Abstract
Background
Patients with end-stage renal disease (ESRD) may exhibit altered pharmacokinetic and pharmacodynamic responses to local anesthetics. But the ropivacaine concentration-response profile for ultrasound-guided T11 thoracic paravertebral block (TPVB) in this population remains undefined. This study aimed to determine the median effective concentration (EC50) of ropivacaine for TPVB in ESRD patients undergoing peritoneal dialysis catheterization (PDC) and evaluate early postoperative recovery.
Methods
In this prospective dose-finding study, patients aged 18–75 years with ESRD and ASA physical status II–III undergoing elective PDC received ultrasound-guided T11 TPVB with 20 mL ropivacaine. Concentrations were assigned by the Dixon up-and-down method, starting at 0.50%: decrease by 0.05% after a successful analgesic or increased by 0.05% after a failed response. A successful response was defined as VAS ≤3 at skin incision without rescue analgesia; a failed response was defined as VAS >3 or rescue analgesia before or during incision. EC50 was estimated primarily by centered isotonic regression with the pool-adjacent-violators algorithm (CIR-PAVA), a nonparametric method suited to small Dixon samples; with probit regression, a parametric approach commonly used in prior EC50 studies, also performed for comparison. Recovery was assessed using the Quality of Recovery-40 (QoR-40) questionnaire at 24 hours postoperatively. This was a small single-arm exploratory study with no formal sample-size calculation, consistent with the sequential design.
Results
27 patients completed the study. EC50 was 0.173% (95% CI: 0.100%–0.500%) by CIR-PAVA and 0.180% (95% CI: 0.109%-0.225%) by probit regression. The wider CIR-PAVA CI reflects the small sample size and limited precision. Median global QoR-40 score at 24 hours was 184.0. Five patients (18.5%) required rescue analgesia. No serious adverse events, local anesthetic systemic toxicity, pneumothorax, or neurological complications occurred.
Conclusion
The EC50 of ropivacaine for TPVB in ESRD patients undergoing PDC was approximately 0.17%-0.18%, with favorable early recovery and acceptable safety. Given that EC50 reflects efficacy in only 50% of patients, EC90/EC95 studies are needed before definitive dosing recommendations.
Keywords: ropivacaine, thoracic paravertebral block, ultrasound guidance, end-stage renal disease, median effective concentration, Dixon up-and-down method
Graphical Abstract
Introduction
End-stage renal disease (ESRD) is a global health burden, and peritoneal dialysis remains an important renal replacement therapy for patients requiring long-term dialysis.1 Peritoneal dialysis catheterization (PDC) is commonly performed under local, regional, or general anesthesia. However, patients with ESRD often present with multiple comorbidities, including cardiovascular dysfunction,2,3 anemia, electrolyte disturbances, acid-base imbalance, and altered drug handling.4 These factors increase perioperative vulnerability and make anesthetic management particularly challenging.
Regional anesthesia may offer potential advantages in this population by reducing the need for systemic anesthetics and opioids, preserving respiratory function, and facilitating early recovery.5,6 TPVB provides unilateral segmental somatic and sympathetic blockade and can cover both the abdominal wall and components of parietal peritoneal nociception.7,8 PDC involves incision of the abdominal wall, subcutaneous tunneling, catheter exit-site creation, and manipulation of the parietal peritoneum, generating pain from both somatic and deeper abdominal structures.9,10 Previous clinical studies have shown that ultrasound-guided TPVB at approximately the T10–T11 level can provide surgical anesthesia or analgesia for PDC procedures in patients with ESRD.11 When performed under ultrasound guidance, TPVB allows direct visualization of relevant anatomical structures and local anesthetic spread, potentially improving precision and safety.12
Ropivacaine is widely used for peripheral nerve blocks because of its favorable sensory-motor differentiation and lower cardiotoxicity compared with bupivacaine.13 Although ropivacaine is primarily metabolized hepatically,14 ESRD is associated with uremia-related physiological changes and alterations in plasma protein binding that may affect the disposition and pharmacological response to local anesthetics.15 Previous pharmacokinetic studies in uremic patients have reported altered total and unbound ropivacaine concentrations, although the overall effect of renal dysfunction on ropivacaine disposition remains complex.16 These considerations suggest that the concentration required to achieve a predefined analgesic response in ESRD patients may differ from that established in other populations. Therefore, minimizing unnecessary local anesthetic exposure while maintaining adequate anesthetic efficacy is clinically relevant.
Despite previous clinical evidence supporting the feasibility of ultrasound-guided TPVB for PDC procedures, the concentration-response relationship of ropivacaine in patients with ESRD has not been established. Existing studies have mainly evaluated fixed-concentration TPVB regimens or compared TPVB with other anesthetic techniques, rather than determining the concentration associated with a predefined probability of analgesic success.9,11 Thus, the optimal ropivacaine concentration for T11 TPVB in this population remains uncertain. The Dixon up-and-down sequential method enables estimation of the EC50 with a relatively small number of participants and is therefore suitable for exploratory dose-finding studies.17
Therefore, an important unanswered question is the concentration of ropivacaine required to achieve adequate analgesia during T11 TPVB in patients with ESRD undergoing PDC. Previous studies have demonstrated the feasibility and clinical utility of TPVB for PDC procedures, but have not established an EC50 based on a concentration-response design. We therefore conducted this prospective dose-finding study to determine the EC50 of ropivacaine for T11 TPVB in this population. We hypothesized that ESRD related physiological alterations, including changes in plasma protein binding, could modify the concentration-response relationship of ropivacaine, and therefore the effective concentration (EC50) in this population might differ from that in patients with normal renal function and required specific determination.
Material and Methods
Study Design and Ethics
This prospective, single-arm, dose-finding study was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University (No. QYFYEC2025-22) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants before enrollment. Because the primary objective was to estimate the EC50 of ropivacaine using the Dixon up-and-down method, no conventional power-based sample size calculation was performed; instead, the sample size was determined by the prespecified stopping criterion of seven independent success-failure crossover pairs. The secondary postoperative outcomes were exploratory and descriptive; therefore, no separate sample size calculation was performed.
This study was conducted as the initial dose-finding phase of a registered clinical trial investigating anesthetic strategies involving TPVB with ropivacaine in patients with ESRD undergoing PDC placement. The trial was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR2500101111) on April 21, 2025, before enrollment of the first participant. Patient recruitment was conducted from April 25, 2025, to June 2, 2026. Although the ESRD population at our institution was relatively large, PDC was performed in a limited proportion of patients because renal replacement therapy was selected according to patients’ clinical circumstances and preferences, and arteriovenous fistula creation for hemodialysis was more commonly performed than PDC. Consequently, the number of eligible patients undergoing PDC during the study period was limited, resulting in a relatively long recruitment period.
The present manuscript reports the dose-finding phase designed to determine the median effective concentration of ropivacaine for ultrasound-guided T11 TPVB. The concentration identified in this phase was intended to inform the subsequent clinical evaluation phase of the registered trial.
Study Population
Patients aged 18–75 years with ESRD who were scheduled for elective PDC and classified as ASA physical status II–III were eligible for enrollment.
The exclusion criteria were refusal to participate, allergy to amide local anesthetics, infection at the puncture site, clinically significant coagulopathy, severe spinal deformity, pre-existing neurological deficits affecting sensory assessment, inability to understand or use the VAS, chronic opioid use, severe psychiatric or cognitive disorders, or any condition judged by the investigators to make study participation unsafe.
Anesthetic Management
Upon arrival in the operating room, standard monitoring, including electrocardiography, non-invasive blood pressure, and pulse oximetry, was initiated, and intravenous access was established. No systemic opioids or sedative agents were administered before assessment of block success. During surgery, mean arterial pressure was maintained within±20% of baseline. Vasoactive drugs were administered if blood pressure deviated by more than 20% from baseline or if heart rate fell below 50 beats/min. Atropine, norepinephrine, and ephedrine were used as clinically indicated to manage bradycardia or hypotension. Supplemental oxygen was provided via face mask if peripheral oxygen saturation fell below 95%. No sedative drugs were administered during surgery. After surgery, if patients reported pain after returning to the ward, they received either Bucinnazine Hydrochloride or compound paracetamol and dihydrocodeine tablets, with the choice of analgesic determined by the attending physician according to the patient’s clinical condition.
Ultrasound-Guided Thoracic Paravertebral Block
All T11 TPVB were performed by a single anesthesiologist with more than 20 years of clinical experience, who routinely performs more than 300 regional anesthesia procedures annually. Patients were placed in the lateral or sitting position according to clinical feasibility. After aseptic preparation, a high-frequency linear ultrasound transducer was positioned in the parasagittal or transverse orientation to identify the T11 vertebral level, transverse process, internal intercostal membrane, superior costotransverse ligament, pleura, and thoracic paravertebral space.
After skin infiltration, a block needle was advanced under real-time ultrasound guidance using an in-plane technique. Following negative aspiration for blood or air, 20 mL of ropivacaine at the assigned concentration was injected incrementally. Appropriate spread was confirmed by anterior displacement of the pleura and expansion of the thoracic paravertebral space. Intermittent aspiration was performed during injection to reduce the risk of intravascular administration. Sensory block was defined as loss of cold sensation to an alcohol swab over the T10–T12 dermatomes, compared with the corresponding contralateral (unblocked) side. Sensory block was assessed once, approximately 30 minutes after completion of the T11 TPVB and before skin incision.18 The interval between TPVB completion and the initiation of surgery was relatively consistent among patients. This assessment was used to clinically confirm the expected anatomical extent of the block but was not used as the criterion for Dixon success/failure classification, which was determined solely by the prespecified VAS based definition described above. Because sensory block assessment was not prospectively recorded as a separate study outcome, quantitative sensory block data were not available for statistical analysis.
Venous blood samples of 3 mL were collected at 15, 30, 45, and 60 minutes after block placement. Plasma was separated by centrifugation at 3000 rpm for 10 minutes at room temperature and stored at −70°C until analysis.19 Ropivacaine plasma concentrations were determined by liquid chromatography-tandem mass spectrometry.20
Surgical Procedure
After block assessment, patients were placed in the supine position and abdominal skin was disinfected and draped. A right paramedian incision was made approximately 10 to 11 cm above the pubic symphysis. The skin and subcutaneous tissue were dissected to expose the anterior rectus sheath, and the rectus abdominis muscle was bluntly separated to access the posterior rectus sheath, where a 0.5 cm incision was made. Purse-string sutures were placed around the peritoneal incision.
A guidewire was inserted, and the peritoneal dialysis catheter was advanced into the abdominal cavity until it reached the rectovesical pouch. Approximately 80mL of normal saline was infused to confirm catheter patency. The peritoneal purse-string suture was tied, the first Dacron cuff was positioned within the rectus abdominis muscle, and the anterior rectus sheath was closed. A subcutaneous tunnel was created in the right abdominal wall, and the exit site was placed approximately 2 cm from the second Dacron cuff. The incision and exit site were covered with sterile dressings, and the titanium connector and extension tube were attached before transfer to the recovery ward.
