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Abstract
Background and objectives Transversus abdominis plane (TAP) blocks are associated with an improvement in postoperative analgesia following kidney transplant surgery. However, these blocks carry inherent risk and require a degree of expertise to perform successfully. Continuous intravenous lidocaine may be an effective alternative. In this randomized, non-inferiority study, we hypothesized that a continuous lidocaine infusion provides similar postoperative analgesia to a TAP block.
Methods Subjects presenting for kidney transplant surgery were randomized in a 1:1 ratio to either an ultrasound-guided unilateral, single-injection TAP block (TAP group) or a continuous infusion of lidocaine (Lido group). The primary outcome of this non-inferiority study was opioid consumption within the first 24 hours following surgery. Secondary outcomes included pain scores, patient satisfaction, opioid-related adverse events, time to regular diet, and persistent opioid use.
Results One hundred and twenty subjects, 59 from the TAP group and 61 from the Lido group, completed the study per protocol. Analysis of the primary outcome showed a cumulative geometric mean intravenous morphine equivalent difference between the TAP (14.6±3.2 mg) and Lido (15.9±2.4 mg) groups of 1.27 mg (95% CI −4.25 to 6.79; p<0.001), demonstrating non-inferiority of the continuous lidocaine infusion. No secondary outcomes showed clinically meaningful differences between groups.
Conclusions This study demonstrates that a continuous infusion of lidocaine offers non-inferior postoperative analgesia compared with an ultrasound-guided unilateral, single-injection TAP block in the first 24 hours following kidney transplant surgery.
Trial registration number NCT03843879.
- analgesia
- drug-related side effects and adverse reactions
- nerve block
- pain
- postoperative
- ultrasonography
Data availability statement
Data are available on reasonable request.
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Introduction
Peripheral nerve blocks, or the injection of local anesthetic adjacent to targeted nerves, have been demonstrated to improve pain scores and decrease opioid consumption in the immediate postoperative period.1 2 Specifically, ultrasound-guided transversus abdominis plane (TAP) blocks have demonstrated improvement in both outcomes following kidney transplant surgery in many studies.3–5 While there still remains some controversy about the true impact of this technique on postoperative analgesia,6 a summation of all the available literature does show a positive effect.7 Though the procedure itself is rather simple to perform and relatively safe,8 9 TAP blocks still carry inherent risks to the patient (eg, bleeding, infection, and nerve injury) and require a degree of expertise to perform successfully. Recently, continuous infusion of intravenous lidocaine has been shown to provide opioid-sparing analgesia in a wide range of surgeries.10 11 Unlike peripheral nerve blocks, the administration of intravenous lidocaine requires no technical proficiency to perform, but can only be provided in a monitored setting as it carries the risk of local anesthetic systemic toxicity (LAST). To date, there have been few studies comparing perioperative continuous administration of intravenous lidocaine to peripheral nerve blocks for postoperative analgesia.
Currently, practice standards for the treatment of acute pain following kidney transplant surgery are heterogeneous. While opioid medications are the default treatment for pain at many institutions, they have a tremendous burden on the healthcare system by increasing patient morbidity.12 Despite evidence that TAP blocks improve analgesia, this intervention has not been universally adopted by many institutions. Limited expertise may have potentially restricted this particular nerve block in becoming standard of practice. With the potential of equipotent analgesia provided by either ultrasound-guided TAP block or a continuous intravenous infusion of lidocaine, clinicians could provide efficacious acute pain management in this cohort of patients with simple medical therapy instead of a more invasive interventional procedure.
We selected a randomized, non-inferiority design to compare continuous intravenous lidocaine to ultrasound-guided TAP block using 24-hour postoperative opioid consumption as the primary outcome. Secondary outcomes include cumulative opioid consumption from 24 to 48 hours following surgery, patient satisfaction with analgesia, incidence of opioid-related and medication-related adverse events, duration of hospitalization, time to resumption of regular diet, and frequency of chronic opioid use after hospital discharge. We hypothesized that the intravenous lidocaine infusion would be non-inferior to TAP block in terms of postoperative opioid consumption.
