Cryoablation of Intercostal Nerves for Pain Management in Early Postoperative Period in Patients With Minimally Invasive Mitral Valve Surgery: a Pilot Prospective Randomized Study
Phase: NA
Conditions: Mitral Regurgitation, Pain, Postoperative
Sponsor: Meshalkin Research Institute of Pathology of Circulation

 
 
 
 
Protocol Clinical Trial 
 
 
Effect of cryoablation of intercostal nerves on 
pain in the early postoperative period in 
patients with minimally invasive mitral valve 
surgery: a pilot prospective randomized 
study (BLOCK trial). 
 
 
 
 
NCT number: NCT06443931 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 05.04.2024 

Background 
Cardiovascular diseases are one of the main causes of death worldwide. According 
to pathological studies, heart defects occur in 4-7% of cases, and the most common 
defect among the defects is damage to the mitral valve [1]. Significant advances in 
surgical practice, instrumentation, tissue manipulation, and perfusion technology 
have made it possible to perform mitral valve surgery using mini-approaches. 
Minimally invasive mitral valve surgery has become the standard of care in some 
specialized cardiac centers around the world due to its excellent results, even 
despite longer cardiopulmonary bypass times and aortic occlusion. In 2008, P. 
Modi and co-authors, a meta-analysis has been published in which the authors 
come to the conclusion that a minimally invasive approach for correcting mitral 
valve pathology actually has significant advantages: early activation of patients, 
shorter duration of stay in the recovery room, shorter wound healing times, 
advantages in case of repeated interventions, less the number of bleedings and 
purulent-septic complications compared to classical sternotomy [2]. But despite all 
the advantages of this approach, severe pain after minimally invasive cardiac 
surgery continues to remain a serious problem [3]. Acute pain occurs after 
dissection of the chest, pleura and pericardium, compression of the intercostal 
nerve with a retractor, as well as dissection of the intercostal and pectoral muscles 
during surgical access. It limits breathing and cough in the postoperative period, 
which can subsequently lead to hypoxemia, sputum stagnation, atelectasis, 
pneumonia, myocardial ischemia, slow recovery, and also an increase in the length 
of hospitalization [4]. Therefore, additional emphasis and attention is paid to 
protocols for early functional restoration and pain reduction for this group of 
patients. There are protocols for “enhanced recovery after surgery” (ERAS - 
Enhanced Recovery After Surgery), their use makes it possible to achieve shorter 
stays in the intensive care unit, reduce hospitalization, improve treatment outcomes 
and reduce financial costs. One of the components of ERAS is the use of additional 
pain management modalities [5]. However, in cardiac surgery, traditional methods 
of regional anesthesia, such as thoracic epidural anesthesia or paravertebral block, 
are not usually used due to intraoperative heparinization and the associated higher 
risk of spinal or epidural hematoma. Finding an optimal and effective pain 
management strategy for this category of patients remains an unsolved problem 
today. 
Intercostal nerve cryoablation is considered a relatively new treatment for 
postoperative pain in patients undergoing minimally invasive mitral valve surgery. 
One of the first studies of cryoneurolysis was conducted back in 1974 in thoracic 
surgery [9]. In 76 patients, the use of intercostal cryoablation resulted in a 
significant reduction in postoperative opioid analgesic consumption. These results 
were subsequently confirmed in several other studies and the data were 
retrospective. In 2000, a prospective randomized controlled trial was published 
involving 30 patients who underwent minimally invasive mitral valve surgery or 
minimally invasive coronary artery bypass grafting and underwent intercostal 

