Postoperative Analgesia after Open Liver Surgery: Systematic Review of Clinical Evidence

Background: The existing recommendations for after open liver surgery, published in 2019, contains limited evidence on the use of regional analgesia techniques. The aim of this systematic review is to summarize available clinical evidence, published after September 2013, on systemic or blended postoperative analgesia for the prevention or treatment of postoperative pain after open liver surgery. Methods: The PUBMED and EMBASE registries were used for the literature search to identify suitable studies. Keywords for the literature search were selected, with the authors’ agreement, using the PICOS approach: participants, interventions, comparisons, outcomes, and study design. Results: The literature search led to the retrieval of a total of 800 studies. A total of 36 studies including 25 RCTs, 5 prospective observational, and 7 retrospective observational studies were selected as suitable for this systematic review. Conclusions: The current evidence suggests that, in these patients, optimal postoperative pain management should rely on using a “blended approach” which includes the use of systemic opioids and the infusion of NSAIDs along with regional techniques. This approach warrants the highest efficacy in terms of pain prevention, including the lower incretion of postoperative “stress hormones”, and fewer side effects. Furthermore, concerns about the potential for the increased risk of wound infection related to the use of regional techniques have been ruled out.


Introduction
Pain after open liver surgery can be attributed to two major mechanisms: peripheral nociceptors stimulation (induced by subcostal incision, rib retraction, diaphragmatic irritation, etc.) and visceral origin transmitted by sympathetic nerves [1][2][3]. Due to its multifactorial origin, it remains a major clinical challenge and current evidence suggests that adequate postoperative pain relief is accomplished in only 20-45% of patients undergoing major abdominal surgery [4][5][6][7][8]. Many perioperative strategies have been evaluated in this group of patients but there is still no consensus on the best practice [9,10]. Commonly used modalities for postoperative pain control are systemic intravenous analgesics, epidural analgesia, and peripheral nerve blocks [11,12]. Systemic intravenous administration of analgesics (as opioids and non-steroidal anti-inflammatory drugs) is effective but associated with potentially harmful side effects, such as respiratory depression, nausea and vomiting, pruritus, gastrointestinal bleeding, and renal failure [13,14]. Epidural analgesia might provide improved pain control, but in the specific setting of open liver surgery, may potentially challenge and have harmful drawbacks as a sympathetic blockade (with hypotension, bradycardia) and intraoperative fluid overload arises and its use might be limited because of the possible perioperative coagulopathy [13,[15][16][17][18]. A peripheral nerve block, such as the paravertebral nerve block (PVB), transversus abdominis plane block (TAP), or quadratus lumborum block (QLB), performed under ultrasound guidance is an emerging alternative that could provide effective analgesia with a potentially low-risk profile after open liver surgery.
In 2015, a comprehensive review, that included fourteen studies published between November 1966 and September 2013, reported the superiority of epidural analgesia in pain relief over alternatives, but without translating into a reduction in length of hospital stay (LOS) and postoperative complication rates [19]. The existing recommendation from ESRA for Procedure-Specific Postoperative Pain Management (PROSPECT) after open liver surgery published in 2020 contains limited evidence on the use of regional analgesia techniques in this setting [20]. Since then, new relevant clinical evidence has emerged, and clinical practice is evolving accordingly.
The aim of this systematic review (SR) is to summarize the available clinical evidence, published after September 2013, on systemic or blended postoperative analgesia for the prevention or treatment of postoperative pain after open liver surgery.

Search Strategy
This SR was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations, and the study was registered in the International Prospective Register Of Systematic Review (PROSPERO registration number CRD42020152836) [21,22]. Systematic research using PUBMED and EMBASE was performed to identify trials suitable for inclusion in this SR. Keywords for the literature search were selected, with the authors' agreement, using the PICOS approach: participants, interventions, comparisons, outcomes, and study design [23]. The terms used as key words are listed in Appendix A.

