Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study

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Mizubuti" }, { "@type": "Person", "name": "Anthony M.-H. Ho" }, { "@type": "Person", "name": "Deborah DuMerton" }, { "@type": "Person", "name": "Rachel Phelan" }, { "@type": "Person", "name": "Wilma M. Hopman" }, { "@type": "Person", "name": "Camilyn Cheng" }, { "@type": "Person", "name": "Jessica Xiong" }, { "@type": "Person", "name": "Jessica Shelley" }, { "@type": "Person", "name": "Elorm Vowotor" }, { "@type": "Person", "name": "Sulaiman Nanji" }, { "@type": "Person", "name": "Diederick Jalink" }, { "@type": "Person", "name": "Lais Helena Navarro e Lima" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": " Background Perioperative thoracic epidural analgesia (TEA) is commonly used in hepatectomy patients since it is opioid-sparing. However, TEA has a high failure rate and is associated with potentially devastating complications (spinal haematoma) and the risk is increased with hepatectomy. Thus, some centres favour systemic opioid-based modalities which, in turn, are associated with inferior analgesia and well-known risks/side-effects. Hence, alternative analgesic methods are desirable. Paravertebral block (PVB) has been used in liver resection with advantages including haemodynamic stability, low failure rates, and low risk of spinal haematoma. The purpose of this pilot RCT is to compare continuous TEA (traditional standard of care is local anesthetic (LA) + opioids) with PVB (traditional standard of care is with LA without opioid) for patients undergoing hepatectomy. We hypothesise that pain outcomes will be comparable between groups, but PVB patients will require fewer perioperative vasopressors/blood products, have fewer opioid-related side effects and a shorter hospital length of stay. Methods With ethics approval, this non-inferiority, pilot RCT with a convenience sample of 50 hepatectomy patients will examine whether PVB imparts analgesia comparable to TEA but with fewer adverse effects. Primary outcomes are surrogates of analgesia for 72 h postoperatively (i.e., opioid consumption, time to first analgesic request and pain scores at rest and with coughing); Secondary outcomes are blood products/fluids administered; side effects/complications until 72 h postoperatively; length of hospital stay. The results will be used to plan a large multicentre trial comparing TEA vs. PVB in hepatectomy patients. This study has a high potential to positively impact the quality/safety of patient care. ClinicalTrials.gov registration NCT02909322 (09-21-2016); Available at URL: https://clinicaltrials.gov/ct2/show/NCT0290932 " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/11-1067/v3", "name": "Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol..." } } ] } Home Browse Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Mizubuti GB, Ho AMH, DuMerton D et al. Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.12688/f1000research.121987.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol Revised Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] Glenio B. Mizubuti https://orcid.org/0000-0002-5515-829X 1 , Anthony M.-H. Ho https://orcid.org/0000-0002-9721-4499 1 , Deborah DuMerton https://orcid.org/0000-0003-0709-468X 1 , [...] Rachel Phelan https://orcid.org/0000-0002-2928-8138 1 , Wilma M. Hopman https://orcid.org/0000-0002-3023-0080 2,3 , Camilyn Cheng https://orcid.org/0000-0002-0815-2610 1 , Jessica Xiong 1 , Jessica Shelley 1 , Elorm Vowotor 1 , Sulaiman Nanji 4 , Diederick Jalink 4 , Lais Helena Navarro e Lima 1 Glenio B. Mizubuti https://orcid.org/0000-0002-5515-829X 1 , Anthony M.-H. Ho https://orcid.org/0000-0002-9721-4499 1 , [...] Deborah DuMerton https://orcid.org/0000-0003-0709-468X 1 , Rachel Phelan https://orcid.org/0000-0002-2928-8138 1 , Wilma M. Hopman https://orcid.org/0000-0002-3023-0080 2,3 , Camilyn Cheng https://orcid.org/0000-0002-0815-2610 1 , Jessica Xiong 1 , Jessica Shelley 1 , Elorm Vowotor 1 , Sulaiman Nanji 4 , Diederick Jalink 4 , Lais Helena Navarro e Lima 1 PUBLISHED 28 Jun 2024 Author details Author details 1 Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, Ontario, K7L2V7, Canada 2 Department of Public Health Sciences, Queen's University, Kingston, Ontario, K7L3N6, Canada 3 Kingston General Hospital Research Institute, Kingston Health Sciences Centre, Kingston, Ontario, K7L2V7, Canada 4 Department of Surgery, Queen's University, Kingston, Ontario, K7L2V7, Canada Glenio B. Mizubuti Roles: Conceptualization, Data Curation, Funding Acquisition, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Anthony M.-H. Ho Roles: Conceptualization, Data Curation, Funding Acquisition, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Deborah DuMerton Roles: Data Curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing Rachel Phelan Roles: Data Curation, Project Administration, Writing – Review & Editing Wilma M. Hopman Roles: Methodology, Writing – Review & Editing Camilyn Cheng Roles: Data Curation, Investigation, Writing – Review & Editing Jessica Xiong Roles: Data Curation, Investigation, Writing – Review & Editing Jessica Shelley Roles: Data Curation, Investigation, Writing – Review & Editing Elorm Vowotor Roles: Data Curation, Investigation, Writing – Review & Editing Sulaiman Nanji Roles: Data Curation, Investigation, Writing – Review & Editing Diederick Jalink Roles: Data Curation, Investigation, Writing – Review & Editing Lais Helena Navarro e Lima Roles: Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Perioperative thoracic epidural analgesia (TEA) is commonly used in hepatectomy patients since it is opioid-sparing. However, TEA has a high failure rate and is associated with potentially devastating complications (spinal haematoma) and the risk is increased with hepatectomy. Thus, some centres favour systemic opioid-based modalities which, in turn, are associated with inferior analgesia and well-known risks/side-effects. Hence, alternative analgesic methods are desirable. Paravertebral block (PVB) has been used in liver resection with advantages including haemodynamic stability, low failure rates, and low risk of spinal haematoma. The purpose of this pilot RCT is to compare continuous TEA (traditional standard of care is local anesthetic (LA) + opioids) with PVB (traditional standard of care is with LA without opioid) for patients undergoing hepatectomy. We hypothesise that pain outcomes will be comparable between groups, but PVB patients will require fewer perioperative vasopressors/blood products, have fewer opioid-related side effects and a shorter hospital length of stay. Methods With ethics approval, this non-inferiority, pilot RCT with a convenience sample of 50 hepatectomy patients will examine whether PVB imparts analgesia comparable to TEA but with fewer adverse effects. Primary outcomes are surrogates of analgesia for 72 h postoperatively (i.e., opioid consumption, time to first analgesic request and pain scores at rest and with coughing); Secondary outcomes are blood products/fluids administered; side effects/complications until 72 h postoperatively; length of hospital stay. The results will be used to plan a large multicentre trial comparing TEA vs. PVB in hepatectomy patients. This study has a high potential to positively impact the quality/safety of patient care. ClinicalTrials.gov registration NCT02909322 (09-21-2016); Available at URL: https://clinicaltrials.gov/ct2/show/NCT0290932 READ ALL READ LESS Keywords Epidural anaesthesia, Non-inferiority trial, Hepatectomy, Paravertebral block, Pilot study, Randomized controlled trial, Regional anaesthesia Corresponding Author(s) Anthony M.-H. Ho ( [email protected] ) Close Corresponding author: Anthony M.-H. Ho Competing interests: No competing interests were disclosed. Grant information: Funding was provided by the Clinical Teachers’ Association of Queen’s (CTAQ) University Endowment Fund (A.M.-H. Ho). The funding agency played no part in study design. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Mizubuti GB et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Mizubuti GB, Ho AMH, DuMerton D et al. Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.12688/f1000research.121987.3 ) First published: 20 Sep 2022, 11 :1067 ( https://doi.org/10.12688/f1000research.121987.1 ) Latest published: 28 Jun 2024, 11 :1067 ( https://doi.org/10.12688/f1000research.121987.3 ) Revised Amendments from Version 2 Changes made between versions 2 and 3: Revised the Abstract, Introduction and Discussion to make it clear that our purpose is to compare 2 anaesthesia practices (as opposed to 2 anaesthesia techniques) for the management of postoperative pain in hepatectomy patients. Specifically, our goal is to compare thoracic epidural anaesthesia with opioid and local anaesthetic to paravertebral (PVB) block with only local anaesthetic. Our hypothesis is that pain outcomes will be comparable between groups but those receiving PVB will require fewer perioperative vasopressors/ blood products, have fewer opioid-related sided effects and have a shorter hospital stay because they did not receive opioids. Changes made between versions 2 and 3: Revised the Abstract, Introduction and Discussion to make it clear that our purpose is to compare 2 anaesthesia practices (as opposed to 2 anaesthesia techniques) for the management of postoperative pain in hepatectomy patients. Specifically, our goal is to compare thoracic epidural anaesthesia with opioid and local anaesthetic to paravertebral (PVB) block with only local anaesthetic. Our hypothesis is that pain outcomes will be comparable between groups but those receiving PVB will require fewer perioperative vasopressors/ blood products, have fewer opioid-related sided effects and have a shorter hospital stay because they did not receive opioids. See the authors' detailed response to the review by Jacques Chelly and Shiv Goel See the authors' detailed response to the review by Heitor J S Medeiros See the authors' detailed response to the review by Andrea De Gasperi READ REVIEWER RESPONSES Introduction Continuous thoracic epidural analgesia (TEA) is commonly used for pain management following hepatectomy 1 – 5 since it is opioid-sparing, reduces cardiovascular/respiratory complications, and improves mobility. 6 However, the safety of TEA in this population has been debated. 7 TEA is associated with rare complications including epidural haematoma/abscess, and spinal cord injury. 5 , 8 These risks may be higher following hepatectomy compared to other surgeries because of postoperative coagulopathy and thrombocytopaenia. 4 , 9 Additionally, up to 37% of TEAs fail due to an inadequate block, a dislodged/leaking catheter, 10 – 13 or because the catheter has veered to the left (providing analgesia opposite to surgical site). TEA is also associated with hypotension, which may necessitate increased volumes of intravenous (i.v.) fluids perioperatively. 11 , 14 , 15 The potential effect of increasing central venous pressure (CVP) with this increased fluid load may exacerbate blood loss and haemodilution. 1 Finally, TEA can delay mobilisation and prolong the need for a urinary catheter. Given these concerns, some centres prefer patient-controlled opioid analgesia (PCA) post-hepatectomy. 16 However, systemic opioids are not as effective for analgesia, and they have serious risk profiles including impaired ventilation, drowsiness, urinary retention, decreased gastrointestinal motility, increased risk of aspiration pneumonia, and postoperative nausea and vomiting (PONV). Thus, there is a continued need for alternative regional analgesic techniques for liver resection patients. Coagulopathy and/or thrombocytopaenia (not uncommon with liver disease), 17 , 18 worsens in the first two postoperative days following hepatectomy and can remain abnormal for up to five days. 4 , 6 , 9 , 19 – 22 This is a consequence of preoperative liver dysfunction (reflected by the Model for End-Stage Liver Disease (MELD) score), 19 the amount of tissue resected, blood loss, and intraoperative liver ischaemia. 14 , 23 , 24 Thoracic paravertebral block (PVB) has been used with several surgical procedures 25 – 36 including ablation of hepatic tumors 35 and hepatectomy. 36 Previous research suggests that advantages include haemodynamic stability, 37 , 38 low failure rate, 39 and a negligible risk of spinal haematoma. 40 , 41 However, there is a small risk of pneumothorax. A right-sided thoracic PVB is a potential alternative to TEA in hepatectomy patients using a right-subcostal incision, but it appears this has not been compared to TEA over an extended time-period. To our knowledge, the only randomised controlled trial (RCT) currently available compared bilateral thoracic PVB to TEA and concluded that TEA provides a modest analgesic benefit. 42 However, patients were only followed for 48 hours which may be insufficient for pain outcomes since hepatectomy patients generally begin to mobilise at 48 hours postoperatively, meaning their pain scores are likely to worsen. Additionally, postoperative coagulopathy and thrombocytopaenia generally peak at 48 hours postoperatively and can persist for extended periods depending upon factors including the capacity of the liver to produce α-1-acid-glycoprotein (AAG), albumin, and coagulation factors, as well as its metabolic capacity (mechanisms which protect against local anaesthetic (LA) systemic toxicity (LAST)). This highlights concerns in the above mentioned study, 42 since even patients with normal liver function can develop LAST with a 48-hour infusion of LA via bilateral PVB. 43 In addition, pain from a right subcostal incision probably does not justify using a left-sided PVB which may further expose potentially “LAST-vulnerable” patients to additional LA. Another study by Richardson et al. (1999) found that thoracotomy patients receiving PVB had less pain and improved pulmonary function than with TEA. 44 The TEA cohort also had a higher incidence of PONV, respiratory complications, hypotension, and consumed more morphine. 44 In another study, PVB patients had less PONV, hypotension, and/or urinary retention compared to TEA. 45 A systematic review of RCTs (comprising 1762 thoracotomy patients) concluded that the most effective analgesic method for preserving spirometric function was PVB. 46 A meta-analysis of thoracotomy studies comparing TEA and PVB concluded that PVB is associated with fewer pulmonary complications and less urinary retention, PONV, and hypotension, albeit with comparable analgesia, 47 and this was later confirmed. 48 Based upon such studies, we decided to compare TEA with opioids (as per widespread traditional standard of care) with right-sided PVB with infusion of LA (as per our institutional standard of care) for perioperative analgesia following hepatectomy. Hypothesis Our hypothesis is that surrogates of pain will be comparable between groups but PVB patients will require fewer vasopressors and i.v. fluids/blood products, have fewer side effects/complications, and have a reduced hospital length of stay (LOS). Protocol Sample size Non-inferiority trials typically require larger samples than superiority trials 49 , 50 ; thus, we anticipate the need to include multiple centres to secure enough participants. Therefore, we propose a single-centre pilot study to generate the data needed to estimate the sample size required for a large, multi-centre trial. Based upon previous studies that compared TEA versus PVB for postoperative analgesia in patients undergoing thoracotomy, 45 , 51 we will aim for a convenience sample of 25 patients per group to generate pilot data upon which to base a larger, multi-centre trial. Our non-inferiority margin will be set at 20% for cumulative opioid consumption at 72 hours postoperatively since we do not consider a difference of <20% to be clinically relevant. Participants, setting and recruitment A convenience sample of 50 patients scheduled to undergo a hepatectomy through a right subcostal incision will be recruited from our medium-sized (~407 beds), tertiary care academic centre. Eligible patients will be approached by research personnel at the preoperative screening clinic or, because of COVID concerns, via telephone at least 24-48 hours before surgery and given information about the study. For patients who are eligible and willing, research personnel will obtain signed consent while they are waiting to be taken to the operating room (OR). In all cases, both the anaesthesiologist and the attending surgeon will be made aware at least one to three days before surgery of the potential involvement of the patient, and time will be allowed for discussion and withdrawal at their request. With the volume of liver resection surgical patients at our centre (i.e., ~30/year), we anticipate recruitment/data collection for 50 patients to require two to three years. Eligibility criteria • Patients will be eligible for inclusion to our study if they are: ○ 18-80 years of age ○ American Society of Anesthesiologists (ASA) physical classification I-III ○ Undergoing elective liver resection through right subcostal incision ○ Proficient in English ○ Competent to provide consent • Patients will not be eligible for our study if they are/have: ○ Pregnant or lactating ○ Do not provide informed consent for participation ○ Body mass index 40 kg.m -2 ○ Dementia or neurological impairment ○ Jaundice (bilirubin >50 μmol/L) ○ Liver resection combined with a secondary surgical procedure ○ Contraindication to neuraxial block (INR ≥1.6, platelet count 8 or predicted liver resection of >500 g) ○ Contraindications to study medications ○ Any type of extended incision that is not restricted to the standard right subcostal incision ○ Remain intubated in the postoperative period ○ Significant heart disease including moderate or severe valvulopathies, left ventricular ejection fraction <35%, moderate or severe cardiomyopathy of any etiology (e.g., ischaemic, dilated, etc.), previous history of malignant arrhythmias (ventricular tachycardia/ventricular fibrillation, prolonged QT syndrome, etc.), or any other cardiac conditions deemed as high surgical risk by anaesthesiologist investigators ○ Pre-existing chronic pain condition requiring chronic opioid intake for >3 months Randomisation This is a randomised, controlled, non-inferiority pilot study. Eligible patients will be randomised using a computer-generated randomisation table prepared by the institutional biostatistician with assignments concealed in envelopes. Participants, surgeons, and dedicated research personnel collecting the data (i.e., study nurses/research assistants) will be blinded to allocation. Anaesthesiologists performing TEA/PVB will not be blinded but will have no involvement in patient assessments/data collection. Data collection and storage To protect confidentiality, patient data on collection sheets/spreadsheets will be identified only by a study identification number that will be linked to the patient identity only on a master sheet/spreadsheet kept securely and separately from the data. Patient data will then be entered into a password-protected REDCAP file and stored on the institutional server behind a firewall. All study data will be retained for the 15-year storage period required by Health Canada following which, it will be permanently deleted and/or destroyed. Only study personnel will have access to identifiable study data and it will not be shared with a third party. Final data may be placed in a public depository but no publicly accessible information will be identifiable. Descriptive demographic data including patient height, weight, age, sex, ASA physical classification, MELD score, comorbidities, type and length of surgical procedure, number of resected liver segments, estimated blood loss, intraoperative complications, surgeon, the main surgical indication, and preoperative functional liver status will be recorded. Study design and ethical approval Ethical approval was provided by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (ANAE-270-15) and the study registered on Clinicaltrials.gov (NCT02909322 09-21-2016) available at URL: https://clinicaltrials.gov/ct2/show/NCT02909322 . This non-inferiority pilot RCT in which hepatectomy patients will be randomly assigned to receive either TEA or PVB for postoperative analgesia, is also in compliance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. As clearly stated in the informed consent, in the unlikely event that participants are injured due to participation in the current study, medical care will be provided to them free of charge until resolution of the problem. By providing consent to participate, they are not waiving their legal rights or releasing the investigator(s) and sponsors from their legal and professional responsibilities. Protocol-version 1.4, 03-23-2022 The standard of care for elective hepatectomy will be followed. Apart from intraoperative management of the regional block and postoperative analgesia, perioperative management will be identical in both groups. After general anaesthesia (GA) induction, invasive monitoring will be with an arterial line with or without a central venous line. Arterial blood gases will be monitored every hour. Fluid management will be at the discretion of the anaesthesiologist. Intraoperative haemodynamics will be managed by adjustment of the depth of GA and vasoactive drugs, and with fluid administration, all at the discretion of the anaesthesiologist. The quantities of crystalloids, colloids and blood products, and the intraoperative fentanyl dosage (up to 5 μg/kg allowed) will be recorded. No long-acting opioid (hydromorphone, morphine) or ketamine will be administered intraoperatively. Prophylactic ondansetron (4 mg) will be administered upon surgical completion. With the exception of unstable patients, tracheal extubation will be carried out in the OR before transfer to the post-anesthetic care unit (PACU). After PACU discharge, patients will be managed in a high dependency unit (step down bed) or the intensive care unit at the discretion of the anaesthesiologist. Interventions Control group: TEA TEA procedures will follow the standard of care at our centre. The TEA catheter will be sited preoperatively at T7-T9 using the landmark technique, and a lignocaine test dose (4-6 mL of 2% lignocaine with epinephrine 1:200,000) will be given. After GA induction, bupivacaine 0.1% with hydromorphone 10 μg/mL will be infused at 6-10 mL/h and five mL boluses will be allowed at 30 min intervals at the discretion of the anaesthesiologist. Upon admission to the PACU, patient-controlled epidural analgesia (PCEA) will be initiated. The PCEA bolus of the same solution will be set at three mL with a lockout period of 30 min, and the epidural infusion of the same solution will be set at six mL/h and adjusted in two mL/h increments (or decrements) up to 10 mL/h depending upon pain scores and sensory block tested with ice in the PACU. If at any time point during the first 72 hours post-surgery patients complain of moderate-severe pain (i.e., >4/10 on a numeric rating scale (NRS) where 0 = no pain, 10 = worst pain imaginable) despite maximal epidural infusion (10 mL/h), a bolus of five mL bupivacaine 0.25% will be given, provided the patient is haemodynamically stable, and the block height will then be re-tested. If two boluses of five mL bupivacaine 0.25% over 60 min (30 min. apart) fail to control pain and there is no demonstrable sensory block upon testing with ice, the catheter will be removed (if coagulation profile allows). The decision to remove the epidural catheter will be made by the clinical management team. Therapeutic failure is defined as catheter removal and/or discontinuation of infusion prior to completion of the study (72 hours postoperative). In this case, patients will be started on a standard i.v. PCA (hydromorphone 0.2 mg/mL, 0.2 mg demand dose, 8 min lockout interval). Intervention group: PVB PVB will be performed following our standard of care protocol. In the institutional block room, a preoperative paravertebral catheter will be sited on the right side at T7-T9 using the landmark technique or under ultrasound guidanceIn the landmark technique, once the appropriate thoracic level is identified, the needle is inserted at 2.5-3 cm lateral to the most cephalad aspect of the spinous process and advanced perpendicular to the skin in all planes to contact the transverse process of the vertebra below. The needle is then walked above the transverse process and gradually advanced until a loss of resistance to saline is felt as the needle tip traverses the thin superior costotransverse ligament. 52 For US-guided PVB, a high-frequency linear US transducer is placed 2.5-3 cm lateral to the most cephalad aspect of the spinous process and oriented vertically at the target thoracic level. Once the transverse process is identified as a “squared” bony structure (note, the identification of a “round” bony structure is usually consistent with the rib, indicating that the probe should be slowly moved medially), the superior/cephalad aspect of the probe is maintained static, while its inferior/caudal aspect is slightly (~30°) rotated counterclockwise until the costotransverse ligament (usually ~0.5 cm superficial to the pleura) is brought into view. The block needle is carefully advanced in plane with the probe in a cephalad direction until it pierces the costotransverse ligament. Correct LA deposition is evidenced by the inferior displacement of the pleura under direct US visualization. A bolus of 20 mL ropivacaine 0.25% will be administered through the block needle followed by catheter advancement into the paravertebral space. An infusion of ropivacaine 0.25% at a rate of 0.1 mL/kg/h will be started shortly after induction of GA. In addition, 5 mL boluses of ropivacaine 0.25% will be allowed at 30 min intervals intraoperatively at the discretion of the anaesthesiologist. Upon transfer to the PACU, patient-controlled paravertebral analgesia (PCPA) will be started. The PCPA bolus will be 5 mL ropivacaine 0.25% with a lockout period of 2 h, and an infusion of ropivacaine 0.25% will be continued at 0.1 mL/kg/h and increased in 2 mL/h increments up to 10 mL/h, depending on the pain scores and sensory block to ice tested in the PACU. This initial infusion will be continued for the first 24 h after surgery, and then reduced by 25% on postoperative day (POD) two, and further reduced another 25% on POD3 to reduce the risk of LAST. Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 μg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids. If at any time point during the first 72 hours post-surgery, patients complain of moderate to severe pain (NRS >4/10) despite maximal PVB infusion (10 mL/h) and if there are no signs of LAST, a bolus of five mL ropivacaine 0.25% will be given, and the sensory block distribution will be re-tested with ice. If two boluses of 5 mL ropivacaine 0.25% over 60 min are unsuccessful in maintaining pain scores <4/10, and there is no demonstrable block on sensory testing with ice, the PVB infusion will be discontinued and the catheter removed (if coagulation profile allows), and the case will be counted as a PVB failure. The decision to remove the PVB catheter will be made by the clinical management team. Therapeutic failure in the PVB group is defined as PVB catheter removal prior to completion of the study at 72 h postoperative. In this case, patients will be started on a standard i.v. PCA (hydromorphone 0.2 mg/mL, 0.2 mg demand dose, eight min lockout interval). All patients will be offered subcutaneous hydromorphone (0.5-1.0 mg) every 1-2 h and upon patient request until they are able to tolerate oral fluids/medications, at which point they will be given oral hydromorphone (1-2 mg every 4 h) as required starting on the morning of POD2. A member of the research team (blinded to randomisation) will assess the presence/severity of pain and PONV. The assessment will be performed 30 min after arrival to the PACU, and at 4, 8, 24, 48, and 72 h postoperatively. We will ask all patients to rate their pain (NRS scale) at rest and with coughing and their PONV at each of the above listed time points. An antiemetic will be offered to any patients with a PONV score ≥ 2 (where 0 = none, 1 = mild, 2 = moderate, 3 = severe (retching/vomiting)). At 72 hours postoperatively, patient satisfaction with analgesia will be assessed. As alluded to, our protocol follows the standard institutional practice for TEA and PVB, including specific LAs used and infusion regimens. Any changes to the study protocol will be amended to the approved ethics application and communicated to all involved in study execution. Adverse events Serious adverse events (SAEs) such as epidural haematoma or abscess, pneumothorax, LAST, serious respiratory depression, massive transfusion, refractory hypotension, myocardial infarction, will be reported as per standard of care for our centre and also to the institutional research ethics board as required. All SAEs will be documented and discussed by investigators. If deemed to have potentially resulted from the study protocol, the study will be halted pending further independent investigation. Outcomes The primary outcomes will be pain surrogates during the first 72 hours postoperatively: cumulative opioid consumption, time between the end of surgery and first analgesic request, pain scores (NRS) at rest and with coughing 30 min following arrival to the PACU and then at 4, 8, 24, 48 and 72 hours postoperatively ( Figure 1 ). Figure 1. Schedule of enrolment, interventions, and assessments. Secondary outcomes will be PONV scores, patient satisfaction with analgesia (where 1 = very poor, 2 = poor, 3 = satisfactory, 4 = good, 5 = excellent) at 72 hours, and success/failure of TEA/PVB ( Figure 1 ). Haemodynamic parameters will also be recorded (i.e., mean arterial pressure (MAP), CVP (if applicable), urine output, acid-base data, total volume i.v. fluids (crystalloids, colloids, and blood products) and vasopressors given perioperatively up to 72 hours postoperatively), the number of days to resume a full oral diet, hospital LOS, and any complications/side effects. Additionally, postoperative adverse events will be recorded, including hypotension (MAP<50 mmHg) requiring intervention, respiratory depression, sedation (Ramsay score), urinary retention, and pruritus. Statistical analyses Data will be entered into REDCAP and then imported to SPSS (ver. 29.0 for Windows, Armonk, NY, 2022) for data analysis. Data will be analysed using an intent-to-treat strategy, regardless of whether the catheter is removed early. Since intent-to-treat strategies are often “anti-conservative” when used in non-inferiority trials, 53 we will also analyse our data using the per-protocol strategy, excluding those participants who were excluded, lost, or deviated from the protocol. All continuous data will be checked for normality using the Shapiro-Wilk test. The two groups will be compared using Student’s t -tests for normally distributed data, and the Mann-Whitney U for non-normally distributed data. Continuous data collected at several points in time, such as pain, PONV, patient satisfaction, and sedation scores, will be compared using the repeated measures ANOVA (Tukey’s post hoc test for comparisons between individual time points), or the Friedman test (Wilcoxon signed rank test with Bonferroni adjustment for comparison between individual time points) for non-normally distributed data. Categorical data will be compared using Pearson’s Chi Square test, or the Fisher’s Exact test, as appropriate. No adjustments will be made for multiple comparisons, no adjustment or imputation will be made for missing data, and a p-value of <0.05 will be used as the criteria for statistical significance. Discussion After major surgery such as hepatectomy and other upper abdominal surgery, inadequate analgesia can adversely affect cardiorespiratory function. Over-reliance on opioids can delay postoperative rehabilitation and may increase the risk of long-term opioid dependence. Use of regional analgesia with LA can mitigate the risks associated with systemic opioids. Although TEA does provide satisfactory postoperative analgesia and remains the current standard of care for liver resection patients, it still has a significant failure rate, and disadvantages (outlined above) with respect to haemodynamic instability, pruritus, urinary retention and lower limb weakness. It is also associated with other rare but potentially devastating complications (i.e., haematoma, abscess and/or spinal cord injury). A right thoracic PVB with LA has a much lower risk of spinal cord injury, and less (or even a negligible) chance of causing hypotension, lower rates of limb weakness, pruritus, urinary retention, and a zero chance of ‘veering to the left’. However, it does carry small risks of pneumothorax and LAST. Because PVB is used less frequently than epidurals, some anaesthesiologists may find a PVB technically more challenging. Study status: Currently recruiting. Dissemination plans This study will be used to design a powered, multi-centre RCT comparing TEA to PVB in hepatectomy patients. This work has a high potential to positively impact the quality and safety of care in the liver resection patient population with a reduction in associated costs. Upon completion, study results will be disseminated through international conferences and peer reviewed publication(s). Results will also be communicated to anaesthesiologists and hepatic surgeons at other centres. Data availability No data are associated with this article. Reporting guidelines Queen’s University Dataverse. SPIRIT checklist. DOI: https://doi.org/10.5683/SP3/M0VO8N 54 This dataset is available under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. Author contributions Glenio B. Mizubuti: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Writing – Original Draft Preparation; Writing – Review and Editing Anthony M-H. Ho: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Writing – Original Draft Preparation; Writing – Review and Editing Deborah DuMerton: Methodology, Investigation, Project administration, Supervision, Data curation, Writing – Review and Editing Rachel Phelan: Data curation, Project administration, Writing – Review and Editing Wilma M. Hopman: Methodology, Writing – Review and Editing Camilyn Cheng: Data curation, Investigation, Writing – Review and Editing Jessica Xiong: Data curation, Investigation, Writing – Review and Editing Jessica Shelley: Data curation, Investigation, Writing – Review and Editing Elorm Vowotor: Data curation, Investigation, Writing – Review and Editing Sulaiman Nanji: Data curation, Investigation, Writing – Review and Editing Diederick Jalink: Data curation, Investigation, Writing – Review and Editing Lais Helena Navarro e Lima: Writing – Review and Editing All authors reviewed and approved the final manuscript for submission and can attest to the originality of this work. In addition, all authors made important intellectual contributions. References 1. Page A, Rostad B, Staley CA, et al. : Epidural analgesia in hepatic resection. J. Am. Coll. Surg. 2008; 206 : 1184–1192. Publisher Full Text 2. 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Jones B, Jarvis P, Lewis A, et al. : Trials to assess equivalence: The importance of rigorous methods. BMJ. 1996; 313 : 36–39. PubMed Abstract | Publisher Full Text | Free Full Text 50. Piaggio G, Elbourne DR, Altman DG, et al. : Reporting of noninferiority and equivalence randomized trials: An extension of the CONSORT statement. JAMA 2006; 295 : 1152–1160. PubMed Abstract | Publisher Full Text 51. Grider JS, Mullet TW, Saha SP, et al. : A randomized, double-blind trial comparing continuous thoracic epidural bupivacaine with and without opioid in contrast to a continuous paravertebral infusion of bupivacaine for post-thoracotomy pain. J. Cardiothorac. Vasc. Anesth. 2012; 26 : 83–89. PubMed Abstract | Publisher Full Text 52. Karmakar MK, Ho AMH: Thoracic and lumbar paravertebral block. The New York School of Regional Anesthesia textbook of regional anesthesia and acute pain management. New York: McGraw-Hill; 2007; pp. 583–597. 