Clinical trial NCT03972397
Conditions: Pain, Postoperative
Keywords: Cryoablation
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2019-07-15; Completion date: 2022-09-22
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to assess the efficacy of intercostal nerve cryoablation on the magnitude and duration of postoperative pain control both in patients undergoing thoracoabdominal incisions for the descending or thoracoabdominal aortic aneurysm repair.

Detailed description:

Arms: arm 1: Standard of Care (SOC) arm 2: None
Interventions: intervention 1: Intercostal Nerve Cryoablation intervention 2: Bupivacaine liposomal injectable suspension intervention 3: Patient-controlled analgesia (PCA)
Intervention descriptions: intervention 1: Patients will receive intraoperative intercostal nerve cryoablation using CryoICE® CRYO2 cryoablation probes (AtriCure, Inc) to intercostal spaces 4th to 10th in thoracoabdominal aortic repairs and 4th to 8th in descending thoracic aortic repair cases prior to wound closure. intervention 2: Patients from both groups will receive the same volume of diluted Exparel®, which will be given in four 20ml syringes using 22-gauge needles (266mg of liposomal bupivacaine, equivalent of one 1.3% 20ml vial of EXPAREL, diluted in 50ml of preservative-free normal (0.9%) sterile saline for a total volume of 70ml). intervention 3: Patients will have access to the standard PCA (Patient-Controlled Analgesia) offered at the Memorial Hermann Hospital - Texas Medical Center. The PCA drug will be Dilaudid (hydromorphone). Initial dosing will be per the standard hospital protocol of 0.2 mg demand dose, 10-minute lockout, 2 mg per hour max, 0.4 mg rescue dose. Adjustments to the PCA dosing will be made based on clinical needs.

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intercostal Nerve Cryoablation for Postoperative Pain Management 
 
 
NCT03972397 
 
 
Version Date: 06/05/2019 
 
 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
I. 
PROTOCOL TITLE 
II. 
PRINCIPAL INVESTIGATOR & RESEARCH TEAM 
III. 
STUDY SITE 
IV 
CONTACT INFORMATION 
V. 
RESEARCH SYNOPSIS 
A. 
Study Title 
B. 
Clinical Phase 
C. 
Study Population 
D. 
Study Design 
E. 
Sample Size 
F. 
Study Duration 
G. 
Study drug and Intervention Description H
 
Primary Objectives 
I. 
Secondary Objectives 
VI. 
BACKGROUND AND SIGNIFICANCE 
VII. 
PRIMARY OBJECTIVES 
VIII. 
SECONDARY OBJECTIVES 
IX. 
STUDY POPULATION 
X 
STUDY DRUGS 
XI 
STUDY SCHEDULE 
XII. STUDY DESIGN/METHODOLOGY Study 
Conduct 
1. 
Screening 
2. 
Quality of life assessment – Brief Pain Inventory 
3. 
Enrollment 
4. 
Randomization and Allocation Concealment 
5. 
Preoperative Assessment 
6. 
Follow-up 
7. 
Termination of enrollment 
8. 
Termination of Study 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
XIII. 
ADVERSE EVENT REPORTING 
XIV. 
STATISTICAL ANALYSIS PLAN 
A. 
Primary Outcomes 
B. 
Secondary Outcomes 
C. 
Sample Size Determination 
XV. 
ETHICS 
A. 
Informed Consent Process 
B. 
Data Handling and Record Keeping 
C. 
Risk/Benefits 
XVI. 
STUDY TIMELINE 
XVII. 
QUALITY CONTROL AND ASSURANCE 
XVIII. 
CONFLICT OF INTEREST 
XIX. 
FUTURE PUBLICATION AND PRESENTATION 
XX. 
REFERENCES 


I. 
PROTOCOL TITLE 
IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
Intercostal Nerve Cryoablation for Postoperative Pain Management 
 
 
II. 
PRINCIPAL INVESTIGATOR & RESEARCH TEAM 
Principal investigator: 
Anthony L. Estrera, MD (Cardiothoracic Surgeon) 
Co-Investigators: 
Akiko Tanaka, MD, PhD (Vascular Surgery Resident) 
Kenton Rommens, MD (Cardiovascular Surgery Fellow) 
Rana O. Afifi, MD (Vascular Surgeon) 
Harleen K. Sandhu, MD, MPH (Biostatistician) 
Charles C. Miller, PhD (Biostatistician) 
Study Coordinator: 
Samuel Leake, BS (Research Coordinator) 
Alexis Offner, MS (Research Coordinator) 
Cristina Sola, RN (Nurse) 
Selena Gonzales, RN (Nurse) 
 
 
III. 
STUDY SITE 
1. Department of Cardiothoracic and Vascular Surgery 
McGovern Medical School at UTHealth 
2. Memorial Hermann Hospital – Texas Medical Center, Houston, Texas 
IV 
CONTACT INFORMATION 
1. 
Anthony L. Estrera, MD 
Principal Investigator 
2. 
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6. 
Samuel Leake, BS (Research Coordinator) 
Research Coordinator 
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IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
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V. 
RESEARCH SYNOPSIS 
A. 
Clinical Phase 
Phase IV 
B. 
Study Population 
The study will include patients aged 18 and over, all gender and race, who 
require thoracoabdominal incisions undergoing the descending thoracic or 
thoracoabdominal aortic aneurysm repair. 
C. 
Study Design 
Prospective single-blinded, controlled randomized clinical trial with 2-armed 
parallel-group sequential design 
D. 
Sample Size 
20 
E. 
Study Duration 
13 months 
F. 
Study drug and Intervention Description 
We will use CryoICE® CRYO2 cryoablation probes (AtriCure, Inc), which is 
an FDA-approved device for the use of intercostal nerve cryoablation. 
Subjects will be randomized into two groups: 
Group A will receive the study procedure, intercostal nerve cryoablation using 
CryoICE® CRYO2 cryoablation probes (AtriCure, Inc) to intercostal spaces 
4th to 10th in thoracoabdominal aortic repairs and 4th to 8th in descending 
thoracic aortic repair cases. This procedure will be performed under 
electromyography to confirm the successful ablation of the nerve. 
Group B will not receive cryoablation but will obtain electromyography to 
evaluate as the control. 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
Both patient groups will receive intraoperative local analgesia infiltration with 
bupivacaine 
liposomal 
injectable 
suspension 
(Exparel®, 
Pacira 
Pharmacoceuticals) and patient-controlled analgesia (PCA) postoperatively. 
H Primary Objectives 
The primary objective of the study is to prove the feasibility of intercostal 
nerve cryoablation in postoperative pain control both in magnitude and 
duration in patients undergoing thoracoabdominal incisions for the 
descending or thoracoabdominal aortic aneurysm repair. 
I. 
Secondary Objectives 
• To compare opioid use between groups. 
• To evaluate and compare patient participation in physical therapy. 
• To evaluate and compare patient length of stay in hospital. 
• To evaluate cost-effectiveness of adding intercostal nerve cryoablation to 
a postoperative pain control regimen. 
 
VI. 
BACKGROUND AND SIGNIFICANCE 
General Information 
This is a pilot study to prove the efficacy of intercostal nerve cryoablation during the 
descending/thoracoabdominal aortic repair with thoracoabdominal incisions to have 
better control of postoperative pain management. 
 