Study Selection and Inclusion Criteria
The inclusion criteria were randomized controlled trials (RCTs) and prospective (POS) and retrospective (RO) studies published between October 2013 and December 2020 in the adult population (older than 18 years) on analgesia in patients who had undergone open liver surgery. Papers examining analgesia in other hepatic procedures were excluded (laparoscopic resections, liver transplant recipients, hepatic ablations, liver biopsy). Only full-text papers in the English language were considered for eligibility. Studies reporting evidence on pharmacological therapies (systemic and blended analgesia) in patients who had undergone open liver surgery that included qualitative or semiquantitative pain assessment were considered suitable for this SR.

Outcomes
The primary outcome measure of this SR is to report evidence in terms of the reduction in pain measured with patient-derived qualitative or semiquantitative scales referable to tested analgesic therapy. The secondary outcome measures are related to safety and clinical complication as recorded in selected studies: safety (the incidences of side effects of the tested analgesic modality), need of rescue analgesia, the total amount of opioid consumption, anesthesia recovery time, hemodynamic stability, vasopressor and fluid requirement, need for blood transfusion, postoperative complication rates, inflammatory and immune response, indicators of patients' recovery, patient satisfaction, and LOS.

Data Extraction and Data Analysis
Two authors (PD, MZ) independently screened and assessed titles, abstracts, and fulltext papers to identify eligible articles, with FB and PA acting as arbiters. Details of the study population, type of interventions, outcomes, and other information were extracted using a standardized data extraction form that included: study design, eligibility and exclusion criteria, duration of follow-up, randomization, blinding, number and characteristics of patients, type of surgery, and drug dose and method of administration. We reported as significant efficacy those treatments that are related to p < 0.05.

Risk of Bias
The risk of bias for all included trials was assessed according to the Cochrane Collaboration's criteria for RCTs and non-randomized controlled trials (non-RCTs) (http: //handbook.cochrane.org, accessed on 1 September 2020).

