Clinical trial NCT05091905: Patient-Titrated Automated Intermittent Boluses of Local Anesthetic vs. a Continuous Infusion Via a Perineural Catheter for Postoperative Analgesia
Official title: Patient-Titrated Automated Intermittent Boluses of Local Anesthetic vs. a Continuous Infusion Via a Perineural Catheter for Postoperative Analgesia
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE4
Conditions: Pain, Acute Postoperative
Trauma Injury
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
First posted: 2021-10-25
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Unmasked, Active-Controlled Human Subjects Clinical Trial
Primary purpose: TREATMENT

Brief summary: This will be a randomized comparison of continuous local anesthetic infusion with patient controlled boluses (PCA) to patient-titratable automated boluses with patient controlled boluses (PCA) for both infraclavicular and popliteal-sciatic perineural catheters. The overall goal is to determine the relationship between method of local anesthetic administration (continuous with PCA vs. titratable intermittent dosing with PCA) for these two perineural catheter locations and the resulting pain control. The investigators hypothesize that, compared with a traditional fixed, continuous basal infusion initiated prior to discharge, perineural local anesthetic administered with titratable automated boluses at a lower dose and a 5-hour delay following discharge will (1) provide at least noninferior analgesia during the period that both techniques are functioning; and, (2) will result in a longer overall duration of administration \[dual primary end points\].

Detailed description: Specific Aim: to determine the relationship between method of local anesthetic administration (continuous with PCA vs. titratable intermittent dosing with PCA) for popliteal-sciatic and infraclavicular perineural catheters and the resulting pain control.

Hypothesis: The investigators hypothesize that, compared with a traditional fixed, continuous basal infusion initiated prior to discharge, perineural local anesthetic administered with titratable automated boluses at a lower dose and a 5-hour delay following discharge will (1) provide at least noninferior analgesia during the period that both techniques are functioning; and, (2) will result in a longer overall duration of administration \[dual primary end points\].

This will be a randomized, controlled investigation.

Enrollment: Consenting adults undergoing painful foot and/or ankle surgery with a planned popliteal-sciatic perineural catheter insertion will be offered enrollment.

Block placement: The nerve block site will be cleaned with chlorhexidine gluconate and isopropyl alcohol (ChloraPrep One-Step, Medi-Flex Hospital Products, Inc., Overland Park, KS, USA), and a clear, sterile, fenestrated drape applied. The ultrasound probe will be readied for use and placed to visualize the short-axis (cross-section) of the target nerve. A skin wheal will be raised at the catheter-placement needle's anticipated point of entry. An 8.9 cm, 17-gauge, insulated needle (FlexTip, Arrow International, Reading, PA, USA) will be used to place all perineural catheters. The catheter-placement 17G needle will be inserted through the skin wheal, advanced in-plane beneath the US transducer and directed toward the target nerve. Normal saline (1-2 mL) will be administered via the needle to open the space around the nerve.

A flexible non-stimulating perineural catheter (FlexTip, Arrow International, Reading, PA, USA) will be inserted 2-3 cm past the needle tip. After catheter insertion, Ropivacaine 0.5% (20 mL) will be administered via the catheter under ultrasound visualization. Sensation in the treated nerve distributions will be checked for anesthetic effect up to 30 minutes following initial local anesthetic bolus. A "successful" regional block will be defined as sensory- and motor-block onset in all expected nerve distributions within the 30 minutes following the local anesthetic injection.

A saphenous nerve block with ropivacaine 0.5% (with epinephrine) may or may not be provided, depending on the surgical procedure, per standard of care.

Intraoperative: The initial local anesthetic bolus may provide complete surgical anesthesia for the procedure. Patients who desire a general anesthetic or experience a partial block that is not adequate for surgical anesthesia will receive a general anesthetic, per standard of care.

Randomization: Subjects will be randomized to one of two treatment groups: (1) titratable automated intermittent bolus or (2) continuous infusion in a computer generated 1:1 ratio using opaque envelopes opened only after successful catheter insertion is documented within 30 minutes of the local anesthetic injection.

