Effects of Intermittent Bolus Paravertebral Block On Analgesia and Recovery in Open Hepatectomy: A Retrospective, Cohort Study.


 Background

Experiences of paravertebral block use in hepatectomy were limited. We aimed to investigate the effects of intermittent bolus paravertebral block on analgesia and recovery in hepatectomy.
Methods

We selected patients receiving two types of analgesia programs, with matched age, sex and body mass index from a prospective perioperative analgesia and nerve block database: (1) PVB: intermittent bolus paravertebral block (0.5% ropivacaine 25ml before surgery plus 0.125ml•kg− 1 0.2% ropivacaine bolus per hour after surgery) and self-controlled intravenous bolus morphine pump till postoperative 48 hours; (2) control: self-controlled intravenous bolus morphine pump till postoperative 48 hours. The baseline, operation, and postoperative analgsia and recovery data were compared between groups.
Results

Thirty-eight patients in each group were included in the analysis. Intraoperatively, PVB group used less sevoflurane (difference − 0.1 (-0.2, 0.0) %, P = 0.019), and more ephedrine (U = 986, P = 0.004) and crystalloid (U = 936, P = 0.024) than control group. The mean arterial pressure in PVB group was lower than that in control group (difference − 4mmHg, 95%CI -8 ~ 0mmHg, P = 0.031) but similar to its baseline level (difference 2, 95%CI -1 ~ 5, P = 0.153). Postoperatively, PVB group had lower cumulative morphine consumption at postoperative 2 (U = 371.5, P < 0.001), 4 (U = 349.5, P < 0.001), 12 (U = 342.0, P < 0.001), 24 (U = 338.5, P < 0.001) and 48 (U = 392.5, P = 0.001) hour, lower pain numerical rating scale score at rest at postoperative 0 (U = 299.5, P < 0.001), 2 (U = 355.5, P < 0.001) and 4 (U = 332.0, P < 0.001) hour, and on movement at postoperative 0 (U = 269.5, P < 0.001), 2 (U = 405.0, P = 0.001), 4 (U = 382.5, P < 0.001) and 12 (U = 1179.5, P = 0.003) hour than control group. PVB group also had lower rescue analgesia rates (OR 0.29, 95%CI 0.08 ~ 1.00, P = 0.044), higher emergence satisfaction (5 (4, 5) vs 4 (4, 5), P = 0.018) and lower drowsiness score (0 (0,1) vs 1(0,1), P = 0.007) than control group. Three months postoperatively, PVB group had lower rates of hypoesthesia (OR 0.28 (0.11, 0.75), P = 0.009), numbness (OR 0.26 (0.07, 0.88), P = 0.024) and sleep disorder (OR 0.84 (0.73, 0.97), P = 0.025) than control group.
Conclusions

Intermittent bolus paravertebral block provided anesthetics- and opioids-sparing effects, and enhanced recovery both in hospital and after discharge in patients receiving hepatectomy.


Conclusions
Intermittent bolus paravertebral block provided anesthetics-and opioids-sparing effects, and enhanced recovery both in hospital and after discharge in patients receiving hepatectomy.
Background Page 3/20 Paravertebral block has been used as an effective perioperative analgesia approach in many types of surgeries, including thoracic, breast, cardiac and abdominal surgeries. (1)(2)(3)(4)(5) It provides good pain relief with less intravenous opioids consumption. Compared to epidural analgesia, paravertebral block carries a lower risk of multiple complications, including hypotension, nausea, vomiting, pruritus and urinary retention. (2,6) Although various paravertebral block approaches and drug delivery programs have been studied, some clinical problems remain controversial or unsolved. Con ict results were drawn in studies comparing continuous and intermittent bolus drug infusion programs, (7,8) and the effects of paravertebral block on preventing chronic postoperative pain remain unclear. (9,10) Open hepatectomy for hepatic tumor often causes severe postoperative pain due to its large incision and extensive surgical damage. Cases of paravertebral block use in hepatectomy have been reported (11,12), but clinical studies were limited (13,14). And we failed to identify studies reporting the effects of intermittent bolus paravertebral block on intraoperative management, and postoperative analgesia and recovery after discharge in patients receiving hepatectomy as far as searched.

Objectives
This retrospective, cohort study aimed to evaluate the effects of intermittent bolus paravertebral block on analgesia and recovery of patients receiving open hepatectomy for hepatic tumor. We hypothesized that intermittent bolus paravertebral block reduced postoperative 48 hours cumulative intravenous opioid consumption, without increase of adverse events. Intraoperative management, postoperative analgesia and recovery, and follow-up data were collected and compared between patients receiving and without receiving paravertebral block.

Study design
This is a retrospective, cohort study of existing medical data that were prospectively entered into an institutional perioperative analgesia and nerve block database. The hospital's institutional review board approved the data review (No. S-K 1574), and patient informed consent was waived.

Participants
We searched medical records of patients receiving open hepatectomy for hepatic tumor with a J-shaped subcostal incision from Jan 2019 to Dec 2019 in the database. Patients receiving intermittent bolus paravertebral blocks (0.5% ropivacaine 25ml before surgery plus 0.125ml•kg − 1 0.2% ropivacaine bolus per hour after surgery) and self-controlled intravenous bolus morphine pumps for postoperative 48 hours were recruited into the paravertebral block (PVB) group. Patients receiving only self-controlled intravenous bolus morphine pumps for postoperative 48 hours, with matched age, sex and body mass index were selected as control group.
Patients comorbid with other pain diseases, received analgesic techniques apart from the studied analgesia program, or failed to complete the analgesia program or follow-up due to reasons that were not related to perioperative analgesia, for instance, postoperative hemorrhage, surgical site infection or selfwithdraw, were excluded from the study.

Baseline data collection
The hospital's perioperative analgesia team consisted of a group of experienced anesthesiologists, they provided all kinds of analgsic services to the surgical patients, including preparing analgesia pump, performing nerve blocks, postoperative follow-up and data recording.
Baseline data included age, sex, body mass index, American Society of Anesthesiologist (ASA) classi cation and preoperative surgical site pain score evaluated by a 11 points-numerical rating scale (NRS). The NRS pain score was evaluated and recorded by the anesthesiologists during preoperative visit, with 0-point indicating no pain and 10-point indicating the maximum degree of insufferable pain. Patients were also educated with a pain control goal of NRS < 4. Laboratory examination data that were collected included preoperative liver, renal and coagulation function and complete blood count.

Paravertebral block
In the PVB group, all paravertebral blocks were performed by the perioperative analgesia team members before anesthesia. The paravertebral block was performed using an in-plane approach(15) to insert a 21gauge 10 cm needle (PlexoLongNanoline; Pajunk Inc, Geisingen, Germany) into the T8 paravertebral space between the internal intercostal membrane and the pleura under the guidance of ultrasonography (CX-50, Philips Inc., USA). After a negative aspiration test, 25 ml of 0.5% ropivacaine was slowly injected into the paravertebral space. Then, a catheter (PlexoLongNanoline; Pajunk Inc, Geisingen, Germany) was inserted through the needle into the paravertebral space with a depth of 1-2 cm, tunneled subcutaneously and secured with Bio-gel to the patients' back. The catheter was connected to a programmable, portable, electronic infusion pump (Apon ambulatory infusion pump ZZB-I, Jiangsu Apon Medical Technology Co., Ltd.) to deliver a bolus of 0.125 ml•kg − 1 0.2% ropivacaine per hour, commencing immediately after surgery. In the control group, no nerve blocks were performed before or after the surgery.

Intraoperative data collection
Both PVB and control groups received general anesthesia with endotracheal intubation. All patients recorded in the studied database adopted similar general anesthesia plan. Induction was performed with intravenous fentanyl, propofol and rocuronium. Anesthesia was maintained with sevo urane and a Intraoperative data that were collected included the baseline and mean value of heart rate and blood pressure, mean sevo urane concentration, intraoperative medication and uid volume. All vital signs and sevo urance concentration were collected by the monitor and ventilator in real-time and transmited to the database via electronic cables at 5 minutes interval during the surgery. All medications and uids were recorded by the anesthesiologists during the surgery.

Postoperative data collection
Both PVB and control groups' patients received self-controlled intravenous bolus morphine pump (Gemstar, Hospiria Inc., USA) after extubation. Intravenous morphine was given with no background infusion, patient-controlled bolus of 1-2 mg, 5-minute lockout interval and an upper limit of 8mg per hour. If the patients still complaint about pain with the upper limit dose, tramadol was given as rescue analgesia.
Postoperative paravertebral and intravenous analgesia were provided for 48 hours. The perioperative analgesia team members visited the patients and assessed the outcomes in the ward at postoperative 2, 4, 12, 24 and 48 hours and follow-ups were done by telephones at postoperative three months.
Primary outcome was postoperative 48 hours cumulative morphine consumption collected from electronic pump record. Secondary outcomes included: (1) cumulative morphine consumption at postoperative 2, 4, 12 and 24 hours and total number of rescue analgesia; (2) pain NRS score at rest and on movement at postoperative 0, 2, 4, 12, 24 and 48 hours; (3) opioid adverse effects including nausea, vomiting, pruritus, respiratory depression, bowel movement recorded as gas time and urinary retention recorded as Foley catheter removal time; (4) recovery data that were evaluated at postoperative 48 hours included drowsiness, thirsty, cold feeling, cognitive decline and shiver. These indices were evaluated using a 0-3 points Likert scale with 0 point de ned as none, 1-point de ned as mild, 2-point de ned as moderate and 3-point de ned as severe. Emergence, analgesia and overall satisfactions were evaluated using a 1-5 points Likert scale with 1-point de ned as very unsatis ed, 2-point de ned as unsatis ed, 3point de ned as no comments, 4-point de ned as satis ed and 5-point de ned as very satis ed; (6) length of hospital stay; (7) recovery data that were evaluated at postoperative three months included incidences of hypoesthesia, numbness and pain, pain NRS scores at rest and on movement, pain characteristics including throbbing, aching, pricking and stabbing pain, and the incidence of sleep disorder.

Statistical analysis
Study sample size was calculated based on a pilot study of ten patients receiving the studied analgesia program, that were randomly selected from the database via computer. The mean postoperative 48 hours cumulative morphine consumptions were (16.8 ± 13.5) mg and (32.7 ± 19.2) mg in the PVB and control groups, respectively. Thirty-ve patients were required in each group to achieve an α level of 0.01 and β level of 0.9.
Statistical analysis was performed using SPSS for Mac version 23.0 (IBM Corp., Armonk, NY, USA).
Normality was tested using the Q-Q plots. Normally distributed variables were expressed as mean ± SD, non-normally distributed variables were expressed as median (quartile), and categorical variables were expressed as frequency (percentage). Normally distributed continuous data were analyzed using the students t test and non-normally distributed continuous data were analyzed using the Mann-Whitney U tests. Categorical data were compared using the Chi-square test when the expected cell counts > 5, otherwise the Fisher's exact test was used. All tests were two-tailed, and a P value less than 0.05 was considered statistically signi cant. The Bonferroni correction was performed on the raw P value where applicable. For the multiple comparison of cumulative morphine consumption and pain score at different time points, the P values for the 0.05 level of signi cance were adjusted to 0.01 and 0.008 based on the number of observed time points.

Results
A total of 234 patients receiving open hepatectomy were screen and 48 received the studied nerve block program. Five patients were dropped due to PVB catheter dislocation, unplanned secondary surgery and ICU admission. Five patients did not complete the follow-up. Finally, thirty-eight patients in the PVB group were included in the analysis. Another thirty-eight patients receiving only self-controlled intravenous bolus morhpine pump with matched age, gender and body mass index were selected from the same database as control group.

Baseline data
Baseline clinical characteristics were listed in Table 1. The age, sex, body mass index, ASA classi cation, preoperative pain score, hemoglobin and platelet counts, liver function and coagulation test results were similar between PVB and control groups (all P > 0.05).

