Articles

Continuous wound infiltration versus epidural analgesia

after hepato-pancreato-biliary surgery (POP-UP):
a randomised controlled, open-label, non-inferiority trial
Timothy H Mungroop, Denise P Veelo, Olivier R Busch, Susan van Dieren, Thomas M van Gulik, Tom M Karsten, Steve M de Castro,
Marc B Godfried, Bram Thiel, Markus W Hollmann, Philipp Lirk, Marc G Besselink

Summary
Background Epidural analgesia is the international standard for pain treatment in abdominal surgery. Although some Lancet Gastroenterol Hepatol
studies have advocated continuous wound infiltration with local anaesthetics, robust evidence is lacking, especially on 2016; 1: 105–13

patient-reported outcome measures. We aimed to determine the effectiveness of continuous wound infiltration in Published Online
July 7, 2016
hepato-pancreato-biliary surgery.
http://dx.doi.org/10.1016/
S2468-1253(16)30012-7
Methods In this randomised controlled, open label, non-inferiority trial (POP-UP), we enrolled adult patients See Comment page 87
undergoing hepato-pancreato-biliary surgery by subcostal or midline laparotomy in two Dutch hospitals. Patients were Department of Surgery
centrally randomised (1:1) to receive either pain treatment with continuous wound infiltration using bupivacaine plus (T H Mungroop MD,
patient-controlled analgesia with morphine or to receive (patient-controlled) epidural analgesia with bupivacaine and Prof O R Busch MD,
sufentanil. All patients were treated within an enhanced recovery setting. Randomisation was stratified by centre and S van Dieren PhD,
Prof T M van Gulik MD,
type of incision. The primary outcome was the mean Overall Benefit of Analgesic Score (OBAS) from day 1–5, a M G Besselink MD) and
validated composite endpoint of pain scores, opioid side-effects, and patient satisfaction (range 0 [best] to 28 [worst]). Department of
Analysis was per-protocol. The non-inferiority limit of the mean difference was + 3·0. This trial is registered with the Anaesthesiology
(T H Mungroop, D P Veelo MD,
Netherlands Trial Registry, number NTR4948.
S van Dieren,
Prof M W Hollmann MD,
Findings Between Jan 20, 2015, and Sept 16, 2015, we randomly assigned 105 eligible patients: 53 to receive P Lirk MD), Academic Medical
continuous wound infiltration and 52 to receive epidural analgesia. One patient in the continuous wound infiltration Centre, Amsterdam,
Netherlands; and Department
group discontinued treatment, as did five in the epidural analgesia group; of these five patients, preoperative
of Surgery (T M Karsten MD,
placement failed in three (these patients were treated with continuous wound infiltration instead), one patient S M de Castro MD) and
refused an epidural, and data for the primary endpoint was lost for one. Thus, 55 patients were included in the Department of
continuous wound infiltration group and 47 in the epidural analgesia group for the per-protocol analyses. Anaesthesiology
(M B Godfried MD, B Thiel MSc),
Mean OBAS was 3·8 (SD 2·4) in the continuous wound infiltration group versus 4·4 (2·2) in the epidural group
OLVG Oost, Amsterdam,
(mean difference –0·62, 95% CI –1·54 to 0·30). Because the upper bound of the one-sided 95% CI did not exceed Netherlands
+3·0, non-inferiority was shown. Four (7%) patients in the continuous wound infiltration group and five (11%) of Correspondence to:
those in the epidural group had an adverse event. One patient in the continuous wound infiltration group had a Dr Marc G Besselink, Academic
serious adverse event (temporary hypotension and arrhythmia after bolus injection); no serious adverse events were Medical Centre, Department of
Surgery, G4-196, PO Box 22660,
noted in the epidural group.
1100 DD Amsterdam,
Netherlands
Interpretation These data suggest that continuous wound infiltration is non-inferior to epidural analgesia in m.g.besselink@amc.nl
hepato-pancreato-biliary surgery within an enhanced recovery setting. Further large-scale trials are required to make
a definitive assessment of non-inferiority.

Funding Academic Medical Centre, Amsterdam, Netherlands.

Introduction for preoperative placement in awake patients, considered

Prevention of postoperative pain is essential for the
recovery of surgical patients. Epidural analgesia is
currently the international standard for perioperative
pain treatment in abdominal surgery.1 The excellent
analgesic effect of epidural analgesia is clearly
established, but there are several potential dis-
advantages—eg, perioperative hypotension with the
need to administer vasopressors; the risk of rare but
serious neurological complications (epidural haematoma
and abscess, with an incidence of one in 1000–6000 for
thoracic epidurals2–4); failure rates in up to 30% of
patients with periods of inadequate analgesia;5 and need
as cumbersome by many patients, sometimes leading to
refusal.6,7
Continuous wound infiltration with local anaesthetics
has been suggested as an alternative for epidural
analgesia for pain control after laparotomy. However,
randomised trials including patient-reported outcome
measures are currently lacking.8 Standard pain scores do
not take adverse effects into account and cannot explain
variance in patients’ satisfaction with pain therapy.9
Additionally, intraoperative hypotension is associated
with adverse outcomes such as acute kidney injury10 and
an increased 30-day mortality.11 Finally, the current

