Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT05091905 |
| Other study ID # |
Patient-Titrated Boluses cPNB |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
February 14, 2022 |
| Est. completion date |
December 2026 |
Study information
| Verified date |
June 2024 |
| Source |
University of California, San Diego |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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].
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.