Background Information 
In the United States, around 48 million inpatient surgical procedures were performed 
in 2009.1 Although pain is a predictable part of the postoperative experience 
(significant in up to 75% of patients),2,3 inadequate management is still common. 
Adequate postoperative pain management has shown to improve healing period, 
contribute to faster patient mobilization, and reduce the hospital length of stay and 
healthcare cost.4-6 Some studies show that the economic load of chronic pain that 
develops from an acute episode of pain in a 30 year-old patient may be as much as $1 
million over a lifetime.7 Lack of postoperative pain control may also result in deep vein 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
thrombosis, pulmonary embolism, coronary ischemia, myocardial infarction, 
pneumonia, poor wound healing, insomnia and demoralization.8,9 A number of drugs 
are available for postoperative pain control, such as opioids, nonsteroidal anti- 
inflammatory drugs (NSAIDS), local anesthetic agents infiltration, as well as combined 
regimens and protocols among them. Opioid use is the backbone of postoperative pain 
control but it does not come without risks. Severe opioid side-effects such as 
respiratory and central nervous system depression must be accounted for when 
overdose can cause renal impairment. Acetaminophen (Tylenol®) is generally safe but 
high doses can cause hepatic toxicity. One of the limitations of many pain control 
regimens, including most local anesthetic infiltrations, is that the effect usually lasts for 
less than 8 hours only.10,11 In our recent trial using liposomal formulation of bupivacaine 
for extended release, with a hope to have improved post-thoracotomy pain, which also 
failed to show adequate pain control. The liposomal formulation may have extend the 
effect of local anesthesia up to 48 hours, but was not sufficient to have satisfactory 
outcomes. The Patient Controlled Analgesia (PCA) method is one that is very 
commonly used in postoperative pain management protocols. This method was 
developed and introduced by Philip H. Sechzer in the late 1960s and described in 1971. 
It consists of allowing people to administer their own pain relief whenever they feel it 
is needed. On the surgical patient and while in hospital, the usual administration route 
is IV (intravenous), and the drugs usually used on a PCA system are from the opioid 
family. The infusion is programmed by the prescriber in terms of demand dose, lockout 
interval, maximum drug delivery per hour, and rescue dose. For example, a morphine 
PCA could be set to deliver 1 mg of morphine sulfate on demand after a lockout interval 
of 10 minutes, a maximum cumulative dose of 8 mg per hour, and a rescue dose of an 
extra 2 mg to be given if there is inadequate pain control. If it is set and functioning as 
intended, the machine is unlikely to deliver an overdose of medication. 
Cryoanalgesia  has  been  used  to  treat  pan  syndromes  including  facial 
neuralgias and peripheral neuropathies.12 In the 1980s, this technique was applied for 
postoperative pain control in patients with thoracotomy with satisfactory improved pain 
control without adverse events.13,14 The Food and Drug Administration (FDA) approved 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
the first commercially available cryoablation probe (CryoICE®, AtriCure, Mason, OH), 
which made the cryotherapy more applicable. Postoperative pain management of 
thoracoabdominal incisions is the most invasive incision and pose a difficult challenge 
to manage pain control. Thus, we propose a pilot study to investigate the effectiveness 
of intercostal nerve cryoablation for postoperative pain control. This pilot study will lead 
to an estimate on its efficacy and utilization as an option for the postoperative pain 
management using the cryoablation. We will perform a larger prospective randomized 
study if this pilot study demonstrates the efficacy of the procedure. 
 
VII. 
PRIMARY OBJECTIVES 
The primary objective of the study is to prove the feasibility of intercostal nerve 
cryoablation in postoperative pain control both in magnitude and duration in patients 
undergoing thoracoabdominal incisions for the descending or thoracoabdominal aortic 
aneurysm repair. 
Specific assessment tools that will be used in our study are: 
1. Numeric Pain Scale (NPS): The NPS measures the intensity of pain. It consists of 
an 11-point scale from 0-10, where 0 means no pain and 10 means the most intense 
pain imaginable. Patients verbally select a value that correlates to the pain experienced 
by them. A written form can also be used. The NPS has good sensitivity and has a 
good capacity of producing data that can be statistically analyzed.15,16,17,18 
2. Brief Pain Inventory (BPI): The Brief Pain Inventory is a medical questionnaire used 
to measure pain, developed by the Pain Research Group of the WHO Collaborating 
Centre for Symptom Evaluation in Cancer Care. Although the BPI is derived from the 
NPS it is more comprehensive and expanded. Besides assessing pain intensity, it 
assesses how much the pain is affecting their lives. The BPI is a powerful tool and, 
having demonstrated both reliability and validity across cultures and languages, is 
being adopted in many countries for clinical pain assessment, epidemiological studies, 
and in studies of the effectiveness of pain treatment.19,20 
3. Five-point satisfaction scale: This scale is used to assess the patient’s pain 
management experience during their postoperative care. It consists of patients rating 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
their overall postoperative pain management experience using a 5-point rating system. 
The scale is from 1 to 5 with 1 being “extremely dissatisfied”, 2 “somewhat dissatisfied”, 
3 “Neutral/Neither satisfied nor dissatisfied”, 4 “somewhat satisfied” and 5 “extremely 
satisfied” with their postoperative pain care. This rating has been used in other clinical 
trials of different analgesia to be a reproducible assessment tool.21 
Primary outcome measures 
• 
The area under the curve (AUC) of Numeric Pain Scale (NPS) scores through 
72 hours after intraoperative injection– Each subject, using the numeric scale 
from 0 to 10 (11 numbers, 0 being no pain, and 10 the highest pain) will self- 
assess pain level at (+/-2 hours) 7am and 7pm of the third to fifth post- 
operative days. The AUC on a graphical plotting will be used to analyze data. 
• 
Brief Pain Inventory (BPI) – Each subject will be asked to complete the BPI 
before the procedure, at 7am (+/-2 hours) of the third to fifth post-operative 
days as well as on their 30th and 180th post-operative days. 
• 5-point satisfaction scale – Each subject, using a 5 number (1 to 5) scale will 
be assessed on post-surgical analgesia satisfaction (from 1 being “very 
dissatisfied” to 5 being “very satisfied”). Patients will be assessed using this 
method around 7am of the third to fifth post-operative days and as well as on 
their 30th and 180th post-operative days. 
 
