Comparative Study of the Efficacy of Intraoperative Intercostal Cryoanalgesia and Thoracic Epidural Block in the Postoperative Period of Minimally Invasive Pectus Excavatum Repair (MIRPE): a Prospective, Randomized Clinical Trial
Phase: NA
Conditions: Funnel Chest, Pectus Excavatum, Postoperative Pain After Video Assisted Thoracic Surgery, Postoperative Pain
Sponsor: University of Sao Paulo

                                                                                                                       
 
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Comparative Study of the Efficacy of Intraoperative Intercostal Cryoanalgesia and 
Thoracic Epidural Block in the Postoperative Period of Minimally Invasive Pectus 
Excavatum Repair (MIRPE): a Prospective, Randomized Clinical Trial 
 
 
 
 
 
 
 
 
Miguel Lia Tedde 
Diego Arley Gomes da Silva 
Paulo Manuel Pego Fernandes 
 
 
 

                                                                                                                       
 
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SUMMARY 
ABSTRACT .................................................................................................................. 3 
INTRODUCTION .......................................................................................................... 4 
OBJECTIVES ............................................................................................................... 7 
Primary objective ....................................................................................................... 7 
Secondary objectives ................................................................................................ 7 
HYPOTHESIS............................................................................................................... 7 
METHODOLOGY ......................................................................................................... 7 
Study Design ............................................................................................................. 7 
Participant Selection .................................................................................................. 8 
Inclusion Criteria ....................................................................................................... 8 
Exclusion Criteria ...................................................................................................... 8 
Randomization .......................................................................................................... 8 
MIRPE procedure and analgesia ............................................................................... 8 
Participants Randomized to Epidural Analgesia ........................................................ 9 
Participants Randomized to Intercostal Nerve Cryoablation (IC) ............................. 10 
Postoperative care .................................................................................................. 10 
Pain Scores ............................................................................................................. 11 
Pain Biomarkers ...................................................................................................... 12 
Patient-Reported Outcome Measures (PROMs) and Patient-Reported Experience 
Measures (PREMs) ............................................................................................. 13 
Hospitalization Costs ............................................................................................... 14 
Follow-up ................................................................................................................ 14 
Endpoints, Power Calculation, and Data Analysis ................................................... 15 
Examinations and Description of Their Analysis ...................................................... 16 
Risks ....................................................................................................................... 18 
Benefits ................................................................................................................... 18 
STUDY TIMELINE ...................................................................................................... 18 
BUDGET ..................................................................................................................... 18 
REFERENCES ........................................................................................................... 19 
 
 
 
 
 

                                                                                                                       
 
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ABSTRACT 
Objective: Minimally invasive repair of pectus excavatum (MIRPE) is associated with 
significant postoperative pain, prolonged hospitalization, and high opioid requirements. 
The objective of this study is to compare the analgesic efficacy of intraoperative 
intercostal nerve cryoablation with epidural analgesia by measuring hospital length of 
stay. 
Design: Randomized clinical trial evaluating 40 consecutive participants undergoing 
MIRPE using two metallic bars placed in parallel or crossed configuration. Participants 
will be randomized in a 1:1 ratio to receive intraoperative intercostal cryoanalgesia or 
thoracic epidural block. 
Setting: Single institution, Heart Institute (InCor), University of São Paulo (USP). 
Participants: Forty consecutive participants scheduled for the Nuss procedure will be 
recruited. Exclusion criteria include age under 13 years, chest wall deformities other than 
pectus excavatum, previous repair or other thoracic surgery, and chronic use of pain 
medications. 
Primary outcomes and measures: The primary outcome was postoperative length of stay 
(LOS). Secondary outcomes include total operative time, total/daily opioid requirements, 
pain scores in hospitalized and outpatient participants, postoperative satisfaction at 6 
months, total hospitalization cost, and postoperative complications within 30 days. 
Primary outcome data will be analyzed using the Mann–Whitney U test for nonparametric 
continuous variables. Other continuous variables will be analyzed using a two-tailed t-
test, while categorical data will be compared using the chi-square test, with alpha = 0.05 
for statistical significance. 
 
 

                                                                                                                       
 
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INTRODUCTION 
 
Pectus excavatum (PE), characterized by an anterior depression of the chest wall, is the 
most common congenital chest wall deformity, with a prevalence of approximately 6.3 to 
12 per 1,000 individuals worldwide. 
First introduced in the 1990s, the Nuss procedure, also known as minimally invasive 
repair of pectus excavatum (MIRPE), is currently the most commonly performed surgical 
procedure for correction. 
Although the benefits of this approach include smaller incisions, shorter operative time, 
and reduced blood loss compared with the open Ravitch repair, the immediate 
remodeling of the chest wall is associated with significant postoperative pain. 
Currently, the two most common pain control strategies after MIRPE are thoracic 
epidural infusion and intravenous patient-controlled analgesia (PCA). 
In addition, a variety of multimodal regimens using indwelling chest wall catheters and 
local or regional nerve blocks have recently been proposed to reduce perioperative pain 
and opioid use. 
However, all these regimens provide relatively short-term control, whereas pain following 
MIRPE typically persists for 2 to 4 weeks. 
To achieve long-lasting pain control at the time of surgery, cryoanalgesia—defined as 
the use of cold temperature to interrupt nerve function—has been employed for 
peripheral nerve blockade. 
The concept of using ice or cold temperatures to anesthetize pain dates back to 
Hippocrates (460–377 BC), who described the use of ice and snow compresses to 
relieve surgical pain. 
The modern version of this concept utilizes a commercially available cryoprobe that 
releases carbon dioxide or nitrous oxide under high pressure, rapidly cooling tissues to 
−50 to −70 °C. This temperature induces Wallerian degeneration of axons, temporarily 
preventing pain transmission. The external fibrous neural structures remain intact, 
facilitating axonal regeneration within approximately 4 to 6 weeks. 
Table 1 lists publications from the last six years that evaluated postoperative pain in 
patients undergoing MIRPE with cryoanalgesia and the methodologies employed. 

                                                                                                                       
 
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Tabela 1 – Estudos entre 2019 e 2024 que avaliaram a resposta analgésica no pós-
operatório de MIRPE 
Study 
Place 
Study 
design 
Patients 
Primary 
outcome 
Secondary 
outcomes 
Jaroszew
ski et al 
(2024) 
[28] 
Mayo 
Clinic 
Arizona, 
USA 
Retrospecti
ve 
729 adults 
Length 
of 
Stay, 
opioid 
comsumpti
on 
Postoperative 
complications, 
pain scales 
Ganescu 
et 
al 
(2022) 
[29] 
The 
Montreal 
Children’s 
Hospital, 
Canada 
Retrospecti
ve 
57 
teenagers 
and adults 
Opioid 
comsumpti
on 
Pain scales 
Downing 
et 
al 
(2023) 
[30] 
The 
Hospital for 
Sick 
Children, 
Canada 
Retrospecti
ve 
53 
teenagers 
Lenght 
of 
stay 
Opioid 
comsumption, 
pain scales 
Arshad et 
al (2023) 
[31] 
Multicentric
, USA 
Retrospecti
ve 
898 
teenagers 
Length 
of 
stay 
and 
opioid 
comsumpti
on 
Postoperative 
complications 
and 
readmissions 
Toselli et 
al (2024) 
[32] 
Buenos 
Aires, 
Argentina 
Retrospecti
ve 
176 
teenagers 
and adults 
Length 
of 
Stay, 
opioid 
comsumpti
on 
Pain scales 
Parrado et 
al (2019) 
[33] 
Phoenix 
Children’s 
Hospital, 
USA. 
Retrospecti
ve 
101 
teenagers 
Late 
pneumotór
ax 
Length of Stay, 
pain 
scales, 
opioid 
comsumption, 
bar 
dislodgement  

                                                                                                                       
 