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Research in context
Evidence before this study
We did a systematic review in PubMed, Embase, and the Cochrane
Library for studies concerning continuous wound infiltration and
epidural analgesia in abdominal surgery published until
Jan 1, 2016. The search terms used were “pain prevention”,
“epidural analgesia”, “continuous wound infiltration”, “wound
catheters”, and synonyms. The most relevant studies were
two systematic reviews. The systematic review by Ventham and
colleagues (2013) concluded that both methods provided a
similar analgesic effect after abdominal surgery. Continuous
wound infiltration proved to be a reliable alternative, with less
urinary retention. When tested in an enhanced recovery setting, as
Hughes and colleagues (2014) showed in their systematic review,
epidural analgesia did not provide benefits for improved recovery
or reduced morbidity. However, none of the included studies have
integrated patient-reported outcomes in the primary endpoint.
Added value of this study
To the best of our knowledge, this is the first study comparing
perioperative continuous wound infiltration and epidural
literature consists of relatively small trials, often with the
use of suboptimal clinical standards in heterogeneous
patient populations. We chose the field of hepato-
pancreato-biliary surgery because the procedures are
comparable in terms of length and location of incision.
The aim of this study was to determine whether
continuous wound infiltration is non-inferior to epidural
analgesia using patient-reported outcome measures in a
homogeneous patient population with optimal clinical
standards.
Methods
Study design and participants
The POP-UP study was a two-centre, randomised
controlled, open label, non-inferiority trial. The rationale
and design of the trial have been described in detail
elsewhere.12
Adults undergoing subcostal or midline laparotomy
for hepato-pancreato-biliary indications at the Academic
Medical Centre Amsterdam and the OLVG teaching
hospital, Amsterdam, Netherlands, were eligible for
inclusion. Patients were informed about the study at the
outpatient department and were contacted afterwards
by the study coordinator. All patients gave written
informed consent. Patients were excluded if any of the
following criteria were present: American Society of
Anesthesiologists status of greater than 3, chronic opioid
use (>1 year), renal failure (estimated glomerular filtration
rate <40), contraindication for epidural analgesia, allergy
for study medication, liver failure (Child-Pugh class C), or
coagulopathies (international normalised ratio >1·5,
partial thromboplastin time >1·5, platelets <80 × 10⁹ per L).
This study was investigator-initiated and investigator-
driven and done in accordance with the principles of the
106
analgesia using a validated instrument for the assessment of
both pain control and patient-reported outcomes. Because of
the reported need for trials about this subject in
homogeneous patient populations, as expressed by the
PROSPECT study group, we chose the field of
hepato-pancreato-biliary surgery. This is a subspecialty
wherein most procedures are done via laparotomy. All patients
were treated according to the current clinical standards,
including an enhanced recovery setting and perioperative
goal-directed fluid therapy.
Implications of all the available evidence
When combining our findings with the available evidence,
continuous wound infiltration could be considered to be
non-inferior to epidural analgesia with regard to quality of
analgesia and patient-reported outcome measures.
This method, which is still relatively unknown and underused,
thus might be regarded as a reliable alternative analgesic
technique in abdominal surgery, although large-scale trials are
needed for the definitive assessment of non-inferiority.
Declaration of Helsinki.13 The study was approved by the
Medical Ethical Committee of the Academic Medical
Centre Amsterdam (MEC2014_329). Secondary approval
was obtained from the board of the OLVG teaching
hospital, according to the Dutch CCMO External Review
Directive 2012 (RET2012). A data monitoring safety board
was not deemed necessary by the Medical Ethical
Committee because of the estimated low study risk.
Randomisation and masking
Patients were randomly allocated (1:1) to continuous
wound infiltration or epidural analgesia. Randomisation
was done centrally using a web-based randomisation
module and stratified according to centre and type of
incision (subcostal vs midline). Computer-generated
permutated block randomisation with a 1:1 allocation ratio
and concealed varying permuted block sizes of two, four,
six, and eight patients was used. Because of the invasive
nature of the interventions, neither the trial participants
nor the investigators were masked to group allocation.
Procedures
The procedures have previously been described.12 Briefly,
in the continuous wound infiltration group, patients
received a total bolus injection of 30 mL bupivacaine
0·25% at the start of the procedure in the subfascial space
(ie, between the peritoneum and the posterior fascia), the
same plane wherein the catheter tip is placed at the end of
the procedure (figure 1).
At the end of the operation, wound catheters were placed
in the subfascial (ie, pre-peritoneal) space under direct
vision. In case of subcostal incision (bilateral, extension to
the right side) the first catheter was positioned in the right
subcostal region, tunnelled via the rectus sheath to the
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skin, and the second placed subcostal under the right A

rectus muscle sheath, tunnelled via the rectus sheath to
the skin, exiting close to catheter 1. Catheters 1 and 2 were
stabilised together with an adhesive pad. A third catheter
was positioned subcostal under the left rectus muscle
Catheter
sheath, tunnelled via the rectus sheath to the skin, rolled
and stabilised with an adhesive pad (figure 1A). In case of
midline incision, catheters were placed in only the latter
two positions (figure 1B).
A second bolus of total 30 mL bupivacaine 0·25% was
administered via the catheters, which were subsequently
connected to pumps with a total of 12 mL/h bupivacaine
0·125%. In case of subcostal laparotomy, this was
delivered as 4 mL/h three times, and in the case of Ribcage
midline laparotomy, as 6 mL/h twice.
In the epidural group, patients were treated with
thoracic epidural analgesia. The epidural was placed
Incision
between the levels of T7 and T10 at the discretion of the
anaesthesiologist and topped up using bupivacaine 0·25%
and sufentanil 1 μg/mL before incision. Postoperatively,
patient-controlled epidural analgesia was used, with a
solution containing bupivacaine 0·125% and sufentanil
1 μg/mL with a fixed rate of 6 mL/h and bolus of 2 mL and
a lockout time of 20 min. The 4 h maximum dose was set
at 1·2 mg bupivacaine per kg. Because patient-controlled
epidural analgesia was not available at the OLVG centre, B
patients allocated to the epidural group were treated with
continuous epidural analgesia with bupivacaine 0·125%
and sufentanil 0·5 μg/mL started at 0·1 mL/kg per h.
Patients received a daily visit by the acute pain service
team until they could be converted to oral analgesics.
The acute pain service team scored the Overall Benefit of Catheter
Analgesic Score (OBAS) daily,9 adjusted analgesia when
necessary, and systematically screened for side-effects.
Both continuous wound infiltration and epidural
analgesia were used until the third postoperative day, on
which a tentative stop was planned when feasible, and
earlier if possible. Dose adjustments or a manual top-up
in case of inadequate analgesia were allowed. If the
preoperative placement of the epidural catheter failed,
patients received continuous wound infiltration according Ribcage
to the study protocol. Urinary catheters were routinely
used until discontinuation of epidural analgesia but could IIncision
be removed earlier with continuous wound infiltration.
Baseline criteria were assessed the day before surgery.
Pain scores on a Numeric Rating Scale (NRS) were
assessed by ward nurses in the morning and the evening
on postoperative days 1–3. Other study endpoints were
retrieved from the patient data managements system.
Complications were assessed at 30 days after surgery.
Except for the interventions, surgical procedures and Figure 1: Location of catheters
perioperative and postoperative care were similar After subcostal laparotomy (A) and after midline laparotomy (B).
between groups. Patients received the standard pain
treatment consisting of paracetamol (1 g four times a inadequate (NRS >4) even after maximum dose
day) and dipyrone (maximum of 4 g per day) or adjustments were made. This included morphine or
naproxen (250 mg twice daily; unless contra-indicated). piritramide patient-controlled analgesia, non-opioids,
Rescue medication was allowed if analgesia remained and continuous infusion of esketamine.

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The enhanced recovery programme consisted of time, length of use of urinary catheters, time to
preoperative nutritional optimisation, normal oral resumption of oral diet, length of hospital stay, need for
nutrition up to 6 h and liquids up to 2 h before surgery, vasopressors (amount and duration), and fluid balance.
anti-thrombotic prophylaxis, early removal of nasogastric A patient could be replaced when no OBAS score was
tubes, normothermia, optimal glycaemic control, no available (at least 1 day was necessary).
drain or early drain removal, maintaining a near-zero
fluid balance with avoidance of salt and water overload, Statistical analysis
and early mobilisation. Fluid management was done We deemed a difference in mean OBAS of less than
according to a goal-directed fluid therapy protocol.14 3 points to be non-inferior. With standard pain scores on
a numeric rating scale (ranging from 0–10), a difference
Outcomes of 2 points is generally considered as a clinically relevant
The primary endpoint was the mean OBAS on difference.16 We expected a relative smaller variance, thus
postoperative days 1–5, a composite endpoint of pain a non-inferiority margin of 3 points was chosen (10% of
scores, opioid side-effects, and patient satisfaction.9 This the 29-point range of the score). In our opinion, this
score consists of a 29-point scale ranging from 0 (best) to difference is the largest that is clinically acceptable, but it
28 (worst). Secondary objectives were pain scores (on a was also a pragmatic choice to obtain a realistic sample
numeric rating scale, at rest and when moving [coughing], size. We calculated that a sample size of 96 patients was
assessed in the morning and evening), cumulative opioid necessary to provide 90% power to be able to detect a
See Online for appendix consumption (appendix p 2), technical failure (defined as difference of 3 points to reject the null hypothesis that
catheter failure, need for specialist intervention, and/or continuous wound infiltration is non-inferior to epidural
need for rescue medication; appendix p 3), complications analgesia. This was with the use of a one-sided α of 0·05,
(severity graded according to the Accordion system with an SD of 5 (which was established after personal
Clavien-Dindo modifications15), complications related to communication with one of the developers of OBAS) and
pain treatment (eg, epidural haematoma and abscess or an expected difference of 0. We aimed for a total of
local anaesthetic toxicity), anaesthesia time, operation 102 patients (51 per group) to correct for an estimated 5%
loss to follow-up.
We expressed data as median and IQR for continuous
157 patients assessed for eligibility variables, or mean and SD when appropriate. Distributions
of dichotomous data were presented in percentages. The
52 ineligible
normal distribution was checked by visually inspecting
26 did not meet inclusion criteria the histograms. For continuous variables, differences
17 declined to participate between groups were tested with Student’s t test for
9 participation in other clinical trials
normally distributed data or Mann-Whitney U test for
non-normally distributed data. Fisher’s exact test was used
105 enrolled for proportions in all cases. A multivariable linear
regression model for the primary endpoint was used to
105 randomised
further examine the non-inferiority for continuous wound
infiltration in the presence of potentially prognostic
variables such as centre and type of incision.
All analyses were done on the basis of a per-protocol
53 assigned to 52 assigned to epidural principle. Our primary endpoint was first analysed
continuous wound analgesia
infiltration per protocol, with a secondary, supportive modified
intention-to-treat analysis, since use of an intention-to-
treat analysis as the primary analysis of a non-inferiority
1 no laparotomy 1 refusal of trial might introduce bias to no difference, which could
epidural
1 no OBAS exaggerate estimates of equivalence.17
score available Missing pain scores on the first or last time point were
imputed with the first observation carried backward and
52 included in modified 50 included in modified
last observation carried forward method (baseline not
intention-to-treat
3 treated with
intention-to-treat used) and interpolation. At least one pain score was
analysis analysis needed for imputation of the missing time points.
continuous wound
infiltration We did a sensitivity analysis to assess the robustness
(preoperative failure
of placement) of the primary analysis using multiple imputation
55 included in 47 included in regarding OBAS and pain scores. All statistical analyses
per-protocol analysis per-protocol analysis were done in consultation with a senior statistician
(SvD). An adjudication committee (DPV and LS)
Figure 2: Trial profile assessed data for correctness.

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Continuous wound Epidural group Continuous wound Epidural (n=47) Mean difference (95% CI)
infiltration group (n=47) infiltration (n=55)
(n=55)
Mean OBAS on postoperative day 1–5 3·8 (2·4) 4·4 (2·2) –0·62 (–1·54 to 0·30)
Sex (per-protocol)
Female 23 (42%) 22 (47%) Mean OBAS on postoperative day 1–5 3·7 (2·3) 4·5 (2·3) –0·78 (–1·69 to 0·13)
Male 32 (58%) 25 (53%) (modified intention-to-treat)

BMI (kg/m²) 25 (22–27) 23 (22–27) OBAS per day

Smoking 14 (25%) 9 (19%) Day 1 4·0 (3·1) 4·3 (3·3) –0·3 (–1·6 to 1·0)

Type of incision Day 2 4·3 (3·1) 4·2 (2·9) 0·1 (–1·1 to 1·3)

Subcostal 47 (85%) 40 (85%) Day 3 3·8 (3·1) 4·3 (2·9) –0·5 (–1·8 to 0·6)

Midline 8 (15%) 7 (15%) Day 4 3·6 (3·0) 4·6 (3·4) –1·0 (–2·3 to 0·3)

Centre Day 5 3·6 (3·2) 4·4 (3·2) –0·8 (–2·1 to 0·5)

Academic Medical Centre 46 (84%) 42 (89%) Data are mean (SD). OBAS=Overall Benefit of Analgesic Score.
OLVG Oost 9 (16%) 5 (11%)
Table 2: Primary endpoint
Pain score (NRS)* 0·4 (1·2) 0·5 (1·6)
ASA class
1 8 (15%) 10 (21%)
opioid-related side-effects; one of these patients was
2 40 (73%) 30 (64%)
replaced because no OBAS was available. Preoperative
3 7 (13%) 7 (15%)
placement of the epidural failed for three patients in the
Disease severity epidural group and they were treated with continuous
Preoperative POSSUM 16 (14–17) 17 (13–22) wound infiltration according to the study protocol, and
Operative POSSUM 16 (14–19) 17 (15–21) analysed in the per-protocol analysis as being in
Preoperative analgesic usage the continuous wound infiltration group. Baseline
Paracetamol 3 (5%) 4 (9%) characteristics did not differ substantially between
NSAID 2 (4%) 1 (2%) groups (table 1). 43 (78%) patients in the continuous
Opioid 5 (9%) 5 (11%) wound infiltration group and 38 (81%) of those in the
Type of surgery epidural group were operated for malignancy (p=0·8091).
Pancreatoduodenectomy 18 (33%) 18 (38%) Mean OBAS on postoperative days 1–5 was 3·8
Distal pancreatectomy 3 (5%) 2 (4%) (SD 2·4) in the continuous wound infiltration group and
Hemihepatectomy 10 (18%) 8 (17%) 4·4 (SD 2·2) in the epidural group; the mean difference
Liver segmental resection 8 (15%) 4 (9%) between groups was –0·62 (95% CI –1·54 to 0·30).
Hepatojejunostomy 5 (9%) 5 (11%) The upper limit of the 95% CI was lower than
Nanoknife/RFA of pancreas 5 (9%) 7 (15%) the predefined limit for non-inferiority, confirming
Other 6 (11%) 3 (6%) non-inferiority for continuous wound infiltration relative
No resection performed 6 (11%) 10 (21%) to epidural analgesia. Only a small percentage (5%)
of the OBAS data were missing. The modified
Data are median (IQR) or n (%), unless otherwise stated. NRS=Numeric Rating
Scale. ASA=American Society of Anesthesiologists. POSSUM=Physiological and
intention-to-treat analysis yielded similar results
operative severity score for the enumeration of mortality and morbidity. (table 2). Mean OBAS per day for both groups are shown
NSAID=non-steroidal anti-inflammatory drug. RFA=radiofrequency ablation. in table 2. A multivariable logistic regression model,
*Pain at rest on a numeric rating scale, assessed before surgery; displayed as mean
including centre (logistic regression coefficient [B] 1·25,
(SD), although not normally distributed.
95% CI –0·74 to 2·58) and incision (B –3·79,
Table 1: Baseline characteristics of study participants (per-protocol 95% CI –1·66 to 0·90) found no significant differences
population) between the groups. The sensitivity analysis of OBAS
using multiple imputation further underpinned our
IBM SPSS version 22.0 was used for statistical analyses. conclusion of non-inferiority (appendix p 4).
This trial is registered with the Netherlands Trial Register, 36 (67%) patients in the continuous wound infiltration
NTR4948. group and 27 (57%) of those in the epidural group had
their catheter or catheters removed on or before the third
Results postoperative day. 53 (98%) patients in the continuous
Between Jan 20, 2015, and Sept 16, 2015, we assessed wound infiltration group and 45 (96%) of those in the
157 consecutive patients for eligibility, of whom we epidural group had their catheters removed during the
randomly allocated 105 to one of the study groups first 5 days. Patient satisfaction did not differ between
(figure 2). Three patients were excluded and replaced, groups (table 3).
and thus excluded from the modified intention-to-treat Pain scores on postoperative day 1–3 did not differ
analysis. Two replaced patients in the epidural group significantly between groups (appendix pp 5–6). In the
had pain scores (NRS) of less than 4 and only minor continuous wound infiltration group, the median total

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The rate of general complications and pain treatment

Continuous Epidural Difference (95% CI) p value*
wound (n=47) related (serious) adverse events did not differ between
infiltration groups (table 3). Anastomotic dehiscence occurred in
(n=55) two (4%) of the 55 patients in the continuous wound
Anaesthesia time (min) 24 (13) 34 (13) –10 (–15 to –4) 0·0002 infiltration group and in seven (15%) of 47 patients in
Surgical time (min) 242 (116) 242 (135) –2 (–50 to 49) 0·8486 the epidural group (p=0·0767). Postoperative bleeding
Post-anaesthesia care unit stay (h) 12·1 (7·1) 15·4 (13·6) –3·3 (–7·7 to 1·1) 0·6507 occurred in respectively one (2%) of 55 patients in the
Technical complications† continuous wound infiltration group and four (9%) of
Catheter failure 4 (7%) 7 (15%) –8% (–20% to 5%) 0·3375 47 patients in the epidural group (p=0·1780). One patient
Need for specialist intervention 13 (24%) 18 (38%) –15% (–33% to 3%) 0·1328 in each group required blood transfusion (p=1·0000);
Need for rescue medication 11 (20%) 11 (23%) –3% (–19% to 13%) 0·8099 two (4%) patients in the continuous wound infiltration
Patient satisfaction‡ 3·4 (0·8) 3·4 (0·6) 0 (–0·3 to 0·3) 0·5397 group and three (6%) in the epidural group required
Urinary catheter (days) 5·6 (10·4) 5·8 (4·5) –0·2 (–3·5 to 3·0) 0·0240 emergency re-operation (p=0·6595).
Resumption of oral diet (days) 5·2 (6·2) 7·6 (7·2) –2·4 (–5·7 to 1·0) 0·0912 One patient in the continuous wound infiltration group
Hospital stay (days) 12·9 (13·7) 10·5 (6·5) 2·4 (–1·0 to 5·7) 0·6685
had a serious adverse event. After bolus bupivacaine was
Cumulative opioid consumption§ 71 (64) 464 (140) –393 (–440 to –346) <0·0001
given at the start of the procedure, this patient became
Cumulative use of PCA (mg) 40 (58) .. .. ..
hypotensive and had arrhythmias, suggestive of local
Any complications¶
anaesthetic toxicity, which required supportive treatment
with vasopressors and titrated doses of epinephrine for
None 32 (58%) 24 (51%) 7% (–9% to 23%) 0·4207
10 min, with complete recovery. Other adverse events
Grade I 3 (5%) 5 (11%) –5% (–5% to 16%)
in the continuous wound infiltration group were
Grade II 5 (9%) 3 (6%) 3% (–8% to 13%)
hallucinations (related to morphine; one patient), diplopia
Grade III 10 (18%) 8 (17%) 1% (–14% to 16%)
(related to esketamine started as rescue medication;
Grade IV 4 (7%) 3 (6%) 1% (–9% to 11%)
one patient), catheter leakage (one patient), and a painful
Grade V (death) 1 (2%) 4 (9%) –7% (–15% to 2%)
catheter removal in one patient. No cases of epidural
Related serious adverse events 1 (2%) 0 .. 1·0000
haematoma or abscess were reported in the epidural
Related adverse events 4 (7%) 5 (11%) –3% (–15% to 8%) 0·7291
group. Two patients in the epidural group had a vasovagal
Operative
response while placing the epidural catheter. Self-limiting
Norepinephrine consumption (mg) 0·6 (0·9) 1·1 (1·3) –0·5 (–0·9 to 0·0) 0·0085
anisocoria was observed in two patients in the epidural
Norepinephrine dependency (%) 35 (64%) 39 (83%) –19% (–36% to 3%) 0·0453 group, which could be caused by a high degree of
Duration of norepinephrine 158 (161) 211 (159) –53 (–117 to 10) 0·0705 sympathetic blockade. The epidural puncture site was
dependency (min)
infected at catheter removal in one patient, without signs
Fluid given (mL) 2551 (1652) 2791 (2263) –241 (–1012 to 531) 0·7447
of deep infection. There were five surgeons involved in
Fluid balance (mL) 1189 (842) 1254 (886) –65 (–405 to 275) 0·6920
the study (ORB, TMvG, TMK, SMdC, and MGB) and
Post-anaesthesia care unit
their experiences were similar (data not shown).
Norepinephrine consumption (mg) 0·2 (0·7) 1·0 (2·0) –0·7 (–1·3 to –0·1) 0·0062
The mean anaesthesia time (time between time-out
Norepinephrine dependency (%) 8 (15%) 19 (40%) –26% (–43% to –9%) 0·0064
procedure and end of induction) was shorter in the
Duration of norepinephrine 1·6 (4·5) 5·1 (9·0) –3·5 (–6·4 to –0·6) 0·0048
continuous wound infiltration group than in the epidural
dependency (h)
group (table 3). The surgical time and length of stay in
Fluid given (mL) 2122 (1465) 2692 (2616) –571 (–1429 to 288) 0·6532
the post-anaesthesia care unit did not differ significantly
Fluid balance (mL) 1099 (1073) 1745 (1699) –645 (–1218 to –72) 0·0875
between groups (table 3). The mean length of urinary
Data are n (%) or mean (SD), unless otherwise indicated. PCA=patient controlled analgesia. *p values for superiority. catheter use was significantly different between groups
Continuous variables were tested with the Mann-Whitney U test because they were non-normally distributed. (table 3). Length of hospital stay did not differ between
†For definitions see appendix p 3. ‡On a 5-point Likert scale, range 0 (worst) to 4 (best). §Post-operative until day 5, in
mg intravenous morphine equivalent. ¶Severity graded according to the Accordion system with Clavien-Dindo groups (table 3).
modifications.15 During surgery, the mean cumulative norepinephrine
consumption was significantly lower in the continuous
Table 3: Secondary endpoints
wound infiltration group than in the epidural group, and
fewer patients were norepinephrine dependent (table 3).
cumulative morphine consumption with patient Length of norepinephrine dependency, fluid given, and
controlled analgesia was 32 mg (IQR 6–65). The mean fluid balance did not differ significantly between groups
cumulative opioid consumption was lower with the use (table 3). During the stay in the post-anaesthesia care unit
of continuous wound infiltration than with epidural there was significantly less norepinephrine consumption
analgesia (71 mg [SD 64] vs 464 [140]; mean difference in the continuous wound infiltration group than in the
–393 [95% CI –440 to –346]; p<0·0001). Rates of technical epidural group, and fewer patients were dependent on
failure (catheter failure, need for specialist intervention, norepinephrine; duration of dependency was also shorter
and/or need for rescue medication) did not differ (table 3). Total fluid administered and fluid balance did
significantly between groups (table 3). not differ significantly (table 3).

110 www.thelancet.com/gastrohep Vol 1 October 2016


In a post-hoc sensitivity analysis, including only the
36 patients undergoing a pancreatoduodenectomy
(the largest group of patients), continuous wound
infiltration remained non-inferior compared with
epidural analgesia (mean OBAS 2·8 [SD 1·8] vs 4·8
[SD 2·3], mean difference –2·0 [95% CI –3·3 to –0·5]).
Discussion
This study shows that continuous wound infiltration is
non-inferior to epidural analgesia for patients undergoing
hepato-pancreato-biliary surgery in terms of mean OBAS
score—a composite endpoint of pain scores, opioid
side-effects, and patient satisfaction—over the first 5 days
after surgery. Continuous wound infiltration also resulted
in significantly less requirement for vasopressors, both
during and after surgery.
The findings of our study are in line with recent
evidence showing the good analgesic effect with both
methods. However, previous randomised studies have
used suboptimal epidural analgesia regimens, with no
opioid in the epidural solution,18 no patient-controlled
epidural analgesia,18–22 or suboptimal standards of care
with either no enhanced recovery18,23,24 or no goal-directed
fluid therapy protocols.18–21,23,24 To the best of our
knowledge, this is the first study to address these issues
and to use the validated OBAS endpoint with integrated
patient satisfaction. We chose to compare two strategies
(including different regimens) and not only two routes of
administration. Patient-controlled epidural analgesia is
currently considered state-of-the-art because patients
require fewer anaesthetic interventions, require lower
doses of anaesthetics, and have less motor block.22
Moreover, we quantified the need for vasopressors (as a
derivative of perioperative hypotension) within the use of
the current best clinical standards. In line with our
results, the increased incidence of hypotension with the
use of epidural analgesia has been described in previous
studies.19,25 Length of hospital stay did not differ in our
study. In other studies there were mixed conclusions
about this topic, even when the time to fulfil discharge
criteria specifically was reported.19,21,26,27
Both analgesic techniques seem to be safe. The only
observed serious adverse event, suggestive of local
anaesthetic toxicity, which was observed in one patient
during pre-peritoneal infiltration, might have been
prevented if usual safety measures relevant to local and
regional anaesthesia had been followed. In 51 randomised
controlled trials of continuous wound infiltration, no
cases of local anaesthetic toxicity have been reported.16
A systematic review by Ventham and colleagues28 reported
a 4–5% risk of catheter-related complications with both
methods, which seems less than that observed in both
groups in our trial (7% vs 15%), possibly due to stricter
definitions. In this study, the anaesthetic time was 10 min
shorter for continuous wound infiltration since the
wound catheters are placed in the surgical time (in median
10 [IQR 9–11] min, based on measurement in 15 patients).
www.thelancet.com/gastrohep Vol 1 October 2016
Articles
Depending on the organisational setting this could be
either be a clinical benefit or make no difference.
Cumulative opioid use was higher in the epidural
group, because sufentanil was routinely added to the
epidural solution. We cannot draw conclusions about
this because the mechanism of opioid absorption is not
comparable between the two groups. Several studies
have reported a lower risk of urinary retention with
continuous wound infiltration.28 Urinary catheters are
strictly speaking not required with thoracic epidural
analgesia, when the bladder filling is monitored
regularly.29 In many institutions, such as ours, urinary
catheters are part of standard care for patients with
epidural catheters for pragmatic reasons.
The total amount of fluid boluses administered did not
differ between groups. This might be because of the use
of goal-directed fluid therapy, which is known to decrease
fluid overloading in the event of hypotension. When
fluid intake is monitored closely, epidural analgesia does
not invariably lead to more fluid intake in the
perioperative period. There was no difference seen in
length of stay in the post-anaesthesia care unit. Because
of our aim to transfer patients on postoperative day 1 to
the ward, this is a semi-artificial endpoint.
This study has some limitations. First, no masking was
used for pragmatic reasons and to avoid a sham thoracic
injection to mask for epidural catheter placement. The
potential effect of the open-label nature of the study is
unknown but is expected to be minor. The OBAS
was obtained by pain team members who were not
involved with the study. Besides, masking might hinder
mobilisation after surgery since patients would have both
epidural and wound infiltration catheters. Second,
although most patients received patient controlled epidural
analgesia, this was not available for 11% of patients in the
epidural group. However, when excluding these patients
in a sensitivity analysis, outcomes remained similar
(data not shown). Third, it could be seen as a limitation
that a subspecialty-specific approach was chosen instead
of a procedure-type approach (with, for example, only
