Clinical trial NCT03743194
Conditions: Post Operative Pain Control
Sponsor: The Cleveland Clinic
Start date: 2021-12-14; Completion date: 2022-03-14
Enrollment: 210 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall research plan is PECS/SAP blocks with liposomal bupivacaine improve the Overall Benefit Analgesia Score averaged over the postoperative days 1, 2, and 3. A 20% reduction on geometric means (i.e., true ratio of geometric means of 0.80) in OBAS will be considered the minimal clinically important benefit.

Detailed description:
The primary aim is to determine whether a PECS/SAP block, using a mixture of bupivacaine and liposomal bupivacaine, provides superior recovery compared to routine parenteral and enteral analgesia in patients recovering from MICS. The primary outcome will be the simple multi-dimensional quality assessment, Overall Benefit Analgesia Score (OBAS score).53 Our secondary aims are to: 1) compare cumulative postoperative opioid consumption (pain medications administered over one-day periods quantified as morphine equivalents and provided by the EMR for the day of surgery and postoperative days 1, 2, and 3; 2) evaluate respiratory mechanics (forced expiratory volume in first minute (FEV1), forced vital capacity (FVC) and peak flow) after extubation on the postoperative days 1, 2 and 3 while patients remain hospitalized; and, (3) evaluate the Quality-of-Recovery-15 score on the postoperative days 1, 2 and 3.

Arms: arm 1: Pectoral fascial plane or serratus anterior plane blocks (PECSII/SAP blocks) with bupivacaine HCl plus liposomal bupivacaine.

An ultrasound guided pectoral fascial plane blocks (PECS I and II blocks) and Serratus anterior plane (SAP) block with injection of the local anesthetic. arm 2: Standard parenteral analgesia technique with or without incisional local anesthetic infiltration: patients randomized to control group will be given parenteral opioids (such as fentanyl or hydromorphone) until they are converted to the enteral medications such as Percocet.
Interventions: intervention 1: Exparel 266 MG Per 20 ML Injection intervention 2: Placebo
Intervention descriptions: intervention 1: The local anesthetic (LA) used for the PECS II or serratus plane blocks will be a 0.5% bupivacaine HCL, not to exceed 2.5mg/kg or up to 150mg. The LA solution can be diluted with preservative free normal saline for smaller patients to allow for appropriate volume of injection. Treatment patients will also be given liposomal bupivacaine (EXPAREL, Pacira Pharmaceuticals, Inc. San Diego, CA) in a dose of 266 mg in 20 ml can be safely combined with bupivacaine HCL at a ratio not exceeding 2:1, but cannot be combined with other local anesthetics due to the concern of rapid release of encapsulated bupivacaine and subsequent local anesthetic toxicity. intervention 2: Patients randomized to standard analgesia technique will be given pain medications.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Pectoralis and Serratus Muscle Blocks for Analgesia After 
Minimally Invasive Cardiac Procedures:  
A randomized clinical trial  
Version 6.0  
July 6, 2022 
Andrej Alfirevic MD FASE1, Donn Marciniak MD1, Andrew Bauer MD1, Andra Duncan MD FASE1, 
Marc Gillinov MD,2 Douglas Johnston MD2, Edward Soltesz MD2, Louis LamMD,3 Natalya 
Makarova MS4, Alparslan Turan MD5, Daniel Sessler MD5 
 
1. Staff Anesthesiologist, Department of Cardiothoracic Anesthesia, Cleveland Clinic  
2. Staff Surgeon, Department of Cardiothoracic Surgery, Cleveland Clinic 
3. Staff Pulmonologist, Respiratory Institute, Cleveland Clinic  
4. Department Of Quantitative Health Science, Cleveland Clinic 
5. Staff Anesthesiologist, Department of Outcomes Research, Cleveland Clinic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
Version 5.0: November 3, 2021 
 
 
 
 
Version 2: January. 2nd, 2019 
Summary of Changes: 
1- Change in the contributors: We added Dr. Louis Lam instead of Dr. Humberto Choi 
2- Change in secondary hypotheses: quality of recovery questionnaire (QoR15) moved from 
secondary to exploratory hypothesis   
3- Change QoR15 follow up days to be day 1 and day 3 
4- Adding exploratory hypothesis  
5- Change inclusion criteria to Mitral valve surgery only (no Aortic valve surgery)  
6- Change the block given to treatment group to PEC 2 and Serratus plane block only ( no 
PECS 1) 
7- In the exclusion criteria: clarifying item # 12 and adding item # 16 
8- In page 7: remove any description related to PECS 1 block ( as it will not be given in the 
study) 
9- In page 8: change volume injected in PEC 2 block to 20-30 ml and SAP block to 40-50 ml 
10- In page 8: add that SAP block might be given deep between Serratus muscle and ribs if it 
is difficult to be given superficial to Serratus ant muscle. 
11- In page 10: Change QoR15 follow up days to be day 1 and day 3 
12- In page 11 : correct the control group description (to standard routine parental and 
enteral analgesia) 
13- In page 11: Add Primary and Secondary analysis 
14- In page 15 : change score range for OBAS score to be from 0 to 4 
 
 
 
Version 3: October 31, 2019 
Summary of Changes: 
1- Page10:  Blood Sample Collection added to the study measurements that will be obtained. 
 
 


3 
 
Version 5.0: November 3, 2021 
 
 
 
 
Version 4: May 10, 2021 
Corrections to protocol amendment  
1- Previous amendment about additional collection for surgical data on data collection sheet:  
Ultrasound record and image of fascial plain blocks (SAP and PECS) was tracked on an older 
version of protocol in error and submitted on 10/23/2020. This amendment is to correct this 
error.  
Additional amendment to this protocol  
1- Twelve patients’ surgery type was planned to be a minimally invasive surgery, however after the 
randomization, their surgery type has been converted to a sternotomy during their surgery. 
Because of this, these patients were not qualified for the study and their follow-ups couldn’t be 
completed.  To be able to keep the power of the study, we would like to add 12 more patients to 
our total enrollment number which was 196 before. Adding 12 more patients, 208 is proposed to 
be the total number.  
Version 5: November 3, 2021 
- 
We would like to add more patients per our statistical team suggestion to increase the power. 
Our total number approximately will be 214.  (page 13) 
Version 6: July 6, 2022 
- 
The primary analysis method was revised due to non-normality of primary outcome from “We 
will report model based P-value and the difference in mean OBAS scores along with confidence 
intervals.”  as “Due to non-normality of OBAS score, it will be log-transformed for analysis. We 
will report model based P-value and the geometric mean ratio for OBAS scores along with 
confidence intervals.  ” 
- 
The smallest clinically important difference of 2 point reduction in OBAS score was corrected as 
20% reduction in geometric means.  
- 
One inclusion criteria was more clearly stated as “Elective MICS for isolated robotically-assisted 
mitral valve repair via anterolateral thoracotomy approach.  “ 
- 
Sample size was more clearly stated for consistency. 
 