Dixon Up-and-Down Allocation
The ropivacaine concentration was determined using the Dixon up-and-down sequential allocation method. The initial concentration was set at 0.50%, based on concentrations commonly used for ultrasound-guided TPVB in patients undergoing PDC and other clinical TPVB procedures,21 as well as safety considerations in this high-risk population. The concentration step size was set at 0.05%, providing sufficient resolution around the anticipated EC50 while avoiding unnecessarily large concentration changes between consecutive participants. This step size has also been used in previous ropivacaine dose-finding studies employing the Dixon up-and-down method.22 Following a successful analgesic response, the concentration for the next participant was decreased by 0.05%, whereas following a failed response, it was increased by 0.05%. No minimum or maximum concentration limit was prespecified; only the starting concentration (0.50%) and the fixed 0.05% step size were predetermined. The range of concentrations actually administered during the sequential allocation was 0.10% to 0.50%, with 0.50% corresponding to the initial concentration and 0.10% representing the lowest concentration reached as a result of the sequential up-and-down adjustments. The sequence was terminated after seven independent success–failure crossover pairs had been observed, a stopping criterion commonly used in Dixon up-and-down dose- finding studies to obtain a stable estimate of the EC50.17,23
For the Dixon up-and-down sequence, the response to a standardized surgical stimulus was assessed at skin incision. A successful response, used solely for Dixon concentration allocation, was defined as a VAS score ≤3 at skin incision without the need for rescue analgesia, whereas a failed response was defined as a VAS score >3 or the requirement for rescue analgesia at or before skin incision. This criterion was used specifically to classify the binary analgesic response at each concentration for dose allocation in the Dixon up-and-down sequence. It was not intended to define complete analgesia throughout the entire surgical procedure. Given the special clinical characteristics of patients with ESRD, the dose-finding strategy aimed to identify an effective concentration while avoiding unnecessary exposure to higher concentrations of ropivacaine. In cases of block failure, local infiltration with 2% lidocaine was performed by the surgeon. Patients whose block was classified as a failure and who received supplemental local infiltration with 2% lidocaine were retained in the analysis. Within the Dixon sequence, these patients were classified as failures for concentration allocation and EC50 estimation. For secondary postoperative outcomes, all 27 patients were included in the descriptive analyses. Because these outcomes were summarized descriptively rather than through formal between-group hypothesis testing, patients receiving supplemental local infiltration were not excluded from the analysis. The study was stopped after seven independent success-failure crossover pairs had been observed. This stopping criterion was prespecified based on the commonly used range of approximately 6–8 independent crossover pairs in Dixon up-and-down dose-finding studies, which provides adequate sequential response information for estimation of the EC50.17
Blinding Method
The anesthesiologist performing the block was not blinded to the assigned ropivacaine concentration and was responsible for performing the ultrasound-guided TPVB. A dedicated data recorder, independent of the block procedure, recorded patient characteristics, concentrations assignments, and study data. The evaluator responsible for assessing block efficacy and postoperative outcomes during the 24h follow-up period was blinded to the assigned ropivacaine concentration. Thus, treatment administration was unblinded, whereas outcome assessment was blinded.
Outcome Measures
The primary outcome was the EC50 of ropivacaine for TPVB, defined as the concentration associated with a successful analgesic response to skin incision, as defined above, in 50% of patients.
Secondary outcomes included postoperative quality of recovery assessed using the QoR-40 questionnaire 24 hours after surgery, VAS scores at rest and during movement at 1, 4, 8, 12, and 24 hours postoperatively, requirement for rescue analgesia within 24 hours, time to first rescue analgesia (from the time the patient left the operating room to the time when the first dose of rescue analgesia was administered), plasma ropivacaine concentrations at 15, 30, 45, and 60 minutes after block placement, and perioperative adverse events. Adverse events of interest included local anesthetic systemic toxicity symptoms, such as perioral numbness, tinnitus, dizziness, metallic taste, altered consciousness, seizure, arrhythmia, or cardiovascular instability, as well as pneumothorax, vascular puncture, hematoma, postoperative nausea and vomiting, and neurological complications.
Statistical Analysis
Continuous variables were assessed for distribution and are presented as mean with standard deviation or median with interquartile range (IQR), as appropriate. Categorical variables are presented as numbers and percentages.
EC50 was estimated primarily by CIR-PAVA, a nonparametric method well suited to small Dixon samples; probit regression, a parametric approach commonly used in prior EC50 studies, was also performed for comparison.24 CI for the CIR-PAVA estimate were calculated using nonparametric bootstrap resampling, with patients resampled with replacement and the EC50 recalculated for each bootstrap sample. The 2.5th and 97.5th percentiles of the resulting bootstrap distribution were used to derive the 95% CI. Postoperative recovery and analgesic outcomes were summarized descriptively. Plasma ropivacaine concentrations were also summarized descriptively at each predefined sampling time point, and no formal statistical hypothesis testing was performed for pharmacokinetic concentration comparisons. Statistical analyses were performed using SPSS version 29.0.2.0 (IBM Corp., Armonk, NY, USA) and R version 4.5.3 (R Foundation for Statistical Computing, Vienna, Austria). A two-sided P value less than 0.05 was considered statistically significant where applicable.
Results
Patient Enrollment and Baseline Characteristics
A total of 27 patients completed the study and were included in the final analysis. The patient flow diagram is shown in Figure 1. Baseline demographic and clinical characteristics are summarized in Table 1.
Figure 1.
Consort flow diagram of the study. A total of 27 ESRD patients were screened and all enrolled without exclusion.
Table 1.
Demographic and Baseline Characteristics of the Patients
| Variable | Value |
|---|---|
| Age (year) | 48.81 ± 11.62 |
| Sex (male/female) | |
| Male | 14 (51.9%) |
| Female | 13 (48.1%) |
| BMI (kg/m2) | 24.02 ± 4.16 |
| Height (cm) | 168.74 ± 8.41 |
| Weight (kg) | 68.59 ± 12.32 |
| ASA (II/III) | |
| II | 4 (14.8%) |
| III | 23 (85.2%) |
| Duration of surgery (min)* | 74.26 ± 18.38 |
Notes: All continuous variables are expressed as mean ± SD or number(proportion). *Defined as time from skin incision to skin closure.
Abbreviations: BMI, the Body Mass Index; ASA, American Society of Anesthesiologists; SD, standard deviation.
Median Effective Concentration of Ropivacaine
The study was stopped after seven independent success-failure crossover pairs were observed, in accordance with the prespecified stopping criterion. The estimated EC50 of ropivacaine for TPVB was 0.180% by probit regression, with a 95% CI of 0.109%–0.225%. CIR-PAVA produced a similar estimate of 0.173%, with a 95% CI of 0.1%–0.5%. Figure 2 visually compares the EC50 point estimates and corresponding 95% CIs derived from the two approaches. The consistency between the two analytical approaches supports the stability of the EC50 estimate, although the wide CI of the isotonic regression estimate reflects the limited sample size inherent to this dose-finding design. The sequence of ropivacaine concentrations and individual block responses is shown in Figure 3.
Figure 2.
Comparison of ropivacaine EC50 estimates by probit regression and CIR-PAVA. Point estimates of the median effective concentration (EC50) of ropivacaine for ultrasound-guided T11 TPVB in patients with ESRD, derived from probit regression (0.180%) and CIR-PAVA (0.173%), are shown as solid circles. Vertical bars indicate 95% confidence intervals, and horizontal dotted lines mark the corresponding EC50 value for each method.
Abbreviations: TPVB, thoracic paravertebral block; ESRD, end-stage renal disease; CIR-PAVA, centered isotonic regression with pool-adjacent-violators algorithm.
Figure 3.
Sequential block outcomes of ropivacaine based ultrasound-guided paravertebral nerve block. The plot illustrates the ropivacaine concentration administered to each patient in sequence, following the Dixon up-and-down titration protocol. Concentration was decreased by one step after a successful block (Orange squares) and increased by one step after an unsuccessful block (blue circles). Seven independent success-failure crossover pairs were observed.
As shown in Table 2, a clear concentration-dependent increase in block success was observed. The success rate reached 75% at a concentration of 0.20%, while complete block success (100%) was achieved at concentrations ≥0.30%. In contrast, block success rates were 0% and 28.6% at concentrations of 0.10% and 0.15%, respectively.
Table 2.
Raw and PAVA-Adjusted Success Rates of Ropivacaine at Different Concentrations
| Concentration (%) | Success/Total (n/n) | Raw Rate (%) | PAVA Rate (%) |
|---|---|---|---|
| 0.5 | 1/1 | 1.000 | 1.000 |
| 0.45 | 1/1 | 1.000 | 1.000 |
| 0.4 | 1/1 | 1.000 | 1.000 |
| 0.35 | 1/1 | 1.000 | 1.000 |
| 0.3 | 2/2 | 1.000 | 1.000 |
| 0.25 | 3/4 | 0.750 | 0.750 |
| 0.2 | 6/8 | 0.750 | 0.750 |
| 0.15 | 2/7 | 0.286 | 0.286 |
| 0.1 | 0/2 | 0.000 | 0.000 |
Notes: Data are presented as proportions. PAVA adjustment was applied to enforce monotonicity; No major violations were detected; Several concentration levels included only 1–2 patients.
Abbreviation: PAVA, pool adjacent violators algorithm.
Postoperative Recovery and Rescue Analgesia
The median global QoR-40 score at 24 hours postoperatively was 184.0 (IQR, 180.0–187.0), indicating favorable early recovery. Domain-specific scores are summarized in Table 3. Rescue analgesia was required in 5 patients (18.5%), with a median time to first analgesic request of 138 minutes (IQR, 115–518 minutes).
Table 3.
QoR-40 Scores at 24 Hours Postoperatively
| QoR-40 | Score, Median (IQR) | Maximum Possible Score |
|---|---|---|
| Global | 184.0 (180.0–187.0) | 200 |
| Physical comfort | 54.0 (50.0–57.0) | 60 |
| Emotional state | 42.0 (41.0–43.0) | 45 |
| Physical independence | 24.0 (23.0–25.0) | 25 |
| Psychological Support | 35.0 (35.0–35.0) | 35 |
| Pain | 30.0 (29.0–32.0) | 35 |
Note: Data are presented as median (IQR).
Abbreviations: QoR-40, Quality of Recovery-40 scale; IQR, interquartile range.
Postoperative Pain Assessment
Serial VAS pain scores at rest and during movement were recorded at 1, 4, 8, 12 and 24 hours postoperatively, and the score distribution at each time point was presented as violin plots in Figure 4. Panel A illustrated resting VAS distributions, and Panel B displayed movement-evoked VAS distributions at corresponding time points. When adequate ropivacaine concentrations were administered for nerve block, early postoperative pain was generally well controlled. The peak distribution of both resting and movement-evoked VAS scores appeared at postoperative 8 h, with a global downward shift of score ranges at 12 h and 24 h.
Figure 4.
Postoperative VAS scores at rest and on movement. Violin plots of serial postoperative visual analogue scale (VAS) pain scores in ESRD patients undergoing ultrasound-guided T11 thoracic paravertebral block. (A) Resting VAS pain scores at postop 1 h, postop 4 h, postop 8 h, postop 12 h and postop 24 h. (B) Movement-evoked VAS pain scores at matching postoperative time points. Within each violin plot, three horizontal dotted lines correspond to the 75th percentile (upper line), median (middle line), and 25th percentile (lower line) of VAS scores, respectively.
Ropivacaine Plasma Concentrations
Plasma ropivacaine concentrations are shown in Figure 5. Concentrations peaked at 15 minutes after TPVB and declined gradually over the 60-minute observation period. Higher administered ropivacaine concentrations were associated with higher plasma levels at corresponding time points.
Figure 5.
Plasma ropivacaine concentration–time profiles after TPVB in patients with ESRD. Plasma ropivacaine concentrations were measured at 15, 30, 45, and 60 minutes after TPVB with ropivacaine concentrations ranging from 0.10% to 0.50%, assigned according to the Dixon up-and-down sequential design. The exact sample sizes (n) for each pharmacokinetic subgroup are indicated in the figure. Solid lines represent concentration subgroups with adequate sample sizes (0.15%, 0.20%, and 0.25%; n>2 each); dashed lines represent the remaining subgroups (0.10%, 0.30%–0.50%), which included fewer participants and are shown for reference only.
Adverse Events
No cases of local anesthetic systemic toxicity, pneumothorax, vascular puncture, hematoma, infection, or neurologic complications were observed. Plasma ropivacaine concentrations in all patients remained below the previously reported toxicity threshold25 throughout the observation period, with no associated clinical symptoms or hemodynamic instability detected. Postoperative nausea and vomiting occurred in 10 patients (37.0%) and was effectively managed with standard antiemetic therapy. All TPVB and surgical procedures were completed successfully without conversion to general anesthesia or premature termination.
Discussion
This prospective dose finding study determined the EC50 of ropivacaine for TPVB in patients with ESRD undergoing PDC. With a fixed volume of 20 mL, the estimated EC50 was approximately 0.17% to 0.18%, and the close agreement between probit regression and CIR-PAVA provided consistent estimates across the two analytical approaches. Although direct comparisons with TPVB in non-ESRD populations are limited, the concentration identified in the present study appears lower than EC50 values reported for several other peripheral nerve blocks.26–29 However, these comparisons should be interpreted cautiously because the referenced studies involved different patient populations, block techniques, anatomical sites, and routes of local anesthetic administration.
This finding may be related to differences in the pharmacokinetic and pharmacodynamic characteristics of patients with ESRD.30 Ropivacaine is primarily metabolized in the liver, but its distribution and clearance are influenced by protein binding, particularly to alpha-1-acid glycoprotein (AAG) and albumin.31 ESRD is often accompanied by hypoalbuminemia and changes in plasma protein profiles,32 which could potentially alter the unbound fraction and pharmacodynamic response to ropivacaine. However, this proposed mechanism remains speculative because free ropivacaine concentrations were not measured in the present study. Therefore, the contribution of altered protein binding to the relatively low EC50 cannot be directly established. In addition, surgical stress may increase AAG levels.33
Notably, plasma ropivacaine concentrations in all patients remained below the commonly cited toxicity threshold of 2.2 μg/mL,25 and no clinical manifestations of local anesthetic systemic toxicity (LAST) were observed. Thus, no apparent clinical safety signal was identified within the tested concentration range (0.10%–0.50%). However, the absence of observed LAST and the measured total plasma concentrations should not be interpreted as evidence of a definitive safety margin, as this commonly cited threshold may not apply universally to patients with ESRD. In addition, plasma concentration–time profiles demonstrated a rapid increase within 15 minutes after administration, followed by a gradual decline over time, without an apparent increase at the later sampling time points. These findings are descriptive and, given the limited sampling schedule, do not permit definitive conclusions regarding drug accumulation or elimination kinetics. Overall, higher block concentrations were generally associated with higher peak plasma levels, but the relationship was not strictly dose-proportional; the small sample size and descriptive nature of the pharmacokinetic assessment preclude firm conclusions regarding the mechanisms underlying this observation.
Given that plasma ropivacaine concentrations were assessed descriptively at a limited number of sampling time points, differences in the decline of concentrations across dosing levels were not subjected to formal statistical hypothesis testing and should therefore not be interpreted as evidence of concentration-dependent differences in distribution or elimination kinetics. Plasma total concentrations should be interpreted cautiously as a surrogate marker of systemic toxicity risk, particularly in patients with altered protein binding, and further studies with more extensive pharmacokinetic sampling and measurement of free ropivacaine concentrations are warranted.
From a clinical perspective, TPVB may be a useful component of an anesthetic and analgesic strategy for PDC. It can provide unilateral somatic and sympathetic blockade over the dermatomes relevant to the surgical incision,9,34 while potentially reducing the need for systemic analgesic or sedative medications.35 This may be particularly beneficial in patients with ESRD, who often have substantial comorbidity burdens and increased risk from general anesthesia.36,37 Postoperative QoR-40 scores suggested acceptable early recovery, and rescue analgesia was required in only a minority of patients, although these findings are descriptive and cannot establish that TPVB itself improved postoperative recovery or reduced opioid or rescue analgesic requirements in the absence of a control group.
Methodologically, the Dixon up-and-down sequential design is appropriate for estimating EC50 with limited sample sizes,38 but it does not permit precise estimation of EC95 or the full concentration-response curve. Therefore, the present findings should be interpreted as a preliminary basis for individualized dosing rather than a routine clinical recommendation.
Several limitations should be acknowledged. First, this was a single-center, single-arm study with a relatively small sample size; patients were unevenly distributed across concentration levels, with some levels including only 1–2 patients, which may have limited the stability and precision of the EC50 estimate. Second, pharmacokinetic sampling was exploratory: free ropivacaine concentrations were not measured, and the limited number of sampling time points precluded characterization of the complete concentration–time profile and definitive conclusions regarding drug accumulation or elimination kinetics. Third, the absence of a non-ESRD control group precludes attributing differences in EC50 specifically to ESRD, and, without any control group, the observed recovery and analgesic outcomes cannot be attributed specifically to TPVB. Fourth, all blocks were performed by a single anesthesiologist, which may limit generalizability to other operators. Finally, the open-label nature of treatment administration may have introduced performance bias. Larger multicenter studies with control groups are needed to confirm these findings and to better characterize the pharmacokinetic and pharmacodynamic behavior of ropivacaine in patients with ESRD.
Conclusion
In patients with ESRD undergoing PDC, the estimated EC50 of ropivacaine for ultrasound-guided T11 TPVB with a fixed volume of 20 mL was approximately 0.17% to 0.18%. At this concentration, the estimated probability of successful block was approximately 50%, consistent with the definition of EC50. These findings provide preliminary evidence to inform further investigation of ropivacaine dose selection in this population.
Acknowledgments
The authors gratefully acknowledge their colleagues and faculty members in the Department of Anesthesiology at The Affiliated Hospital of Qingdao University, as well as the dedicated nursing staff in the operating room, for their invaluable assistance and steadfast support throughout the conduct of this study. Special appreciation is also extended to all the patients who consented to participate in this research, without whose cooperation this work would not have been possible.
Funding Statement
This study was supported by the Public Project of Jumei Ruiyan Anesthesia Research Fund (Grant No. Y2024080039).
Abbreviations
BMI, body mass index; ASA, American Society of Anesthesiologists physical status; TPVB, thoracic paravertebral block; US, ultrasound; ESRD, end-stage renal disease; QoR-40, Quality of Recovery-40; VAS, visual analog scale; PAVA, pool-adjacent violators algorithm; CIR-PAVA, centered isotonic regression with PAVA.
Data Sharing Statement
Deidentified individual participant data underlying the results reported in this article, together with the statistical analysis plan and statistical analysis code, will be available upon reasonable request to the corresponding author immediately following publication and for a period of 3 months thereafter, subject to ethical and institutional requirements. Requests should be directed to Zejun Niu (nzj16niu@sina.com).
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Deidentified individual participant data underlying the results reported in this article, together with the statistical analysis plan and statistical analysis code, will be available upon reasonable request to the corresponding author immediately following publication and for a period of 3 months thereafter, subject to ethical and institutional requirements. Requests should be directed to Zejun Niu (nzj16niu@sina.com).