Postoperative Procedures: Following completion of the procedure in the operating room, an infusion pump (Infutronix, Natick, Massachusetts) with a 500 mL ropivacaine 0.2% reservoir will be attached to the perineural catheter. For patients in the continuous infusion group, the pump will provide an 8 (infraclavicular) or 6 (sciatic) mL/h basal infusion and a 4 mL patient-controlled bolus with a 30-minute lockout (standard at UCSD). For patients in the titratable automated intermittent bolus group, the pump will provide an automatic 11 (infraclavicular) or 8 (sciatic) mL bolus once every 2 hours and have a 4 mL patient-controlled bolus with a 30 minute lockout. In addition, for those in the titratable automated intermittent bolus group, the infusion pump will be set in a "pause" mode that delays initiation of the automated bolus doses by 5 hours (this can be over-ridden by patients if they would like to initiate their perineural infusion earlier than 5 hours). Lastly, subjects in the titratable automated intermittent bolus group will be able to titrate the volume of their automated bolus up or down within the range of 1-16 mL.

Per standard of care, the pump will not administer more than 20 mL during each hour (below the current institutional maximum). Prior to discharge, the functioning of the infusion pump will be explained, so that they understand that they should push the bolus button if they have pain. This is accurate regardless of which treatment group the patient is randomized to, ensuring that all subjects will receive adequate analgesia.

Data Collection: Subjects will be contacted via phone for the 9 days following surgery to collect outcome measures. When 500 mL has been infused or on postoperative Day 8-whichever comes first-subjects will remove the catheter and place the pump in a pre-addressed and -stamped package for return.

Data Acquisition. Data will be gathered from the patients' electronic medical record, by telephone follow-up, and from the memory of each infusion pump. Subjects will be contacted by phone for the 9 days following surgery. Data will be recorded on paper Case Report Forms, including: patient name, medical record number, age, sex, height, weight, surgical procedure, data of procedure, anesthesiology attending overseeing/placing catheter, randomization number, whether a femoral/saphenous block was placed, if the catheter was placed per protocol, if the block set up successfully, intraoperative fentanyl, morphine and dilaudid, and the time of infusion initiation.

Statistics: The infraclavicular and popliteal-sciatic groups will be analyzed separately as two distinct analyses, each a completely separate investigation from the other. This study will be powered for two primary end points: (1) the average pain level measured with the Numeric Rating Scale queried on postoperative day 1; and (2) the duration of treatment from when the infusion pump was initially turned on until the local anesthetic reservoir was exhausted \[recorded by the infusion pump memory\]. The dual hypotheses will be tested with a serial testing strategy, such that Hypothesis 2 will not be formally tested unless the conclusion of Hypothesis 1 is at least "noninferiority". Following the approach described in Althunian et al, noninferiority will be assessed by comparing the lower limit of the 95% confidence interval for the difference (CB minus AB) on the NRS (range: 0 to 10) to a pre-specified noninferiority margin of 1.7 NRS units. This will provide evidence that the analgesia provided by the novel automated boluses is no worse than 1.7 NRS units compared to CB.

Baseline characteristics of the randomized groups will be summarized with means, standard deviations, and quartiles. Balance between groups will be assessed following the approach described by Schober, et al. Specifically, standardized differences will be calculated using Cohen's d whereby the difference in means or proportions is divided by the pooled standard deviation estimates. Any key variables (age, sex, height, weight, and BMI) with an absolute standardized difference \>0.47 (based on Austin, 2009 with 1.96×√(2/n)=0.47) will be noted and included in a linear regression model to obtain an estimate of the treatment group differences adjusted for the imbalanced covariate(s). If residuals from the linear regression indicate violations of key assumptions (i.e. homoscedasticity or Guassian distribution), data transformations and/or alternative generalized linear models will be applied as appropriate.

Secondary outcomes will also be analyzed by Wilcoxon-Mann-Whitney test, or linear models (or generalized linear models) as appropriate with covariates for any imbalanced covariates. No multiplicity adjustments will be applied for these analyses. End points will be analyzed for each day (e.g., opioid consumption on Day 2) as well as all days combined (e.g., cumulative opioid consumption Days 1-9).