cryoablation. According to the results, a decrease in postoperative pain syndrome 
was observed, and less painkillers were required [10]. 
In the study O'Connor LA et al. in patients undergoing surgical stabilization of the 
ribs, cryoablation of the intercostal nerves resulted in a 25% reduction in opioid 
analgesics consumption compared with patients who received an extrapleural 
catheter, and pain scores were reduced by 22% in the cryoablation group [7]. 
Similar results (cryoablation made it possible to significantly reduce morphine 
consumption compared to the control group and reduce pain ) were also described 
inrecent retrospective studies through 2023 in other patient groups: patients who 
have undergone pulmonary resectionusing single-port thoracic video-assisted 
access, where cryoablation was used as a method of postoperative pain relief [8] 
and patients undergoing lung transplantation [12].   
In the FROST study for 2021 the use of this method in patients with lateral 
thoracotomy showed significant improvement in spirography parameters (FEV1, 
FVC) after 48 hours, as well as 30 and 60 days after surgery [6]. Studying the 
influence of pain was not the main objective of this work; pain was assessed using 
VAS and did not show a difference. However, improvement in breathing 
parameters in the early postoperative period may indirectly be associated with a 
lower level of pain and a more comfortable state of the patient; the consumption of 
opioid analgesics was not properly assessed in this study. 
In 2021 Peter I Cha and others published a systematic review of 23 studies on the 
effectiveness of intercostal cryoneurolysis in patients with pectus excavatum, 
lateral thoracotomy, post-thoracotomy pain syndrome, traumatic rib fracture and 
chest wall malignancy. Most studies have demonstrated a reduction in opioid 
analgesic use with intercostal nerve cryoablation compared with traditional pain 
management techniques. In patients requiring lateral thoracotomy, intercostal 
cryoablation results in decreased opioid analgesic dosage (grade 2A) and improved 
pain scores (grade 2C) postoperatively (PICO guidelines) [11]. 
Finding an effective and at the same time simple strategy for pain relief in the early 
postoperative period in patients undergoing minimally invasive mitral valve 
surgery is an urgent task; it is advisable to conduct a prospective clinical study 
with a well-thought-out design in this direction. 
 
Study design 
 
A single-center pilot prospective randomized clinical trial is planned, with a 1:1 
allocation ratio. 
 
Objectives 

To determine whether cryoablation of intercostal nerves provides a clinically 
significant analgesic effect, which is reflected in a decrease in opioid analgesics 
consumption and in a decrease in pain according to VAS in patients undergoing 
minimally invasive mitral valve surgery. To obtain preliminary data for planning a 
subsequent larger prospective randomized trial. 
 
Research aims: 
 
1. Conduct a comparative analysis of the data on the opioid analgesic consumption 
necessary for pain relief when using cryoablation of intercostal nerves and the 
standard treatment protocol in patients with minimally invasive mitral valve 
surgery. 
2. To conduct a comparative assessment of pain syndrome according to VAS in 
patients in the intercostal nerve cryoablation groups and the standard treatment 
protocol in patients with minimally invasive mitral valve surgery. 
3. Assess spirography parameters (FEV1, FVC) before surgery, 48 hours after 
surgery and before discharge when using cryoablation of intercostal nerves and the 
standard treatment protocol in patients with minimally invasive mitral valve 
surgery.4. To evaluate the incidence of side effects and the need for inotropic and 
vasopressor support in the early postoperative period in the intercostal nerve 
cryoablation and standard treatment protocol groups in patients undergoing 
minimally invasive mitral valve surgery. 
5. To evaluate the duration of mechanical ventilation in the postoperative period 
when using cryoablation of intercostal nerves and the standard treatment protocol 
in patients with minimally invasive mitral valve surgery. 
6. Assess the length of stay in the ICU and the duration of hospitalization when 
using cryoablation of intercostal nerves and the standard treatment protocol. 
7. Assess the presence of chronic post-thoracotomy pain syndrome in the 
postoperative period after 2 and 6 months and the presence of side effects after 
cryoablation of intercostal nerves (paresthesia in the area of surgical access and in 
the right arm). 
 
Research participants 
 
30 patients (15 patients in each group) who are scheduled to undergo minimally 
invasive mitral valve surgery under cardiopulmonary bypass. 
 
Inclusion criteria 
 
- Written informed consent; 

- Minimally invasive mitral valve surgery. 
Non-inclusion criteria: 
-patient refusal; 
- pregnancy; 
- treatment with antidepressants or epileptic drugs; 
- depression, which can significantly affect the perception of pain; 
- chronic use of analgesics; 
- participation in competing randomized clinical trials. 
Exclusion criteria: 
- Extended mechanical ventilation, more than 12 hours. 
Randomization, allocation, blinding 
A block will be used to distribute participants into groups randomization with 
block lengths of 2 and 4. Masking will be performed for the statistician. Sample 
size calculation was not performed because no data were available to estimate 
sample size. 
Description and rationale for the route of administration, dosage, dosage 
regimen and course of treatment 
Patients undergoing minimally invasive mitral valve surgery while on 
cardiopulmonary bypass will be randomized into two groups: 
1. Patients receiving cryoablation of intercostal nerves (CryoINB) as a method 
of pain relief. 
2. Patients who will undergo a standard pain management protocol. 
 
Patients in the CryoINB group will undergo cryoablation of the intercostal nerves,  
at the end of surgery before weaning from CPB, using the «ArtiCue» device for 
120 seconds at a temperature of -50°C to -70°C, in the intercostal spaces where the 
surgical approach is located, one intercostal space above and one below it. Cold 
leads to axonotmesis, in which the axon and myelin sheath are damaged, 
preventing the pain signal from traveling along the sensory nerve. However, the 
structural elements of the nerve are preserved, which promotes complete 
regeneration at a rate of 1–2 mm per day, thereby restoring normal function within 
several months. 

Patients in the group with the standard anesthesia protocol will  receive an 
intercostal block in the area of surgical access - a single injection of 0.75% 
ropivacaine solution 20 ml. A local anesthetic will be injected into the area of the 
posterior wall of the chest 2 cm lateral to the sympathetic trunk under the parietal 
pleura in the intercostal space along the intercostal nerve, where the surgical 
approach is located [14]. 
All study participants will receive postoperative pain management according to the 
protocol described below: 
If VAS >4 points on the scale, patients will receive NSAIDs (paracetamol 1 g IV) 
[15, 16]. The maximum daily dose will be 4 g/day. 
If there is no effect after 30 minutes, opioid analgesics will be administered 
(MORPHINE 10 mg). The maximum daily dose of opioids for adults will be 50 
mg. 
If other opioid analgesics are administered, they will be converted to morphine 
equivalent (MME) [13]. 
 
 
(Dott D., Sobey CM Common Opioids //Hospitalized Chronic Pain Patient: A 
Multidisciplinary Treatment Guide. – 2022. – P. 151.) 
 
Primary outcome: 
The opioid analgesic consumption within 48 hours after surgery, calculated in 
milligram morphine equivalent (MME). 
 
Secondary endpoints: 
• The intensity of pain, assessed using a visual analogue scale (VAS) after 
extubation, 
6, 12, 24, 36, 48 hours after surgery 
• Dynamics of spirography (FEV1, FVC) before surgery, 48 hours after 
surgery, before the patient’s discharge 
• Frequency of side effects (nausea, vomiting, etc.) 
• Need for inotropic/vasopressor support 
• Duration of mechanical ventilation 
• Duration of ICU stay 
• Duration of hospital stay 
• Follow-up after 2 and 6 months (CPPS, numbness in the right arm and in the 
area of surgical access) 

Statistical analysis 
Comparisons of continuous outcomes will be made using the Mann-Whitney test 
for non-normal variables and the Welsh t test for normal variables. Comparisons of 
binary outcomes will be made by the chi-square test or Fisher's exact test. 
Data processing 
All information will be collected by staff using paper documentation, the data of 
which will then be entered into an electronic database. 
Initial data 
 
1. Demographic indicators: age, gender, height, weight, body mass index. 
2. Disease severity: left ventricular ejection fraction, left ventricular EDV, 
presence of mitral regurgitation, degree of mitral regurgitation, peak mitral 
valve gradient, pulmonary artery pressure, FAC (Fractional Area Change), 
history of cardiac surgery, NYHA class, EuroSCORE II risk. 
3. Concomitant diseases: myocardial infarction, arterial hypertension, diabetes 
mellitus, atrial fibrillation, ventricular extrasystole, COPD, chronic kidney 
disease, stroke, epilepsy. 
4. Taking the following medications: antidepressants, antiepileptic drugs, long-
term use of NSAIDs (more than 14 days), opioid analgesics. 
 
During the operation: 
1. Type of surgery (mitral valve repair or replacement). 
2. Time of heart-lung bypass (minutes). 
3. Aortic occlusion time (minutes). 
4. Minimum temperature during surgery. 
5. Dose of fentanyl per operation (mg/kg). 
6. Inotropic index. 
 
Period of hospitalization and stay in the ICU: 
1. Dose of opioid analgesics 48 hours after surgery (morphine in MME). 
2. Assessment of pain intensity using a visual analogue scale (VAS) after 
extubation, 6, 12, 24, 36, 48 hours after surgery. 
3. Duration of mechanical ventilation (in days).4. The presence of side effects 
(nausea, vomiting). 
5. Need for inotropic and vasopressor support, VIS. 
6. Surgery complications (pulmonary edema, bleeding, febrile seizures, heart 
failure, respiratory failure, myocardial infarction). 
7. Duration of stay in the ICU (in days). 
8. Duration of hospitalization (in days). 
9. The result of spirography before surgery, 48 hours after surgery and before 

discharge. 
 
Ethical issues 
The study will not be launched until approved by the Ethics Committee. Eligible 
patients will be included in the study after signing informed consent. 
Funding and support 
The research will be supported by the “E.Meshalkin National Medical Research 
Center” of the Ministry of Health of the Russian Federation. 
 
Registration 
After Ethics Committee approval, the study will be registered on 
ClinicalTrials.gov. 
 
References: 
 
1. Bogachev-Prokofiev A. V. et al. Pathology of the mitral valve in connective 
tissue dysplasia // Russian Journal of Cardiology. – 2016. – No. 11 (139). – pp. 81-
86. 
2. Navia JL, Cosgrove DM Minimally invasive mitral valve operations. Ann. 
Thorac. Surg. 1996; 62 (5): 1542–1544. PMID: 8893611 
3. Sherazee EA et al. Pain management strategies for minimally invasive 
cardiothoracic surgery //Innovations. – 2022. – T. 17. – No. 3. – pp. 167-176. 
4. Hoan DT et al. Continuous Unilateral Erector Spinae Plane Block versus 
Intravenous Analgesia in Minimally Invasive Cardiac Surgery: A Randomized 
Controlled Trial //Open Access Macedonian Journal of Medical Sciences. – 2022. 
– T. 10. – No. B. – pp. 1340-1346. 
5. Borys M. et al. Erector spinae-plane block as an analgesic alternative in patients 
undergoing mitral and/or tricuspid valve repair through a right mini-thoracotomy–
an observational cohort study //Videosurgery and Other Miniinvasive Techniques. 
– 2020. – T. 15. – No. 1. – pp. 208-214. 
6. Lau WC et al. Intercostal cryo nerve block in minimally invasive cardiac 
surgery: the prospective randomized FROST trial //Pain and Therapy. – 2021. – T. 
10. – P. 1579-1592. 
7. O'Connor LA et al. Intercostal cryonerve block versus elastomeric infusion 
pump for postoperative analgesia following surgical stabilization of traumatic rib 
fractures //Injury. – 2023. – T. 54. – No. 11. – P. 111053. 

8. Maxwell CM et al. Intercostal cryoablation during video-assisted lung resection 
can decrease postoperative opioid use //Innovations. – 2023. – T. 18. – No. 4. – pp. 
352-356. 
9.Nelson KM, Vincent RG, Bourke RS, et al. Intraoperative intercostal nerve 
freezing to prevent postthoracotomy pain. Ann Thorac Surg 1974; 18: 280–285.10. 
Bucerius J, Metz S, Walther T, et al. Pain is significantly reduced by cryoablation 
therapy in patients with lateral minithoracotomy. Ann Thorac Surg 2000; 70: 
1100–1104.  
11. Cha PI et al. Efficacy of intercostal cryoneurolysis as an analgesic adjunct for 
chest wall pain after surgery or trauma: systematic review //Trauma Surgery & 
Acute Care Open. – 2021. – T. 6. – No. 1. – P. e000690. 
12. Koons B. et al. Cryoablation in lung transplantation: Its impact on pain, opioid 
use, and outcomes //JTCVS open. – 2023. – T. 13. – P. 444-456. 
13.Dott D., Sobey CM Common Opioids //Hospitalized Chronic Pain Patient: A 
Multidisciplinary Treatment Guide. – 2022. – P. 151.) 
14.Bolotin G. et al. The efficacy of intraoperative internal intercostal nerve block 
during video-assisted thoracic surgery on postoperative pain //The Annals of 
thoracic surgery. – 2000. – T. 70. – No. 6. – S. 1872-1875. 
15.Ovechkin A. M. et al. Postoperative pain relief. Clinical recommendations // 
Bulletin of intensive care named after AI Saltanov. – 2019. – No. 4. – P. 9-33. 
16. Mamoun NF, Lin P, Zimmerman NM, et al. Intravenous acetaminophen 
analgesia after cardiac surgery: a randomized, blinded, controlled superiority trial. 
J Thorac Cardiovasc Surg. 2016; 152: 881– 889.e1. DOI: 
10.1016/j.jtcvs.2016.04.078