Results
The literature search led to the retrieval of a total of 1454 studies; after the initial screening for eligibility, 1285 studies were excluded as they did not match the inclusion criteria. A total of 36 studies (involving 3560 patients, with an age range between 18 and 86) including 24 RCTs, 5 prospective observational (POS), and 7 retrospective observational (RO) studies were selected as suitable for this SR, and risk of bias was evaluated (Figure 1, Tables 1 and 2). In 35 of the 37 studies, patients who underwent elective open liver surgery were selectively recruited, while 2 also included patients who underwent hepato-pancreatobiliary surgery; 28 studies included patients scheduled for tumor resection, and 9 studies included living donors. In the selected trials, 9 different analgesic modalities and their combinations were assessed: wound infiltration (WI), transversus abdominal plane (TAP) block, thoracic epidural analgesia (TEA), non-steroidal anti-inflammatory drugs (NSAIDs), intrathecal morphine (ITM), paravertebral block (PVB), quadratus lumborum block (QLB), dexmedetomidine, and ketamine. The evaluation of postoperative pain was assessed using various quantitative and semi-quantitative pain-rating scales and the consumption of opioid/non-opioid analgesics ( Table 3). The duration of follow-up ranged from the immediate postoperative period up to 6 months after surgery. The evidence supported by the larger number of recruited patients will be displayed first.     Higher NRS scores on PoD 0, afternoon of PoD 1, and morning of PoD 2 in the WI group than in the TEA group. Greater opioid consumption in the WI group on PoD 0, 1, and 2. No differences in side effects of analgesia and complication rates between the groups. No difference in LOS and functional recovery time between the groups. No difference in the volume of intraoperative fluid between the groups. Vasopressor support often required in the TEA group. No difference in baseline peak flow between the groups, but change in peak flow from the baseline level was worse in WI group. Lower NRS score at 6 h in the WI group than in the control group.
No differences in opioid consumption between the groups.
No difference in transfusion requirements, solid food intake, ambulation, or LOS between the groups. Patients in the control group could sit in a chair earlier than those in the WI group. No wound complication was recorded.   Lower NRS scores, reduced rate of analgesic usage, ambulation time, and GI function recovery time in the WI group than in the control group. Lower NRS scores at 12 postoperative hours in WI group than in IV-PCA group with no differences at the later time points. Increased mean survival time in WI and IV-PCA groups than in the control group. More side effects of analgesia and hepatic dysfunction in the IV-PCA group than in the WI and control groups with no differences between the WI and the control group. Higher incidences of incision exudation in the WI group than in the IV-PCA group and the control group.   In both groups: Intraoperatively remifentanil infusion.
IV-PCA with morphine and iv acetaminophen postoperatively.
Postoperative hours: 0, 2, 4, 6, 12 and 24 Total opioid consumption VAS score at rest and on movement sedation scores PONV Need for antiemetic medication Lower VAS scores at rest and movement and lower opioid consumption in the TAP block group than in the control group.
No difference between the two groups in terms of PONV and sedation scores.      Lower VAS scores at rest and at movement in TEA group than in the IV-PCA group. Lower total opioid consumption in TEA group than in IV-PCA group. Lower VAS scores at 2, 6, 12, and 24 h after surgery in parecoxib group than in the control group. No differences in VAS scores between the two groups at 48 h after surgery. Lower total opioid consumption in the parecoxib group than in the control group. No differences in the incidence of side effects of analgesia between the groups. Longer median disease-free survival time of patients in the parecoxib group than in the control group. No difference in overall survival between the groups. Higher percentages of CD3+ T cells at 24 h after surgery in the parecoxib group than that in control group. Higher percentages of NK cells in the parecoxib group than that of control group. Lower VAS scores on 30-54 postoperative hours, lower opioid consumption, rescue analgesic usage and rate of incidence of PONV in the parecoxib group than in the control group.  No difference in the VAS scores between the groups. No difference in total opioid consumption, satisfactory score, the incidence of side effects, and the need of rescue analgesia between the groups. Lower NRS scores in the ITM group than in the IV-PCA group.
No difference in total opioid consumption between the groups. Need for additional rescue opioid often in IV-PCA group. No differences in complication and side effects related to the analgesia and recovery parameters between the groups. Lower VAS score on coughing in the first 12 postoperative hours in TEA group than in the ITM group with no differences afterward. Shorter LOS in ITM group than in the TEA group. Higher opioid consumption, intraoperative CVP and blood loss in ITM group than in the TEA group. Faster mobilization, lower iv fluid administration, and vasopressors requirement in ITM group than in the TEA group. No difference in quality of recovery and mortality and morbidity between the groups.   Lower NRS scores on coughing and at all time points in the QLB group than in the IV-PCA group. No differences of postoperative self-administered analgesic counts, rate of rescue analgesic usage, and incidences of analgesic-related side effects between the groups. Lower intraoperative consumption of propofol and remifentanil in QLB group. Faster recovery from anesthesia and earlier time to first out-of-bed activity QLB group. Dexmedetomidine group (DEX): n = 26 Dexmedetomidine infusion at an initial loading dose of 0.5 µg/kg before intubation then 0.3 µg/kg/h till the end of surgery. After surgery, for 48 h, 60 mg oxycodone and 360 µg dexmedetomidine diluted to 120 mL and administered at a bolus dose of 2 mL, with 5 min lockout interval and a 1 h limit of 20 mL.
Control group: n = 26 with saline. Postoperatively: 60 mg Oxycodone alone with the same regimen in the DEX group than in the control group. Lower opioid consumption after surgery in the DEX group than in the control group. Higher patient satisfaction with pain control, shorter time to the first exhaust, and less incidence of PONV in the DEX group than in the control group. No difference in sedation between the groups. Decreased intraoperative consumption of propofol and remifentanil during surgery in the DEX group compared with the control group. TEA with ketamine: n = 23 6 mL of ketamine 0.5 mg/kg + morphine 4 mg + 1% of lidocaine before surgical incision. No infusion during surgery. Before skin closure iv bolus of morphine 0.05 mg/kg and then the TEA-PCA pump 5 mL/h of ketamine 1.5 mg/mL+ morphine 15 µg/mL + ropivacaine 0.15%a till PoD5 IV-PCA: n = 21 iv bolus of ketamine 0.5 mg/kg before surgical incision and iv infusion of morphine 0.025 mg/kg/h during surgery iv bolus of morphine 0.05 mg/kg before skin closure and then IV-PCA 1 mL/h of ketamine 7.5 mg/mL +morphine 1 mg/mL+ ketorolac 1.5 mg/mL till PoD5 Both groups received iv acetaminophen (1 g every 6 h)

