Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03917823 |
| Other study ID # |
Cryoneurolysis & Rib Fracture |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 20, 2019 |
| Est. completion date |
March 25, 2020 |
Study information
| Verified date |
February 2021 |
| 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 randomized, double-masked, sham-controlled study is to evaluate the
potential of cryoanalgesia to decrease pain and improve pulmonary mechanics in patients with
rib fractures.
Description:
Rib fractures represent a significant source of morbidity in trauma patients, with
approximately 10% of trauma patients presenting with rib fractures.1 Pain from rib fractures
is associated with decreased ability to cough and inspire deeply, predisposing patients to
atelectasis and pulmonary complications. Neuraxial blocks, both thoracic epidurals and
paravertebral blocks, have been associated not only with decreased pain, but also decreased
pulmonary complications and overall mortality in patients with rib fractures.2 Furthermore,
intercostal nerve blocks with local anesthetic have been shown to improve pain scores, peak
expiratory flow rates, and arterial oxygen saturation on room air.3 However, intercostal
nerve blocks are not without risk and incidence of pneumothorax has been reported as 1.4% for
each individual intercostal nerve that is blocked.4 Although it is possible that the use of
in-plane ultrasound guidance may decrease the risk of pneumothorax, this has not been
evaluated. Additionally, intercostal blocks with bupivacaine have been reported to resolve in
as little as six hours,5 likely due to the high vascularity and consequent uptake of local
anesthetic from the intercostal space.
An alternative analgesic technique is cryoneurolysis, consisting of the application of
exceptionally low temperatures to reversibly ablate peripheral nerves, resulting in temporary
pain relief termed "cryoanalgesia".6 The intense cold temperature at the probe tip produces
Wallerian degeneration-a reversible breakdown of the nerve axon-subsequently inhibiting
transmission of afferent and efferent signals. Because the nerve endoneurium, perineurium,
and epineurium remain intact, the axon regenerates along the exoskeleton at a rate of
approximately 1-2 mm/day. While cryoneurolysis of peripheral nerves through surgical
incisions has been commonly used to treat pain since 1961, the development of cryo probes
that may be inserted percutaneously promise a revolution in the use of this modality. The
combination of newly-designed narrow-gauge probes (upper right) and ultrasound now make
percutaneous cryoanalgesia as simple as placing a peripheral nerve block: the probe tip is
inserted adjacent to the target nerve under ultrasound guidance, and a series of 2-minute
freezing cycles are administered followed by probe withdrawal. The procedure is essentially
the same as placing an ultrasound-guided peripheral nerve block; however, instead of
injecting local anesthetic, a gas circulates through the probe, inducing cold at the tip and
freezing the target nerve. Nothing remains within the patient and there is no external
equipment to prepare or manage. Importantly, cryoneurolysis and the probes are already
approved by the United States Food and Drug Administration for the treatment of acute and
chronic pain, so no additional regulatory approval is required for the proposed clinical
trial.
Theoretical benefits of cryoneurolysis include an ultra-long duration of pain control without
opioid involvement, no catheter management/removal (reducing infection risk), the lack of an
infusion pump and anesthetic reservoir to carry, an extraordinarily-low risk of infection
(approaching zero), and no risk of local anesthetic toxicity, catheter dislodgement or
leakage. With a single 8-minute percutaneous cryoneurolysis procedure consisting of several
freeze/defrost cycles, a truncation of sensory nerve conduction is induced for 6-8 weeks,
with the complete restoration of nerve structure and function following remyelination.
Cryoneurolysis offers the possibility of potent, side effect-free analgesia outlasting the
surgical pain, and obviating the need for postoperative opioids.
All subjects would continue to receive standard and customary analgesics, so there is no risk
of subjects receiving a lower degree of analgesia than if they otherwise did not enroll in
the study. The cryoneurolysis procedure will be done in addition to the investigator's
current UCSD standard practice.
Study Overview
Day 0 Subjects randomized and cryoneurolysis/sham procedure administered
Days 0-4, 7, 14, 21, and Months 1, 3, 6 Data collection
Subjects will be individuals who present to one of the UCSD hospitals with rib fracture(s)
and significant pain. Those who consent to participate in this study will have standard
intercostal nerve blocks administered.
Treatment group assignment (randomization). Subjects will be allocated to one of two possible
treatments:
1. cryoneurolysis
2. sham procedure (placebo control)
Computer-generated randomization lists will be used to create sealed, opaque randomization
envelopes with the treatment group assignment enclosed in each envelope labeled with the
randomization number.
The specific intercostal nerves targeted will depend on the injury site. The cryoneurolysis
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.
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 may be inserted beneath the ultrasound
transducer and directed until the probe tip is immediately adjacent to the target nerve
(lidocaine 1% will be administered, as needed, to anesthetize the angiocatheter track). The
target nerves will be the intercostal nerves above and below each fractured rib. 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 3 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 average pain score the day following treatment.
The primary inference will be based on the Mann-Whitney U test of the difference between
groups with an exact test with two-sided Type I error of 5%. Highest spirometry reading for
each period of time will be the secondary end point of highest interest [so designated after
the 4th subject was enrolled on September 23, 2019].
Patient baseline characteristics will be summarized by group with mean, standard deviation,
quartiles, range, and boxplots for continuous data; and counts and percentages for binary and
categorical data. Group differences will be assessed with Mann-Whitney U test for continuous
data and Pearson chi-square test for categorical data. If any key characteristics are
significantly different between groups, a proportional odds model will be used to test for a
group difference in the primary outcome adjusting for the potential confounding variable.
Pilot parameters for sample size justification are based on Osinowo et al (2004).3 Of the
initial pain scores for n=21 patients, n=18 (86%) had scores of 3.0 and n=3 (14%) had scores
of 2.0 (mean 2.86 ± 0.36). After 24 hours n=13 (62%) had scores of 0 and n=8 (38%) had scores
of 1.0 (mean 0.38 ± 0.50).
To simulate power with Mann-Whitney U test, we simulate controls groups assuming the
distribution of initial average pain scores from Osinowo et al. scores in the cryoneurolysis
groups are simulated assuming a score distribution 10% 0, 15% 1, 25% 2, and 50% 3 (resulting
in mean 2.12 ± 1.04 compared to control group mean 2.86 ± 0.36).
Under these assumptions a sample size of n=25 per group attains power 84% with two-sided Type
I error 5%. To allow for drop-outs, we will enroll up to a maximum of 60 subjects.
