Clinical trial NCT04198662: Rib Fracture Analgesia Using Cryoanalgesia
Official title: Intercostal Cryoneurolysis Following Traumatic Rib Fractures
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Traumatic Rib Fracture(s)
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
First posted: 2019-12-13
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, randomized, double-masked, sham-controlled, parallel design, clinical trial
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: Inclusion Criteria:

* Adult patients of at least 18 years of age
* having a total of 1-6 rib fractures at least 3 cm distal to the costo-transverse joint sustained within the previous 3 days (bilateral fractures are acceptable, but the total of the two sides combined must not exceed 6 fractures)
* regional anesthetic requested by the admitting service
* accepting of a cryoneurolysis procedure

Exclusion Criteria:

* chronic opioid use (daily use within the 2 weeks prior to surgery and duration of use \> 4 weeks
* pregnancy
* incarceration
* inability to communicate with the investigators
* morbid obesity (body mass index \> 40 kg/m2)
* possessing any contraindication specific to cryoneurolysis such as a localized infection at the treatment site, cryoglobulinemia, cold urticaria and Reynaud's Syndrome
* any patient unable to correctly perform incentive spirometry as this is the primary outcome measure
* any patient with any degree of decreased mental capacity as determined by the surgical service
* any reason an investigator believes study participation would not be in the best interest of the potential subject
* flail chest
* chest tube
* fracture of the 1st rib on either side
* any moderate or severe pain (NRS\>3) unrelated to the rib fracture(s), as best determined by the patient and investigator

Primary outcomes:
measure: Maximum Inspired Volume
timeFrame: Day 1 of study treatment
Secondary outcomes:
measure: Maximum Inspired Volume
timeFrame: Days 0, 1, 2, 7, 14, and Months 1, 1.5, and 2
measure: Spirometry Pain
timeFrame: Days 0, 1, 2, 7, 14, and Months 1, 1.5, and 2
measure: Brief Pain Inventory (Pain Scale)
timeFrame: Days 1, 2, and 7
measure: Brief Pain Inventory (Interference Scale)
timeFrame: Day 14, and Months 1, 1.5, 2, 3, 6, and 12
measure: Sleep Disturbances Due to Pain
timeFrame: Days 1, 2, 7, 14; Months 1, 1.5, 2, 3, 6, and 12
measure: Oral Opioid Consumption
timeFrame: Days 1, 2, 7, 14; Months 1, 1.5, 2, 3, 6, and 12
measure: Intravenous Opioid Consumption
timeFrame: Days 1, 2, 7, 14
measure: Day of Discharge
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University California San Diego
state: California
Study officials:
affiliation: University California San Diego
name: Brian M Ilfeld, MD, MS
role: PRINCIPAL_INVESTIGATOR
References: