FROST-STERN Trial: A Trial of Intraoperative Cryoablation for Post Operative Pain Management After Full Sternotomy (FROST-STERN)

FROST-STERN Research Protocol

1. Study Rationale and Background Median sternotomy remains the gold standard surgical approach for complex open-heart surgeries, including coronary artery bypass grafting (CABG) and valve replacements. However, it is inherently associated with severe acute and chronic postoperative pain. Approximately 28% of patients experience chronic post-sternotomy pain, with 4% characterizing it as severe.

   Inadequate acute pain management often results in patient "splinting" and impaired respiratory effort. This poor bronchopulmonary hygiene significantly increases the risks of acute postoperative lung complications, such as atelectasis and pneumonia, which can extend intensive care unit (ICU) and hospital length of stay (LOS). The pathophysiology of this pain stems from direct surgical trauma to peripheral nerve pathways, traction-induced brachial plexus injury, and intercostal neuralgia resulting from internal mammary artery harvesting.

   While traditional pain protocols rely heavily on systemic opioids, high narcotic burdens carry substantial side effects, including respiratory depression, sedation, and ileus. Traditional regional plane blocks offer relief that lasts only hours rather than months. This trial introduces intraoperative intercostal nerve cryoablation (INC) into a standardized cardiac Enhanced Recovery After Surgery (ERAS) pathway. By utilizing extreme cold to induce temporary, reversible Wallerian degeneration, INC offers a localized, non-addictive, long-acting analgesic solution designed to reduce early postoperative opioid reliance and accelerate the recovery of objective pulmonary function.

2. Participant Recruitment, Screening, and Consent Potential subjects will be identified and recruited from the Cardiac Surgery Clinic (outpatients) or the Inpatient Cardiac Surgery Service days to weeks prior to their scheduled operation.

   • Screening: The Principal Investigator (PI) or a designated Study Nurse will review patients' electronic medical charts against strict eligibility criteria.
   • Consent Process: Eligible patients will be approached in a private clinic room or at their hospital bedside. The study team will spend 5 to 10 minutes presenting the trial, emphasizing its voluntary nature. Patients will be provided with the written Informed Consent Form (ICF) to read over. Ample time will be provided to answer all questions. To verify comprehension prior to signing, the investigator will ask the patient several validating questions about the study. Once consent is obtained, it will be documented via a formal clinical note in the patient's medical record, and a copy of the ICF will be given to the participant.

3. Randomization, Allocation, and Blinding The FROST-STERN trial is a prospective, randomized, double-blind, parallel-group, sham-controlled trial with a target enrollment of 100 subjects.

   • Allocation: Randomization will be executed in blocks of 10 (5 ERAS-only and 5 ERAS+INC). Prior to surgery, designated study staff who are entirely independent of post-operative patient assessments will draw 1 of 10 sequentially numbered, sealed opaque envelopes to determine the group assignment.
   • Blinding: The independent staff member will communicate the assignment directly to the operating surgeon. The patient, post-operative clinical teams, intensive care staff, and data assessors will remain completely blinded to the treatment arm throughout the duration of the trial.

4. Intraoperative Intervention Protocol All surgeries will be performed according to standard institutional care. The active study intervention takes place after the patient has been safely decannulated from cardiopulmonary bypass (CPB) and surgical hemostasis has been fully achieved, but before the placement of sternal wiring.

   • Experimental Arm (Cryoablation Group): Under direct internal visualization from within the open mediastinum/pleural space, the attending cardiothoracic surgeon will apply a specialized cryo-anesthesia probe directly to the intercostal neurovascular bundles. Bilateral treatment will be delivered across five distinct dermatomal levels: T2 through T6. Each individual nerve bundle will undergo an ablation cycle lasting 60 to 90 seconds at an operating temperature between -50 degrees Celsius and -70 degrees Celsius to induce temporary nerve conduction block.
   • Active Comparator Arm (Control Group): Patients assigned to the control group will receive the institutional standard of care, which involves standard multimodal analgesia and regional thoracic plane blocks utilizing bupivacaine infiltration. To preserve the double-blind architecture, surgeons may perform a sham application by placing the unactivated cryoprobe against the designated anatomical landmarks without delivering thermal energy.

5. Postoperative Management and Rescue Analgesia

   To ensure patient safety, a strict, standardized multimodal rescue analgesia framework is mandated across both study arms to ensure no patient is left with unmanaged breakthrough pain:

   • First-Line Therapy: Scheduled Acetaminophen (e.g., 1000mg IV or PO every 6 hours).
   • Second-Line Therapy: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), provided there are no clinical contraindications related to renal function or active bleeding risks.
   • Third-Line (Breakthrough Rescue): Opioid Patient-Controlled Analgesia (PCA) using either Hydromorphone or Fentanyl programmed with a fixed, standardized lockout interval.

6. Primary and Secondary Endpoint Assessments Data collection spans from the baseline pre-operative clinic visit through a 3-month follow-up window.

   • Primary Endpoint: The percent recovery of Forced Expiratory Volume in 1 second (FEV1) and volumetric incentive spirometry at 48 and 72 hours postoperatively. This is calculated as a direct ratio comparing the absolute values (measured in liters) obtained on Postoperative Days (POD) 2 and 3 against the patient's preoperative baseline values. Bedside testing will be facilitated by trained research or respiratory staff using a standard sternal stabilization pillow to mitigate incisional strain.
   • Secondary Pain Intensity: Visual Analog Scale (VAS) pain scores (0 to 10 integer scale, where 0 = no pain and 10 = worst imaginable pain) captured dynamically during the performance of incentive spirometry at the day of extubation, 48 hours, and 72 hours.
   • Secondary Opioid Consumption: Cumulative systemic narcotic use recorded every 24 hours up to 72 hours, mathematically converted into total Morphine Milligram Equivalents (MME).
   • Secondary Recovery Milestones: Granular tracking of time to first extubation (measured in hours from surgery end), time to first independent ambulation (hours), and total length of stay (LOS) within both the ICU and general hospital wards (tracked in hours, divided by 24 for final day-count reporting).
   • Secondary Safety Endpoints: Tracking the cumulative incidence of procedure-related complications through the follow-up period, specifically focusing on pneumothorax, prolonged intercostal neuralgia, or localized skin numbness.
   • Secondary Chronic Pain: At the 3-month post-operative mark, patients will be contacted via telephone or an outpatient clinic visit to complete the Brief Pain Inventory Short Form (BPI-SF) and the SF-12 health survey. The BPI-SF will specifically capture pain severity (0-10 scale), pain interference with daily activities (0-10 scale), and perceived percentage of pain relief (0% to 100%).
7. Statistical Plan and Sample Size Justification The study is powered at 90% (with a significance level alpha = 0.05) to detect a statistically and clinically meaningful 15% improvement in baseline FEV1 values and a concurrent 30% reduction in total MME requirements in the cryoablation cohort compared to controls. Factoring in an anticipated post-operative attrition rate of 20% to 25% due to technical or clinical variances, the final sample size is set at 100 patients split equally between the two arms.

Continuous variables (such as FEV1, MME, LOS hours, and VAS scores) will be assessed for normality. Normally distributed continuous data will be analyzed using parametric independent t-tests, while skewed continuous data will be evaluated using the non-parametric Mann-Whitney U test. Categorical safety outcomes and complication rates will be compared utilizing Chi-squared tests or Fisher's exact tests. To account for baseline variances in pulmonary function, primary endpoints will be formally evaluated using an Analysis of Covariance (ANCOVA) model, integrating baseline pre-operative FEV1 as a continuous covariate. Paired t-tests will be applied to assess longitudinal changes in individual baseline-to-3-month BPI-SF and SF-12 scores. All raw endpoints will be managed securely within a blinded REDCap database environment.