Sample size estimate: Power is simulated based on the distribution of pain measured with the Numeric Rating Scale (NRS) observed in the "Above bifurcation" group in Monahan, et al, for the sciatic catheter group. For the infraclavicular group, we simulated NRS scores from the basal/bolus treatment from Ilfeld et al. (2004). Specifically, the investigators simulate NRS scores from a discrete distribution as depicted in Figure 2 of the IRB-approved protocol (figures unavailable in this registry). This results in an expected interquartile range of approximately 1 to 4, and a median of approximately 3 NRS units. The investigators simulated 1,000 trials in which the two groups, n=35 per group, were assumed to follow the same discrete distribution, submitted each trial to a Wilcoxon-Mann-Whitney test, and derived 95% confidence intervals (Bauer 1972; Hothorn, et al. 2008). Out of the 1,000 trials, 792 (79.2%) correctly resulted in a conclusion of non-inferiority; suggesting that the probability that the trial correctly concludes non-inferiority is about 80% when the groups follow exactly equivalent distributions.

If the test for Hypothesis 1 concludes noninferiority, the investigators will test for a difference in overall duration of administration again using the Wilcoxon-Mann-Whitney test. Power is approximated by a two-sample t-test calculation. Assuming a standard deviation of SD=37 hours (corresponding to an interquartile range of 50 to 100 hours), the investigators expect that a sample size of n=35 provides 80% power to detect a mean group difference of 25 hours with a two-sided alpha of 5%.

Total enrollment: For each of the popliteal-sciatic and infraclavicular catheters, 70 subjects plus 30 for misplaced catheters or subjects otherwise unable to be randomized; and subjects who withdraw. This allows for a possible total of 100 subjects in each sub-study, and therefore a combined total of a maximum of 200 enrolled patients.

Eligibility criteria: Inclusion Criteria:

- patients undergoing ulnar and/or radial fracture open reduction internal fixation or painful foot and/or ankle surgery with a planned infraclavicular or popliteal sciatic perineural catheter, respectively, for postoperative analgesia

Exclusion Criteria:

* daily opioid use within the previous 4 weeks
* clinical neuro-muscular deficit of either the brachial plexus (infraclavicular) or sciatic nerve (sciatic catheters) and its branches and/or innervating muscles
* morbid obesity \[body mass index \> 35 kg/m2\]
* surgery outside of the ipsilateral sciatic and saphenous nerve distributions for sciatic catheters \[e.g., iliac crest bone graft\]
* pregnancy
* incarceration

Primary outcomes:
measure: Average Pain queried on First postoperative day
timeFrame: Postoperative day 1
measure: Duration of local anesthetic administration
timeFrame: The first 8 days postoperatively
Secondary outcomes:
measure: Worst pain
timeFrame: Each of 9 days postoperatively
measure: Average pain
timeFrame: Each of 9 days postoperatively
measure: Least pain
timeFrame: Each of 9 days postoperatively
measure: Current pain
timeFrame: Each of 9 days postoperatively
measure: Opioid consumption
timeFrame: Each of 9 days postoperatively
measure: Cumulative opioid consumption
timeFrame: The first 9 postoperative days following recovery room discharge
measure: Awakenings due to pain
timeFrame: The first 9 postoperative evenings queried on the following day
measure: Satisfaction with analgesia
timeFrame: The first 9 postoperative days
measure: Numbness in foot and ankle for popliteal-sciatic catheters (or hand/forearm for infraclavicular catheters)
timeFrame: Each of 9 postoperative days
measure: Pain Interference Subscale of the Brief Pain Inventory
timeFrame: Each of 9 days postoperatively
Other outcomes:
Locations:
city: San Diego
country: United States
facility: UCSD Medical Center
state: California
Study officials:
affiliation: University of California, San Diego
name: Brian M Ilfeld, MD, MS
role: PRINCIPAL_INVESTIGATOR
References: