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Efficacy of local anaesthetic infiltration via wound catheters after open hepatic surgery: a systematic review and meta-analysis

Open AccessPublished:October 15, 2022DOI:https://doi.org/10.1016/j.hpb.2022.10.006

      Abstract

      Background

      This study analysed whether local anaesthetic wound catheter infiltration (LA-WCI) as an adjunct to intravenous patient-controlled analgesia (IV-PCA) provides superior outcomes compared to IV-PCA alone following liver resection.

      Methods

      A systematic review and meta-analysis was conducted for randomised control trials (RCTs) comparing LA-WCI with IV-PCA(LA-WCI group) versus IV-PCA alone (IV-PCA group). PubMed and the Cochrane Library were searched for relevant articles.

      Results

      Six RCTs with a total of 440 patients were included. Opioid use in the initial 48 h was less in the LA-WCI group [MD -21.27 mg (-39.39,-3.15), p = 0.02]. Pain scores were lower in the LA-WCI group at rest at POD0 (post-operative day 0)6–8 h (p = 0.0009), POD1AM(p = 0.01), POD1PM(p = 0.02) and POD2 (p = 0.0006), and exertion at POD0 0–2 h (p = 0.05), POD1AM(p = 0.03), POD1PM(p = 0.03), POD2 (p = 0.03) and POD3 (p = 0.01). LA-WCI group had reduced length of hospital stay [MD -1.32 days (-2.23,-0.40),p = 0.005], time to ambulation [MD -5.94 h (-8.47,-3.42),p = 0.00001] and incidence of nausea and vomiting (PONV) [OR 0.17 (0.07,0.43),p = 0.0002]. No differences were observed in length of intensive care unit (ICU) stay or incidence of surgical site infections.

      Discussion

      LA-WCI as an adjunct to opiate IV-PCA post-hepatectomy reduces opioid use, pain scores at multiple time points at rest and exertion, length of hospital stay, time to ambulation and PONV. However, LA-WCI use does not alter length of ICU stay or incidence of wound infection.

      Introduction

      Pain remains a significant cause of post-operative complications and leads to delayed recovery following abdominal surgery.
      • Ramsay M.A.
      Postoperative pain management: is the surgical team Approach finally getting it right?.
       Good analgesic control is important for early mobilisation and improved respiratory function, both of which are associated with better outcomes.

      Kehlet H. Postoperative pain relief–what is the issue? Br J Anaesth. 72. England 1994. p. 375-378.

       Multimodal analgesia with subsequent adequate pain relief are key to modern Enhanced Recovery After Surgery (ERAS) guidelines.
      • White Paul F.
      • Kehlet H.
      Improving postoperative pain management: what are the unresolved issues?.
       Epidurals are the mainstay of perioperative analgesia for most open abdominal procedures; a recent Cochrane review concluded that there is high quality evidence for their use to accelerate the return of gastrointestinal transit and moderate quality evidence for a reduction in post-operative pain.
      • Guay J.
      • Nishimori M.
      • Kopp S.
      Epidural local anaesthetics versus opioid-based analgesic regimens for postoperative gastrointestinal paralysis, vomiting and pain after abdominal surgery.
       However, as demonstrated by the lack of consensus in ERAS guidelines for liver surgery, open liver resection still remains an analgesic challenge.
      • Ramsay M.A.
      Postoperative pain management: is the surgical team Approach finally getting it right?.
      ,
      • Melloul E.
      • Hübner M.
      • Scott M.
      • Snowden C.
      • Prentis J.
      • Dejong C.H.C.
      • et al.
      Guidelines for perioperative care for liver surgery: enhanced recovery after surgery (ERAS) society Recommendations.
       Options for analgesia post-hepatectomy include: thoracic epidural analgesia (TEA), intrathecal (spinal) central neuraxial block, opiate intravenous patient-controlled analgesia (IV-PCA), local anaesthetic (LA) blocks including subcostal transversus abdominus plane (TAP) blocks, LA wound catheter infiltration (LA-WCI), paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs).
      Pain after liver resection is multi-factorial arising from the extent and type of skin incision, muscle trauma, parenchymal dissection and resection, capsular distention and referred pain (shoulder tip) from peritoneal irritation. Furthermore, the perception of pain experienced by the individual is not solely dependent on the post-operative analgesic regimen, rather it is a sequalae of contributing variables; patient related risk factors, intraoperative surgical and anaesthetic management as well as the post-operative analgesic regimen.
      • Feizerfan A.
      • Sheh G.
      Transition from acute to chronic pain.
      ,
      • Richebé P.
      • Capdevila X.
      • Rivat C.
      Persistent postsurgical pain: pathophysiology and preventative pharmacologic considerations.
       Such variability in intra-operative practice has in recent years been potentiated by not only a desire to optimise practice in fidelity with ERAS pathways, but also tentatively influenced by the spectre of anaesthetic management possibly influencing oncological outcomes.
      • Hiller J.G.
      • Perry N.J.
      • Poulogiannis G.
      • Riedel B.
      • Sloan E.K.
      Perioperative events influence cancer recurrence risk after surgery.
       This has been the case particularly around the use of volatile anaesthetics and opioids,
      • Wall T.
      • Sherwin A.
      • Ma D.
      • Buggy D.J.
      Influence of perioperative anaesthetic and analgesic interventions on oncological outcomes: a narrative review.
       where the almost ubiquitous use of opioids for analgesic regimens has been questioned.
      The use of epidural anaesthesia in hepatic surgery is controversial, partly due to the increased incidence of coagulopathy post-operatively and potential resultant increased risk of spinal haematoma formation.
      • Agarwal V.
      • Divatia J.V.
      Enhanced recovery after surgery in liver resection: current concepts and controversies.
      • Siniscalchi A.
      • Gamberini L.
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      • Laici C.
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      • Francorsi L.
      • et al.
      Role of epidural anesthesia in a fast track liver resection protocol for cirrhotic patients - results after three years of practice.
      • Elterman K.G.
      • Xiong Z.
      Coagulation profile changes and safety of epidural analgesia after hepatectomy: a retrospective study.
       In 2016, the ERAS liver guidelines did not recommend the use of TEA in open liver surgery and instead suggested that LA-WCI and intrathecal opiates could be a good alternative when combined with multimodal analgesia.
      • Melloul E.
      • Hübner M.
      • Scott M.
      • Snowden C.
      • Prentis J.
      • Dejong C.H.C.
      • et al.
      Guidelines for perioperative care for liver surgery: enhanced recovery after surgery (ERAS) society Recommendations.
       Subsequent randomised controlled trials (RCTs) have mostly affirmed these recommendations.
      • Hausken J.
      • Fretland Å.A.
      • Edwin B.
      • Andersen M.H.
      • Dagenborg V.J.
      • Bjørnelv G.M.W.
      • et al.
      Intravenous patient-controlled analgesia versus thoracic epidural analgesia after open liver surgery: a prospective, randomized, controlled, noninferiority trial.
      ,
      • Gavriilidis P.
      • Roberts K.J.
      • Sutcliffe R.P.
      Local anaesthetic infiltration via wound catheter versus epidural analgesia in open hepatectomy: a systematic review and meta-analysis of randomised controlled trials.
       In contrast, a meta-analysis of four RCTs concluded that the use of TEA was superior to IV-PCA.
      • Li J.
      • Pourrahmat M.-M.
      • Vasilyeva E.
      • Kim P.T.
      • Osborn J.
      • Wiseman S.M.
      Efficacy and safety of patient-controlled analgesia compared with epidural analgesia after open hepatic resection: a systematic review and meta-analysis.
      There are concerns regarding the use of opiate IV-PCA as the predominant analgesic modality, due to the relatively high doses required to produce adequate post-operative analgesia. Higher doses are associated with an increased risk of toxicity, particularly in the context of liver resection where opioid pharmacokinetics are altered. Even low doses of opioids can induce oxidative stress on the liver,
      • Skrabalova J.
      • Drastichova Z.
      • Novotny J.
      Morphine as a potential oxidative stress-causing agent.
       therefore minimising exposure to opioids may be particularly relevant in the context of hepatic resection. In addition to the often-recited anticipated benefits of sparing opioid usage (reduced sedation, post-operative nausea and vomiting (PONV), respiratory depression, ileus and potential for opioid dependence) which coincide with the aspirations of ERAS,
      • Melloul E.
      • Hübner M.
      • Scott M.
      • Snowden C.
      • Prentis J.
      • Dejong C.H.C.
      • et al.
      Guidelines for perioperative care for liver surgery: enhanced recovery after surgery (ERAS) society Recommendations.
       opioids have also been shown to promote angiogenesis, increase tumour cell proliferation and suppress natural killer cells (the primary defence against circulating cancer cells).
      • Snyder G.L.
      • Greenberg S.
      Effect of anaesthetic technique and other perioperative factors on cancer recurrence.
      LA-WCI is hypothesised to facilitate opioid sparing, reduced pain scores and improved functional recovery post-surgery. It is clear that the evidence base remains mixed, therefore decisions regarding post-operative analgesia for open liver resections should be made using a patient-centred multimodal approach.
      • Wrighton L.J.
      • O'Bosky K.R.
      • Namm J.P.
      • Senthil M.
      Postoperative management after hepatic resection.
       The aim of this study was to evaluate the efficacy of LA-WCI after open hepatectomy by performing a meta-analysis of randomized controlled trials.

      Methods

      Protocol

      A review was conducted and subsequently reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • The P.G.
      Preferred reporting Items for systematic reviews and meta-analyses: the PRISMA statement.

      Eligibility criteria

      Inclusion criteria was defined using a PICO approach. The population was defined as patients over the age of 18 undergoing liver resection for any reason. The intervention was defined as LA-WCI post-operatively and IV-PCA (with or without transversus abdominus nerve block). The comparator (or control group) were patients using IV-PCA with or without placebo. The primary outcomes assessed were total opioid use in 48 h and pain scores at rest and exertion at multiple time points; secondary outcomes were length of hospital stay, length of ITU stay, time to ambulation, time to first bowel movement, incidence of wound infection and incidence of nausea and vomiting.
      Only RCTs were included. Only publications in English were included. Only studies that reported at least one of the two primary outcomes were included in the meta-analysis.

      Information sources and search

      A systematic search was performed on 22nd March 2020 utilising PubMed and the Cochrane Library. The following search terms were used: (((liver AND surgery) OR (hepatic AND surgery) OR (hepatic AND resection) OR (liver AND resection) OR (hepatectomy) OR (liver AND donor) OR (liver AND transplant) OR (liver AND donation) OR (HPB AND surgery) OR (hepatopancreatobiliary AND surgery)) AND ((transversus AND abdominis) OR (nerve AND block) OR (regional AND block) OR (plane AND block) OR ((abdominal AND wall) AND block) OR (rectus AND sheath AND block) OR (TAP AND block) OR (peripheral AND block) OR (wound AND infiltration) OR (wound AND instillation) OR (local AND infiltration))).

      Study selection

      All studies were independently screened by two reviewers (HS and ND) for eligibility by title and abstract. Full-text articles were retrieved for studies that may have met the inclusion criteria. These were then screened for relevance and a decision was made whether to include them. Any disagreements were resolved by consensus. References of all included studies were then reviewed to manually identify any further studies that may have been relevant. If a title may have been relevant, the abstract then full-text publication was reviewed to determine inclusion or exclusion. Disagreements due to differences in interpretation between reviewers were resolved by a third reviewer (NW), to reach a consensus. Data was extracted from all included texts for review.

      Data collection

      A data extraction table was developed, and pilot tested on four randomly chosen studies, before being refined prior to use. Data was collected from included studies by one author (HS) and reviewed by a second author (ND). Any disagreements were discussed with a third author (NW) until consensus was reached. The following data was retrieved: country of study, patient characteristics, inclusion criteria, exclusion criteria, treatments (including intervention, comparator and other analgesia) and outcome measures. Where data was missing for pain scores (mean and SD), opioid consumption (mean and SD) for each time point, authors of the relevant studies were contacted to request the full data. Of six studies identified, four were able to send complete data sets. In the two remaining studies, computer software was used to estimate the data values from figures included in the publications. In some studies, outcomes were reported as median and inter-quartile range (IQR), so the mean and SD were estimated.
      • Wan X.
      • Wang W.
      • Liu J.
      • Tong T.
      Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range.
       All pain scores reported in RCTs that met the inclusion criteria were retrieved but these were only included in the analysis where two or more RCTs reported pain scores at similar time points.

      Risk of bias in individual studies and across studies

      Two authors (HS and ND) independently assessed the risk of bias for each RCT and categorised it as low risk of bias, some concerns or high risk of bias, using the Cochrane Risk of Bias tool (RoB 2).
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • Elbers R.G.
      • Blencowe N.S.
      • Boutron I.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
       Following this, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) summary of evidence tool was utilised to rate the quality of evidence and accordingly grade the recommendations.
      • Guyatt G.H.
      • Oxman A.D.
      • Schünemann H.J.
      • Tugwell P.
      • Knottnerus A.
      GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology.
       Disagreements due to differences in interpretation between reviewers were resolved by a third reviewer (NW), to reach a consensus.

      Statistical analysis

      Statistical analysis was conducted using Review Manager 5.4 software (Cochrane Collaboration, Oxford, England).

      Review manager (RevMan) Version 5.4 ed. [Computer Program]: The Cochrane Collaboration; 2020.

       For continuous data, mean and standard deviation were extracted from the papers, where mean and standard deviation were not provided this was requested from the authors. The mean difference (MD) with 95% confidence intervals (CI) was then calculated. Data was analysed using the inverse variance method. For dichotomous data, odds ratios (OR) were calculated with 95% CIs. The studies were then combined using the Mantel-Haenszel method. Heterogeneity was explored using the χ2 test and I2 was interpreted in accordance to the Cochrane Handbook for Systematic Reviews of Interventions (0%–40%: might not be important; 30%–60%: may represent moderate heterogeneity; 50%–90%: may represent substantial heterogeneity; 75%–100%: considerable heterogeneity).
       In cases of heterogeneity, random-effects models were applied, otherwise fixed-effects models were used. A p-value of <0.05 was considered statistically significant. Data was summarised graphically in forest plots.
      Five sensitivity analyses were undertaken for total opioid use in the first 48 h post-operatively. The first and second related to the choice of opioid IV-PCA used, the first included only trials using fentanyl and the second included only trials using morphine. The third excluded studies with high risk of bias using Cochrane Risk of Bias tool (RoB 2).
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • Elbers R.G.
      • Blencowe N.S.
      • Boutron I.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
       The fourth and fifth related whether a TAP block was performed, either by direct instillation or as a local anaesthetic bolus given through a TAP catheter post-operatively.

      Results

      Literature search findings and study selection

      The systematic literature search identified 958 articles that required screening. Of the 958 articles screened 30 articles were identified as eligible for full-text screenings, and 928 articles were excluded based on the title. A total of six RCTs were identified as suitable for inclusion in the systematic review and meta-analysis with 24 articles excluded (Fig. 1).
      • Serag Eldin M.
      • Mahmoud F.
      • El Hassan R.
      • Abdel Raouf M.
      • Afifi M.H.
      • Yassen K.
      • et al.
      Intravenous patient-controlled fentanyl with and without transversus abdominis plane block in cirrhotic patients post liver resection.
      • Yassen K.
      • Lotfy M.
      • Miligi A.
      • Sallam A.
      • Hegazi E.A.R.
      • Afifi M.
      Patient-controlled analgesia with and without transverse abdominis plane and rectus sheath space block in cirrhotic patients undergoing liver resection.
      • Karanicolas P.J.
      • Cleary S.
      • McHardy P.
      • Kiss A.
      • Sawyer J.
      • Behman R.
      • et al.
      Medial open transversus abdominis plane (MOTAP) catheters reduce opioid requirements and improve pain control following open liver resection: a multicenter, blinded, randomized controlled trial.
      • Dalmau A.
      • Fustran N.
      • Camprubi I.
      • Sanzol R.
      • Redondo S.
      • Ramos E.
      • et al.
      Analgesia with continuous wound infusion of local anesthetic versus saline: double-blind randomized, controlled trial in hepatectomy.
      • Chan S.K.
      • Lai P.B.
      • Li P.T.
      • Wong J.
      • Karmakar M.K.
      • Lee K.F.
      • et al.
      The analgesic efficacy of continuous wound instillation with ropivacaine after open hepatic surgery.
      • Xin Y.
      • Hong Y.
      • Yong L.Z.
      Efficacy of postoperative continuous wound infiltration with local anesthesia after open hepatectomy.
      Figure 1
      Figure 1PRISMA flow diagram for selection of included studies [RCT: randomised controlled trial].

      Study and patient characteristics

      Six RCTs were identified which included 440 patients. Of these patients, 220 patients were from a cohort that received LA-WCI with IV-PCA and 220 from a cohort receiving IV-PCA alone. The majority of patients were male (276/440, 62.7%). All included studies reported no difference in baseline characteristics between LA-WCI with IV-PCA and IV-PCA alone groups. Five of the included studies were double-blinded, randomised, placebo-controlled trials, one was open-label and not placebo-controlled. One RCT involved two centres, the other five were single-centre studies. All patients included had open liver surgery via a right subcostal incision, with or without upper midline extension depending on operative need. Liver resection was carried out in all patients, except for eight in Chan et al.
      • Chan S.K.
      • Lai P.B.
      • Li P.T.
      • Wong J.
      • Karmakar M.K.
      • Lee K.F.
      • et al.
      The analgesic efficacy of continuous wound instillation with ropivacaine after open hepatic surgery.
      where liver resection was deemed unsafe and radio-frequency ablation (RFA) was carried out only. Total opioid consumption via IV-PCA at 48 h was reported in all studies, but the choice of opiate varied. Two studies used and reported IV fentanyl, one used IV hydromorphone but reported IV mg morphine equivalent, one used and reported IV morphine and one used and reported IV sufentanil. For data analysis, IV fentanyl was converted to an IV morphine dosage using a 50:1 conversion ratio
      • Patanwala A.E.
      • Duby J.
      • Waters D.
      • Erstad B.L.
      Opioid conversions in acute care.
      • Treillet E.
      • Laurent S.
      • Hadjiat Y.
      Practical management of opioid rotation and equianalgesia.
      • Kawano C.
      • Hirayama T.
      • Kuroyama M.
      Dose conversion in opioid rotation from continuous intravenous infusion of morphine hydrochloride injection to fentanyl patch in the management of cancer pain.
      and IV sufentanil was converted to IV morphine dosage using a 375:1 conversion ratio.
      • Reynolds L.
      • Rauck R.
      • Webster L.
      • DuPen S.
      • Heinze E.
      • Portenoy R.
      • et al.
      Relative analgesic potency of fentanyl and sufentanil during intermediate-term infusions in patients after long-term opioid treatment for chronic pain.
       No studies reported information on opioid usage following cessation of IV-PCA or on discharge from hospital. Visual analogue pain scores were reported by all studies at varying time points. Pain scores at two time points were analysed for post-operative day (POD) 0 and POD1, whereas scores were included at one time point for POD2 and POD3. All patients LA-WCI cohorts received ropivacaine (four studies) or bupivacaine (two studies) infiltration of their wound via surgically placed catheters. Study characteristics are summarised in Table 1. Patient characteristics are summarised in Supplementary Table 1.
      Table 1Study characteristics [TAP: transversus abdominus plane, IV PCA: intravenous patient-controlled analgesia, VAS: visual analogue score, POD: post-operative day]
      Author, year, countryStudy typeNo. of patientsProtocol
      InterventionControlInterventionControlBoth groupsPrimary outcomeSecondary outcomes
      Eldin, 2014, EygptOpen-label, randomised, controlled, parallel-arm, single-centre trial2525
      • TAP block – bupivacaine 0.375% 15 ml bilaterally via US guidance preop
      • TAP catheter - bupivacaine 0.375% 8 h via TAP catheter depending on VAS (<3, 5 ml; 3–6, 10 ml; 6–10, 15–20 ml) according to weight (maximum 2 mg/kg)
      No placebo
      • IV PCA – 15 μg fentanyl bolus with 10 min lockout
      • IV meperidine 50 mg for breakthrough pain
      VAS at 6, 8, 12, and 24 h, and again on days 2 and 3 postoperativelyOpioid consumption POD 1, 2, 3 and complications, such as sedation, nausea, vomiting, pruritus, respiratory depression, and signs of local toxicity, as well as length of stay in the intensive care unit
      Karanicolas, 2018, USADouble-blinded, randomised, placebo- controlled, two-centre trial7182TAP and posterior rectus sheath catheter −20 ml of ropivacaine 0.2% through each post op + continuous infusion through each ropivacaine 0.2% 5 ml per hour for 72 hPlacebo TAP + post rect sheath −20 ml normal saline post op through each + continuous infusion 5 ml/h for 72 h
      • IV PCA – 0.2 mg hydromorphone bolus with 5 min lockout
      • Celecoxib 200 mg orally twice daily
      Cumulative postoperative opioid consumption over the first 2 postoperative days (48 h).Pain score at coughing and rest, sedation scores, opioid-related adverse events, complications and time to first ambulation, first bowel movement, and hospital discharge
      Dalmau, 2017, SpainDouble-blinded, randomised, placebo-controlled, single-centre trial5346Subfascial wound catheter – 10 ml ropivacaine 0.23% bolus followed by 5 ml/h for 48 hSubfascial wound catheter – 10 ml normal saline bolus followed by 5 ml/h for 48 h
      • IV morphine boluses 2 mg post op every 5 min until the VNRS score <4;
      • IV PCA 0.5 mg morphine with 8min lockout time
      • IV Dexketoprofen 50 mg and IV paracetamol 1 g BD
      total amount of morphine used during surgery and the following 48 h.Pain scores, number of PCA doses, blood transfusion requirements, time to ambulation, time to solid food intake without nausea or vomiting, adverse events, wound infection, wound culture, time to discharge
      Yassen, 2019, EgyptDouble-blinded, randomised, placebo-controlled, single-centre trial3025TAP and post rectus sheath catheter – 0.2 ml/kg bupivacaine 0.25% in each catheter at closure and 8 hTAP and post rectus sheath – 0.2 ml/kg Normal saline in each catheters and 8 hIV PCA - 15 μg fentanyl bolus with 10min lockoutVAS at 30min, 1hr, 2 h, 4 h, 8 h – day 1 and 2 on movementTotal IV fentanyl used postop day 1 and 2, PONV, sedation scores, signs and symptoms of local anaesthetic drug toxicity, plasma bupivacaine levels, complications
      Chan, 2010, Hong KongDouble-blinded, randomised, placebo-controlled, single-centre trial2222
      • Wound block - ropivicaine 0.25% – 20 ml local infiltration after closure
      • Wound catheter - two 12.5 cm multi-hole 18-G Soaker catheters within the musculo-fascia at 4 ml/h for 68 h
      Placebo wound block and catheters with placebo infusionsIV PCA – 1-mg morphine bolus with 5-min lock-out and 4-h dose-limit of 0.3 mg kgMean total morphine consumption at 72 h post opTime to first rescue analgesia or first use of the PCA, the pain scores at rest and after spirometry at 4, 12, 24, 48 and 72 h, and the plasma concentrations of ropivacaine during the postoperative period
      Xin, 2014, ChinaDouble-blinded, randomised, placebo-controlled, single-centre trial2020Subfascial and subcut catheters −10 ml of 0.5% ropivacaine bolus followed by 2 ml/h infusion of 0.3% ropivacaineSubfascial and subcut catheters - 10 ml of 0.5% ropivacaine bolus followed by 2 ml/h infusion of 0.9% salineIV PCA – sufentanil 2 mg bolus dose, 5min lockout time, 40 mg dose limit over 4 h for 48 hVAS at rest and movement 8 h from 0 to 48 h post opSedation score 8 h, sufentanil PCA consumption 8 h, nausea and vomiting, patient satisfaction, changes in liver function at 3 days post op, time to first flatus, length of hospitalization, adverse events to time of discharge

      Risk of bias and GRADE quality of evidence assessment

      Overall, the individual studies were assessed as having low risk of bias with some concerns. All studies were assessed as having low risk of bias from randomisation. Eldin et al.
      • Serag Eldin M.
      • Mahmoud F.
      • El Hassan R.
      • Abdel Raouf M.
      • Afifi M.H.
      • Yassen K.
      • et al.
      Intravenous patient-controlled fentanyl with and without transversus abdominis plane block in cirrhotic patients post liver resection.
      was assessed as having some concerns regarding deviations from the intended interventions because patients and clinicians were not blinded, all other studies were assessed as low risk. Eldin et al.
      • Serag Eldin M.
      • Mahmoud F.
      • El Hassan R.
      • Abdel Raouf M.
      • Afifi M.H.
      • Yassen K.
      • et al.
      Intravenous patient-controlled fentanyl with and without transversus abdominis plane block in cirrhotic patients post liver resection.
      and Yassen et al.
      • Yassen K.
      • Lotfy M.
      • Miligi A.
      • Sallam A.
      • Hegazi E.A.R.
      • Afifi M.
      Patient-controlled analgesia with and without transverse abdominis plane and rectus sheath space block in cirrhotic patients undergoing liver resection.
      were assessed as some concerns regarding risk of bias for missing outcome data because the outcome data for some patients in the LA-WCI group was not reported due to displacement of the wound catheter, all other studies were assessed as low risk. Eldin et al.
      • Serag Eldin M.
      • Mahmoud F.
      • El Hassan R.
      • Abdel Raouf M.
      • Afifi M.H.
      • Yassen K.
      • et al.
      Intravenous patient-controlled fentanyl with and without transversus abdominis plane block in cirrhotic patients post liver resection.
      was assessed as some concerns for risk of bias due to measurement of the outcome because outcome assessors were not blinded. Only Karanicolas et al.
      • Karanicolas P.J.
      • Cleary S.
      • McHardy P.
      • Kiss A.
      • Sawyer J.
      • Behman R.
      • et al.
      Medial open transversus abdominis plane (MOTAP) catheters reduce opioid requirements and improve pain control following open liver resection: a multicenter, blinded, randomized controlled trial.
      was assessed as low risk of bias for selection of reported results, all other studies were as assessed as some concerns due to the lack of a comprehensive pre-published analysis intention plan. Risk of bias for each RCT assessed using the Cochrane Risk of Bias tool (RoB 2)
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • Elbers R.G.
      • Blencowe N.S.
      • Boutron I.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      can be found in Supplementary Table 2, individual responses to signalling questions within the tool can be found in Supplementary Table 3. Quality of evidence for each outcome was assessed using GRADE analysis
      • Guyatt G.H.
      • Oxman A.D.
      • Schünemann H.J.
      • Tugwell P.
      • Knottnerus A.
      GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology.
      (Supplementary Table 4). Overall quality ranged from moderate to high for all outcomes investigated.

      Primary outcomes

      Total opioid use in first 48 h post-operatively

      LA-WCI with IV-PCA group used significantly less opioid in mg morphine equivalent via IV-PCA compared to the IV-PCA alone group in the first 48 h post-operatively [MD -21.27 mg (−39.39, −3.15), I2 = 98%, p = 0.02] (Fig. 2). In the sensitivity analyses, this result remained significant when fentanyl IV-PCA was used [MD -38.22 mg (−58.13, −18.31), I2 = 90%, p = 0.0002] and a TAP block or LA bolus via a TAP catheter was given post-operatively [MD -29.28 mg (−51.27, −7.28), I2 = 94%, p = 0.009]. However, it did not remain significant when morphine IV-PCA was used [MD -9.12 mg (−26.95, 8.72), I2 = 74%, p = 0.32], one study with high risk of bias was removed [MD -20.01 mg (−40.45, 0.44), I2 = 98%, p = 0.06] and if a TAP block or LA bolus via TAP catheter was not given [MD -12.32 mg (−26.05, 1.41), I2 = 92%, p = 0.08] (Table 4).
      Figure 2
      Figure 2Total opioid use via IV-PCA in mg morphine equivalent by 48 h post-hepatectomy. Inverse variance method using random effects model. Mean difference <0 indicates reduced total IV-PCA opioid use.
      Table 2Summary of pain scores at rest and exertion. Inverse variance method using random effects model. Mean difference <0 indicates reduced pain in the WCI + IV-PCA group compared to IV-PCA group
      Rest or exertionTime post opNumber of studies, patientsMean difference estimated effect, 95% CIp-ValueI2 (%)
      At RestPOD0 0–2 h3, 2910.08 [−0.39, 0.55]0.7439
      POD0 6–8 h4, 336−1.07 [1.71, −0.44]0.0009∗82
      POD1 AM4, 335−0.94 [1.68, −0.20]0.01∗90
      POD1 PM4, 335−0.81 [1.49, −0.14]0.02∗86
      POD24, 335−1.09 [1.71, −0.47]0.0006∗81
      POD32, 197−0.98 [−2.15, 0.20]0.1085
      On exertionPOD0 0–2 h2, 208−2.49 [4.94, −0.04]0.05∗94
      POD0 6–8 h4, 302−0.21 [−2.01, 1.60]0.8296
      POD1 AM5, 341−1.68 [3.18, −0.19]0.03∗97
      POD1 PM5, 341−1.02 [1.91, −0.12]0.03∗93
      POD24, 286−1.66 [3.18, −0.13]0.03∗94
      POD33, 247−1.84 [3.28, −0.40]0.01∗91
      Table 3Summary of secondary outcomes. Inverse variance method using random effects model for continuous data, unless specified. Mantel-Haenszel method for dichotomous data. Mean difference <0 indicates reduced time to secondary outcome in WCI + IV-PCA group compared to IV-PCA group. Odds ratio <1 indicated reduced complications in WCI + IV-PCA group compared to IV-PCA group
      Secondary outcomeNumber of studies, patientsStatistical method, estimated effect, 95% CIp-ValueI2 (%)
      Length of hospital stay (days) -fixed effects model4, 332MD: −1.32 [2.23, −0.40]0.005∗0
      Length of ICU stay (hours)3, 158MD: −8.67 [−27.12, 9.78]0.3698
      Time to ambulation (hours) – fixed effects model2, 249MD: −5.94 [8.47, −3.42]<0.00001∗0
      Time to first bowel movement (days)2, 192MD: −0.68 [−2.00, 0.65]0.3291
      Incidence of nausea and vomiting - fixed effects model3, 201OR: 0.17 [0.07, 0.43]0.0002∗0
      Incidence of wound infection2, 140OR: 0.58 [0.05, 7.20]0.6768
      Table 4Summary of sensitivity analyses for total opioid use via IV-PCA in mg morphine equivalent by 48 h post-hepatectomy. Inverse variance method using random effects model. Mean difference <0 indicates reduced total IV-PCA opioid use
      CriteriaNumber of studies, patientsStatistical method, estimated effect, 95% CIp-ValueI2 (%)
      Type of IV opioid usedFentanyl2, 105MD: −38.22 [58.13, −18.31]0.0002∗90
      Morphine2, 140MD: −9.12 [−26.95, 8.72]0.3274
      Risk of biasExcluding studies with high Risk of Bias (RoB 2)5, 387MD: −20.01 [−40.45, 0.44]0.0698
      Whether TAP block was performedTAP block/TAP catheter bolus3, 258MD: −29.28 [51.27, −7.28]0.009∗94
      No TAP block/No TAP catheter bolus3, 179MD: −12.32 [−26.05, 1.41]0.0892

      Pain scores

      LA-WCI with IV-PCA group had significantly reduced pain at rest at time points: POD0 6–8 h (p = 0.0009), POD1 AM (p = 0.01), POD 1 PM (p = 0.02) and POD2 (p = 0.0006), as well as reduced pain on exertion at POD0 0–2 h (p = 0.05), POD1 AM (p = 0.03), POD1 PM (p = 0.03), POD2 (p = 0.03) and POD3 (p = 0.01), when compared to the IV-PCA alone group (Table 2). Differences in pain scores at other time points were not statistically significant between the two groups (Figure 3, Figure 4).
      Figure 3
      Figure 3Pain scores at rest post-operatively at (a) 0–2 h (b) 6–8 h (c) morning on post-operative day 1 (d) afternoon on post-operative day 1 (e) post-operative day 2 (f) post-operative day 3. Inverse variance method using random effects model. Mean difference <0 indicates lower pain scores in local anaesthetic wound catheter infiltration (LA-WCI) group.
      Figure 4
      Figure 4Pain scores on exertion post-operatively at (a) 0–2 h (b) 6–8 h (c) morning on post-operative day 1 (d) afternoon on post-operative day 1 (e) post-operative day 2 (f) post-operative day 3. Inverse variance method using random effects model. Mean difference <0 indicates lower pain scores in local anaesthetic wound catheter infiltration (LA-WCI) group.

      Secondary outcomes

      LA-WCI with IV-PCA group had significantly reduced length of hospital stay [MD -1.32 days (−2.23, −0.40), I2 = 0%, p = 0.005], time to ambulation [MD -5.94 h (−8.47, −3.42), I2 = 0%, p = 00001) and incidence of nausea and vomiting [OR 0.17 (0.07, 0.43), I2 = 0, p = 0.0002], when compared to the IV-PCA alone group (Table 3). Length of ICU stay, time to first bowel movement and incidence of wound infection were not statistically different between the two groups (Fig. 5).
      Figure 5
      Figure 5Secondary outcomes (a) time to first bowel movement in days – random effects (b) length of hospital stay in days – fixed effects (c) time to ambulation in hours – fixed effects (d) length of ICU stay in hours – random effects. Inverse variance method, mean difference <0 indicates reduced time period in local anaesthetic wound catheter infiltration (LA-WCI) group. (e) Incidence of nausea and vomiting – fixed effects (f) Incidence of wound infection – random effects. Mantel–Haenszel method, odds ratio <1 indicates reduced incidence in local anaesthetic wound catheter infiltration (LA-WCI) group.

      Discussion

      This meta-analysis of six RCTs, with a total of 440 patients, found that LA-WCI combined with opioid IV-PCA post-hepatectomy reduces opioid use in the post-operative period, pain scores at multiple time points at rest and exertion, length of hospital stay, time to ambulation and incidence of nausea and vomiting. However, LA-WCI use does not alter length of ICU stay, time to first bowel movement and incidence of surgical site infections. Treatment effect of pain score reduction was greater on exertion compared to rest at all time points except for POD0 6–8 h (Table 2), supporting the notion that LA-WCI can aid early mobilisation and coughing. This is consistent with our finding that LA-WCI provides statistically significant reduced times to ambulation. These results support the existing evidence base that LA-WCI is a good method of analgesia for open liver surgery. The quality of evidence for each main outcome analysed varied from moderate to high. However, the measured effect of LA-WCI on total opioid consumption in the first 48 h post-operatively diminished from MD: −21.27 mg (−39.39, −3.15), I2 = 98%, p = 0.02 to MD: −20.01 mg (−40.45, 0.44), I2 = 98%, p = 0.06 when the one trial with high risk of bias was excluded during a sensitivity analysis. Reducing the number of studies included in the analysis from six to five reduces the power of the pooled analysis which also has its own implications.
      Considerable heterogeneity exists between the RCTs due to varying local anaesthetic administration regimes, catheter placement sites and time points used to assess pain scores.
      The protocol for intra-operative and post-operative local anaesthetic administration varied between studies, both with regards to the specified location of administration and timing of delivery (Table 1). Eldin
      • Serag Eldin M.
      • Mahmoud F.
      • El Hassan R.
      • Abdel Raouf M.
      • Afifi M.H.
      • Yassen K.
      • et al.
      Intravenous patient-controlled fentanyl with and without transversus abdominis plane block in cirrhotic patients post liver resection.
      gave a single dose of local anaesthetic in the transversus abdominis plane via ultrasound guidance prior to skin incision, Chan
      • Chan S.K.
      • Lai P.B.
      • Li P.T.
      • Wong J.
      • Karmakar M.K.
      • Lee K.F.
      • et al.
      The analgesic efficacy of continuous wound instillation with ropivacaine after open hepatic surgery.
      gave a single dose of local anaesthetic into the musculo-fascial layer after mass closure and the remaining authors administered local anaesthetic via wound catheter at the conclusion of surgery. Eldin
      • Serag Eldin M.
      • Mahmoud F.
      • El Hassan R.
      • Abdel Raouf M.
      • Afifi M.H.
      • Yassen K.
      • et al.
      Intravenous patient-controlled fentanyl with and without transversus abdominis plane block in cirrhotic patients post liver resection.
      and Yassen
      • Yassen K.
      • Lotfy M.
      • Miligi A.
      • Sallam A.
      • Hegazi E.A.R.
      • Afifi M.
      Patient-controlled analgesia with and without transverse abdominis plane and rectus sheath space block in cirrhotic patients undergoing liver resection.
      administered boluses of local anaesthetic, whereas the remaining authors used a continuous infusion. Delivery of boluses in the absence of a continuous infusion may result in higher pain scores depending on the time assessed and may compound the usage of additional opioid IV-PCA.
      Catheter placement has a significant effect on efficacy of pain relief; catheters placed above the abdominal wall fascia may provide ineffective analgesia,
      • Fredman B.
      • Zohar E.
      • Tarabykin A.
      • Shapiro A.
      • Mayo A.
      • Klein E.
      • et al.
      Bupivacaine wound instillation via an electronic patient-controlled analgesia device and a double-catheter system does not decrease postoperative pain or opioid requirements after major abdominal surgery.
       whereas catheters placed in the pre-peritoneal layer reduce post-operative pain.
      • Beaussier M.
      • El'Ayoubi H.
      • Schiffer E.
      • Rollin M.
      • Parc Y.
      • Mazoit J.X.
      • et al.
      Continuous preperitoneal infusion of ropivacaine provides effective analgesia and accelerates recovery after colorectal surgery: a randomized, double-blind, placebo-controlled study.
       There is some variation in the description of catheter placement and number of catheters placed in these studies (Table 1) which may contribute to the efficacy of local anaesthesia. However, all studies placed one catheter in the preperitoneal/subfascial plane, therefore sufficient analgesic efficacy should have been obtained.
      Time points used to assess pain scores post-operatively varied between studies, this introduces greater variability in comparative pain scores. Varying methods were used to measure pain on exertion (coughing, movement or spirometry), these manoeuvres largely cause pain in the same way, via tension on the incision wound and peritoneal irritation, therefore we deemed comparability acceptable. In addition, no study stated their policy on early mobilisation or adherence to ERAS protocols which could introduce heterogeneity across studies. Finally, cultural and societal factors varied across trials which could also affect outcome variables including subjective pain scores, time to ambulation and length of hospital stay.
      These variations in study design, particularly with respect to local anaesthetic protocol, should induce caution in interpretation of the results. However, despite the aforementioned heterogeneity, it should be noted that effect direction is consistent across all studies. Heterogeneity in statistically significant outcomes is limited to absolute effect rather than effect direction. It is therefore safe to conclude that this meta-analysis provides moderate to high quality evidence to support the findings that LA-WCI with IV-PCA is superior to IV-PCA alone.
      Whilst studying the use of pain scores and total opioid usage is overtly intuitive, there may be more legitimate end points that reconcile with contemporary practice, for example mobilising within 24 h, eating and drinking, liberation from medical devices, catheters and drains or patient satisfaction.
      Centre NHSR
      Perioperative quality improvement programme annual report.
       Furthermore, longer term end-points like the occurrence of CPSP (chronic post surgical pain), return to intended oncological therapy (RIOT) or overall or disease-free survival which is now often used as a Standardised Endpoint in Peri-operative Medicine (StEP) in onco-anaesthesia may be more relevant to the patient.
      • Finnerty D.T.
      • Buggy D.J.
      Return to intended oncologic therapy: a potentially valuable endpoint for perioperative research in cancer patients?.
       In using such endpoints, a distinction should be made between statistically significant and clinically significant differences. For example, whilst a reduction in pain scores at a fixed time point is commendable, it may not necessarily correlate to patient satisfaction.
      Centre NHSR
      Perioperative quality improvement programme annual report.
       Future research should explore these endpoints, in addition to cost-effectiveness analyses, with a view to expanding the evidence base for open hepatic surgery.
      These results suggest a conferred benefit from the use of LA-WCI in conjunction with opioid IV-PCA in patients undergoing open liver resection. However, further double-blinded, randomised, placebo-controlled trials are needed to determine the optimal intraoperative and postoperative regime for LA-WCI in open hepatic surgery.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Statement of contribution

      These authors contributed equally: Hatem Sadik, Naomi Watson.
      Conception and design: H.S., N.W., N.D., I.R., M.P., B.B.; Acquisition of data: H.S., N.W., N.D.; Analysis and interpretation of data: H.S., N.W., N.D., I.R., M.P., J.C., R.P.S., B.B.; Drafting the article: H.S., N.W., N.D.; Critically revising the article for important intellectual content: H.S., N.W., N.D., I.R., M.P., J.C., R.P.S., B.B.; Approval of final submitted manuscript: H.S., N.W., N.D., I.R., M.P., J.C., R.P.S., B.B.

      Conflicts of interest

      None to declare.

      Acknowledgements

      A protocol was registered at PROSPERO [CRD42020223977] after formal screening of search results against eligibility criteria was completed but prior to data extraction.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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