pancreatoduodenectomies). However, the procedures are
similar in terms of length and location of incision. In daily
practice a subspecialty-specific analgesic approach is more
likely than a procedure-specific one. We did a sensitivity
analysis including only pancreatoduodenectomies, which
confirmed non-inferiority. Fourth, two different wound
catheter configurations were used; however, the same
amount of local anaesthetic was infiltrated into the
pre-peritoneal plane. Lastly, one could argue that the
predefined non-inferiority limit of +3 on the OBAS score
was chosen arbitrarily and a limit of 1 would have been
preferable. Although we do not necessarily agree with this,
it is also questionable whether a limit of 1 on a 29 point
scale is feasible to demonstrate, since this would need
858 patients. Furthermore, based on the results of this
study, non-inferiority would also be likely to be proven
with a non-inferiority limit of +1.
111
 Articles
Strengths of this study include the primary endpoint,
the OBAS, which is in our opinion superior to pain scores
on a visual analogue scale in assessing the effectiveness of
analgesic therapy, as well as our focus on practice-related
benefits. Because of the secondary benefits such as
avoidance of the risk of epidural haematoma or abscess,
decreased vasopressor use, and also a broader range
of application (eg, after unexpected conversion from
laparoscopy, refusal of epidural analgesia, failure of
preoperative epidural catheter placement, coagulopathies,
emergency surgery), we consider continuous wound
infiltration to be a valuable addition to the perioperative
analgesic repertoire. Continuous wound infiltration
requires a parallel multimodal treatment regimen.
However, by contrast with both epidural analgesia and
alternatives such as the transversus abdominis plane
block, wound catheters are more easily placed. Continuous
wound infiltration might be an ideal interim solution with
the opioid-sparing benefits of local anaesthetics but
without the need for preoperative (often cumbersome)
placement in an awake patient, and without the risk of
epidural haematoma and abscess.
Future studies could focus on finding the optimal local
anaesthetic dosage and the use of a combination device to
connect two or three wound catheters on one pump or
other (eg, elastomeric) device. Besides, the study could be
repeated with other types of surgery. Considering the
mechanism of action we cannot rule out that the benefits
of continuous wound infiltration are related to systemic
absorption of the local anaesthetic, thus further studies
should set out to determine the exact mechanism of action.
In conclusion, our study suggests that continuous
wound infiltration is non-inferior to epidural analgesia
in hepato-pancreato-biliary surgery regarding quality
of analgesia and patient-reported outcome measures.
Further large-scale trials are required for a definitive
assessment of non-inferiority; however, in our opinion
there is sufficient evidence for the addition of continuous
wound infiltration to the current analgesic repertoire.
Contributors
THM and MGB supervised the study. THM, MGB, DPV, PL, MWH, ORB,
TMvG, TMK, SMdC, MBG, and BT contributed to the study design,
coordination of the trial and/or data collection. THM did the literature
review and the data management. THM, MGB, and SvD contributed to
the data analysis. THM, MGB, DPV, PL, and MWH contributed to the
data interpretation. THM, MGB, DPV, PL, MWH, OB, SvD, TMvG, TMK,
SMdC, MBG, and BT critically revised the content and approved the final
manuscript. All authors had full access to the data in the study and had
final responsibility for the decision to submit for publication.
Declaration of interests
MWH reports grants from the European Society of Anaesthesiology
(ESA), grants from The Netherlands Organisation for Heath Research
and Development (ZonMW), grants from Technology Foundation STW,
(part of the Netherlands Organisation for Scientific Research [NWO]),
grants and personal fees from Eurocept, personal fees from ECHO
Pharmaceuticals BV, grants from B Braun, grants and personal fees
from CSL Behring, grants from MSD, and grants from Edwards, all
outside the submitted work. DPV reports grants and non-financial
support from Edwards Lifesciences and grants from Merck, all outside
the submitted work. All other authors declare no competing interests.
112
Acknowledgments
This study was solely funded by departmental sources of the Departments
of Surgery and Anaesthesiology of the Academic Medical Centre,
University of Amsterdam, Netherlands. We thank the trial investigators,
trial staff, and the patients and family for their participation in this study.
We also appreciate the efforts of all health-care providers, and especially
the Acute Pain Service and the nursing staff, at both participating
institutions. We acknowledge the assistance of Nicoletta I Daniolos with
the data collection of the study and Lianne Scholten for her participation in
the adjudication committee. We acknowledge the hepato-pancreato-biliary
surgery and anaesthesiology team at University Hospital Southampton
NHS Foundation Trust for demonstrating their technique of continuous
wound infiltration.
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