Ultrasound-Guided Percutaneous Cryoneurolysis to Treat Pain Following Thoracic Trauma

The investigators propose a pragmatic, multicenter, randomized, triple-masked (investigators, participants, statisticians), sham/placebo-controlled, parallel-arm, human-subjects clinical trial to determine if cryoneurolysis is an effective non-opioid treatment for pain following traumatic rib fractures. Participants will be recruited at 6 enrolling centers:

* Brigham and Women's Hospital, Boston, Massachusetts * University of Texas, Houston, Houston, Texas * Massachusetts General Hospital, Boston, Massachusetts * University of California, San Diego, San Diego, California * Walter Reed National Military Medical Center, Bethesda, Maryland

For individuals of childbearing potential, a sample of urine will be collected before any study interventions to confirm a non-pregnant state \[this is standard for any trauma regardless of study participation\]. Participants will have a peripheral intravenous (IV) catheter inserted, standard noninvasive monitors applied (blood pressure cuff, pulse oximeter, 5-lead ECG), and oxygen administered via a facemask. Midazolam and fentanyl (IV) will be titrated for patient comfort as needed throughout the procedure, while ensuring that patients remain responsive to verbal cues.

Treatment group allocation (randomization). Participants will be allocated to one of two possible treatments groups:

1. Cryoneurolysis 2. Local anesthetic nerve block (Control)

Randomization will be stratified by enrolling institution and fracture laterality (unilateral vs. bilateral) in a 1:1 ratio, and in randomly chosen block sizes. Randomization lists will be created using Statistical Analysis Software computer-generated tables by the informatics division of the Department of Outcomes Research (Cleveland Clinic, Cleveland, OH). Treatment group assignment will be conveyed to the enrolling sites via the same secure web-based system (RedCap) used to collect study endpoints. The investigator administering the study intervention will access the treatment group assignment using the secure web-based system and attach the appropriate probe to the cryoneurolysis device. Therefore, all investigators, participants, and clinical staff will be masked to treatment group assignment, with the only exception being the investigator and coordinator who perform the procedure (and will not have subsequent contact with the participant). This protocol will enable a randomized, triple-masked (including statistician), sham/placebo-controlled trial. It is impossible to mask the individuals performing the cryoneurolysis procedure because the ice ball forming at the distal end of the probe-with active treatment-is clearly visible by ultrasound; and the lack of an ice ball for placebo participants is equally clear. It is essential to continuously visualize the probe and target nerve throughout the two freeze/thaw cycles to ensure the entire nerve diameter is adequately treated and remains relatively motionless. This cannot be achieved if the ultrasound is turned off during nitrous oxide administration to mask the provider; and the investigators prioritize patient safety over masking of the physician administering the intervention.

All participants will be positioned seated or prone (investigator preference), have a peripheral intravenous (IV) catheter inserted, standard noninvasive monitors applied (blood pressure cuff, pulse oximeter, 5-lead ECG), and oxygen administered via a facemask. Midazolam and fentanyl (IV) will be titrated for patient comfort, while ensuring that patients remain responsive to verbal cues. The treatment sites will be cleansed with chlorhexidine gluconate and isopropyl alcohol.

Peripheral nerve block. Due to the pragmatic design of this trial, study participation will not alter an institution's current practice. Examples of peripheral nerve blocks include paravertebral, erector spinae plane, and serratus anterior nerve blocks using a long-acting local anesthetic (ropivacaine or bupivacaine, both with epinephrine). The injectate through the introducer will depend on the treatment group: for participants allocated to the cryoneurolysis group (experimental group), normal saline will be injected for the peripheral nerve block. For participants of the control group, ropivacaine 0.5% or bupivacaine 0.375% (both with epinephrine 1:400,000) will be injected (volume determined by institutional standard-of-care). This will provide a placebo nerve block for the experimental group and actual peripheral nerve block for the control group.

Cryoneurolysis procedure. The intercostal nerve of each fractured rib along with one cephalad and one caudad will be targeted. For example, if ribs 3-5 are fractured, then the ipsilateral nerves for thoracic levels 2-6 will receive treatment. Using a linear- or curved-array transducer, the intercostal nerve will be visualized using ultrasound just inferior to each treated rib immediately distal to the costotransverse joint. A skin wheal of local anesthetic will be raised immediately inferior to the transducer to anesthetize the skin.

There are multiple types of cryoneurolysis machines cleared by the US FDA, all of which work on the same principle of a gas being passed through a small annulus, resulting in a dramatic pressure drop and accompanying temperature drop due to the Joule-Thomson effect. This study will utilize two different consoles: the Epimed International (Farmers Branch, TX) and Varian Medical Systems (Palo Alto, CA) machines. Which machine is used is determined simply by the machine that each enrolling center has at its disposal.

Varian: This machine uses argon for the freeze cycle and helium to help decrease the thaw period duration. Sham probes are not available for this type of machine, and therefore an active probe will be used for all participants. For participants randomized to active treatment, the probe placed in the patient will be triggered and the argon (and helium) passed through the probe and then back into the machine, and finally vented out from the console. For participants randomized to sham treatment, the probe in the patient will simply not be activated; instead, a second probe that is not inserted in the patient will be triggered which will create the same visual and auditory cues as for the active participants retaining the masked feature. The investigator administering the study intervention will access the treatment group assignment using the secure web-based system and activate the correct probe depending on the treatment group assignment. Therefore, all investigators, participants, and clinical staff will be masked to treatment group assignment, with the only exception being the unmasked investigator and coordinator who perform the procedure (and will not have subsequent contact with the participant).

Epimed: This machine uses nitrous oxide for the freeze cycle with a passive thaw (no gas flow). Cryoneurolysis probes are available that either (1) pass nitrous oxide to the distal end inducing freezing temperatures; or (2) vent the nitrous oxide at the proximal end of the probe so that no gas reaches the distal end, 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. Importantly, these probes are indistinguishable in appearance and will be differentiated only by an identifying stamp on the underside of the connector which is not visible during use. The investigator administering the study intervention will access the treatment group assignment using the secure web-based system and attach the appropriate probe to the cryoneurolysis device. Therefore, all investigators, participants, and clinical staff will be masked to treatment group assignment, with the only exception being the unmasked investigator and coordinator who perform the procedure (and will not have subsequent contact with the participant).

These protocols will enable a randomized, triple-masked (including statistician), sham/placebo-controlled trial. For both types of machines, it is impossible to mask the individuals performing the cryoneurolysis procedure because the ice ball forming at the distal end of the probe-with active treatment-is clearly visible by ultrasound; and the lack of an ice ball for sham participants is equally clear. It is essential to continuously visualize the probe and target nerve throughout the freeze/thaw cycle(s) to ensure the entire nerve diameter is adequately treated and remains relatively motionless. This cannot be achieved if the ultrasound is turned off during nitrous oxide or argon administration in an attempt to mask the provider; and the investigators prioritize patient safety over masking of the physician administering the intervention.

The cryoneurolysis sites will already be cleansed with chlorhexidine gluconate and isopropyl alcohol. The intercostal nerve of each fractured rib along with one cephalad and one caudad will be targeted. For example, if ribs 3-5 are fractured, then the ipsilateral intercostal nerves 2-6 will receive treatment. The intercostal nerve will be visualized using ultrasound just inferior to each treated rib immediately distal to the costotransverse joint. A skin wheal of lidocaine will be raised inferior to the transducer to anesthetize the skin.

A portable cryoneurolysis console device (Varian Medical Systems or Epimed International) will be used with the appropriate probe (either active or sham).

Varian: The probe will be inserted adjacent to the intercostal nerve. The cryoneurolysis device will be triggered using 1 cycle of 5.5-minute \[all but 5 participants\] or 3-minute \[5th - 12th participants; changes based on new laboratory and subsequently clinical data\] argon activation (2000 psi starting at 100% power but decreased to keep return gas flow temperature warmer than -100C) followed by a 30-second helium defrost. The Varian machine provides its own timer so that the gas cycle timing is precise to the second. The probe will be withdrawn, and this process repeated for each additional intercostal nerve to be treated. For bilateral fractures, the study intervention will be repeated on the contralateral side with the same probe.

Epimed: The probe will be inserted adjacent to the intercostal nerve. The cryoneurolysis device will be triggered using 2 cycles of 2-minute gas activation (active or sham) separated by a 1-minute defrost. An observer (usually the research coordinator) will time the cycles and indicate to the investigator when the 2- \& 1-minute periods have concluded to ensure adequate treatment duration. The probe will be withdrawn, and this process repeated for each additional intercostal nerve to be treated. For bilateral fractures, the study intervention will be repeated on the contralateral side with the same probe.

Post-treatment course. Standard local supplemental analgesics will be used due to the pragmatic design of this trial. For analysis purposes, all opioids will be converted to oral oxycodone equivalents. Following a cryoneurolysis treatment, no action is required by patients. For example, in contrast to epidural infusions, there is no infusion pump to manage or anesthetic fluid to replenish. Patients will be provided with a hand-held incentive spirometer to keep at their bedside both while admitted and at home. Participants will be instructed in their use based on the American Association of Respiratory Care (AARC) clinical practice guideline, and then use the spirometer unsupervised at least hourly.

Following study completion, the results will be mailed electronically or by the United States Postal Service to all enrolled participants in written form using non-technical (e.g., "layperson") language.

Statistical Plan.

Primary Aim: To determine the effect of cryoneurolysis on opioid requirements and analgesia following traumatic rib fracture.

Hypothesis 1: Cumulative opioid consumption will be decreased in the first 2 months wi

• Opioid consumption [Срок оценки: Collected on post-intervention days 1, 2, 3, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Average pain [Срок оценки: Collected on post-intervention days 1, 2, 3, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Worst/maximum pain [Срок оценки: Collected on post-intervention days 1, 2, 3, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Least/lowest/minimal pain [Срок оценки: Collected on post-intervention days 1, 2, 3, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Current pain [Срок оценки: Collected on post-intervention days 1, 2, 3, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Brief Pain Inventory, short form (interference subscale) [Срок оценки: Collected on post-intervention days 3, 7, 14, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• First 2 months area under the curve of the Brief Pain Inventory, short form (interference subscale) [Срок оценки: Collected on post-intervention days 3, 7, 14, 30, 45 and 60]
• Pain during spirometry [Срок оценки: Collected on post-intervention days 1, 2, 3, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Maximum voluntary inspiratory volume individual time points [Срок оценки: Collected on post-intervention days 1, 2, 3, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• First 2 months area under the curve of the maximum voluntary inspiratory volume [Срок оценки: Collected on post-intervention days 1, 2, 3, 7, 14, 21, 30, 45, and 60]
• Awakenings due to pain [Срок оценки: Collected on post-intervention days 1, 2, 3, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Post-Traumatic Stress Disorder checklist (PCL-5) [Срок оценки: Day of intervention (prior to intervention)]