Discussion
This study showed that perioperative intermittent bolus paravertebral block in patients receiving hepatectomy provided good anesthetics-and opioids-sparing effects, and enhanced postoperative recovery both in-hospital and three months after discharge. The study results showed that intermittent bolus paravertebral block could reduce intraoperative sevo urane consumption and postoperative intravenous opioid consumption up to 48 hours after hepatectomy, and provided better analgesia at rest and on movement up to postoperative 4 and 12 hours, respectively. Patients receiving paravertebral block also had lower drowsiness score, higher emergence satisfaction during hospital stay, and lower incidences of hypoesthesia, numbness and sleep disorder three months after discharge.
Intermittent bolus paravertebral block could reduce postoperative intravenous morphine consumption for 48 hours in patients receiving hepatectomy. While early studies on thoracic surgery showed superior analgesic effects of continuous infusion than intermittent bolus infusion,(4) three recent studies suggested that analgesics delivered in intermittent bolus modality provided comparable or even superior pain relief, and wider dermatome spreads of sensory block than analgesics delivered in continuous infusion modality. (7,8,17) Our study used an intermittent bolus paravertebral block program initiated preoperatively on patients receiving hepatectomy for hepatic tumor. Compared to Chen et al's thoracic paravertebral block study starting with an initial dose of 10 mL 0.2% ropivacaine administered at the completion of right lobe hepatectomy and followed by a continuous infusion of 0.2% ropivacaine at 6 mL•h − 1 for 24 hours postoperatively, we administered an initial dose of 25 mL 0.5% ropivacaine preoperatively and followed by 0.125mL•kg − 1 •h − 1 0.2% ropivacaine bolus infusion for 48 hours postoperatively. The results showed that at postoperative 24 hours, the cumulative intravenous morphine consumption reduced by 21% in Chen et al's study and reduced by 50% in our study. This suggested that the analgesic programme we used provided a better opioid-sparing effect than the programme described by Chen et al. (13) Paravertebral block also had an impact on intraoperative hemodynamics and anesthetic management.
Previous study on mastectomy showed that paravertebral block helped maintain a higher heart rate and shorter duration of mean aterial pressure < 55mmHg, with reduced intraoperative sevo urane and opioids consumption, and similar ephedrine doses.(18) Study on thoracoscopic surgery revealed lower intraoperative opioids consumption in the paravertebral block group than placebo group,but changes of heart rate and blood pressure were not reported. (19) Our study on patients receiving hepatectomy showed that the mean arterial pressure in the PVB group was lower than that in the control group, but similar to patient's baseline level. As for intraoperative management, a lower sevo urane and higher ephedrine and crystalloid consumption were noted in the PVB group than control group. Though no difference in fentanyl consumption was detected between groups, lower pain scores both at rest and on movement at postoperative 0 hour were achieved in PVB group. These results showed that paravertebral block reduced anesthetic dose and provided better intraoperative analgesia. Although induced slight hemodynamic instability, it could be easily corrected with prompt intraoperative management, including the use of vasoactive agents and increase of uid infusion.
Although two studies have been conducted to investigate the perioperative analgesia effects of paravertebral block on hepatectomy, (13,14) we failed to nd reports on chronic postoperative pain and recovery after discharge in this group of patients, as far as searched. The reported effects of paravertebral block on chronic postoperative pain in other types of surgeries were controversial. (9,20) While one study on patients receiving mastectomy suggested that paravertebral block could not reduce the incidence of chronic pain at postoperative 3 and 6 months, but reduced the pain score and improved their overall health related quality of life,(21) the other study suggested that preemptive paravertebral block reduced the prevalence of chronic postoperative pain one year after mastectomy, regardless of whether axillary dissection was performed.(22) Study on thoracotomy suggested that paravertebral block could not reduce chronic postoperative pain.(23) Our study found that paravertebral block did not affect the incidence, severity and characteristics of pain, but reduced the incidence of hypoesthesia, numbness and sleep disorder three months after hepatectomy. Possible explanations might be reduced central sensitization due to nerve block, which should be applied as early as possible. (21) Further studies with larger sample size and longer follow-up time are required to fully illustrate this issue.
This study has several limitations. Firstly, although all data were prospectively entered into the database, this study remains a retrospective review of the experiences of a single center and suffers from all of the shortcomings of this type of study. Secondly, the unique clinical pro le of patients from a single medical center may not be generalizable to other clinical situations. Further extensive multicenter studies are required to validate our ndings.

Conclusions
In conclusion, intermittent bolus paravertebral block provides good anesthetics-and opioids-sparing effects, and enhanced recovery both in hospital and after discharge in patients receiving hepatectomy for hepatic tumor. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

List Of Abbreviations
Competing interests: The authors declare that they have not competing interests.
Funding: This research did not receive any speci c grant from funding agencies in the public, commercial or not-for-pro t sectors.  Postoperative pain numerical rating scale at rest at different time points.

Figure 3
Postoperative pain numerical rating scale on movement at different time points.