VIII. 
SECONDARY OBJECTIVES 
• To compare opioid use between groups. 
• To evaluate and compare patient participation in physical therapy. 
• To evaluate and compare patient length of stay in hospital. 
• To evaluate cost-effectiveness of adding intercostal nerve cryoablation to 
a postoperative pain control regimen. 
Secondary outcome measures 
• 
The total amount in mg of opioid medication consumed through third to 
fifth post-operative days after surgery. 
• 
Requirement of opioids at the time of discharge 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
• 
Requirement of PCA use and amount of PCA used 
• 
Patient participation during physical therapy rehabilitation duration to 
reach an optimal functional level 
• 
Length of hospital stay 
• 
Hospital cost for patient care during hospitalization will be estimated 
from hospital charges and financial records. 
 
IX. 
STUDY POPULATION 
The target population of our study will be comprised of patients that are 18 years-old 
and above that present to our group at the McGovern Medical School at UTHealth and 
will require thoracoabdominal incision for the descending/thoracoabdominal aortic 
aneurysm repair. Our plan is to enroll 20 patients over a period of 6 months. 
 
Inclusion/Exclusion Criteria 
Patients will be eligible for the study if: 
• 
18 years-old or older, and 
• 
Descending/thoracoabdominal incision is planned 
• 
There is reasonable expectation that the patient will be extubated within 
48 hours after surgery 
Patients will be excluded from the study if: 
• 
The patient has a known allergy to morphine or any opioid 
• 
The patient has a known chronic pain disorder or takes daily opioid 
medication > 1 month prior to surgery 
• 
The surgeon/anesthesiologist concludes that the period for intubation will 
be likely be for more than 48 hours after surgery There is anticipated 
difficulty communicating pain status due to language or other barriers at 
the investigator discretion. 
 
Protocol Deviation: 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
It will be considered a protocol deviation if patients receive, during the first three days 
after surgery, any type of analgesic other than opioids. 
Withdrawal criteria: 
• 
Voluntary: patients who had consented and enrolled in the trial will 
maintain their right to withdraw at any point during the study as explained 
in the informed consent. 
• 
In case of unexpected/unpredicted 
 
 
X. 
STUDY DRUGS 
CryoICE® CRYO2 cryoablation probe (AtriCure, Inc) is an FDA-approved device for 
the use of intercostal nerve cryoablation. Subjects will be randomized into two groups: 
Group A will receive the study procedure, intercostal nerve cryoablation using 
CryoICE® CRYO2 cryoablation probes (AtriCure, Inc) to intercostal spaces 4th to 10th 
in thoracoabdominal aortic repairs and 4th to 8th in descending thoracic aortic repair 
cases. This procedure will be performed under electromyography to confirm the 
successful ablation of the nerve.Group B will not receive cryoablation but will obtain 
electromyography to evaluate as the control. 
Both patient groups will receive intraoperative local analgesia infiltration with 
bupivacaine liposomal injectable suspension (Exparel®, Pacira Pharmacoceuticals) 
and patient-controlled analgesia (PCA) postoperatively. 
 