Methods
Study design
This trial was prospectively registered at clinicaltrials.gov by NAH (principal investigator) on March 1, 2019. The study was conducted at Virginia Mason Franciscan Health, Seattle, Washington from March 2019 to February 2021. Adults subjects (>18 years old) scheduled for living donor or cadaveric renal transplant were approached for inclusion. Exclusion criteria were limited to chronic opioid use, allergies to local anesthetics, severe hepatic disease, or seizure disorder. Written informed consent was obtained from all subjects.
Using a 1:1 ratio with a computer-generated simple randomization obscured in sealed envelopes, each subject was randomized to one of two groups: ultrasound-guided unilateral, single-injection TAP block (TAP group) or a continuous intravenous lidocaine infusion (Lido group). Randomization assignments were not blinded due to institutional review board concern for safety monitoring in subjects with renal insufficiency receiving a continuous lidocaine infusion.
Perioperative management
In the absence of any contraindications, subjects received a preoperative oral analgesic regimen consisting of a single-dose acetaminophen (975 mg). Acetaminophen 650 mg every 6 hours was continued postoperatively. General anesthesia was induced with propofol (1–2 mg/kg) and tracheal intubation was facilitated with 0.2 mg/kg of cisatracurium or 0.6 mg/kg rocuronium at the treating anesthesia team’s discretion. Maintenance of general anesthesia was performed with at least one minimum alveolar concentration of sevoflurane throughout the procedure. A standardized opioid algorithm was used intraoperatively, with 25 μg intravenous fentanyl given for increases in heart rate or blood pressure greater than 20% from baseline. Total intraoperative fentanyl use was recorded. All surgeries were performed using an extraperitoneal approach through a unilateral Gibson incision.13 Vascular anastomoses were made to the external iliac artery and vein, while the ureteral anastomoses were performed using an extravesical Lich-Gregoir implant technique. No surgical local infiltration was performed.
Block placement and continuous infusions
For subjects randomized into the TAP group, immediately after induction of general anesthesia, an ultrasound-guided unilateral TAP block ipsilateral to the surgical site was performed. A high-frequency linear array transducer (M-Turbo; Sonosite, Bothell, Washington) was placed along the mid-axillary line of the abdominal wall, between the lower costal margin and the iliac crest in order to identify the relevant anatomy. After prepping the skin with chlorhexidine gluconate (Chloraprep), a clear sterile drape was placed over the area. Following identification of the appropriate anatomy, a 22-gauge echogenic needle was inserted with ultrasound guidance, from an anterior to posterior approach through the external and internal oblique muscles. A 30 mL of 0.25% bupivacaine with 1:400 000 epinephrine solution was then deposited between the internal oblique and transversus abdominis muscles.
For subjects randomized to the Lido group, immediately following induction of general anesthesia, an intravenous lidocaine infusion was initiated (lidocaine hydrochloride in 5% dextrose injection, 2 g/250 mL, Baxter) at a rate of 0.5–1 mg/kg/hour of ideal body weight (<60 kg=0.7 mg/min, 60–79 kg=1 mg/min, 80–99 kg=1.3 mg/min, >100 kg=1.7 mg/min) without initial bolus. The infusion was continued for up until 48 hours postoperatively, as is standard practice at our institution.
Recordings and measurements
Research personnel performed all clinical assessments and data collection.
Opioid consumption and pain
Prior to initiation of a regular diet, subjects received intravenous hydromorphone through a patient-controlled analgesia (PCA) pump (BD, Franklin Lakes, New Jersey, USA). The PCA pump was initially programmed to deliver a bolus of 0.2 mg of hydromorphone on subject demand with a 10 min lockout time and without any baseline infusion. After diet advancement, supplemental oxycodone was available at the treating surgical team’s discretion. Oral hydromorphone was substituted for oxycodone in the instances of patient allergy or intolerance. All opioid consumption, both intraoperatively and during the first 48 hours postoperatively, was retrieved from the electronic medical record and converted to intravenous morphine equivalents (MEQ) for analysis. Verbal Numeric Rating Scale (NRS) pain scores at rest, with activity, average, and worst were recorded by unblinded investigators at 24 and 48 hours postoperatively. Subjects were asked to rate their pain from 0 to 10; 0 representing ‘no pain’ and 10 representing the ‘worst pain imaginable.’