Trials Assessing WI
The role of WI with local anesthetics to prevent postoperative pain after open liver surgery was evaluated in ten studies, which included a total of 1412 patients: five compared to TEA (2 RCTs, 2 POS, and 1 RO), four to placebo (RCTs), and one to systemic opioids (RCT) [24][25][26][27][28][29][30][48][49][50]. When compared to TEA, the use of WI produced conflicting evidence: two studies proved WI less effective in pain control than TEA while three studies proved no difference; of the three studies that reported data on LOS, one proved WI was associate with shorter LOS compared to TEA and two recorded no differences; no differences in surgical complication after WI or TEA were reported (Table 3) [24,25,[48][49][50]. When compared to the placebo, results showed WI as being more effective in preventing pain and it reduced opioid consumption, but no differences in patient satisfaction were proven; the use of WI was associated with a less systemic release of "stress hormones" (plasma concentration of epinephrine, norepinephrine, and cortisol) than the placebo; there were no differences in the side effects rates between the two treatments ( Table 3) [26][27][28][29]. In a 3-arms RCT, treatment with WI resulted in better pain control and a lower side effects or serious complications rate than assignment to systemic PCA fentanyl or tramadol. Of note, patients assigned to receive tramadol had a higher mortality rate at the 25 months follow-up than those in the two other study groups (Table 3) [30].

Trials Assessing TAP Block
The efficacy of a TAP block in preventing postoperative pain after open liver surgery was tested in nine studies, which included a total of 816 patients: two compared to neuraxial analgesia (2 RO), two to placebo (2 RCTs), three to systemic opioids (2 RCTs and 1 RO), one assessed the combination with NSAID-parecoxib-(RCT) and one to WI (RCT) [31][32][33][34][35][36][51][52][53]. According to results reported in an RO that included four study groups (combination of TAP block plus neuraxial analgesia; TAP block alone; neuraxial analgesia alone; or systemic opioids), patients that received a TAP block in combination with TEA showed the lowest pain scores and required less opioid consumption; those treated with the remaining approaches resulted in progressively lower efficacy (Table 3). Of note, the use of a TAP block is associated with the shortest LOS compared to the other treatments (Table 3) [51]. Data on better pain control with a TAP block vs. intrathecal morphine is also confirmed by an RO that proved lower pain scores on day 1, but no difference on the subsequent days (Table 3) [52]. When compared to the placebo, to the use of systemic opioids or parecoxib, the use of a TAP block proved to be consistently more effective in preventing pain and reducing opioid consumption (Table 3) [31][32][33][34][35]53]. Compared to WI, the TAP block was equally effective in pain control and led to lower opioid consumption (Table 3) [36].

Trials Assessing TEA
The effectiveness of TEA in pain management after open liver surgery was evaluated in four studies, which included a total of 393 patients: three compared to systemic opioids (2 RCTs and 1 POS) and one compared to a combination of systemic opioids and WI (RCT) [37][38][39]54]. When compared to systemic opioids, the use of TEA resulted in more effective pain control and in being associated with less opioid consumption and greater patient satisfaction with pain control (Table 3) [38,39,54]. Furthermore, the association of systemic opioids with WI provided greater pain control than TEA.