4 
 
Version 5.0: November 3, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Introduction 
Over the past several decades the popularity of minimally invasive cardiac surgery (MICS) 
increased consequent to advances in imaging, instrumentation, and surgical skills.1,2 An increase 
in the age-related prevalence of the valvular heart disease3 also prompted novel surgical 
approaches.4 In addition to non-inferior operative mortality, the intermediate and long-term 
survival results are comparable to the traditional median sternotomy approach for both mitral5-
10 and aortic valve11-14 procedures. The reported advantages are also seen in terms of decreased 
infection rate, shorter time to extubation and hospital length of stay, decreased postoperative 
bleeding and transfusion rate, improved cosmesis, better postoperative respiratory dynamics 
and patient’s satisfaction.5-7,15,16  
Both mitral and aortic valve repairs or replacements can be performed using right 
thoracotomies.2,4 A medial (anterior, parasternal; 3rd intercostal space) incision including rib 
disarticulation is often needed for the aortic valves (AV), whereas a more lateral (inframammary, 
mid-axillary line; 4th intercostal space) incision is needed for mitral valves (MV). Robotically 
assisted MV repair is performed via slightly smaller thoracotomy and 3 additional stab incisions 


5 
 
Version 5.0: November 3, 2021 
 
 
for the robotic instruments. Port-accessed robotically assisted surgery avoids thoracotomy 
incision and totally depends on the percutaneous approach.1,4  
Pain following thoracotomy is a serious complication which may delay patients’ recovery, 
prolong hospitalization, and increase morbidity and mortality,17 — all of which impair recovery 
through the post-operative day 3.18 Although long-term pain is usually reduced with MICS19, the 
short term benefits of the MICS approach are inconsistent and vary based on the surgical 
approach and analgesia techniques used.20 Indeed, the thoracotomy approach may be a more 
painful procedure than sternotomy due to the need for rib spreading or disarticulation as well as 
chest tube placement.1,4,21 Compared to the standard sternotomy, patients with “J” 
hemisternotomy for both MV and AV procedures had better postoperative pain control, but only 
30% (compared to 20% in the sternotomy group) were pain-free in the first 24 hours.6,15 
Furthermore, the reports of the MICS for MV using right thoracotomy approach showed no 
difference in visual analog scale (VAS) pain scores and similar amount of additional analgesics 
used compared to the standard approach.20,22  
Parenteral opioids remain the most common analgesic approach. To decrease use of 
opioids, a supplemental regional technique may be used. However, neuroaxial analgesia is rarely 
used due to the concern for developing epidural hematoma as well as perioperative 
hemodynamic instability related to bilateral sympathectomy.23,24 Paravertebral blocks provide 
pain relief that is comparable to epidural blockade, with an improved hemodynamic profile, but 
without incremental benefit in VAS scores compared to the intravenous analgesia in patients 
undergoing robotic MV procedure.25,26 An infusion of longer-acting local anesthetic via the 
subcutaneous tissue catheters facilitates early extubation but has questionable overall 
efficacy.27,28 Further, extrapleural intercostal catheters improved pain control, but inability to 
strip the pleura posteriorly from the incision may lead to inadequate positioning and added 
safety concerns due to systemic toxicity limit its application.29  
An evolving technique of truncal blocks for perioperative pain management has recently 
been reported.30 Blanco et al. first developed and described a novel ultrasound guided pectoral 
fascial plane blocks (PECS I and II blocks) as an analgesia technique for surgeries of the anterior 
and anterolateral chest wall.31,32 The blocks showed a reliable but limited sensory coverage to 
the antero-lateral T2-T4 (with variable spread to T6) with interfascial plane injection of the local 
anesthetic. In order to achieve more caudad and postero-lateral sensory coverage, a serratus 
anterior plane (SAP) block was introduced showing dermatomal coverage in T2-T7 with a variable 
spread to T9.33  
Cadaver studies show spread of dye into the tissue plane adjacent to the long thoracic as 
well as lateral cutaneous braches of the intercostal nerves.34 Indeed, inadequate nociceptive 
block of those nerves may be why analgesia control after thoracic surgery is often unsatisfactory 
with traditional regional analgesia techniques.34,35 The posterior cutaneous branches may not be 
directly blocked, but the clinical efficacy of the PECS and SAP blocks is not diminished, probably 
because the local anesthetic spreads retrogradely.34,36 Because of the unique anatomical 


6 
 
Version 5.0: November 3, 2021 
 
 
communication between the muscular planes, wide LA spread is possible into the large thoracic 
area.33 Thus combing both PECS and serratus blocks at the same instance provides analgesia for 
the large thoracic area. 
The PECS and SAP blocks are easy to perform, and have a high success rate with few 
complications, particularly when performed with ultrasound guidance. Unlike epidural and 
paravertebral blocks, PECS and serratus blocks do not cause a sympathectomy which facilitates 
their use in the hemodynamically compromised patients.37 Because of the superficial nature of 
the blocks, the risk of pneumothorax is minimal, particularly with the in-plane ultrasound needle 
guidance.37 The local anesthetic toxicity syndrome is not been reported and could easily be 
avoided with a dilution of the local anesthetic and standard precautions.38 Indeed, compared to 
the intercostal, interpleural, or paravertebral techniques, pain control was achieved with much 
smaller LA doses which suggests that there was less intravascular absorption. Under the 
ultrasound guidance, the blocks can be easily to perform with the patients asleep, thus avoiding 
discomfort and multiple injections.  
Liposomal bupivacaine (Exparel; bupivacaine liposome injectable suspension, Pacira 
Pharmaceuticals, Inc., Parsippany, NJ USA) is a prolonged-release formulation of the bupivacaine 
used for a single-shot infiltration of the surgical site. The advantage of the prolonged-release 
formulation is analgesia lasting up to 72 h which should improve analgesia after MICS. In a small 
retrospective study of robotically assisted cardiac endoscopic procedures, comparing incisional 
infiltration with bupivacaine vs liposomal bupivacaine, Balkhy et al. demonstrated lower pain 
scores, reduced opioid consumption, and less postoperative nausea and vomiting — although 
none of the differences were statistically significant.18 The Exparel formulation containing a 
mixture of bupivacaine HCL and liposomal bupivacaine has demonstrated acceptable tolerability 
and incidence of adverse events relative to its non-liposomal counterpart, mainly in infiltration 
during hemorrhoid surgery, bunionectomy, breast augmentation, knee arthroplasty, and inguinal 
hernia repair.39 Liposomal bupivacaine is FDA approved for infiltrative field blocks, such as the 
transversus abdominis plane (TAP) block which is similar to PECS and SAP blocks.40     
A decrease in pulmonary mechanics associated with respiratory complications is one of 
the leading causes of postcardiac surgical morbidity.41 Less invasive surgical approaches may 
decrease respiratory morbidity, particularly in already compromised patients.42 However, the 
benefits of MICS in terms of pulmonary morbidity remain unclear.20,22 Indeed, respiratory 
complications are directly related to the incisional pain consequent to thoracotomy, rib 
disarticulation, and muscle distortion. Epidural and paravertebral analgesia reduce pulmonary 
complications and infections, and improve respiratory mechanics in patients having thoracic 
surgery43,44 but are rarely used. Other analgesia modalities including intercostal blocks did not 
comparably preserve pulmonary mechanics or reduce respiratory complications compared to 
neuroaxial techniques.44,45  
A combination of the PECS and SAP blocks provide good analgesia for mastectomy,46-48 
thoracotomy35,36,49-51 and multiple rib fractures.38,52 However, their use in cardiac surgery and 
their effects on postoperative pain control or pulmonary mechanics have yet to be reported. 


7 
 
Version 5.0: November 3, 2021 
 
 
PECS and SAP blocks seem likely to enhance postoperative recovery after minimally invasive 
cardiac surgery. Pain after minimally invasive cardiac surgery is worst over the initial few 
postoperative days and compromises respiratory function. PECS and SAP blocks with liposomal 
bupivacaine thus seems likely to promote good analgesia and improved respiratory function.   
 
Aims of the study  
 
Our primary aim is to determine whether a PECS/SAP block, using a mixture of 
bupivacaine and liposomal bupivacaine, provides superior recovery compared to routine 
parenteral and enteral analgesia in patients recovering from MICS. Our primary outcome will be 
the simple multi-dimensional quality assessment, Overall Benefit Analgesia Score (OBAS score).53  
 
  
Our secondary aims are to: 1) compare cumulative postoperative opioid consumption 
(pain medications administered over one-day periods quantified as morphine equivalents and 
provided by the EMR for the day of surgery and postoperative days 1, 2, and 3; 2) evaluate 
respiratory mechanics (forced expiratory volume in first minute (FEV1), forced vital capacity (FVC) 
and peak flow) after extubation on the postoperative days 1, 2 and 3 while patients remain 
hospitalized 
 
 
Primary hypothesis: 
PECS/SAP blocks with liposomal bupivacaine improve the Overall Benefit 
Analgesia Score averaged over the postoperative days 1, 2, and 3. A 20% reduction in 
OBAS geometric mean, a-priori, was defined as minimal clinically important difference. 
Secondary hypotheses:  
(1) PECS/SAP blocks decrease postoperative cumulative opioid consumption over 
the initial three postoperative days. 
(2) PECS/SAP blocks improve pulmonary mechanics, on each of the postoperative 
days 1, 2 and 3, from the baseline.  
 
 
Exploratory Hypothesis:  
(1) PECS/SAP blocks improve the Quality-of-Recovery score averaged over the 
postoperative days 1 and 3, with a difference of 8 points being considered the 
minimum clinically important difference.54 
(2) PECSII and SAP blocks reduce persistent postoperative surgical pain 
 


8 
 
Version 5.0: November 3, 2021 
 
 
Methods 
The study will be conducted at the Cleveland Clinic Main Campus with IRB approval and written 
informed consent from participating patients.  
Inclusion Criteria 
1. 18-85 years old; 
2. Elective MICS for isolated robotically-assisted mitral valve repair via anterolateral thoracotomy 
approach.   
Exclusion Criteria 
1. Weight less than 50 kg; 
2. Pregnancy or lactation; 
3. Emergency surgery and patients transferred from the ICU to the operating room; 
4. Redo cardiothoracic surgery or post-operative reoperation within 72 hours of index procedure 
(including minor chest wall procedures including tube thoracostomy, thoracentesis or 
percutaneous drain placement); 
5. Anticipated endotracheal intubation > 24 hours; 
6. Anticipated non-study nerve block that provides analgesia to the intercostal nerves; 
7. Active systemic or cardiopulmonary infection; 
8. Mechanical circulatory support; 
9. Allergy or contraindication to study local anesthetics; 
10. Current chronic pain or routine opioid use (patients on chronic enteral opioids like Percocet or 
Vicodin) in a dose of > 30 mg of morphine-milligram-equivalents for at least 10 days in last 30 
days; 
11. Poorly controlled psychiatric disorders; 
12. Clinically important current neurologic deficit; e.g. spinal cord injury, paralysis of extremity, any 
neurologic deficit in the region of the block 
13. Active liver disease or cirrhosis; 
14. Pacemaker generator or breast implants ipsilateral to surgery; 
15. Previous participation in this study. 
16. eGFR <30 or chronic kidney disease 
 
Study protocol  
Consent will be obtained at least a day before surgery. Patients will be randomized the 
day of surgery upon presentation to the operating room to either a treatment group (PECS/SAP 
blocks) or a control group (standard parenteral analgesia technique with or without incisional LA 
infiltration) using secure web-based randomization. Randomization will be stratified by aortic or 
mitral valve surgery, with random blocking in each case. The system will be accessed shortly 


9 
 
Version 5.0: November 3, 2021 
 
 
before surgery to conceal allocation as long as possible. Clinicians will not be blinded to the 
intervention, but all outcomes will be assessed by research personnel who are blinded to the 
group assignment.   
Anesthetic and Surgical Management 
Anesthetic care will be performed as usual for Cleveland Clinic cardiothoracic surgical 
procedures.  This includes use of standard ASA monitors and may include the use of arterial or 
central venous pressure monitoring, trans-esophageal echocardiography, and lung isolation 
using a bronchial blocker or a double lumen endotracheal tube.  Medication administration for 
induction and maintenance of anesthesia will also be consistent with usual care and will include 
intravenous opioids such as fentanyl and hydromorphone. Intravenous lidocaine will not be 
administered upon induction of anesthesia.   
Pressure-control ventilation will be used with a tidal volume not exceeding 6-10 ml/kg 
ideal body weight during two- and one-lung ventilation. Fluids will be managed conservatively 
per routine.  Patients not extubated at the end of the procedure will be sedated with propofol. 
Surgical procedures with the assistance of the cardio-pulmonary bypass will be performed in their 
usual manner. The general approach for the AV replacement will be via the right anterior 
thoracotomy in the 3rd intercostal space.4 The MV repair/replacement procedures will be 
approached via the right lateral thoracotomy inframammary incision in the 4th intercostal space 
in the mid-axillary line and augmented, as needed, with the stab incisions for the robotic ports.4 
Chest Wall Analgesia  
The anatomic basis for chest wall analgesia has been described in detail previously.31-33,49  
We describe the conduct of the blocks as used for MICS procedures at our institution. The 
patients randomized to the “blocks” will receive PECS II and serratus anterior for the MVR 
requiring antero-lateral thoracotomy and port incisions. The PECS/serratus blocks will be 
performed with the patient under the general anesthesia before incision. If proves impossible to 
perform blocks preoperatively because of surgical urgency, they will be done at end of surgery. 
PECS II blocks: 
Patients will be positioned supine, and prepped and draped in a sterile fashion. An 
ultrasound probe will be placed just below the clavicle in the mid-clavicular line.  
For the PECS II block, the probe will be scanned inferiorly and laterally until the plane 
between the pectoralis minor and serratus muscle is identified. The serratus muscle can be 
clearly seen coursing over the ribs, while the intercostal muscles are seen in the interspaces 
between the ribs.  Once the plane is identified the needle is again advanced in an “in-plane” 
fashion. Once the needle location is confirmed by normal saline hydro-dissection, a 20-30 ml of 
local anesthetic solution is administered into the space.   


10 
 
Version 5.0: November 3, 2021 
 
 
Serratus plane block: 
With the patient in a supine position, a will be placed under the operative side to achieve 
a slightly lateral tilt. The arm is abducted to expose the costal margin. The patient is prepped and 
draped in a sterile fashion. The positioning and prepping can be done prior to the PECS block to 
avoid repositioning if both blocks are being performed. The ultrasound probe is scanned laterally 
from the pectoralis to the axillary region at approximately the level of the 4th rib. The plane 
between the serratus muscle and the latissimus dorsi muscle is identified and the needle 
advanced in an “in-plane” fashion until the tip is between the muscles (superficial SAP block). A 
small bolus of 0.5 ml of normal saline is used for hydro-dissection of the tissue planes to confirm 
that the needle is not intramuscular. The needle is then aspirated every 5 ml as 40-50 ml of local 
anesthetic solution is deposited into the plane. As these are field blocks, adequate volume of 
infiltration is important in achieving optimal analgesia. If proves impossible to perform as 
superficial SAP block, it will be given between the posterior border of the Serratus anterior 
muscle and the corresponding surface of the rib (deep SAP block). 
Local anesthetic:  
The local anesthetic used for the blocks will be a 0.5% bupivacaine HCL in a dose not to 
exceed 2.5 mg/kg. The local anesthetic solution can be diluted for smaller patients to allow for 
appropriate volume of injection. Typically the block has duration of action of less than 12 hours 
after infiltration.55 Patients will therefore also be given liposomal bupivacaine (Exparel, Pacira 
Pharmaceuticals, Inc. San Diego, CA) in a dose of 266 mg in 20 ml can be safely combined with 
bupivacaine HCL at a ratio not exceeding 2:1, but cannot be combined with other local 
anesthetics due to the concern of rapid release of encapsulated bupivacaine and subsequent 
local anesthetic toxicity.56  
Liposomal bupivacaine dosing is not weight-based and the full 266-mg bottle can be 
administered to adult thoracic patients. A maximum of 150 mg bupivacaine HCl can be mixed 
with Exparel. This equates to one 30-mL bottle of 0.5% bupivacaine HCl or two (2) bottles of 
0.25% bupivacaine HCl. If a higher volume of the local anesthetic is needed a 10 ml of normal 
saline can be added to the mixture of bupivacaine HCL and liposomal bupivacaine. Thus patients 
≥60 kg will receive 150 mg of bupivacaine HCL, while patients weighing <60 kg need to have the 
bupivacaine dose calculated but can still receive full 20 ml of Exparel.  
Patients randomized to standard analgesia technique will be given parenteral opioids 
(such as fentanyl or hydromorphone) until they are converted to the enteral medications such as 
Percocet.   
Study Measurements  
Patent demographics will be collected from preoperative interviews and chart review 
(Table 1). Cumulative opioid consumption, non-opioid analgesics, and length of stay will be 


11 
 
Version 5.0: November 3, 2021 
 
 
captured electronically using Epic and/or PHDS. Other secondary and descriptive outcome data 
as well as surgical and intraoperative data will be collected prospectively (Table 2). 
Data will be obtained from the following sources: The Society of Thoracic Surgeons (STS) 
database, Cardiovascular Information Registry (CVIR) of the Heart and Vascular Center at the 
Cleveland Clinic, the electronic medical record (EPIC), and the electronic Anesthesia Record 
Keeping System (ARKS).   
a) OBAS score 
The OBAS score questionnaire (Table 3) will be obtained and score calculated by the research 
team on post-operative days 1-3. We will calculate the average of the OBAS scores obtained. The 
OBAS score is a validated postoperatively calculated, multi-dimensional questionnaire that 
consists of 7 items (Table 3) encompassing not only scale-rated pain score but different aspects 
of analgesia benefits, side effects and overall patient’s satisfaction.53  
The OBAS score is based on 7 questions and ranges from 0 to 28 points that will be 
administered on POD 1 – POD 3. Although these are longitudinal ordinal data, we will be able to 
treat OBAS scores as continuous data in the analyses with the lower score correlating with better 
resolution of the analgesia treatment. A 20% reduction in OBAS geometric mean, a-priori, was 
defined as minimal clinically important difference..57,58  
b) Pain assessments 
Pain scores on a 0-10 verbal response scale will be evaluated, per routine, by the nursing staff 
every four hours while patients remain hospitalized. Pain scores (0-10) will be recorded along 
with the OBAS measurements at rest and then after provocation in the form of a vigorous 
coughing.  
Total opioid consumption as well as intraoperative and postoperative day 1, 2, and 3 totals 
will be collected and converted to milligram morphine equivalents (Table 4).  Patients will not be 
given opioid patches because there is no known conversion to morphine equivalents.  
c) FEV1, FVC and peak flow   
FEV1, FVC and peak flow will be recorded preoperatively at baseline and at bedside, on the 
first postoperative mornings 1, 2 and 3. The FEV1, FVC and peak flows will be measured using 
Easy on-PC Spirometry System (ndd Medical, Andover MA) with the patient in the sitting position. 
The measurements and will be obtained by the qualified research personnel and interpreted by 
the staff pulmonologist. The average of three tests will be considered to be the final result. 
d) Quality-of-Recovery-15 (QoR-15) score  


12 
 
Version 5.0: November 3, 2021 
 
 
The QoR-15 is a quality of recovery score that provides a patient-centered global measure of 
overall health status after surgery and anesthesia. It comprises 15-item questionnaire with range 
of responses from 0-150 (http://links.lww.com/ALN/B274). The patients will be given a 
questionnaire on the first and the third postoperative days, the response collected and the 
difference from the previous days calculated. Myles et al. reported a minimal clinically important 
difference in the QoR-15 score of 8 which will be used in this study.54  
e) Pharmacokinetic (PK) Sample Collection 
Blood samples (4 mL each) will be collected from 16 subjects from the treatment group in order 
to determine pharmacokinetic parameters of liposomal bupivacaine. These samples will be 
collected at the following time stamps after the injection of the liposomal bupivacaine through 
PECS/SAP blocks: 15±5 min, 30±5 min, 1h±5 min, 4h±10 min, 24h±20 min, 32h±20 min, 40h±20 
min, 48h±20 min, 72h±20 min, 84h±20. The samples will be obtained from a dedicated IV line in 
a separate location or from an arterial line. 
The Blood samples will be collected into K2EDTA tubes and will be centrifuged at 1000 to 1200g 
for 10 min to obtain plasma within 1 hour of collection. After centrifugation, the plasma will be 
transferred into polypropylene tubes. The plasma samples will be stored frozen at -20°C or colder 
until shipment. All samples will be shipped frozen with dry ice to ABS Laboratories, Inc. The 
shipment address is as follows: Dr. Mira V. Doig ABS Laboratories, Ltd. 36 Hospital Fields Road 
York, YO10 4DZ, UK 
 
Descriptive and Safety Outcomes 
a) Total ICU length of stay; 
b) Hospital length of stay; 
c) Cumulative non-opioid analgesics included acetaminophen, ketorolac, ibuprofen, gabapentin, 
and pregabalin will be recorded and compared over the initial three postoperative days;  
d) Anxiolytics such as alprazolam, lorazepam, and diazepam will be recorded and compared. 
 
Statistical analysis 
We will compare groups on potentially confounding demographic and preoperative risk factors 
listed in Table 1 using appropriate summary statistics (i.e., mean ± standard deviation, median 
[Q1, Q3], or N (%) as appropriate) as well as surgical and intraoperative data will be collected 
prospectively (Table 2). Randomized groups will be compared on balance on these characteristics 
using absolute standardized difference, defined as the absolute difference in means, mean ranks, 
or proportions divided by the pooled standard deviation.  
Analyses will be modified intent-to-treat, including all randomized patients who received 
PECSII/serratus blocks (regardless of whether it’s consistent with the randomization).  


13 
 
Version 5.0: November 3, 2021 
 
 
 
We will summarize descriptive and safety outcomes by randomized groups using appropriate 
summary statistics (i.e., mean ± standard deviation, median [Q1, Q3], or N (%) as appropriate). 
No statistical tests will be performed on these outcomes. 
We will use an alpha of 0.05 for both the primary and secondary analyses, with a significance 
criterion of 0.05 for the primary analysis and 0.0167 for each secondary analysis (i.e., 0.05/3, 
Bonferroni correction). Analyses will be completed using SAS version 9.4 or newer (SAS Institute, 
Carey, North Carolina) or R version 3.2.4 or newer (R Project for Statistical Computing, Vienna, 
Austria). 
 
Primary analysis 
 
We will estimate the PECS/SAP blocks effect on OBAS scores using a repeated measures linear 
regression model with an autoregressive correlation structure, adjusting for ALL imbalanced 
confounders (if any).  Based on these model we would be able to claim if the PECS/SAP blocks 
had any effect on the OBAS score compared to standard routine analgesia during any of the 
postoperative time up to third postoperative day. Due to non-normality of OBAS score, it will be 
log-transformed for analysis. We will report model based P-value and the geometric mean ratio 
for OBAS scores along with confidence intervals.  To assess whether the PECS/SAP blocks effect 
is heterogeneous over three postop days, we will assess the treatment-by-time interaction using 
a significance criterion of 0.20. If it appears that the treatment effect is heterogeneous, we will 
report the treatment effect separately for each postoperative day POD 1, POD 2 and POD 3 using 
a Bonferroni correction as appropriate (e.g., 0.05/3; 3 postoperative days).  
 
Secondary Analysis 
 
Morphine equivalents will be calculated based on the conversions specified in Table 4 below. 
Total opioid consumption as well as intraoperative and postoperative day 1, 2, and 3 totals will 
be collected and converted to milligram morphine equivalents.  Patients will not be provided 
opioid patches for pain relief because there is no known conversion to morphine equivalents. 
Cumulative opioid consumption data is typically right skewed, so we will normalize it for analyses 
using a log transformation. Opioid consumption will be reported separately for postoperative day 
(POD) 0 after surgery, POD 1, POD2, and POD3. We will estimate the effect of PECS/SAP blocks 
to standard routine analgesia on log cumulative opioid consumption using a repeated measures 
linear regression model with an autoregressive correlation structure, adjusting for any 
imbalanced baseline or surgical characteristics between groups.  
To assess whether the effect of PECS/SAP blocks is heterogeneous over time, we will assess the 
treatment-by-time interaction using a significance criterion of 0.20. If it appears that the 
treatment effect is heterogeneous, we will report the treatment effect separately for each 
postoperative day using a Bonferroni correction as appropriate (e.g., 0.05/3; 3 postoperative 
days).  


14 
 
Version 5.0: November 3, 2021 
 
 
We will estimate the effect of PECS/SAP blocks on FEV1 ,  FVC and peak flow rate using three 
separate repeated measures regression models with an autoregressive correlation structure, 
adjusting for baseline FEV1 ,  FVC , peak flow rate and imbalanced confounders (if any).   
The Wald tests for regression model coefficients will be used to test each of the secondary 
hypotheses; the Bonferroni correction for four outcomes will be employed to control the overall 
Type I error rate at 0.05 for the secondary outcomes. 
 
Exploratory Analysis 
Two separate linear regression models will be developed to assess the relationship between 
analgesia strategy and each of the two exploratory outcomes (quality of recovery after 
anesthesia survey and persistent postoperative surgical pain).  To compare patients from two 
groups on these outcomes mean difference will be reported along with 95% confidence intervals.   
 
Descriptive and Safety Analyses 
We will summarize descriptive and safety outcomes by randomized groups using appropriate 
summary statistics (i.e., mean ± standard deviation, median [Q1, Q3], or N (%) as appropriate). 
No statistical tests will be performed on these outcomes. 
 
 
Sample Size Considerations 
Per Mamoun, observed a coefficient of variation (CV) of 53% in the placebo group of cardiac 
surgery patients.59 We assumed a slightly more conservative CV of 50% and that the treatment 
effect favored PECS/SAP blocks by 20% (i.e., true ratio of geometric means of 0.80). We will need 
to enroll approximately 192 patients (96 per group) to have 90% power at the 0.05 significance 
level to detect superiority of PECS/SAP blocks to standard routine parental and enteral analgesia 
in patients recovering from MICS .  
 
We also plan for two interim analyses at 1/3 and 2/3 of the planned enrollment to assess safety, 
feasibility and formal efficacy and futility. Therefore, interim adjusted sample size is N=98 
patients per group, or N=196 total.  We will use the conservative gamma spending function with 
parameters -5 and -5 for alpha (efficacy) and beta (futility), respectively.  If the alternative 
hypothesis is true (the treatment effect exists) there will be a cumulative probability of 10%, 53% 
and 100% of crossing either an efficacy or futility boundary at the 1st, 2d  and final analyses, 
respectively (Table A and Figure 1 below contains boundary Information). Planned first and 
second interim analyses will be performed upon accrual of 66 and 132 patients respectively. 
Therefore, planned number of patients for the analysis is N=98 patients per group, or N=196 
total. 
 
We will also enroll at least 5 pilot patients in the beginning of the study to test the feasibility of 
protocol adherence and data collection. 


15 
 
Version 5.0: November 3, 2021 
 
 
 
Table A.  Boundary Information for interim analysis (3 analyses = 3 stages): 
Boundary Information (Standardized Z Scale) 
Null Reference = 0 
_Stage_ Information 
Level 
Alternative 
Boundary Values 
Reference 
Lower 
Upper 
Proportion 
Lower 
Upper 
Alpha 
Beta 
Beta 
Alpha 
1 
0.3333 -1.88730 1.88730 -3.18319 -0.02167 0.02167 3.18319 
2 
0.6667 -2.66904 2.66904 -2.64022 -0.53609 0.53609 2.64022 
3 
1.0000 -3.26890 3.26890 -1.97517 -1.97517 1.97517 1.97517 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


16 
 
Version 5.0: November 3, 2021 
 
 
Figure 1. Boundary plot 
 
 
 
Table 1: Patient demographic and preoperative risk factors 
Sex 
Age (years) 
Surgery Type (Robot MVR, thoracotomy MVR, AVR 
through RAT) 
Coronary Artery Disease 
Hypertension 
Pervious Myocardial infarction 
Peripheral Arterial Disease 
Previous vascular surgery 
Smoker (current or former) 
Cerebrovascular disease 
Diabetes mellitus 


17 
 
Version 5.0: November 3, 2021 
 
 
Renal failure:  Indicate whether the patient has 1) a 
documented history of renal failure and/or 2) a history of 
creatinine > 2.0. Prior renal transplant patients are not 
included as pre-op renal failure unless since 
transplantation their creatinine has been or currently is > 
2.0. 
Left ventricular EF 
 
Table 2: Surgical, intraoperative and postoperative data 
Time on CPB 
X-clamp time 
RBCs 
Plt 
FFP 
Cryo 
Inotropes in the OR 
Time to extubation 
Length of ICU stay 
Length of hospital stay 
 Comps-Pulm-Pneumonia 
 Indicate whether the patient had Pneumonia diagnosed by any of 
the following: positive cultures of 
sputum, transtracheal fluid, bronchial washings, and/or clinical 
findings consistent with the diagnosis 
of pneumonia. May include chest X-ray diagnostic of pulmonary 
infiltrates 
 Comps-Pulm-Vent Prol 
 Indicate whether the patient had Pulmonary Insufficiency requiring 
ventilator. Include (but not 
limited to) causes such as ARDS and pulmonary edema and/or any 
patient requiring mechanical 


18 
 
Version 5.0: November 3, 2021 
 
 
ventilation > 24 hours postoperatively 
 Comps-Other-GI Comps 
 Indicate whether the patient had a postoperative occurrence of any 
GI complication including: 
a. GI bleeding requiring transfusion 
b. pancreatitis with abnormal amylase/lipase requiring nasogastric 
(NG) suction therapy 
c. cholecystitis requiring cholecystectomy or drainage 
d. mesenteric ischemia requiring exploration 
e. other GI complication 
 
 
Table 3: OBAS score – To calculate the OBAS score, obtain sum of scores in questions 1–6 and 
add ‘4 minus score in question 7’.   
1 
Please rate your current pain at rest  
0 minimal pain, 1 mild pain, 2 moderate 
pain, 3 severe pain, and 4 maximum 
imaginable pain 
2 
Please grade any distress and bother from vomiting in the past 24 h  
0 = not at all to 4 = very much 
3 
Please grade any distress and bother from itching in the past 24 h  
0 = not at all to 4 = very much  
4 
Please grade any distress and bother from sweating in the past 24 h  
0 = not at all to 4 = very much  
5 
Please grade any distress and bother from freezing in the past 24 h  
0 = not at all to 4 = very much  
6 
Please grade any distress and bother from dizziness in the past 24 h  
0 = not at all to 4 = very much  
7 
How satisfied are you with your pain treatment during the past 24 h  
0 = not at all to 4 = very much  
 
 
 
Table 4: Morphine Equivalent Conversion Table 
Agent 
PO (mg) 
IV (mg) 


19 
 
Version 5.0: November 3, 2021 
 
 
Morphine 
30 
10 
Hydromorphone 
7.5 
1.5 
Fentanyl 
- 
0.1 
Oxycodone 
20 
- 
Hydrocodone 
30 
- 
 
Table 4: Surgical, intraoperative and postoperative data 
Time on CPB 
X-clamp time 
RBCs 
Plt 
FFP 
Cryo 
Inotropes in the OR 
Time to extubation 
Length of ICU stay 
Length of hospital stay 
Intraoperative ultrasound record and image 
of fascial plain blocks (SAP and PECS)   
 