Adverse events and patient satisfaction with analgesia
As part of the postoperative assessments at 24 and 48 hours, subjects were asked to report any opioid-related adverse events, which included nausea, vomiting, pruritus, and sedation. Systemic local anesthetic or block-related adverse effects or events were also collected. Time to resumption of a regular diet was monitored in patients. Subjects were also asked to give a verbal assessment representative of the quality of analgesia at 24 and 48 hours postoperatively. Response to this assessment was recorded as ‘satisfied’ or ‘unsatisfied.’
Thirty-day follow-up
Telephone calls were placed 30 days following hospital discharge to all subjects. Assessment of verbal NRS pain scores (rest, activity) and opioid use were recorded. Hospital length of stay and readmission events were obtained from the electronic medical record.
Statistical methodology
The sample size was calculated assuming a mean intravenous MEQ utilization rate of 16.9 mg with an SD of 14.7 mg within the first 24 hours following kidney transplant surgery based on institutional data. Our non-inferioirty margin, 8 mg intravenous MEQ, is approximately 50% of the known opioid usage and consistent with prior studies use of 10 mg or greater as a clinically relevant difference.14 A non-inferiority margin any smaller would have limited clinical consequence. To have a significance level of 5% and a power of 90%, 58 subjects were required in each arm. Four additional subjects per group (for a total of 124 subjects) were recruited to prevent loss of power due to early withdrawal or protocol violations.
Categorical variables were tested using the χ2 test or Fisher’s exact test as appropriate. Evidence of departure from a normal distribution was detected for all continuous variables presented in this analysis,15 thus all continuous variables (age, body mass index (BMI), estimated blood loss, organ ischemic time, length of surgery, opioid consumption, pain scores, creatinine values, time to regular diet, and hospital length of stay) were analyzed as geometric means using the natural log transformation. The SAS NLEstimate macro, which uses the delta method16 to calculate the variance of functions of parameters from the variance/covariance matrix, was used to calculate 95% CIs and p values for the difference in geometric means. SAS V. 9.4 was used for analysis. Two-sided p values<0.05 were considered statistically important, but the non-inferiority test for the primary endpoint was tested using a one-sided threshold of 0.025 as the criterion for significance.
Results
One hundred and twenty-four subjects were recruited and provided written informed consent to participate in this study. One hundred and twenty completed the study, 59 from the TAP group and 61 from the Lido group. Four subjects were excluded from analysis due to missing primary outcome data, three from the TAP group and one from the Lido group (figure 1). Demographic data and perioperative characteristics were similar between groups (table 1).
Consolidated Standards of Reporting Trials statement flow diagram.
Demographic data and perioperative characteristics
Primary outcome: 0–24 hours opioid consumption non-inferiority
Analysis of the primary outcome of this study showed a difference in 24-hour cumulative geometric mean intravenous MEQ consumption between the TAP (14.6±3.2 mg) and Lido (15.9±2.4 mg) groups of −1.27 mg (95% CI −4.25 to 6.79; p<0.001). The upper CI of the difference, 6.79 mg, was smaller than the prespecififed non-feriority margin (figure 2). Median 24-hour cumulative MEQ consumption for the TAP group was 18 mg (IQR: 7–30.5) and for the Lido group was 15 mg (IQR: 8.5–28).
Non-inferiority diagram with observed difference between intravenous lidocaine and TAP groups in geometric mean cumulative 24-hour intravenous morphine equivalent consumption. The dashed line designates the non-inferiority margin (Δ). The error bar designates the 95% CI of the difference between the intravenous lidocaine and TAP groups. TAP, transversus abdominis plane.
Individual comparisons of opioid consumption
Geometric mean intraoperative opioid consumption was 7±2.5 mg in the TAP group compared with 9±2.5 mg in the Lido group (p<0.0001). Median intraoperative opioid consumption for the TAP group was 7.5 mg (IQR: 5–14) and for the Lido group was 10 mg (IQR: 5–15). There was no significant difference between groups in terms of opioid consumption from 24 to 48 hours (table 2).
