Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04198662 |
| Other study ID # |
Rib Fracture & Spirometry/Cryo |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
April 3, 2020 |
| Est. completion date |
August 27, 2024 |
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
Rib fractures are one of the most common injuries in trauma patients. These fractures are
associated with significant pain as well as decreased ability to inspire deeply or cough to
clear secretions, which together lead to pulmonary complications and a high degree of
morbidity and mortality. Peripheral nerve blocks as well as epidural blocks have been used
with success to improve pain control in rib fracture patients and have been associated with
decreased pulmonary complications and improved outcomes. However, a single-injection nerve
block lasts less than 24 hours; and, even a continuous nerve block is generally limited to
3-4 days. The pain from rib fractures usually persists for multiple weeks or months. In
contrast to local anesthetic-induced nerve blocks, a prolonged block lasting a few
weeks/months may be provided by freezing the nerve using a process called "cryoneurolysis".
The goal of this multicenter, randomized, double-masked, sham-controlled, parallel-arm study
is to evaluate the potential of cryoanalgesia to decrease pain and improve pulmonary
mechanics in patients with rib fractures.
Description:
The ultimate objective of the proposed line of research is to determine if cryoanalgesia is
an effective treatment for pain associated with rib fractures; and, if this analgesic
modality improves pulmonary mechanics measured with incentive spirometry.
Specific Aim 1: To determine if, compared with current and customary analgesia for rib
fracture(s), intercostal nerve cryoneurolysis improves maximum inspiratory volume.
Hypothesis 1a: The maximum inspired volume will be significantly increased on the day
following the procedure [primary endpoint] as well as at other time points following the
procedure [secondary end points] with intercostal cryoanalgesia as compared single-injection
local anesthetic-based intercostal nerve blocks [measured with an incentive spirometer].
Hypothesis 1b: The maximum inspired volume as a percentage of the baseline will be
significantly increased on the day following the procedure [secondary endpoint of greatest
interest], as well as at other time points following the procedure [secondary end points]
with intercostal cryoanalgesia as compared with single-injection local anesthetic-based
intercostal nerve blocks [measured with an incentive spirometer].
Specific Aim 2: To determine if, compared with current and customary analgesia, intercostal
nerve cryoneurolysis decreases the pain associated with rib fracture(s).
Hypothesis 2a: The severity of rib fracture pain at rest will be significantly decreased
within the 12 months following the procedure with intercostal cryoneurolysis as compared with
subjects receiving single-injection local anesthetic-based intercostal nerve blocks [measured
using the Numeric Rating Scale for pain].
Hypothesis 2b: The severity of rib fracture pain when using the spirometer or coughing will
be significantly decreased within the 12 months following the procedure with intercostal
cryoneurolysis as compared with subjects receiving single-injection local anesthetic-based
intercostal nerve blocks [measured using the Numeric Rating Scale for pain].
Hypothesis 2c: The incidence of chronic pain will be significantly decreased 6 and 12 months
following a rib fracture with intercostal cryoeurolysis as compared with subjects receiving
single-injection local anesthetic-based intercostal nerve blocks [measured using the Numeric
Rating Scale for pain].
Hypothesis 2d: The severity of chronic pain will be significantly decreased 6 and 12 months
following a rib fracture with intercostal cryoneurolysis as compared with subjects receiving
single-injection local anesthetic-based intercostal nerve blocks [measured using the Numeric
Rating Scale for pain].
Study Overview Day 0 Baseline pain levels and spirometry Subjects randomized and
cryoneurolysis/sham procedure administered Post-block pain levels and spirometry repeated
Days 1, 2, 7 Pain levels, opioid consumption, sleep disturbances due to pain, and incentive
spirometry values collected [as well as the day of discharge]
Months 0.5, 1, 1.5 , 2, 3, 6, and 12 Pain levels, opioid consumption, sleep disturbances due
to pain, and pain interference collected [and incentive spirometry if subject has spirometer
available]
Subjects will be individuals who present to one of the UCSD hospitals with rib fracture(s)
and significant pain. All will be following the same protocol and the subjects from all
institutions will be combined for the analysis.
Treatment group assignment (randomization). Subjects will be allocated to one of two possible
treatments stratified by unilateral vs. bilateral fractures:
1. active cryoneurolysis (sham local anesthetic intercostal blocks)
2. sham cryoneurolysis (active local anesthetic intercostal blocks)
Computer-generated randomization lists created by the UC San Diego Investigational Drug
Service will be used to create sealed, opaque randomization envelopes with the treatment
group assignment enclosed in each envelope labeled with the randomization number. The lists
will be kept by the Investigational Drug Service and not provided to the investigators until
completion of data collection (1 year following enrollment of the final subject).
The specific intercostal nerves targeted will depend on the injury site. The treatment sites
will be cleansed with chlorhexidine gluconate and isopropyl alcohol. Using the optimal
ultrasound transducer for the specific anatomic location and subject anatomy (linear vs
curvilinear array), the target nerves will be identified in a transverse cross-sectional
(short axis) view. The intercostal nerve of each fractured rib as well as the level above and
below will be treated with the protocol below:
Intercostal nerve block procedure: The target nerve will be visualized with ultrasound. Local
anesthetic (1% lidocaine) will be used to infiltrate the skin and underlying muscle at each
entry point. A 20 g Tuohy needle will be introduced through the skin wheel and along the
anesthetized muscle tract. For subjects randomized to active cryo, 3 mL of normal saline will
be injected into the muscle superficial to the nerve; and for subjects randomized to sham
cryo, 3 mL of ropivacaine 0.5% (with epinephrine) will be injected perineurally to provide
the intercostal nerve block.
Cryoneurolysis procedure: Cryoneurolysis probes are available for a console neurolysis device
(PainBlocker, Epimed, Farmers Branch, Texas) that either (1) pass nitrous oxide to the tip
inducing freezing temperatures; or, (2) vent the nitrous oxide at the base of the probe so
that no gas reaches the probe tip, resulting in no temperature change. The latter is a sham
procedure since without the temperature change, no ice ball forms and therefore the target
nerve is not affected. An angiocatheter/introducer will be inserted beneath the ultrasound
transducer and directed until the probe tip is immediately adjacent to the target nerve. The
angiocatheter needle will be removed, leaving the angiocatheter through which the appropriate
Epimed probe will be inserted until it is adjacent to the target nerve. The cryoneurolysis
device will be triggered using 2 cycles of 2-minute gas activation (active or sham) separated
by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip
where a drop in temperature to -70°C will result in cryoneurolysis. For the sham probes, the
nitrous oxide will be vented prior to reaching the probe shaft, resulting in a lack of
perineural temperature change.
The process will be repeated with the same treatment probe for any additional nerves (e.g.,
all nerves will receive either active cryoneurolysis or sham/placebo, and not a mix of the
two possible treatments).
Statistical Analysis: The primary endpoint is the maximum inspired volume measured by
incentive spirometry the day following treatment. There is no accepted minimal
clinically-relevant change in incentive spirometry volume. However, the median (IQR) of
inspired volume for patients with rib fracture(s) is 1250 (750-1750) mL; and, ISV<1000 mL is
associated with an increased risk of acute respiratory failure. The investigators will
therefore use the difference between 1250 and 1000 (250 mL) as the minimal
clinically-relevant difference. However, there is high variability in the reported increase
in inspired volume with various regional analgesic interventions such as continuous
intercostal nerve blocks and serratus plane blocks, and the investigators will therefore
increase our enrollment to account for an unpredicted increase in variability or non-normal
data distribution.
But, assuming a normal distribution, the interquartile range is approximately 1.35 standard
deviations (SDs). Therefore an interquartile range of 250-50 = 200 mL (Hernandez et al. 2019)
corresponds to, approximately, an SD of 200/1.35 = 148 mL. Assuming this SD of 148 mL, a
sample size of n=7 per group provides 80% power to detect a group difference of d=250 mL per
group with two sided Type 1 Error 5%. To allow for a larger-than-anticipated SD, we will
enroll 10 subjects per group with an evaluable primary outcome measure (n=20 for both groups
combined). Accounting for drop-outs, we request a maximum enrollment of 30 subjects.
Continuous data will be summarized with mean, SDs, medians, quartiles, and ranges; and
displayed with box-and-whisker plots by group and in aggregate. Key baseline characteristics
will be tested between groups using two-sample t-tests, and summarized with Cohen's D, for
continuous measures; and Fisher's Exact test for categorical variables. The primary outcome
is maximum incentive spirometry volume (ISV) measured in mL on POD 1. The group difference
will be tested using Welch's two-sample test. Secondary outcomes will also be tested with the
two-sample t-test. No multiplicity adjustments will be applied for these secondary outcomes.
The Wilcoxon signed-rank test will be used as a sensitivity analysis. Secondary analyses will
include a Mixed Model of Repeated Measures with fixed-effects for time, time-by-group,
unilateral vs bilateral, and the number of fractures. The model will treat time as a
categorical variable and will assume a compound symmetric correlation and heterogeneous
variance with respect to time. The estimated mean difference between groups at the final
scheduled timepoint will be the parameter of interest and will be tested using Kenward-Roger
degrees of freedom. Outcomes only measured at baseline and a single follow-up timepoint will
be analyses with Analysis of Covariance (ANCOVA). The dependent variable will be change from
baseline, and covariates will include group, baseline outcome, unilateral vs bilateral, and
the number of fractures. Missing data is not expected due to the short follow-up in this
study. However, if missing data issues arise, the investigators will use multiple imputation
which is robust to covariate-dependent Missing at Random, and tipping point analyses under
various Missing Not at Random assumptions.
The Investigational Drug Pharmacists and investigators doing the study procedures will be the
only individuals aware of the treatment group assignments. The Investigational Drug Service
will not provide the treatment group assignments to the investigators until the completion of
data collection for all subjects; and will only provide "Treatment A" vs "Treatment B"
assignments for the initial statistical analysis. Only at the completion of statistical
analysis will each treatment be revealed to the investigators.