Trials Assessing NSAIDs
The role of NSAIDs in preventing postoperative pain after open liver surgery was evaluated in three studies, which included a total of 186 patients: two compared to placebo (RCTs) and one compared parecoxib to ketorolac (RO) [40,45,55]. When compared to the placebo, the use of NSAIDs proved to be more effective in pain control and associated with a higher opioid-sparing effect. These studies also suggest that NSAID use is possibly associated with a more preserved immune function (by increasing CD3+ and NK cell levels), reduced systemic inflammatory response (decreased levels of IL-4 and increased TGF-β), associated with a longer tumor-free interval and disease-free survival time (Table 3) [40,45]. The use of parecoxib or ketorolac leads to similar results in terms of postoperative pain control (Table 3) [55].

Trial Assessing ITM
The efficacy of ITM in preventing postoperative pain after open liver surgery was evaluated in four studies, which included a total of 374 patients: three compared to systemic opioids (RO and 2 RCTs) and one to TEA (PO) [42,43,56,57]. When compared to systemic opioids, the use of ITM proved to be associated with lower pain, but not the reduction in complications or the side effects of analgesia rates; no differences in functional recovery time were proven (Table 3) [42,43,56]. When compared to TEA, ITM was less effective in controlling pain during the first 12 postoperative hours, but there were no observed differences afterward, and patients receiving ITM had larger intraoperative blood loss (Table 3) [57].

Trials Assessing PVB
The role of PVB in preventing postoperative pain after open liver surgery was tested in three studies, which included a total of 150 patients: one compared to TEA (RCT), one to placebo (RCT), and one to systemic opioids (RO) [41,44,58]. When compared to TEA, bilateral PVB was less effective in preventing pain; the two groups had a similar rate of side effects, associated complications, rate of ICU admission, and LOS (Table 3) [44]. When compared to the placebo, the use of the right PVB was superior for pain control and was also associated with greater patient satisfaction; there were no differences reported in side effects, associated complications, and LOS between the study groups (Table 3) [41]. When compared to systemic opioids, the use of the right PVB was associated with lower opioid consumption, but there were no differences in pain scores and there were similar rates of side effects between the two study groups (Table 3) [58].

Trial Assessing QLB
The effects of continuous QLB in preventing postoperative pain after open liver surgery was evaluated and compared to systemic opioids in 1 RCT that enrolled a total of 63 patients [46]. When compared to systemic opioids, the use of QLB resulted in more effective pain control, shorter recovery time from anesthesia, and earlier independent mobilization after surgery; no differences in the rate of side effects were recorded between the two treatment groups (Table 3).

Trial Assessing Dexmedetomidine
Adding dexmedetomidine to pain management after open liver surgery was tested in one study (RCT) and compared to a placebo in a total of 52 patients [47]. Dexmedetomidine infusion, started at anesthesia induction and continued for 48 postoperative hours, was associated with better pain control than the placebo (Table 3) [47].

Trial Assessing Ketamine
Differences in ketamine administration routes, intravenous vs. epidural, were tested to prevent pain after open liver surgery in one study (POS) which included a total of 44 patients [59]. The two tested approaches resulted in similar efficacy in controlling postoperative pain. Of note, in patients that received intravenous ketamine, there was a higher rate of cognitive side effects: hallucinations, acute confusional syndrome, and nightmares (Table 3) [59].

Discussion
This SR is intended to update a previous review and PROSPECT guidelines on postoperative analgesia in open liver surgery and includes studies published between September 2013 and December 2020. Current evidence suggests that, in these patients, optimal postop-erative pain management should rely on using a "blended approach" that includes the use of systemic opioids and NSAID infusion along with regional techniques (WI, TAP blocks, TEA, ITM, PVB, QLB). This approach warrants the highest efficacy in terms of pain prevention, including lower incretion of postoperative "stress hormones", and fewer side effects. Furthermore, concerns on the potential for the increased risk of wound infection related to the use of regional techniques have been ruled out.
Compared to the evidence reported in the review published by Hughes and Coll [19], there are several notable differences: it is now clear that the systemic infusion of analgesics (opioids and NSAIDs) is an essential component of postoperative analgesia and there are specific indications for the most appropriate prescription considering that opioids should be better used as PCA and NSAIDs according to a pre-scheduled, TEA and other regional approaches, WI and TAP blocks, associate with similar effectiveness. Furthermore, when compared to the PROSPECT recommendation of ESRA for pain management after open liver resection, new evidence has emerged about the efficacy of QLB, dexmedetomidine infusion, and few benefits in ITM utilization in these settings [20]. As with other subspecialty procedures, postoperative pain management should be addressed considering the specific evidence-based principles [60][61][62]. This SR now provides a detailed and comprehensive summary of specific clinical evidence targeted to postoperative analgesia in open liver surgery. Of note, it is important to consider that implementing TEA into routine clinical management is affected by the so-called "team approach" [63]. It means that when an experienced team (surgeon, anesthesiologist, perioperative nurses, pharmacists, physical and respiratory therapist) takes care of patients it improves the functional outcome.
The present SR is intended to update a previous review article and has unique methodological features. First, the current SR presented was conducted in accordance with the PRISMA guidelines as with the previous one but was also approved and recorded by the PRISMA board. Data extraction was accomplished, with a dedicated data extraction form, using a PICOS approach intended to identify specific primary and secondary end points that namely included the efficacy and safety of the tested approaches. The current primary end point was selected to report on the efficacy of the tested therapies, thus, introducing a distinct perspective when compared to the previous review that primarily reported an "overall systemic complication rate". The previous approach led the authors to find no differences among the reported approaches, while in the present SR the benefits of a blended approach are shown, as is the superiority of the pre-scheduled administration of NSAIDs, while opioids should be better prescribed as PCA. As secondary end points, the previous review reported LOS and pain scores at 24 postoperative hours both at rest and when moving proved unbeneficial. In the present SR, safety was the main focus of the selected secondary end points, and collected evidence excluded the potential for additional risk associated with regional analgesic strategies. Studies that included patients who underwent liver transplants have been excluded from the present SR because it was selectively intended to present the clinical management of patients undergoing an elective surgical procedure. This SR has several limitations including the methodological approach that relied on the literature search being limited to two databases (PubMed and EMBASE). Despite the potential for having missed other published studies, it is appropriate to underline that the most prestigious journals are referred to in these databases and therefore the risk of omitting major information was limited. Another possible limitation refers to the exclusion of studies that presented mixed cases of open, laparoscopic, and percutaneous procedures. This might have prevented adding details collected in some studies however enabled the selection of evidence from patients with a more homogeneous clinical background. Of note, most of the studies in each treatment section have widely different design and clinical relevance. As a result of this and other shortcomings, there are often contradicting results. We acknowledge that utilizing the GRADE approach to evaluation might have added strength to data extraction. Nevertheless, as mentioned among the study's limitations, the limited number and heterogeneity of retrieved studies prevent reaching ultimate con-clusions and the present systematic review should be considered as an updated summary of available evidence and the proposal for future studies.
In conclusion, the latest evidence on postoperative analgesia in open liver surgery provides new relevant information on the effectiveness and safety of various tested approaches and supports "blended" approaches with systemic analgesic infusion (opioids and NSAIDs) along with regional techniques. Patients undergoing open liver surgery have unique clinical problems and requirements that include: the risk for hemodynamic instability due to intraoperative vascular clamping and fluid shift, potential postoperative pulmonary complications, coagulation disturbances, and metabolic abnormalities after excessive parenchymal resection, altered drugs metabolism, etc. Blended multimodal approaches were associated with the highest effectiveness and the least side effects. The NSAIDs should be better administered on a pre-scheduled structured prescription and opioids have the highest efficacy/safety profile when administered as PCA. Continuous opioid infusion, along with scheduled NSAID administration, emerged as a possible treatment after the careful analysis of available clinical evidence in this setting. None of the referenced studies specifically tested this approach that is a part of the new information presented in this systematic review as possible future research proposals. Future studies should also be addressed to identify how postoperative analgesia can effectively contribute to shortening LOS and improving functional recovery of physical and cognitive abilities.