Secondary outcomes 24–48 hours following surgery
Secondary outcomes 0–24 hours following surgery
Pain scores and patient satisfaction
There were no significant differences in NRS pain scores between groups at 24 and 48 hours postoperatively (tables 2 and 3), however, subjects reported greater rates of satisfaction with analgesia in the Lido group at 24 hours (p=0.03).
Opioid-related and medication-related adverse events
There was no significant difference in opioid-related adverse events between groups (tables 2 and 3). There were two reports of LAST symptoms in the Lido group at 24 hours, one subject reporting tinnitus with a serum lidocaine level of 2 μg/mL and another reporting a metallic taste in their mouth with a serum lidocaine level of 1.8 μg/mL. Two additional cases of LAST symptoms were reported at 48 hours in two additional subjects, both of whom reported tinnitus. The average lidocaine infusion rate was 0.84±0.1 mg/kg/hour, with a median rate of 0.85 mg/kg/hour. The average lidocaine level at 24 hours postoperatively was 3.2±1.3 μg/mL, with a minimum level of 1.2 μg/mL, a maximum level of 5.8 μg/mL, and a median lidocaine level of 2 μg/mL. There were no reported serious adverse events related to LAST.
Hospital length of stay and time to regular diet
There were no significant differences in resumption of regular diet and length of hospitalization between groups (table 4).
Secondary outcomes during hospitalization
Thirty-day outcomes
There were no significant differences between readmission rates, NRS pain scores, or persistent opioid use between groups (table 5).
Secondary outcomes at 30 days following surgery
Discussion
This study demonstrates that a continuous intravenous infusion of lidocaine offers non-inferior analgesia compared with ultrasound-guided unilateral, single-injection, TAP block within the first 24 hours following kidney transplant surgery. To our knowledge, this is one of the first studies comparing analgesic efficacy of truncal peripheral nerve blocks against the use of continuous systemic local anesthesia.
There are both clinically relevant and practical implications to these results. First, the findings of non-inferior analgesia between ultrasound-guided TAP block and continuous intravenous lidocaine should reassure clinicians that either choice will not compromise analgesic efficacy. This is an important discovery, as the impact of effective multimodal analgesia has been shown in many studies to produce improved outcomes in this surgical cohort,3–5 17 despite a small number of studies being negative.6 If individual patient characteristics (BMI, challenging anatomy) or lack of experience with the performance of the TAP block would make the procedure difficult, clinicians may choose the alternative of continuous lidocaine infusion instead. Furthermore, there are a number of relative contraindications (coagulopathy, pre-existing neuropathy), which can limit the placement of this block in certain patients. Second, while renal failure has been a concern for the use of continuous intravenous lidocaine due to the potential accumulation of metabolites18 in this patient cohort, our study results showed that the incidence of symptoms of LAST are still quite low. Also, none of the reported symptoms in this study were serious in nature. Interestingly, in those subjects who had objective serum lidocaine levels above the threshold of toxicity we observed no signs of LAST. Rather, it was in subjects with completely normal serum lidocaine values who reported minor symptoms, highlighting the importance of frequent clinical evaluation of those patients receiving continuous lidocaine infusions. Caution should be made in drawing any definitive conclusions about the safety of intravenous lidocaine from these results, as this study was not appropriately powered to detect the true incidence of LAST in this patient population. These data should be considered hypothesis generating for future studies.
The majority of secondary outcomes from our study confirm the similarity between continuous intravenous lidocaine and TAP block for postoperative analgesia following kidney transplant surgery. There were no statistically significant differences between NRS pain scores, postoperative opioid consumption, opioid-related adverse events, time to regular diet, duration of hospitalization, readmission rate, or persistent opioid use. Interestingly, the TAP group did show a numerical reduction in intraoperative opioid utilization but this difference was too small to be clinically important. Also, the Lido group had improved patient satisfaction scores with analgesia in the first 24 hours following surgery. This might have been due to the occurrence of rebound pain19 20 following the resolution of the block, however, there was no difference in overall postoperative opioid consumption or opioid-related adverse events between groups. Performance bias also remains possible as subjects were not blinded to the treatment arm.