XI. 
STUDY SCHEDULE 
Expected start date: 
Jan 1st, 2019 
Expected end-date for enrollment: June 30th, 2019 
Length of enrollment for each patient: 6 months 
Length of follow-up for each patient: 6 months 
Expected end-date of study: 
January 31st, 2020 
 
XII. 
STUDY DESIGN/METHODOLOGY 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
This will be a single institution, prospective, single-blinded, randomized, controlled 
effectiveness study with 2-armed parallel-group sequential design to assess the 
efficacy of intraoperative intercostal nerve croyablation in postoperative pain control 
when compared to our current standard care, local anesthesia infiltration of 
Exparel®. 
Screened patients meeting the eligibility criteria will be randomized into one 
of the two study groups. Both patient groups will receive intraoperative local analgesia 
infiltration with Exparel® prior to wound closure and patient-controlled analgesia (PCA) 
postoperatively. Each patient will choose whether or not they will use PCA. The first 
group (A) of patients will receive intraoperative intercostal nerve cryoablation using 
CryoICE® CRYO2 cryoablation probes (AtriCure, Inc) to intercostal spaces 4th to 10th 
in thoracoabdominal aortic repairs and 4th to 8th in descending thoracic aortic repair 
cases prior to wound closure. This procedure will be performed under 
electromyography to confirm the successful ablation of the nerve. The second group 
(B) of patients will be injected with Exparel® in the surgical wound. We will obtain 
intraoperative electromyography to evaluate as the control. 
On the screening visit, patients should present prior to surgery to receive 
training on the NPS and BPI and to be assessed on their preoperative baseline pain 
level, using BPI. This may be performed prior to surgery in the preoperative holding 
area, on the inpatient ward, or in the outpatient settings of the McGovern Medical 
School at UTHealth. 
Patients from both groups will receive the same volume of diluted Exparel®, 
which will be given in four 20ml syringes using 22-gauge needles (266mg of 
liposomal bupivacaine, equivalent of one 1.3% 20ml vial of EXPAREL, diluted in 
50ml of preservative-free normal (0.9%) sterile saline for a total volume of 70ml). 
Intercostal muscle electromyogram will be performed in both groups. Group A will 
have it done before and after the cryoablation. This assessment is to confirm the 
completeness of the intercostal nerve cryoablation, as the waveform of the 
electromyogram is expected to disappear after an adequate cryoablation. Group B 
will have the electromyogram prior to wound closure. The surgical wound length will 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
be measured. Patients will be injected according to the surgical incision required. 
Patients that require thoracotomies or thoracoabdominal incisions will undergo serial 
intercostal nerve blocks. Intercostal nerve block will be done injecting 10 cc (of the 
total 70cc) on each side of the incision, from two above to two below the incision 
(total 50 cc for intercostal nerve block). In addition, all patients (including all surgical 
incisions) will be injected in the fascia, subcutaneous tissues, periosteum (if 
applicable) and parietal pleura (if applicable). The total volume injected will be 70cc 
regardless of incision type. 
All patients will be blinded to having the cryoablation or not. The surgical 
team will be blinded up only until the time of wound closure as the knowledge of 
cryoablation is inevitable. 
Patients will have access to the standard PCA (Patient-Controlled 
Analgesia) offered at the Memorial Hermann Hospital – Texas Medical Center. The 
PCA drug will be Dilaudid (hydromorphone). Initial dosing will be per the standard 
hospital protocol of 0.2 mg demand dose, 10-minute lockout, 2 mg per hour max, 0.4 
mg rescue dose. Adjustments to the PCA dosing will be made based on clinical 
needs. Patients will receive PCA until the third postoperative day, and at that point, 
PCA will be switched to an oral analgesic, at the health-care team discretion. 
Modifications to the PCA regimen can be made by the health care team based on 
clinical need and will not be deemed a protocol deviation. 
Pain assessment should start just after the patient is extubated and can 
adequately evaluate his/her own pain through the Numeric Pain Scale. NPS will be 
repeated and recorded at: twice daily (AM and PM) during the third and fifth post- 
operative day. NPS will also be done right before the first opioid rescue medication 
postoperatively (if applicable and if NPS had not been assessed within the last hour). 
Patients in the study should also complete the Brief Pain Inventory (BPI) 
before the procedure, at (+/- 2 hours) of the during the third and fifth post-operative 
day, as well as on their 30th and 180th post-operative days. Patients will be assessed 
on their satisfaction with the postsurgical analgesia. This will be done using the 5- 
point satisfaction scale with 1 being “very dissatisfied” to 5 being “very satisfied” at 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
7am (+/- 2 hours) of the third to fifth post-op day and as well as on their 30th and 
180th post-operative days. After the 180-day follow-up and BPI reporting, the patient 
terminates his/her enrollment. This enrollment termination does not mean 
severance of the physician-patient relationship. Patients will be consented and their 
medical records pertinent to the study will be collected on a case report form and this 
information will be kept on a secured HIPAA-compliant web-accessed database. No 
protected health information (PHI) will be maintained on the web-accessible 
database. 
 
Study Conduct 
1. Screening 
The research group will assess patients as possible candidates for enrollment based 
on the inclusion criteria and the planned surgical exposure: median sternotomy, 
thoracotomy, midline laparotomy, and/or thoracoabdominal incision. Once the 
eligibility is met, an informed written consent will be collected. A member of the 
research team - the PI, Co-PI, research coordinator, or nurse will obtain the consent 
from the surgical candidates who met the preliminary inclusion criteria. The consent 
process will take place either during the preoperative clinic visit, upon inpatient 
admission, or in the preoperative holding area. Patients will be consented before their 
surgical procedures and will be given the appropriate time to think and discuss with 
family about being part of the study. There will also be given enough time for the 
patients to ask questions about the protocol and research study. A copy of the signed 
informed consent shall be provided to the patient, a copy will be placed in the patient’s 
hospital chart, and a copy will be kept by the research team. Medical/surgical history, 
vital signs measurements, drug/alcohol screening, and standard preoperative testing 
will also be performed as per the usual surgical practice. 
2. Quality of life assessment - Brief Pain Inventory 
The impact of pain on patient’s quality of life will be assessed through a brief pain 
inventory (BPI) that should be done before surgery, at 7am (+- 2 hours) of the third to 
fifth post-operative day as well as on their 30th and 180th post-operative days. The BPI 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
will be presented in an easy to comprehend questionnaire for the patients to quantify 
and communicate their pain experience and how it is affecting their life. It is designed 
such that patients with 6th-grade education should be able to complete the 
questionnaire on their own. Question and answers will be provided in a check-box 
format. The BPI that will be used on this study will be the short version. Patients with 
difficulty reading or who are physically unable to complete the questionnaire will be 
assisted by the research team based on their verbal responses to the BPI questions. 
4. Enrollment 
After the screening is done, the eligibility criteria are met, and the patient is consented; 
the patient will be enrolled in the trial. At this point, the study coordinator/research office 
will be notified so that the patient can be randomly allocated to one of the study groups. 
5. Randomization and Allocation Concealment 
Randomization and allocation concealment will be performed via a web- 
based/computer generated block randomization sequence/list secured in a password- 
protected secure computer in the trial office accessible only to the research staff 
independent of the trial administration process, who are not involved in the recruitment, 
data collection, analysis, assessment and/or follow-up. This office/research staff will 
be contacted by the blinded research assistant/investigator to provide certain specific 
6. Preoperative assessment 
Pain assessment will be also done using the BPI form. 
7. Follow-up 
After the surgical procedure is done, the follow-up will be: 
i. 7am (+ or - 2 hours) of the third post-op day: the NPS and the the BPI and 5 
-point scale analgesia satisfaction survey will be assessed 
ii. 7pm (+ or - 2 hours) of the third post-op day: the NPS will be assessed 
iii. 7am (+ or - 2 hours) of the fourth post-op day: the NPS and the the BPI and 5 
-point scale analgesia satisfaction survey will be assessed 
iv. 7pm (+ or - 2 hours) of the third post-op day: the NPS will be assessed 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
v. 7am (+ or - 2 hours) of the fifth post-op day: the NPS and the the BPI and 5 
-point scale analgesia satisfaction survey will be assessed 
vi. 7pm (+ or - 2 hours) of the fifth post-op day: the NPS will be assessed 
vii. 30 days after the procedure, the BPI and 5-point scale analgesia satisfaction 
survey will be assessed. 
xiii. Final visit, 180 days after procedure, the BPI and 5-point scale analgesia 
satisfaction survey will be performed. 
8. Termination of enrollment 
Patient will be considered to have his/her enrollment terminated: 
i. After the 180-day follow-up visit, or 
ii. If follow-up is lost after several attempts to contact patient, or 
iii. If any medical/surgical/environmental condition develops that would affect or 
impair primary or secondary outcomes measurements results, or 
iv. If the study is terminated, or 
v. If the patient dies. 
9. Termination of Study 
i. End of study period 
ii. If a clinically/statistically significant difference is achieved early during an interim 
analysis. 
 
XIII. 
ADVERSE EVENT REPORTING 
Patients enrolled in the trial will be informed to report any unwanted effect at any time 
during the study. Adverse effects of intercostal nerve cryoablation will be made plain 
to the patients during the screening/enrollment as well as in the informed consent 
process. Most adverse side effects are injury of the lung or other surrounding 
organs/tissues, which may happen if cryoablation probe is misplaced to the 
organ/tissue. This is extremely rare amongst trained and board-certified vascular 
surgeons. All the surgeons involved in our study have been extensively trained on the 
cryoablation technique required for appropriate use. Other adverse effects include 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
allodynia like-pain after the degeneration of the affected nerve is reported after 
cryoablation of the nerve, but this is often associated with thoracotomy procedure and 
not specific to the cryoablation. Safety monitoring will include assessment of: 
i. Adverse Effects (AE) 
ii. Vital Signs 
iii. Wound healing status 
iv. Scarring 
v. Cardiac monitoring 
All items above will be closely monitored in a continuous manner, as part of our 
standard postoperative care. Any abnormalities found will be promptly assessed and 
described in the patient’s medical records. Once the patient is discharged it is very 
unlikely that any of the study drugs or procedure will cause any abnormalities. Despite 
this fact, patients will be asked to contact the hospital in case they feel anything 
unusual. Definitions and examples of the standard or known adverse events 
associated with cryoablation is tingling, burning sensation, etc., will be presented to 
the patient for reference. Patients will be also assessed on the above items on their 
postoperative clinic visits. In addition, emergency contact information of the office in 
order to speak to someone regarding documentation of these adverse events will be 
provided. If need be, an immediate unscheduled visit shall be arranged if the patient 
so desires. The PI will review AE as they occur, changes to the study design or drug 
use will be determined on an ongoing basis. 
 
XIV. 
STATISTICAL ANALYSIS PLAN 
A. Primary Outcomes 
NPS measures will be plotted for each subject over the initial third to fifth 
postoperatively and the area under the curve (AUC) integrated to produce a cumulative 
numeric pain score. The primary endpoint will be measured by a statistical comparison 
of AUC between the groups, using a Wilcoxon rank-sum test. Randomization is 
expected to balance the groups with respect to preoperative risk factors. 
B. Secondary Outcomes 


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Cumulative dose of opioid medication will be assessed as the sum of morphine doses 
dispensed by PCA pump during the admission. In addition, we will evaluate the amount 
of opioid usage using morphine milligram equivalences.22 This will be compared by 
unpaired t test. We will also evaluate for the opioid prescription need at the time of 
discharge, and will be compared by chi-square test. Length of hospital stay will be 
transformed to log scale to normalize the distribution if necessary and will be compared 
between groups by an appropriate unpaired statistic. Attainment of physical therapy 
goal that justifies discharge from inpatient physical therapy within 72 hours will be 
assessed by an appropriate contingency table test. 
 
C. Sample Size Determination 
This is a pilot study to prove the feasibility of intercostal nerve cryoablation in patients 
undergoing 
the 
descending/thoracoabdominal 
aortic 
aneurysm 
repair 
with 
thoracoabdominal incision. 
Although the study is designed as a pilot trial to collect preliminary data for assessment 
of feasibility, the proposed sample size of 20 subjects would be large enough to detect 
a seven point decrease (from 21 to 14) in the cumulative three-day postoperative BPI, 
with 80% power at alpha <0.05. This would equate to an average reduction of roughly 
two points per day in the 10-point pain scale over three postoperative days, or about a 
1/3 reduction in total pain during that period with cryoablation compared to the control 
treatment. These estimates are based on prior work by our group with a randomized 
trial of injectable liposomal bupivacaine (the control treatment in this trial). This would 
be a large effect, but certainly within the realm of feasibility. 
 
 
 
XV. 
ETHICS 
A. Informed Consent Process 
All eligible patients who meet the inclusion criteria will be consented, if willing, after an 
in-depth description of the study, the study drug and its adverse effects, the risks and 
benefits, follow-up routine, enrollment and termination terms. The importance of follow- 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
up will be emphasized; however, the patient will retain the right to voluntarily withdraw 
from the study at any point. It will also be stressed that patient confidentiality will be 
kept at all times during study through de-identification of data. Information will be stated 
clearly in a written consent form that will be designed at a 6th grade level of 
understanding. Information will also be presented verbally. A member of the research 
team, either the principal investigator, or co-investigators will obtain the consent of the 
patient or other the legally authorized representative of the patient. The consent 
process will take place either during the preoperative clinic visit, upon inpatient 
admission, or in the preoperative holding area. The member of the team who is 
obtaining the written consent will describe the research project in its entirety and 
answer the questions of the patient and/or family members should they ask any. 
Sufficient time will be provided to the patient party to review the study before making 
an informed decision to participate or decline. We will make sure the patient have time 
to deliberate on the risk/benefits of joining the study. If they require, patients will be 
given at least one hour for deliberation and discussion with the research staff, friends 
and/or family members about enrolling or not the study Should they decide to 
participate, three copies of the consent form would be attested by the patient or legally 
authorized individual for the patient’s medical record, the study record, and one copy 
will be provided to the patient. 
 
B. Data Handling and Keeping 
The study will be conducted in compliance with all HIPAA guidelines to protect patient 
confidentiality. All sensitive information or patient identifiers will be stored in form of a 
patient linkage file that will link the patient study/trial number to their clinical records 
and secured on the Zone 100 drive on specific networked computers of our department. 
We have a password protected electronic database that, along with the case report 
forms, will be de-identified and contain only study relevant data points and the patient’s 
trial number. Access to any data pertaining to the study will be restricted to approved 
research team members, the FDA, institutional review boards of the McGovern Medical 
School at UTHealth and Memorial Hermann Hospital. 


IRB NUMBER: HSC-MS-19-0283 
IRB APPROVAL DATE: 06/05/2019 
 
 
 
C. Risk/Benefits 
Risks to participants 
There is a small increased risk to the patients by participating in the study in addition 
to a possible chance of breach in patient confidentiality as the study involves evaluation 
of an FDA-approved device. As detailed in the informed consent, the subjects are at 
risk of developing adverse effects from cryoablation, abdominal muscle bulging or 
sympathetic nerve pararesis. Patients will be offered standard optimal medical therapy 
options, even if that will culminate in withdrawal from the study. In addition, there is 
risk of an unintentional disclosure of personal health information. 
Benefits to participants 
The patients stand to receive no direct benefit from the study. However, in the event 
our results endorse the published reports of reduction in postoperative pain by 
cryoablation, the group of patients receiving it might be indirectly benefitted through 
participation. 
 
 
 
XVI. 
STUDY TIMELINE 
Considering our group’s monthly average for the given procedures and the enrollment 
rates, drop-outs and withdrawal, and interim analyses we estimate recruitment of our 
sample size will take 6 months. Once the follow-up of all enrolled participants is 
finished, data will be analyzed and published. The following is a chronological estimate 
of the stages: 
Stage 1: Patient screening and enrollment 0 - 6 months 
Stage 2: Follow-up up to 180 days from the last patient enrolled (0 – 12 months) 
Stage 3: Data collection and analysis 1 month 
Stage 4: Presentation and publication period (at the end of data analysis) 
 
 
XVII. 
QUALITY CONTROL AND ASSURANCE 


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The PI will be responsible for monitoring the progress and safety of this pilot trial. Any 
serious or unanticipated events will be reported in a timely manner to the CPHS. 
 
 
 
XVIII. 
CONFLICT OF INTEREST 
There is no relationship between the principal investigator or any other research staff 
member and AtriCure Inc. The 10 probes are provided from the AtriCure Inc. for the 
current study. 
 
XIX. 
FUTURE PUBLICATION AND PRESENTATION 
The results of this study will be analyzed and published after the approval of the 
principal investigator and biostatistician in a peer-reviewed scientific journal and/or 
presented at an international/national scientific conference or meeting regardless of 
outcome. The publication will acknowledge members of the study research group for 
their contributions and will maintain patient data protection. 
 
XX. 
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