality data
were not reported widely enough for us to examine for-
mally 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 achiev-
ing good analgesia; a finding which is supported by litera-
ture 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 per-
ceived pain. Their conclusions are not supported by our
findings. Adjuvant clonidine increased the risk of sedation.8
633
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 ver-
tebral column and thus covers a number of spinal seg-
ments. 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 mech-
anics 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 para-
vertebral space has been shown to be rapid, with accumu-
lation to toxic levels shown after prolonged infusion at 0.5
mg kg21 h21, 6 12 17 25 but not when dosage is reduced to
0.25 mg kg21 h21 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 success-
fully 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 con-
fusion 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 rec-
ommended 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 mor-
tality or pulmonary morbidity across trials. The exclusion
of two small trials not published in English is unlikely
materially to affect our results.
 Kotzé et al.

Table 8 Conclusions continuous extrapleural intercostal nerve block. Eur J Cardiothorac

Surg 1990; 4: 407– 11
Evidence from head-to-head Continuous infusion techniques are
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regression analysis techniques for maintenance of PVB Clonidine as an analgesic adjuvant to continuous paravertebral
Bupivacaine and lidocaine are equally bupivacaine for post-thoracotomy pain. Anaesth Intensive Care
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PVB increases the risk of undue
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