This study has several limitations. First, there is no known standard in defining a clinically relevant decrease in postoperative opioid consumption following surgery. Thus, we chose a non-inferiority margin less than prior published studies,14 but one that was still clinically meaningful. Our non-inferiority margin of 8 mg intravenous MEQ is equivalent to approximately 15–20 mg oxycodone, a difference we would consider clinically relevant. A further reduction in the non-inferiority margin may have been able to detect a smaller difference in opioid consumption but would have been clinically insignificant to our practice.
Second, this study was not blinded which may have led to bias both on the part of the investigators and subjects. While it would have been ideal to blind this study in some fashion, we were unable to do so for both ethical and practical reasons. At our institution it is standard of practice to draw serum lidocaine levels for any patient receiving a continuous lidocaine infusion, thus any attempt at blinding investigators would have been immediately compromised by such results. Furthermore, as continuous intravenous lidocaine is relatively contraindicated in patients with renal insufficiency, it has not been widely studied in this patient cohort. Thus, our institutional review board wanted to ensure safety of all subjects enrolled in this trial by forgoing blinding of the Lido group. This was also the reason a bolus of lidocaine was not delivered prior to the initiation of the infusion and likely resulted in the increased intraoperative opioid consumption demonstrated in the Lido group. Nonetheless, there did not appear to be any improvement in analgesia from 24 to 48 hours in the Lido group over the TAP group. Given that the duration of the peripheral nerve block was not expected to exceed 24 hours, these results were unexpected. This may be explained by the nature of the surgery itself, which may not be as painful as initially projected after the initial 24 hours.
Third, prior studies3 have used continuous perineural techniques in this surgical cohort but our comparator was a single-injection TAP block, as it is our standard of practice. We recognize single-injection techniques have vastly different drug pharmacodynamics than continuous perineural techniques and thus extrapolation of these results to continuous TAP blocks cannot be made. Nonetheless, the placement of continuous blocks requires additional expertise that is not necessarily representative of the majority of practices. Consequently, we felt that these results would be more generalizable to the anesthesiology community at large.
Finally, within the literature there is a wide range of lidocaine infusion rates,10 11 but given the renal dysfunction of our subjects, we chose the lowest effective dose. Had we chosen greater continuous infusion rates, we may have been able to see greater differences in outcomes between groups. However, our primary concern was for the safety of our subjects and not ensuring superior analgesia with a given technique.
In conclusion, this study demonstrates that a continuous infusion of intravenous lidocaine offers non-inferior analgesia compared with an ultrasound-guided unilateral, single-injection, TAP block following kidney transplant surgery. These findings offer clinicians alternative acute pain management options in those patients in whom peripheral nerve block is challenging or contraindicated without compromising analgesic efficacy. Future studies are necessary to validate these results.
Data availability statement
Data are available on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This randomized, non-inferiority trial received approval by the Benaroya Research Institute, Seattle, Washington.
Acknowledgments
The authors thank Octavio Preciado for his contributions during the data collection phase of this study.
References
Footnotes
Twitter @JosephStrunkMD
Contributors NAH helped design the study, conduct the study, analyze the data, and write the manuscript. JS helped design the study, conduct the study, analyze the data, and write the manuscript. GS helped conduct the study, analyze the data, and write the manuscript. NGC helped design the study, conduct the study, analyze the data, and write the manuscript. JB helped design the study, conduct the study, analyze the data, and write the manuscript. CSK helped design the study, conduct the study, analyze the data, and write the manuscript. CO helped conduct the study, analyze the data, and write the manuscript. DW helped conduct the study, analyze the data, and write the manuscript. AS helped analyze the data and write the manuscript. WS helped conduct the study, analyze the data, and write the manuscript.
Funding Department of Anesthesiology, Virginia Mason Franciscan Health, Seattle, Washington, USA
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.