 
 
 
 
References 


20 
 
Version 5.0: November 3, 2021 
 
 
1. 
Goldstone AB, Joseph Woo Y. Minimally invasive surgical treatment of valvular heart 
disease. Seminars in thoracic and cardiovascular surgery 2014;26:36-43. 
2. 
Malaisrie SC, Barnhart GR, Farivar RS, et al. Current era minimally invasive aortic valve 
replacement: techniques and practice. J Thorac Cardiovasc Surg 2014;147:6-14. 
3. 
Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden 
of valvular heart diseases: a population-based study. Lancet 2006;368:1005-11. 
4. 
Langer NB, Argenziano M. Minimally Invasive Cardiovascular Surgery: Incisions and 
Approaches. Methodist Debakey Cardiovasc J 2016;12:4-9. 
5. 
Goldstone AB, Atluri P, Szeto WY, et al. Minimally invasive approach provides at least 
equivalent results for surgical correction of mitral regurgitation: a propensity-matched 
comparison. J Thorac Cardiovasc Surg 2013;145:748-56. 
6. 
Svensson LG, Atik FA, Cosgrove DM, et al. Minimally invasive versus conventional mitral 
valve surgery: a propensity-matched comparison. J Thorac Cardiovasc Surg 2010;139:926-32 e1-
2. 
7. 
Iribarne A, Russo MJ, Easterwood R, et al. Minimally invasive versus sternotomy 
approach for mitral valve surgery: a propensity analysis. Ann Thorac Surg 2010;90:1471-7; 
discussion 7-8. 
8. 
Suri RM, Schaff HV, Meyer SR, Hargrove WC, 3rd. Thoracoscopic versus open mitral 
valve repair: a propensity score analysis of early outcomes. Ann Thorac Surg 2009;88:1185-90. 
9. 
Mihaljevic T, Jarrett CM, Gillinov AM, et al. Robotic repair of posterior mitral valve 
prolapse versus conventional approaches: potential realized. J Thorac Cardiovasc Surg 
2011;141:72-80 e1-4. 
10. 
Glauber M, Miceli A, Canarutto D, et al. Early and long-term outcomes of minimally 
invasive mitral valve surgery through right minithoracotomy: a 10-year experience in 1604 
patients. Journal of cardiothoracic surgery 2015;10:181. 
11. 
Kim BS, Soltesz EG, Cohn LH. Minimally invasive approaches to aortic valve surgery: 
Brigham experience. Seminars in thoracic and cardiovascular surgery 2006;18:148-53. 
12. 
Sharony R, Grossi EA, Saunders PC, et al. Propensity score analysis of a six-year 
experience with minimally invasive isolated aortic valve replacement. The Journal of heart valve 
disease 2004;13:887-93. 
13. 
Mihaljevic T, Cohn LH, Unic D, Aranki SF, Couper GS, Byrne JG. One thousand minimally 
invasive valve operations: early and late results. Annals of surgery 2004;240:529-34; discussion 
34. 
14. 
Glauber M, Gilmanov D, Farneti PA, et al. Right anterior minithoracotomy for aortic 
valve replacement: 10-year experience of a single center. J Thorac Cardiovasc Surg 
2015;150:548-56 e2. 
15. 
Johnston DR, Atik FA, Rajeswaran J, et al. Outcomes of less invasive J-incision approach 
to aortic valve surgery. J Thorac Cardiovasc Surg 2012;144:852-8 e3. 
16. 
Schmitto JD, Mokashi SA, Cohn LH. Minimally-invasive valve surgery. Journal of the 
American College of Cardiology 2010;56:455-62. 
17. 
Bottiger BA, Esper SA, Stafford-Smith M. Pain management strategies for thoracotomy 
and thoracic pain syndromes. Seminars in cardiothoracic and vascular anesthesia 2014;18:45-
56. 


21 
 
Version 5.0: November 3, 2021 
 
 
18. 
Balkhy HH, Arnsdorf S, Krienbring D, Urban J. Liposome Bupivacaine for Postsurgical 
Analgesia in Patients Undergoing Robotically Assisted Cardiac Surgery. Innovations (Phila) 
2015;10:416-9. 
19. 
Suri RM, Antiel RM, Burkhart HM, et al. Quality of life after early mitral valve repair 
using conventional and robotic approaches. Ann Thorac Surg 2012;93:761-9. 
20. 
Falk V, Cheng DC, Martin J, et al. Minimally invasive versus open mitral valve surgery: a 
consensus statement of the international society of minimally invasive coronary surgery 
(ISMICS) 2010. Innovations (Phila) 2011;6:66-76. 
21. 
Rehfeldt KH, Mauermann WJ, Burkhart HM, Suri RM. Robot-assisted mitral valve repair. 
Journal of cardiothoracic and vascular anesthesia 2011;25:721-30. 
22. 
Cheng DC, Martin J, Lal A, et al. Minimally invasive versus conventional open mitral valve 
surgery: a meta-analysis and systematic review. Innovations (Phila) 2011;6:84-103. 
23. 
Anderson MB, Kwong KF, Furst AJ, Salerno TA. Thoracic epidural anesthesia for cardiac 
surgery via left anterior thoracotomy in the conscious patient. The heart surgery forum 
2002;5:105-8. 
24. 
Vernick WJ, Woo JY. Anesthetic considerations during minimally invasive mitral valve 
surgery. Seminars in cardiothoracic and vascular anesthesia 2012;16:11-24. 
25. 
Mehta Y, Arora D, Sharma KK, Mishra Y, Wasir H, Trehan N. Comparison of continuous 
thoracic epidural and paravertebral block for postoperative analgesia after robotic-assisted 
coronary artery bypass surgery. Annals of cardiac anaesthesia 2008;11:91-6. 
26. 
Rodrigues ES, Lynch JJ, Suri RM, et al. Robotic mitral valve repair: a review of anesthetic 
management of the first 200 patients. Journal of cardiothoracic and vascular anesthesia 
2014;28:64-8. 
27. 
Sostaric M, Gersak B, Novak-Jankovic V. Early extubation and fast-track anesthetic 
technique for endoscopic cardiac surgery. The heart surgery forum 2010;13:E190-4. 
28. 
Sostaric M, Gersak B, Novak-Jankovic V. The analgesic efficacy of local anesthetics for 
the incisional administration following port access heart surgery: bupivacaine versus 
ropivacaine. The heart surgery forum 2010;13:E96-E100. 
29. 
Ganapathy S. Anaesthesia for minimally invasive cardiac surgery. Best Pract Res Clin 
Anaesthesiol 2002;16:63-80. 
30. 
Go R, Huang YY, Weyker PD, Webb CA. Truncal blocks for perioperative pain 
management: a review of the literature and evolving techniques. Pain Manag 2016;6:455-68. 
31. 
Blanco R. The 'pecs block': a novel technique for providing analgesia after breast 
surgery. Anaesthesia 2011;66:847-8. 
32. 
Blanco R, Fajardo M, Parras Maldonado T. Ultrasound description of Pecs II (modified 
Pecs I): a novel approach to breast surgery. Rev Esp Anestesiol Reanim 2012;59:470-5. 
33. 
Blanco R, Parras T, McDonnell JG, Prats-Galino A. Serratus plane block: a novel 
ultrasound-guided thoracic wall nerve block. Anaesthesia 2013;68:1107-13. 
34. 
Mayes J, Davison E, Panahi P, et al. An anatomical evaluation of the serratus anterior 
plane block. Anaesthesia 2016;71:1064-9. 
35. 
Chu GM, Jarvis GC. Serratus Anterior Plane Block to Address Post-thoracotomy and 
Chest Tube-related Pain: A Report on 3 Cases. A A Case Rep 2017. 


22 
 
Version 5.0: November 3, 2021 
 
 
36. 
Khalil AE, Abdallah NM, Bashandy GM, Kaddah TA. Ultrasound-Guided Serratus Anterior 
Plane Block Versus Thoracic Epidural Analgesia for Thoracotomy Pain. Journal of cardiothoracic 
and vascular anesthesia 2017;31:152-8. 
37. 
Tighe SQ, Karmakar MK. Serratus plane block: do we need to learn another technique 
for thoracic wall blockade? Anaesthesia 2013;68:1103-6. 
38. 
Durant E, Dixon B, Luftig J, Mantuani D, Herring A. Ultrasound-guided serratus plane 
block for ED rib fracture pain control. Am J Emerg Med 2017;35:197 e3- e6. 
39. 
Viscusi ER, Sinatra R, Onel E, Ramamoorthy SL. The safety of liposome bupivacaine, a 
novel local analgesic formulation. Clin J Pain 2014;30:102-10. 
40. 
<Pacira Letter final.pdf>. 
41. 
Weissman C. Pulmonary complications after cardiac surgery. Seminars in cardiothoracic 
and vascular anesthesia 2004;8:185-211. 
42. 
Albacker TB, Roselli EE, Pettersson GB, et al. Surgical management of right aortic arch 
with tailored surgical approach. Journal of cardiac surgery 2012;27:511-7. 
43. 
Ballantyne JC, Carr DB, deFerranti S, et al. The comparative effects of postoperative 
analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, 
controlled trials. Anesthesia and analgesia 1998;86:598-612. 
44. 
Matyal R, Montealegre-Gallegos M, Shnider M, et al. Preemptive ultrasound-guided 
paravertebral block and immediate postoperative lung function. Gen Thorac Cardiovasc Surg 
2015;63:43-8. 
45. 
Meierhenrich R, Hock D, Kuhn S, et al. Analgesia and pulmonary function after lung 
surgery: is a single intercostal nerve block plus patient-controlled intravenous morphine as 
effective as patient-controlled epidural anaesthesia? A randomized non-inferiority clinical trial. 
British journal of anaesthesia 2011;106:580-9. 
46. 
Blanco R, Parras Maldonado T. Reply to the article entitled "Ultrasound description of 
Pecs II (modified Pecs I): a novel approach to breast surgery". Reply of the authors. Rev Esp 
Anestesiol Reanim 2013;60:296-7. 
47. 
Piracha MM, Thorp SL, Puttanniah V, Gulati A. "A Tale of Two Planes": Deep Versus 
Superficial Serratus Plane Block for Postmastectomy Pain Syndrome. Regional anesthesia and 
pain medicine 2017;42:259-62. 
48. 
Zocca JA, Chen GH, Puttanniah VG, Hung JC, Gulati A. Ultrasound-Guided Serratus Plane 
Block for Treatment of Postmastectomy Pain Syndromes in Breast Cancer Patients: A Case 
Series. Pain Pract 2017;17:141-6. 
49. 
Madabushi R, Tewari S, Gautam SK, Agarwal A, Agarwal A. Serratus anterior plane block: 
a new analgesic technique for post-thoracotomy pain. Pain Physician 2015;18:E421-4. 
50. 
Barbera C, Milito P, Punturieri M, Asti E, Bonavina L. Serratus anterior plane block for 
hybrid transthoracic esophagectomy: a pilot study. J Pain Res 2017;10:73-7. 
51. 
Broseta AM, Errando C, De Andres J, Diaz-Cambronero O, Ortega-Monzo J. Serratus 
plane block: the regional analgesia technique for thoracoscopy? Anaesthesia 2015;70:1329-30. 
52. 
Fu P, Weyker PD, Webb CA. Case Report of Serratus Plane Catheter for Pain 
Management in a Patient With Multiple Rib Fractures and an Inferior Scapular Fracture. A A 
Case Rep 2017;8:132-5. 


23 
 
Version 5.0: November 3, 2021 
 
 
53. 
Lehmann N, Joshi GP, Dirkmann D, et al. Development and longitudinal validation of the 
overall benefit of analgesia score: a simple multi-dimensional quality assessment instrument. 
British journal of anaesthesia 2010;105:511-8. 
54. 
Myles PS, Myles DB, Galagher W, Chew C, MacDonald N, Dennis A. Minimal Clinically 
Important Difference for Three Quality of Recovery Scales. Anesthesiology 2016;125:39-45. 
55. 
Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of 
preemptive analgesia for postoperative pain relief: the role of timing of analgesia. 
Anesthesiology 2002;96:725-41. 
56. 
Kharitonov V. A review of the compatibility of liposome bupivacaine with other drug 
products and commonly used implant materials. Postgrad Med 2014;126:129-38. 
57. 
Mungroop TH, Veelo DP, Busch OR, et al. Continuous wound infiltration versus epidural 
analgesia after hepato-pancreato-biliary surgery (POP-UP): a randomised controlled, open-
label, non-inferiority trial. Lancet Gastroenterol Hepatol 2016;1:105-13. 
58. 
Dirkmann D, Groeben H, Farhan H, Stahl DL, Eikermann M. Effects of parecoxib on 
analgesia benefit and blood loss following open prostatectomy: a multicentre randomized trial. 
BMC Anesthesiol 2015;15:31. 
59. 
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;152:881-9 e1.