Intercostal Nerve Cryoablation Versus Epidural Analgesia for Nuss Repair of Pectus Excavatum

Study Overview
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Brief Summary
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Primary objective of the current study is to determine the impact of intercostal nerve cryoablation on postoperative length of hospital stay compared to standard pain management of young pectus excavatum patients (12-24 years) treated with the minimal invasive Nuss procedure. The study is designed as a single center, prospective, unblinded, randomized clinical trial.

Detailed Description
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Rationale: The minimal invasive Nuss procedure is currently considered the treatment of choice for pectus excavatum. This procedure is usually associated with severe postoperative pain as great forces are employed on the thoracic cage to correct the sternal depression. Pain is the main limiting factor for early discharge. Epidural analgesia is currently considered gold standard for postoperative pain treatment. Alternative pain management strategies (e.g., patient-controlled analgesia and paravertebral nerve block) have also been described but fail in accomplishing adequate prolonged post-operative pain management. Alternatively, continuous use of opioids comes with side-effects like severe nausea, urinary retention and obstipation. Intercostal nerve cryoablation seems a promising novel technique for postoperative analgesia. Prior studies comparing intercostal cryoablation to other pain treatment modalities after pectus excavatum repair through the minimal invasive Nuss procedure report promising results, but pose significant limitations (e.g., small sample size, retrospective nature with non-matched patient groups or considerable confounders). Objective: Primary objective of the current study is to determine the impact of intercostal nerve cryoablation on postoperative length of hospital stay compared to standard pain management of young pectus excavatum patients treated with the minimal invasive Nuss procedure. Study design: The study protocol is designed for a single center, prospective, unblinded, randomized clinical trial. Study population & intervention: Intercostal nerve cryoablation will be compared to thoracic epidural analgesia in young pectus excavatum patients (i.e., 12-24 years of age) treated with the minimal invasive Nuss procedure. Block randomization, including stratification based on age (12-16 years and 17-24 years) and sex, with an allocation ratio of 1:1 will be performed. Main study parameters/endpoints: Postoperative length of hospital stay will be recorded as the primary endpoint. Secondary outcomes include: 1) pain intensity; 2) operative time; 3) opioid usage; 4) procedure and analgesia-related complications, including neuropathic pain; 5) intensive care unit admissions; 6) readmissions; 7) postoperative mobility; 8) health related quality of Life; 9) days to return to work/school; 10) number of postoperative outpatient visits and 11) hospital costs. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The risks for study participants are negligible as the cryoablation technique has already been effectively used in the Nuss procedure without any serious side effects. Also, participants will be monitored daily by nursing staff and surgeons while admitted to the hospital. Burden associated with participation in the current study consists of completion of several questionnaires preoperatively and postoperatively.

Official Title
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Intercostal Nerve Cryoablation Versus Thoracic Epidural Analgesia for Minimal Invasive Nuss Repair of Pectus Excavatum: a Randomized Clinical Trial (ICE Trial)

Conditions
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Pectus Excavatum, Funnel Chest

Intervention / Treatment
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* Procedure: Intercostal nerve cryoablation
* Drug: Thoracic epidural analgesia (continuous infusion with sufentanyl (1 µg/ml) and bupivacaine (1.25 mg/ml))
* Drug: Intercostal nerve block (single shot bupivacaine (1.25 mg/ml))
* Drug: Opioids (oxycodone with prolonged discharge 10 mg PO every 12 hours and oxycodone 5 mg every 6 hours, as needed)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients undergoing the minimal invasive Nuss procedure for surgical repair of pectus excavatum. Young patients (12-24 years of age) according to the definition used by the World Health Organization. This cut-off point is chosen to create a more homogenous patient sample, as the thoracic cage is fully matured by the age of 24, in size and density, which will have an effect on postoperative pain. Exclusion Criteria: A chest wall deformity other than pectus excavatum; Opioid use in the 3 months prior to surgery; Pain syndrome (e.g., fibromyalgia) or neuropathic pain prior to surgical repair of pectus excavatum; Connective tissue disease (e.g., Marfan syndrome, Ehlers-Danlos syndrome); Previous thoracic surgery or pectus excavatum repair; Contraindication for intercostal nerve cryoablation or thoracic epidural analgesia (e.g., patient refusal, infection at the site of cannulation, uncontrolled systemic infection, bleeding diathesis, increased intracranial pressure, mechanical spine obstruction); Psychiatric disease currently receiving treatment; Not mastering the Dutch language; Participation in another clinical trial that may interfere with the current trial.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single center, prospective, unblinded, randomized clinical trial. Block randomization, including stratification based on age (12-16 years and 17-24 years) and sex, with an allocation ratio of 1:1 will be performed.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intercostal nerve cryoablation<br>When a patient is allocated to the intercostal nerve cryoablation group, cryoablation will be performed prior to bar placement. In brief, cryoablation will be performed at the level of the bar and two levels above and below, bilaterally. For this, a second portal access will be placed for video guidance on the contralateral side, and the cryoprobe (cryoICE, Atricure, Masion, OH, USA) will be inserted through the thoracic incisions that are already made for bar placement. The probe will be placed at the inferior aspect of the ribs, posterior to the midaxillary line, directly on the neurovascular bundle. One freezing cycle takes 2 minutes, and a temperature of -60 ⁰C will be applied. The probe will be warmed to room temperature before removing it from the pleura to prevent additional trauma. Furthermore, intercostal nerve cryoablation will be combined with single shot bupivacaine (1.25 mg/ml) intercostal nerve blocks placed just anterior to the side of the cryoablation. | Procedure: Intercostal nerve cryoablation<br>* Intercostal nerve cryoablation is applied during Nuss procedure.<br>* Other names: Cryoablation;Drug: Intercostal nerve block (single shot bupivacaine (1.25 mg/ml))<br>* Single shot bupivacaine (1.25 mg/ml) intercostal nerve blocks are placed just anterior to the side of the cryoablation.<br>* Other names: Intercostal nerve block;Drug: Opioids (oxycodone with prolonged discharge 10 mg PO every 12 hours and oxycodone 5 mg every 6 hours, as needed)<br>* Opioids<br>* Other names: opioids, oxycodone (with prolonged discharge);|
| Active Comparator: Thoracic epidural (local continuous infusion with sufentanyl (1 µg/ml) and bupivacaine (1.25 mg/ml))<br>Prior to surgery, an anesthesiologist will place the thoracic epidural at T5-T6 or T6-T7 interspace in the awake patient. After correct placement, a local continuous infusion with sufentanyl (1 µg/ml) and bupivacaine (1.25 mg/ml) will be started. At the third postoperative day, thoracic epidural analgesia will be ceased and transitioned to oral pain medication at discretion of the pain management team. In general, opioids (oxycodone with prolonged discharge 10 mg PO every 12 hours and oxycodone 5 mg every 6 hours as needed) will be provided 12 hours before thoracic epidural analgesia is ceased. | Drug: Thoracic epidural analgesia (continuous infusion with sufentanyl (1 µg/ml) and bupivacaine (1.25 mg/ml))<br>* Thoracic epidural is placed prior to Nuss procedure<br>* Other names: Epidural;Drug: Opioids (oxycodone with prolonged discharge 10 mg PO every 12 hours and oxycodone 5 mg every 6 hours, as needed)<br>* Opioids<br>* Other names: opioids, oxycodone (with prolonged discharge);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of hospital stay | Number of days of hospital admittance after the Nuss procedure. | Hospitalization period, average of 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain intensity | Pain intensity at rest and during mobilization. Pain scores will be rated on the numeric rating scale (NRS, 1-10) | Preoperative care unit before surgery, in the morning on postoperative day 1 and 2, and 7 days, 14 days, 3 months and 6 months post operation | 
| Operative time | Operative time in minutes. Duration of cryoablation will be assessed separately. Operative time will not include the time needed for the placement of the thoracic epidural as placement will be performed in the preoperative care unit. | During Nuss procedure | 
| Opioid usage | A) Opioid usage during postoperative day 1 and 2; B) Opioid usage within the first 2 weeks after surgery. Opioid usage will be converted to oral morphine milligram equivalents (MME). Epidural infusion medication does not distribute systematically and therefore cannot be converted to MME. Epidural infusion medication will be omitted in calculation of opioid usage and opioid usage in the Thoracic epidural group will therefore be an underestimation of the actual usage. Upon discharge, patients will be prescribed opioids for 9 days. The need for a refill prescription will be assessed via a telephone appointment. | postoperative day 1 and 2, and first 2 weeks after surgery | 
| Procedure- and analgesia-related complications | Procedure- and analgesia-related complications as defined in Supplementary Materials Table 1-2, including neuropathic pain, graded according to the Clavien-Dindo classification. | 6 months postoperative | 
| Intensive care unit admission | Intensive care unit admission due to the occurrence of perioperative complications in absolute numbers | Hospitalization period, average of 5 days | 
| Length of intensive care unit admission | Length of admission due to the occurrence of perioperative complications in absolute numbers. | Hospitalization period, average of 5 days | 
| Number of readmissions | Number of readmissions denoted as absolute numbers. | 6 months postoperative | 
| Length of readmissions | length of readmissions denoted as absolute numbers. | 6 months postoperative | 
| Degree of mobility | Degree of mobility measured on a 4-point scale (i.e., 1. on the bed, 2. to the chair, 3. to the toilet, 4. outside the patient's hospital room) during postoperative day 1 and 2. | Postoperative day 1 and 2 | 
| HRQOL - PEEQ | HRQOL, measured by the Dutch version of the pectus evaluation questionnaire (PEEQ). The PEEQ is a validated disease specific questionnaire evaluating the quality of life in pectus excavatum patients (37,38). | Before surgery as a baseline measurement, and at 2 weeks, 3 months and 6 months after the surgical procedure | 
| HRQOL - SF-36 | HRQOL, measured by the Dutch version of the short form health survey (SF-36)(37-40). The SF-36 is a generic questionnaire that taps health in eight dimensions (39). | Before surgery as a baseline measurement, and at 2 weeks, 3 months and 6 months after the surgical procedure | 
| HRQOL - EQ-5D-5L | HRQOL, measured by the Dutch version of the EuroQol 5 dimensions 5 levels (EQ-5D-5L) (37-40). For the EQ-5D-5L, participants will rate their health in 5 dimensions on 5 levels and will give an overall score of their health on a visual analogue scale (VAS) (40). | Before surgery as a baseline measurement, and at 2 weeks, 3 months and 6 months after the surgical procedure | 
| Days to return to work/school | Days to return to work/school, reported as days between discharge from hospital and return to work or school. | 6 months postoperative | 
| Postoperative visits | Number of postoperative outpatient visits and telephone appointments denoted as absolute numbers in the first 6 months after the surgical procedure. | 6 months postoperative | 
| Hospital costs | Hospital costs, reported as hospital costs during initial hospitalization (e.g., medication, patient care supply, surgical equipment), and hospital costs after discharge until 6 months follow-up (e.g., medications, outpatient visits, (opioid related) readmissions). | 6 months postoperative | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pectus Excavatum, Funnel Chest, Intercostal nerve cryoablation, Analgesia