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Song et al 
(2022) 
[34] 
Sanggye 
Paik 
Hospital, 
South 
Korea 
Retrospecti
ve 
64 
teenagers 
Opioid 
comsumpti
on 
and 
length 
of 
stay 
Pain scales 
Graves et 
al (2019) 
[35] 
UCSF-
Benioff 
Children's 
Hospital, 
USA 
Prospective
, 
randomized 
20 patients 
(1:1) 
Length 
of 
stay 
Operative time, 
opioid 
comsumption, 
pain 
scales, 
postoperative 
complications 
 
The only randomized trial in the literature concluded that intercostal nerve cryoablation 
during MIRPE reduces length of stay and opioid requirements compared with thoracic 
epidural analgesia. 
However, that study did not differentiate whether one or multiple metallic bars were used 
during MIRPE. One of the most feared complications of MIRPE is postoperative bar 
rotation, and the search for solutions to this problem is longstanding. 
The placement of more than one bar is one strategy that may minimize this complication. 
Additionally, two metallic bars may distribute the pressure exerted on the sternum, which 
could have implications for postoperative pain. Despite this, traditional bars were 
designed to be used individually, and when more than one bar is used, technical 
adaptations such as steel sutures are required for fixation. 
Recently, a new material for performing MIRPE has become available in our setting. 
One of the characteristics of this material is a dedicated system that allows fixation of 
more than one metallic bar, providing greater adaptability and enhanced stability of the 
system on the patient’s chest wall. Furthermore, the use of more than one metallic bar 
has become a trend in MIRPE, not only for safety reasons but also for improved 
corrective outcomes. 
Thus, the objective of the present study is to compare intraoperative intercostal 
cryoanalgesia with thoracic epidural block in the postoperative period of MIRPE 
performed with more than one metallic bar. 
 

                                                                                                                       
 
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OBJECTIVES 
Primary objective 
Minimally invasive repair of pectus excavatum (MIRPE) is associated with significant 
postoperative pain, prolonged hospitalization, and high opioid requirements. The 
objective of this study is to compare the analgesic efficacy of intraoperative intercostal 
nerve cryoablation with epidural analgesia by measuring hospital length of stay (in days). 
Secondary objectives 
To compare the analgesic response between perioperative intercostal cryoablation and 
epidural analgesia using visual analog scale (VAS) and numeric rating scale (NRS) pain 
scores. 
To compare intravenous opioid consumption in the postoperative period of MIRPE 
between the intercostal cryoablation group and the thoracic epidural block group, 
expressed as oral morphine equivalents. 
To compare the rate of perioperative complications within 30 days in patients undergoing 
MIRPE using the Clavien–Dindo classification. 
To compare the frequency of emergency department visits or hospital readmissions 
between the intercostal cryoablation and thoracic epidural block groups within 30 days 
after hospital discharge. 
To observe the incidence of chronic neuropathic pain and paresthesia up to 1 year 
postoperatively in the intercostal cryoablation group. 
To compare patient-reported experience measures (PREMs) between the intercostal 
cryoablation and thoracic epidural block groups using postoperative satisfaction at 6 
months assessed by the Single Step Questionnaire (SSQ). 
To compare total hospitalization costs (in Brazilian Reais) and costs per hospital sector 
(ward, operating room, and intensive care unit) between the two groups. 
HYPOTHESIS 
Intraoperative intercostal cryoablation used as an analgesic method in minimally invasive 
repair of pectus excavatum (MIRPE) is more effective in reducing postoperative pain 
than thoracic epidural block, thereby reducing postoperative hospital length of stay. 
METHODOLOGY 
Study Design 

                                                                                                                       
 
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Prospective randomized clinical trial of participants undergoing MIRPE at a single 
academic institution. Participants will be randomized in a 1:1 ratio to receive 
cryoanalgesia or thoracic epidural analgesia for perioperative pain control. All 
procedures were reviewed and approved by the institutional review board. 
Participant Selection 
Participants will be consecutively recruited from among those who sought care at the 
Chest Wall Outpatient Clinic of InCor and who had already been scheduled to undergo 
MIRPE through routine hospital care. Only healthy participants with pectus excavatum 
deformity will be included. 
Inclusion Criteria 
1) Diagnosis of pectus excavatum; 
2) Signed informed consent form for participation in the study. 
Exclusion Criteria 
1) Age < 13 years at the time of the procedure; 
2) Chronic use of analgesics in the preoperative period; 
3) Pectus carinatum, Poland syndrome, or other chest wall anomalies; 
4) Previous repair of pectus excavatum using any technique; 
5) Previous thoracic surgery; 
6) Congenital heart disease; 
7) Hemorrhagic diathesis; 
8) Major anesthetic risk factors or history of previous anesthetic complications; 
9) Pregnancy. 
Randomization 
On the day of surgery, in the preoperative area, shortly before the surgical procedure, a 
list generated by a computerized random sequence generator (http://www.random.org/) 
will be consulted in a 1:1 ratio between the cryoanalgesia and thoracic epidural groups. 
The list will be handled by third parties not involved in the study. 
MIRPE procedure and analgesia 

                                                                                                                       
 
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All participants will undergo the MIRPE procedure, performed by two attending surgeons 
experienced in the technique. Specific aspects of the procedure (i.e., size and positioning 
of bars in crossed or parallel configuration, size of transverse stabilizing bars) will be left 
to the surgeon’s discretion based on individual participant factors. However, the same 
surgical technique will be applied throughout the protocol for all participants. The 
technique used has been previously described [38,39] and is summarized below. 
After measuring the lengths of the metallic bars to be used for surgical correction, two 
lateral incisions of approximately three centimeters are made on each side of the chest. 
The incisions begin approximately one centimeter below the point where the bar will be 
positioned and extend two centimeters medially. Blunt dissection is performed to create 
a subcutaneous tunnel to the point of entry into the thoracic cavity (hinge point), where, 
after ventilatory pause, the thoracic cavity is opened and the optic device is introduced 
for cavity exploration. 
Next, two screws are fixed into the anterior sternal table to allow performance of the 
Crane maneuver, which consists of elevating the sternum using a Thompson retractor. 
The sternum is kept elevated not only for dissection of the retrosternal tunnels but also 
throughout the entire surgery. 
Under thoracoscopic visualization, the retrosternal tunnels are dissected from left to right 
as previously described, and 28 French thoracic drains are passed through the tunnels 
to serve as guides for insertion of the metallic bars. 
The metallic bars are shaped for the participant, attached to the end of the drain, and 
passed through the retrosternal tunnels in a concave position. Subsequently, one bar at 
a time is rotated to its convex position, the sternal elevation is released, and the effect 
obtained by the presence of the bar elevating the sternum is evaluated. The same 
sequence is then performed with the second bar, and the process is repeated until the 
result is considered satisfactory. 
Subsequently, the bars are fixed with bridges to prevent displacement. The thoracic 
cavities are drained, air is evacuated from the pleural cavities, and the surgical incisions 
are closed in layers. 
Participants Randomized to Epidural Analgesia 
Participants will be intubated with a single-lumen endotracheal tube. A thoracic epidural 
catheter will be placed by the pediatric anesthesia team immediately before the MIRPE 
procedure. Catheters will be placed using sterile technique at approximately interspaces 
T5–6 or T6–7; specific details of the procedure will be left to the discretion of the 

                                                                                                                       
 
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attending anesthesiologist. After placement, the epidural infusion will be initiated with 
0.1% ropivacaine and fentanyl 2 μg/cc. No bolus doses will be administered. Participants 
in the cryoanalgesia arm will not receive preoperative thoracic epidural placement, and 
participants in the epidural arm will not receive intraoperative cryoanalgesia. 
Participants Randomized to Intercostal Nerve Cryoablation (IC) 
Intercostal cryoablation is performed prior to placement of the retrosternal metallic bars. 
Participants randomized to cryoanalgesia will be intubated with a double-lumen 
endotracheal tube to allow better lung isolation and exposure of the posterolateral 
trajectory of the intercostal nerves. 
Next, a 5-mm trocar is inserted into the right thorax inferior to the incision made for 
metallic bar placement. Using the incision created for bar placement, the cryoablation 
probe is inserted above the rib deep to the incision. Under thoracoscopic guidance, the 
probe is positioned on the inferior portion of the neurovascular bundle posterolaterally 
and away from the spine without contacting the lungs. Intercostal nerves between T3 
and T7, corresponding to the incision level and two interspaces above and below, are 
subjected to cryoablation for two minutes each at −60 °C. Each nerve receives one 
cryoablation cycle. After freezing, the probe is warmed to room temperature to allow 
detachment from the chest wall. 
Subsequently, the intercostal nerve bundle in the contralateral thoracic cavity is 
subjected to cryoablation using the same technique [40]. 
Postoperative care 
Postoperative care and the analgesic protocol will be identical for all participants, except 
for continuous epidural infusion (without bolus or patient-controlled epidural analgesia). 
All participants will be admitted to the thoracic surgery ward. 
The study team will quantify daily the total dose of analgesics and adjuvants 
administered during hospitalization, via parenteral and enteral routes (Table 2), in both 
treatment groups. Local field block will be performed intraoperatively at all incision sites. 
All participants, in the absence of hypersensitivity restrictions, will receive 48 hours of 
dipyrone (metamizole) and nonsteroidal anti-inflammatory drugs (ketorolac trometamol, 
ketoprofen, or similar agents available at the institution) intravenously. Once participants 
tolerate oral intake, they will be converted to oral oxycodone, acetaminophen or 
dipyrone, and nonsteroidal anti-inflammatory drugs (ibuprofen, ketorolac trometamol, or 
ketoprofen). 
Table 2 – Administration of Analgesics and Anti-inflammatory Drugs in the Postoperative 
Period 

                                                                                                                       
 
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Postoperative day (POD) 
0 
1 
2 
3 
4 
5 
6 (...) 
Epidural, 
0.1% 
ropivacaine, 
fentanyl 
2 
μg/cc at 6 cc/h 
  
  
  
  
  
  
  
Ketoprofen 100 mg IV 
  
  
  
  
  
  
  
Ketorolac trometamol 30 
mg 
  
  
  
  
  
  
  
Hydromorphone PCA, 0.1 
mg 
  
  
  
  
  
  
  
Oxycodone 5 mg 
  
  
  
  
  
  
  
Oxycodone 10 mg 
  
  
  
  
  
  
  
Acetaminophen 650 mg 
  
  
  
  
  
  
  
Ibuprofen 10 mg/kg/dose 
  
  
  
  
  
  
  
Ondansetron 4 mg IV 
  
  
  
  
  
  
  
Gabapentin 300 mg 
  
  
  
  
  
  
  
Baclofen 10 mg 
  
  
  
  
  
  
 
 
According to institutional protocol, all epidurals will be weaned off at the discretion of the 
pain management team in consultation with the surgical team. The use of narcotics will 
be recorded and tracked through the hospital's electronic medical record. 
Pain Scores 
In addition to standard postoperative nursing assessments, participants’ pain (including 
specific neuropathic pain described as “burning,” “electric,” or “tingling” sensations) will 
be assessed by a study questionnaire using visual analog and numeric pain scales (0 to 
10) in seated and supine positions, and according to reported pain location in quadrants 
(anterior, posterior, superior, inferior, lateral, medial). 
On the numeric scale, the value 0 represents no pain, while the value 10 identifies the 
most intense pain experienced by the patient [41]. 
Patients frequently experience difficulty using numeric values alone due to the absence 
of clear definitions of what each number represents, given that pain is subjective and 
such scales attempt to transform it into an objective representation [42]. 
The visual pain score is displayed with digits ranging from 0 to 10 and is determined 
using a standard, such as a spectrum of cold and warm colors or facial expressions 
[41,43] (Figures 1 and 2). 
Figure 1 – Visual analog pain scale based on a color spectrum (warm and cool colors). 

                                                                                                                       
 
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Reproduced from Fortunato JGS (2013), Revista HUPE, 12(3), 110-118 [43]. 
 
Figura 2 – Conversion between numeric and analog visual pain scales. 
 
Adapted from International Living Donor Liver Transplant Registry. 
 
Hospital discharge will be determined by the surgical team based on adequate pain 
control with oral medications, ability to ambulate independently, and tolerance of oral 
diet. 
Pain Biomarkers 
The National Institutes of Health (NIH) led the creation of a consortium to validate 
existing biomarkers (previously identified in small studies) and to develop and discover 

                                                                                                                       
 
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new biomarkers and biosignatures related to the evolution of postoperative pain into 
chronic pain. 
Thus, the Food and Drug Administration’s (FDA) Biomarkers, Endpoints, and Other 
Tools 
(BEST) 
framework 
defined 
multiple 
types 
of 
biomarkers, 
including 
susceptibility/risk, prognostic, predictive, and monitoring biomarkers. These biomarkers 
provide a broader perspective and include psychosocial measures, which serve as 
indirect indicators of more complex biological processes. 
Among the primary patient-reported biomarkers are overall and local pain intensity, 
diffuse pain, movement-evoked pain, and pain trajectory. Among laboratory and imaging 
markers, primary biomarkers include C-reactive protein and other inflammatory 
substances such as interleukins 6 and 12, as well as sensory testing and neuroimaging. 
The literature contains only one publication, available as a preprint, that evaluated 
biomarkers and their association with acute and chronic postoperative pain in MIRPE. 
This prospective observational study identified an association between levels of pro-
inflammatory and anti-inflammatory cytokines and the development of acute and chronic 
pain, respectively. 
 
Patient-Reported Outcome Measures (PROMs) and Patient-Reported Experience 
Measures (PREMs) 
Patient-reported experience measures (PREMs) are tools that allow assessment of what 
occurred during a treatment and how it occurred from the patient’s perspective, whereas 
patient-reported outcome measures (PROMs) allow measurement of the patient’s health 
status, including patient-related factors and pain-related condition factors, as well as 
external factors that may be associated with pain. 
The PROMs listed in the NIH Acute to Chronic Pain Signatures (A2CPS) initiative have 
the most robust evidence encompassing pain and other symptoms, psychosocial factors, 
and function. These PROMs are subdivided into the following domains: pain, function, 
disability, mood/affect, sleep, cognitive function, resilience, trauma, and social support. 
Table 3, adapted from Sluka et al. (2023), lists the primary and secondary biomarkers 
assessable within the PROMs domain and Pain category. 
 
Table 3 – Primary and secondary biomarkers in the assessment of chronic and acute 
pain – PROMs domain, Pain category – adapted from Sluka et al. (2023). 
Primary biomarkers 
Secondary biomarkers 
- Overall pain intensity 
- Pain duration 
- Local pain intensity 
- Pain impact/quality of life 
- Widespread body pain 
- Pain interference 
- Movement-evoked pain 
 
- Pain trajectory 
 
Primary biomarkers 
 
 

                                                                                                                       
 
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Among the PREMs, the Single-Step Questionnaire (SSQ) is a validated tool used to 
assess general and health-related satisfaction, self-image, and postoperative pain, as 
well as improvement in quality of life related to physical and psychosocial domains, in 
adolescent and young adult patients undergoing minimally invasive repair of pectus 
excavatum. It is administered at a single time point starting from the fifth postoperative 
month. 
For calculation of the total score: the preoperative self-esteem score is subtracted from 
the postoperative self-esteem score. The difference between the two values is used as 
a single contributor to the total score. 
 
Hospitalization Costs 
Two retrospective studies evaluated hospitalization costs for admissions related to 
MIRPE associated with cryoanalgesia. Based on univariate and multivariate analyses, a 
trend toward cost savings associated with the use of cryoanalgesia during MIRPE was 
observed, which is likely related to improved analgesic response and reduced total length 
of hospital stay when compared with patients undergoing conventional analgesia (with 
or without epidural block) without intercostal cryoablation. 
 
Follow-up 
After hospital discharge, participants will be sent home with acetaminophen or dipyrone, 
a nonsteroidal anti-inflammatory drug, and oxycodone, and will be instructed to maintain 
a medication log. Participants will be scheduled for follow-up visits at 2 weeks, 1 month, 
3 months, 6 months, and 12 months from the date of surgery. Each visit will consist of 
an interval history and a focused physical examination, including specific assessment of 
incision sites, chest wall sensation, and the epidural catheter insertion site. 
At each visit, participants will also complete a questionnaire including questions 
regarding the type and severity of pain, satisfaction with the pain control regimen, level 
of physical activity, and side effects or adverse events (Table 4). 
Table 4 – Adverse effects related to analgesia 
Adverse event 
POD 0 POD 1 
POD 2 
POD 3 
POD 4 
POD 5 
- Nausea, vomiting 
  
  
  
  
  
  
- Pruritus 
  
  
  
  
  
  
- Urinary retention 
  
  
  
  
  
  
- Respiratory depression 
  
  
  
  
  
  
- Naloxone administration 
  
  
  
  
  
  
- SpO₂ < 90% 
  
  
  
  
  
  
- Respiratory rate < 8 
breaths per minute 
  
  
  
  
  
 

                                                                                                                       
 
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Endpoints, Power Calculation, and Data Analysis 
The primary endpoint will be postoperative length of stay (in days). Secondary endpoints 
will include total operating room time and procedure time, narcotic use (expressed as 
milligrams of oral morphine equivalents per day), use of adjuvant analgesia, side effects 
related to epidural analgesia or cryoanalgesia, visual analog pain scores, presence of 
neuropathic pain, presence and duration of thoracic numbness, procedure-related 
complications, and frequency of hospital readmissions within 30 days postoperatively. 
Postoperative length of stay was selected as an objective measure that synthesizes 
multiple aspects of a procedure and its subsequent postoperative course, including 
adverse events, pain control, and psychosocial factors. This primary endpoint has also 
been used in other studies evaluating the effectiveness of cryoanalgesia in patients 
undergoing MIRPE. The adoption of other variables as the primary endpoint would 
require an initial pilot study, as there are no studies evaluating analgesic response using 
these variables as primary endpoints. 
The study was designed to demonstrate a statistically significant effect (type I error rate 
of 0.05 and type II error rate of 0.05), based on preliminary studies demonstrating a 
reduction in hospital length of stay of approximately 2 days in participants undergoing 
cryoanalgesia. 
Based on the results of Jaroszewski et al., which demonstrated a mean postoperative 
length of stay of 1.9 ± 1.5 days in the intervention group (intercostal cryoanalgesia) and 
4.2 ± 1.2 days in the control group (thoracic epidural analgesia), sample size power 
calculation was performed with 1:1 allocation between the intervention and control 
groups using G*Power software version 3.1.9.7.  
Figure 3 – Calculating the power of the study using randomization and 1:1 matching. 

                                                                                                                       
 
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Accordingly, using a sample of 11 participants in the intervention group and 11 
participants in the control group, the statistical power of the study would exceed 96% 
with a type I error rate of 0.05. Therefore, a total sample size of 40 participants will be 
used, maintaining 1:1 allocation, preserving study power even with potential losses of up 
to 45% in both groups. 
Primary outcome data will be analyzed by comparing the median postoperative length of 
stay using the Mann–Whitney U test for nonparametric continuous variables. All other 
continuous variables will be analyzed by comparison of means using a two-tailed t test, 
while categorical data will be arranged in contingency tables and compared using the 
Pearson chi-square test. 
Examinations and Description of Their Analysis 
OUTPATIENT EVALUATION 
Chest computed tomography – routine preoperative evaluation of patients with pectus 
excavatum, from which the Haller index will be derived. 
Echocardiography – routine preoperative evaluation of patients with pectus excavatum, 
used to exclude the presence of concomitant cardiac malformations. 
 
PREOPERATIVE EVALUATION FOR SURGICAL CANDIDATES 

                                                                                                                       
 
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Complete blood count, coagulation profile, urea, creatinine, sodium, and potassium – 
routine laboratory tests performed in all surgical patients at the institution. 
 
POSTOPERATIVE IMAGING STUDIES 
Chest radiography – routine postoperative examination for all thoracic surgeries. 
 
PROTOCOL ASSESSMENT METHODS 
Visual Analog Scale (VAS) and Numeric Rating Scale (NRS) for pain – assessment 
methods performed in the postoperative period in both groups, without increasing 
hospitalization costs. Patient-reported outcomes included in the FDA BEST biomarker 
initiative will be evaluated regarding local and generalized pain intensity, pain duration, 
and pain exacerbation related to movement. 
Daily postoperative opioid use will be calculated based on doses administered via oral, 
intravenous, 
and 
epidural 
routes, 
expressed 
as 
mg/kg/day. 
Fentanyl 
and 
hydromorphone will be converted to intravenous morphine-equivalent doses using 
standard equianalgesic conversion ratios (100 mcg of intravenous fentanyl = 10 mg of 
intravenous morphine; 1 mg of intravenous hydromorphone = 5 mg of intravenous 
morphine), and epidural-to-intravenous conversion ratios of 1:10 for morphine and 1:1 
for fentanyl. 
Patient-reported experience measures (PREMs) will be evaluated using the SSQ score 
at the sixth postoperative month. 
Postoperative complications within 30 days will be evaluated using the Clavien–Dindo 
classification. 
Total hospitalization cost will be assessed based on total values obtained from hospital 
billing performed by the hospital unit at the end of each admission. Costs will be stratified 
according to the sector in which they were incurred: inpatient ward, intensive care unit, 
and operating room. All values will be adjusted at the end of the study using official 
inflation data, corrected by the Brazilian National Consumer Price Index (IPCA/IBGE). 
Costs related to the donation of intercostal cryoablation probes and devices will not be 
included in the hospital cost calculation, as this procedure is not currently listed in the 
Brazilian Unified Health System (SUS) Table of Procedures, Medications, and Medical 
Devices.  

                                                                                                                       
 
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Risks 
There is a risk of loss of data confidentiality. However, measures will be implemented by 
the investigators to ensure the confidentiality of stored data. 
There are reports in the literature of chronic pain and paresthesia following the use of 
intercostal cryoablation. Follow-up of participants for 12 months postoperatively will allow 
identification of and targeted intervention for this condition. 
Other potential risks are associated with postoperative complications of thoracic surgery, 
including bleeding, surgical site infection, pneumothorax, pleural effusion, prolonged 
pleural drainage, reaction or rejection of implanted materials, displacement of metallic 
prostheses, and death. 
 
Benefits 
Reduction of postoperative pain and hospital length of stay in the period following 
surgery. 
STUDY TIMELINE 
PROCEDURES / ACTIVITIES BY 
SEMESTER 
1st 
semester 
2nd 
semes. 
3rd 
semes. 
4th 
semes. 
5th 
semes. 
6th 
semes. 
7th 
semes. 
Theoretical background 
X 
X 
 
 
 
 
 
Participant selection 
X 
X 
X 
X 
 
 
 
Assessment 
of 
inclusion 
and 
exclusion criteria 
X 
X 
X 
X 
 
 
 
Signing of informed consent/assent  
forms 
X 
X 
X 
X 
 
 
 
Surgical treatment 
 
X 
X 
X 
X 
 
 
Postoperative follow-up 
 
X 
X 
X 
X 
X 
X 
Data collection 
 
X 
X 
X 
X 
X 
X 
Presentation of results 
 
 
 
 
 
X 
X 
This timeline was validated after approval by the Research Ethics Committee. 
 
BUDGET 

                                                                                                                       
 
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The present project will not generate costs for this institution, as it is a prospective study 
evaluating patients who are routinely treated surgically at the institution. The only 
additional devices to be used will be the probes for intraoperative intercostal 
cryoanalgesia, which will be donated by the company Novelty Comércio e Importação, 
according to the letter of agreement attached. 
 
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