53. Brittain E, Lin D: A comparison of intent-to-treat and per-protocol results in antibiotic non-inferiority trials. Stat. Med. 2005; 24 : 1–10. PubMed Abstract | Publisher Full Text 54. Mizubuti GB, Ho AM-H, DuMerton D, et al. : Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): protocol for a randomized controlled pilot study. Borealis 2022; V1 . Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 20 Sep 2022 ADD YOUR COMMENT Comment Author details Author details 1 Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, Ontario, K7L2V7, Canada 2 Department of Public Health Sciences, Queen's University, Kingston, Ontario, K7L3N6, Canada 3 Kingston General Hospital Research Institute, Kingston Health Sciences Centre, Kingston, Ontario, K7L2V7, Canada 4 Department of Surgery, Queen's University, Kingston, Ontario, K7L2V7, Canada Glenio B. Mizubuti Roles: Conceptualization, Data Curation, Funding Acquisition, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Anthony M.-H. Ho Roles: Conceptualization, Data Curation, Funding Acquisition, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Deborah DuMerton Roles: Data Curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing Rachel Phelan Roles: Data Curation, Project Administration, Writing – Review & Editing Wilma M. Hopman Roles: Methodology, Writing – Review & Editing Camilyn Cheng Roles: Data Curation, Investigation, Writing – Review & Editing Jessica Xiong Roles: Data Curation, Investigation, Writing – Review & Editing Jessica Shelley Roles: Data Curation, Investigation, Writing – Review & Editing Elorm Vowotor Roles: Data Curation, Investigation, Writing – Review & Editing Sulaiman Nanji Roles: Data Curation, Investigation, Writing – Review & Editing Diederick Jalink Roles: Data Curation, Investigation, Writing – Review & Editing Lais Helena Navarro e Lima Roles: Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information Funding was provided by the Clinical Teachers’ Association of Queen’s (CTAQ) University Endowment Fund (A.M.-H. Ho). The funding agency played no part in study design. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (3) version 3 Revised Published: 28 Jun 2024, 11:1067 https://doi.org/10.12688/f1000research.121987.3 version 2 Revised Published: 03 Jun 2024, 11:1067 https://doi.org/10.12688/f1000research.121987.2 version 1 Published: 20 Sep 2022, 11:1067 https://doi.org/10.12688/f1000research.121987.1 Copyright © 2024 Mizubuti GB et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Mizubuti GB, Ho AMH, DuMerton D et al. Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.12688/f1000research.121987.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 3 VERSION 3 PUBLISHED 28 Jun 2024 Revised Views 0 Cite How to cite this report: De Gasperi A. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.168365.r296648 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v3#referee-response-296648 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 08 Jul 2024 Andrea De Gasperi , [Retired], ASST Great Metropolitan Niguarda, Milan, Italy Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.168365.r296648 I am not full convinced of the answers I had from the Authors' revisions and response. Since this is an ongoing trial still recruiting patients as assessed by the authors, I dare suggest to wait for the results to study ... Continue reading READ ALL I am not full convinced of the answers I had from the Authors' revisions and response. Since this is an ongoing trial still recruiting patients as assessed by the authors, I dare suggest to wait for the results to study the completed series and to submit a proof of concept article and not only a project. Then, my suggestion is "Not to Accept" the article as it is. Competing Interests: No competing interests were disclosed. Reviewer Expertise: anesthesia , intensive care, abdominal organ transplants, infections I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT De Gasperi A. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.168365.r296648 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v3#referee-response-296648 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 2 VERSION 2 PUBLISHED 03 Jun 2024 Revised Views 0 Cite How to cite this report: Medeiros HJS. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.166251.r285904 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v2#referee-response-285904 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 18 Jun 2024 Heitor J S Medeiros , DACCPM, Massachussets General Hospital, Boston, MA, USA Approved VIEWS 0 https://doi.org/10.5256/f1000research.166251.r285904 The authors comments sufficiently ... Continue reading READ ALL The authors comments sufficiently address my previous concerns. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Anesthesiology, regional anesthesia I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Medeiros HJS. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.166251.r285904 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v2#referee-response-285904 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Chelly J and Goel S. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.166251.r285905 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v2#referee-response-285905 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 08 Jun 2024 Jacques Chelly , Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Shiv Goel , Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.166251.r285905 The proposed solution to be infused following a PVB block or an epidural remain the same as in the original version. They authors really need to understand that it is not possible to compare the efficacy of these 2 techniques ... Continue reading READ ALL The proposed solution to be infused following a PVB block or an epidural remain the same as in the original version. They authors really need to understand that it is not possible to compare the efficacy of these 2 techniques when one technique (Epidural is infused with opioid) and the other only receive local anesthetics (PVB). In these conditions, the authors give me no choice but to again recommend that this not be approved unless it is clearly stated in the background that the proposed protocol is based on the standard technique being used in your institution and that the goal of the study is to compare an Epidural infused with a solution of ............ to a continuous PVB infused with ............ in term of a/ b/ .......... It is understood that the proposed protocol is not to compare the use of epidural vs continuous PVB because our standard of care is based of using different solutions for Epidural and PVB. Basically the authors have not addressed my comment about the use of 2 different solutions one specific to the epidural with opioid and the second got PVB containing no opioids. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Regioaal Anesthesia and Pain We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Chelly J and Goel S. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.166251.r285905 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v2#referee-response-285905 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 29 Jun 2024 Anthony Ho , Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada 29 Jun 2024 Author Response Dear Drs. Chelly and Goel, Thank you for taking the time to review the second version of our protocol. Please see our responses to your comments below and the ... Continue reading Dear Drs. Chelly and Goel, Thank you for taking the time to review the second version of our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Comments from Drs Chelly and Goal and authors responses NOT APPROVED The proposed solution to be infused following a PVB block or an epidural remain the same as in the original version. They authors really need to understand that it is not possible to compare the efficacy of these 2 techniques when one technique (Epidural is infused with opioid) and the other only receive local anesthetics (PVB). In these conditions, the authors give me no choice but to again recommend that this not be approved unless it is clearly stated in the background that the proposed protocol is based on the standard technique being used in your institution and that the goal of the study is to compare an Epidural infused with a solution of ............ to a continuous PVB infused with ............ in term of a/b/ Apologies that we did not previously make this clear. In fact, our objective is to compare two standard of care anesthesia practices used for postoperative pain control in hepatectomy patients. The whole reason we hypothesise that PVB will have comparable analgesia but with reduced side-effects is because there is LA in the PVB to provide pain relief but no opioid infusion to cause adverse side effects and prolong the length of hospital stay. .......... It is understood that the proposed protocol is not to compare the use of epidural vs continuous PVB because our standard of care is based of using different solutions for Epidural and PVB. Basically the authors have not addressed my comment about the use of 2 different solutions one specific to the epidural with opioid and the second got PVB containing no opioids. Our intention was never to compare the “techniques” in isolation which would definitely require equal solutions and we never stated this as our aim. However, we have now better clarified what our aim was both in the Abstract and the end of the Introduction. We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. Dear Drs. Chelly and Goel, Thank you for taking the time to review the second version of our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Comments from Drs Chelly and Goal and authors responses NOT APPROVED The proposed solution to be infused following a PVB block or an epidural remain the same as in the original version. They authors really need to understand that it is not possible to compare the efficacy of these 2 techniques when one technique (Epidural is infused with opioid) and the other only receive local anesthetics (PVB). In these conditions, the authors give me no choice but to again recommend that this not be approved unless it is clearly stated in the background that the proposed protocol is based on the standard technique being used in your institution and that the goal of the study is to compare an Epidural infused with a solution of ............ to a continuous PVB infused with ............ in term of a/b/ Apologies that we did not previously make this clear. In fact, our objective is to compare two standard of care anesthesia practices used for postoperative pain control in hepatectomy patients. The whole reason we hypothesise that PVB will have comparable analgesia but with reduced side-effects is because there is LA in the PVB to provide pain relief but no opioid infusion to cause adverse side effects and prolong the length of hospital stay. .......... It is understood that the proposed protocol is not to compare the use of epidural vs continuous PVB because our standard of care is based of using different solutions for Epidural and PVB. Basically the authors have not addressed my comment about the use of 2 different solutions one specific to the epidural with opioid and the second got PVB containing no opioids. Our intention was never to compare the “techniques” in isolation which would definitely require equal solutions and we never stated this as our aim. However, we have now better clarified what our aim was both in the Abstract and the end of the Introduction. We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. Competing Interests: No competing interests Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 29 Jun 2024 Anthony Ho , Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada 29 Jun 2024 Author Response Dear Drs. Chelly and Goel, Thank you for taking the time to review the second version of our protocol. Please see our responses to your comments below and the ... Continue reading Dear Drs. Chelly and Goel, Thank you for taking the time to review the second version of our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Comments from Drs Chelly and Goal and authors responses NOT APPROVED The proposed solution to be infused following a PVB block or an epidural remain the same as in the original version. They authors really need to understand that it is not possible to compare the efficacy of these 2 techniques when one technique (Epidural is infused with opioid) and the other only receive local anesthetics (PVB). In these conditions, the authors give me no choice but to again recommend that this not be approved unless it is clearly stated in the background that the proposed protocol is based on the standard technique being used in your institution and that the goal of the study is to compare an Epidural infused with a solution of ............ to a continuous PVB infused with ............ in term of a/b/ Apologies that we did not previously make this clear. In fact, our objective is to compare two standard of care anesthesia practices used for postoperative pain control in hepatectomy patients. The whole reason we hypothesise that PVB will have comparable analgesia but with reduced side-effects is because there is LA in the PVB to provide pain relief but no opioid infusion to cause adverse side effects and prolong the length of hospital stay. .......... It is understood that the proposed protocol is not to compare the use of epidural vs continuous PVB because our standard of care is based of using different solutions for Epidural and PVB. Basically the authors have not addressed my comment about the use of 2 different solutions one specific to the epidural with opioid and the second got PVB containing no opioids. Our intention was never to compare the “techniques” in isolation which would definitely require equal solutions and we never stated this as our aim. However, we have now better clarified what our aim was both in the Abstract and the end of the Introduction. We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. Dear Drs. Chelly and Goel, Thank you for taking the time to review the second version of our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Comments from Drs Chelly and Goal and authors responses NOT APPROVED The proposed solution to be infused following a PVB block or an epidural remain the same as in the original version. They authors really need to understand that it is not possible to compare the efficacy of these 2 techniques when one technique (Epidural is infused with opioid) and the other only receive local anesthetics (PVB). In these conditions, the authors give me no choice but to again recommend that this not be approved unless it is clearly stated in the background that the proposed protocol is based on the standard technique being used in your institution and that the goal of the study is to compare an Epidural infused with a solution of ............ to a continuous PVB infused with ............ in term of a/b/ Apologies that we did not previously make this clear. In fact, our objective is to compare two standard of care anesthesia practices used for postoperative pain control in hepatectomy patients. The whole reason we hypothesise that PVB will have comparable analgesia but with reduced side-effects is because there is LA in the PVB to provide pain relief but no opioid infusion to cause adverse side effects and prolong the length of hospital stay. .......... It is understood that the proposed protocol is not to compare the use of epidural vs continuous PVB because our standard of care is based of using different solutions for Epidural and PVB. Basically the authors have not addressed my comment about the use of 2 different solutions one specific to the epidural with opioid and the second got PVB containing no opioids. Our intention was never to compare the “techniques” in isolation which would definitely require equal solutions and we never stated this as our aim. However, we have now better clarified what our aim was both in the Abstract and the end of the Introduction. We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. Competing Interests: No competing interests Close Report a concern COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 20 Sep 2022 Views 0 Cite How to cite this report: Medeiros HJS. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.133913.r249114 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v1#referee-response-249114 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 23 May 2024 Heitor J S Medeiros , DACCPM, Massachussets General Hospital, Boston, MA, USA Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.133913.r249114 The study's purpose and goals are clearly explained. It addresses the risks and downsides of TEA and explores if PVB can provide the same pain relief with fewer complications. Design flaws: Different drugs are used for ... Continue reading READ ALL The study's purpose and goals are clearly explained. It addresses the risks and downsides of TEA and explores if PVB can provide the same pain relief with fewer complications. Design flaws: Different drugs are used for TEA and PVB, which could affect the results - Is the result coming from technique or simply by drug differences? This needs to be well adressed in discussion. Using the same anesthetic for both groups would provide a clearer comparison. The study uses both blind and ultrasound-guided PVB, which adds variability. Sticking to one method (eg ultrasound) would have improved consistency. The protocol for intravenous hydromorphone administration is not ideal as it doesn’t consider patient pain levels - why is this done this way? institutional protocol? please clarify and adress accordingly . Adjusting doses based on pain levels would be more effective? Are the datasets clearly presented in a usable and accessible format? Partly : While data storage and recording are described, the format isn't clear. This could impact external validity. Providing examples as supplementary material or templates of the datasets would improve clarity. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Anesthesiology, regional anesthesia I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Medeiros HJS. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.133913.r249114 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v1#referee-response-249114 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 05 Jun 2024 Anthony Ho , Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada 05 Jun 2024 Author Response Dear Dr. Medeiros, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revisions made to the second version ... Continue reading Dear Dr. Medeiros, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revisions made to the second version of the manuscript uploaded to F1000. Best Regards, Anthony Ho Dr. Medeiros’ comments and the authors responses: NOT APPROVED The study's purpose and goals are clearly explained. It addresses the risks and downsides of TEA and explores if PVB can provide the same pain relief with fewer complications. Response: Thank you. Design flaws: Different drugs are used for TEA and PVB, which could affect the results - Is the result coming from technique or simply by drug differences? This needs to be well adressed in discussion. Using the same anesthetic for both groups would provide a clearer comparison. Response: Your comment is very similar to one asked by Chelly and Goel in the first review to which we responded: “As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” The study uses both blind and ultrasound-guided PVB, which adds variability. Sticking to one method (eg ultrasound) would have improved consistency. RESPONSE: Once again your concern is virtually the same as one noted by previous reviewers to which we responded: “US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice.” We have now described both the blind and US-guided methods within the text (page 8). The protocol for intravenous hydromorphone administration is not ideal as it doesn’t consider patient pain levels - why is this done this way? institutional protocol? please clarify and adress accordingly . Adjusting doses based on pain levels would be more effective? Response: Once again, your comment is very similar to one made by Drs. Chelly and Goel to which we responded: “Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency.” Are the datasets clearly presented in a usable and accessible format? Partly : While data storage and recording are described, the format isn't clear. This could impact external validity. Providing examples as supplementary material or templates of the datasets would improve clarity. Response: Given that this is a protocol manuscript and not a final manuscript with results, the authors believe the data collection processes are adequately described. As stated previously, final data may be placed into a public depository although no identifiable information will be used. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Anesthesiology, Regional anesthesia I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Dear Dr. Medeiros, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revisions made to the second version of the manuscript uploaded to F1000. Best Regards, Anthony Ho Dr. Medeiros’ comments and the authors responses: NOT APPROVED The study's purpose and goals are clearly explained. It addresses the risks and downsides of TEA and explores if PVB can provide the same pain relief with fewer complications. Response: Thank you. Design flaws: Different drugs are used for TEA and PVB, which could affect the results - Is the result coming from technique or simply by drug differences? This needs to be well adressed in discussion. Using the same anesthetic for both groups would provide a clearer comparison. Response: Your comment is very similar to one asked by Chelly and Goel in the first review to which we responded: “As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” The study uses both blind and ultrasound-guided PVB, which adds variability. Sticking to one method (eg ultrasound) would have improved consistency. RESPONSE: Once again your concern is virtually the same as one noted by previous reviewers to which we responded: “US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice.” We have now described both the blind and US-guided methods within the text (page 8). The protocol for intravenous hydromorphone administration is not ideal as it doesn’t consider patient pain levels - why is this done this way? institutional protocol? please clarify and adress accordingly . Adjusting doses based on pain levels would be more effective? Response: Once again, your comment is very similar to one made by Drs. Chelly and Goel to which we responded: “Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency.” Are the datasets clearly presented in a usable and accessible format? Partly : While data storage and recording are described, the format isn't clear. This could impact external validity. Providing examples as supplementary material or templates of the datasets would improve clarity. Response: Given that this is a protocol manuscript and not a final manuscript with results, the authors believe the data collection processes are adequately described. As stated previously, final data may be placed into a public depository although no identifiable information will be used. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Anesthesiology, Regional anesthesia I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Competing Interests: The authors have no competing interests to declare. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 05 Jun 2024 Anthony Ho , Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada 05 Jun 2024 Author Response Dear Dr. Medeiros, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revisions made to the second version ... Continue reading Dear Dr. Medeiros, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revisions made to the second version of the manuscript uploaded to F1000. Best Regards, Anthony Ho Dr. Medeiros’ comments and the authors responses: NOT APPROVED The study's purpose and goals are clearly explained. It addresses the risks and downsides of TEA and explores if PVB can provide the same pain relief with fewer complications. Response: Thank you. Design flaws: Different drugs are used for TEA and PVB, which could affect the results - Is the result coming from technique or simply by drug differences? This needs to be well adressed in discussion. Using the same anesthetic for both groups would provide a clearer comparison. Response: Your comment is very similar to one asked by Chelly and Goel in the first review to which we responded: “As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” The study uses both blind and ultrasound-guided PVB, which adds variability. Sticking to one method (eg ultrasound) would have improved consistency. RESPONSE: Once again your concern is virtually the same as one noted by previous reviewers to which we responded: “US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice.” We have now described both the blind and US-guided methods within the text (page 8). The protocol for intravenous hydromorphone administration is not ideal as it doesn’t consider patient pain levels - why is this done this way? institutional protocol? please clarify and adress accordingly . Adjusting doses based on pain levels would be more effective? Response: Once again, your comment is very similar to one made by Drs. Chelly and Goel to which we responded: “Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency.” Are the datasets clearly presented in a usable and accessible format? Partly : While data storage and recording are described, the format isn't clear. This could impact external validity. Providing examples as supplementary material or templates of the datasets would improve clarity. Response: Given that this is a protocol manuscript and not a final manuscript with results, the authors believe the data collection processes are adequately described. As stated previously, final data may be placed into a public depository although no identifiable information will be used. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Anesthesiology, Regional anesthesia I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Dear Dr. Medeiros, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revisions made to the second version of the manuscript uploaded to F1000. Best Regards, Anthony Ho Dr. Medeiros’ comments and the authors responses: NOT APPROVED The study's purpose and goals are clearly explained. It addresses the risks and downsides of TEA and explores if PVB can provide the same pain relief with fewer complications. Response: Thank you. Design flaws: Different drugs are used for TEA and PVB, which could affect the results - Is the result coming from technique or simply by drug differences? This needs to be well adressed in discussion. Using the same anesthetic for both groups would provide a clearer comparison. Response: Your comment is very similar to one asked by Chelly and Goel in the first review to which we responded: “As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” The study uses both blind and ultrasound-guided PVB, which adds variability. Sticking to one method (eg ultrasound) would have improved consistency. RESPONSE: Once again your concern is virtually the same as one noted by previous reviewers to which we responded: “US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice.” We have now described both the blind and US-guided methods within the text (page 8). The protocol for intravenous hydromorphone administration is not ideal as it doesn’t consider patient pain levels - why is this done this way? institutional protocol? please clarify and adress accordingly . Adjusting doses based on pain levels would be more effective? Response: Once again, your comment is very similar to one made by Drs. Chelly and Goel to which we responded: “Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency.” Are the datasets clearly presented in a usable and accessible format? Partly : While data storage and recording are described, the format isn't clear. This could impact external validity. Providing examples as supplementary material or templates of the datasets would improve clarity. Response: Given that this is a protocol manuscript and not a final manuscript with results, the authors believe the data collection processes are adequately described. As stated previously, final data may be placed into a public depository although no identifiable information will be used. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Anesthesiology, Regional anesthesia I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Competing Interests: The authors have no competing interests to declare. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: De Gasperi A. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.133913.r235497 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v1#referee-response-235497 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 04 Mar 2024 Andrea De Gasperi , [Retired], ASST Great Metropolitan Niguarda, Milan, Italy Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.133913.r235497 1) Postoperative hemostatic profile is not by default pro-hemorrhagic particularly in case of neoplastic diseases or in HCC in patients included in CHILD A / MELD < 11. 2) Viscoelastic tests should be strongly considered (TEG/ROTEM) to describe the ... Continue reading READ ALL 1) Postoperative hemostatic profile is not by default pro-hemorrhagic particularly in case of neoplastic diseases or in HCC in patients included in CHILD A / MELD < 11. 2) Viscoelastic tests should be strongly considered (TEG/ROTEM) to describe the pre/intra/post hemostatic profile.: to be considered the "rebalanced hemostasis " in cirrhotic patiens (Tripodi et al Am J Gastroenterol, 2017; 112: 274-81 1 3) for the periop hemostatic profile in liver resection please consider also a) Cerutti et al Liver transplantation 2004; 10: 289-94 2 ---b) DePietri et al, World J Gastroenterol, 2018; 24: 2931-48 3 4) 50 pts to be randomized : please provide the statistical justification of this number (enough power ??) 5) First lines of the "Discussion" seem to be to too dramatic" "Inadequate analgesia can lead to hypertension, tachycardia, pulmonary splinting, and inability to breathe deeply and cough. The result could be myocardial ischaemia, pneumonia, and/or the need for prolonged respiratory support.". I would be much more concerned for these complications (particularly for MACEs, respiratory complications ) for the intraop anesthetic management 6) CFR to be provided Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Partly References 1. Tripodi A, Primignani M, Mannucci PM, Caldwell SH: Changing Concepts of Cirrhotic Coagulopathy. Am J Gastroenterol . 2017; 112 (2): 274-281 PubMed Abstract | Publisher Full Text 2. Cerutti E, Stratta C, Romagnoli R, Schellino MM, et al.: Thromboelastogram monitoring in the perioperative period of hepatectomy for adult living liver donation. Liver Transpl . 2004; 10 (2): 289-94 PubMed Abstract | Publisher Full Text 3. De Pietri L, Montalti R, Nicolini D, Troisi RI, et al.: Perioperative thromboprophylaxis in liver transplant patients. World J Gastroenterol . 2018; 24 (27): 2931-2948 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: anesthesia , intensive care, abdominal organ transplants, infections I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT De Gasperi A. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.133913.r235497 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v1#referee-response-235497 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 21 Jun 2024 Anthony Ho , Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada 21 Jun 2024 Author Response Dear Dr. De Gasperi, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript ... Continue reading Dear Dr. De Gasperi, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Postoperative hemostatic profile is not by default pro-hemorrhagic particularly in case of neoplastic diseases or in HCC in patients included in CHILD A / MELD < 11. RESPONSE: We acknowledge that preoperative liver functional status is one of several major factors influencing postoperative hemostatic function (please see 2 nd paragraph of Introduction). Viscoelastic tests should be strongly considered (TEG/ROTEM) to describe the pre/intra/post hemostatic profile.: to be considered the "rebalanced hemostasis " in cirrhotic patients (Tripodi et al Am J Gastroenterol, 2017; 112: 274-81 1 3) for the periop hemostatic profile in liver resection please consider also a) Cerutti et al Liver transplantation 2004; 10: 289-94 2 ---b) DePietri et al, World J Gastroenterol, 2018; 24: 2931-48 RESPONSE: Thank you for emphasizing the potentially crucial role of thromboelastometry/graphy in discerning hemostatic status. We acknowledge the complex nature of coagulation in many clinical situations, including liver resection with or without cancer and/or cirrhosis. However, TEG/ROTEM’s role in liver resection and neuraxial block is still not well established. This area is indeed ripe for more research endeavors but is not the goal of our project. Future research may very well show that TEG/ROTEM results can be important indicators as to whether neuraxial blocks should be contraindicated but at the present time, platelet count and INR remain the standard tests (however imperfect). As we are only using the platelet count and INR to exclude patients preoperatively as per industry standard and are not studying hemostatic changes associated with liver resection, we respectfully decline to include the Tripodi, Cerutti, and De Pietri references thoughtfully suggested. 3) 50 pts to be randomized: please provide the statistical justification of this number (enough power ??) RESPONSE: Please see the Protocol section (under Sample size, page 5) where it reads: “Non-inferiority trials typically require larger samples than superiority trials; 49,50 thus, we anticipate the need to include multiple centres to secure enough participants. Therefore, we propose a single-centre pilot study to generate the data needed to estimate the sample size required for a large, multi-centre trial. Based upon previous studies that compared TEA versus PVB for postoperative analgesia in patients undergoing thoracotomy, 45,51 we will aim for a convenience sample of 25 patients per group to generate pilot data upon which to base a larger, multi-centre trial.” 4) First lines of the "Discussion" seem to be to too dramatic" "Inadequate analgesia can lead to hypertension, tachycardia, pulmonary splinting, and inability to breathe deeply and cough. The result could be myocardial ischaemia, pneumonia, and/or the need for prolonged respiratory support.". I would be much more concerned for these complications (particularly for MACEs, respiratory complications) for the intraop anesthetic management CFR to be provided RESPONSE: We have shortened and softened the argument on the importance of good postoperative pain management without excessive reliance on opioids in the Discussion section (bottom page 10). We agree that intraoperative stable management is vital to avoid cardiorespiratory complications. We did not think it was necessary to explicitly mention that as such is the universal goal of all anesthetic management. Dear Dr. De Gasperi, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Postoperative hemostatic profile is not by default pro-hemorrhagic particularly in case of neoplastic diseases or in HCC in patients included in CHILD A / MELD < 11. RESPONSE: We acknowledge that preoperative liver functional status is one of several major factors influencing postoperative hemostatic function (please see 2 nd paragraph of Introduction). Viscoelastic tests should be strongly considered (TEG/ROTEM) to describe the pre/intra/post hemostatic profile.: to be considered the "rebalanced hemostasis " in cirrhotic patients (Tripodi et al Am J Gastroenterol, 2017; 112: 274-81 1 3) for the periop hemostatic profile in liver resection please consider also a) Cerutti et al Liver transplantation 2004; 10: 289-94 2 ---b) DePietri et al, World J Gastroenterol, 2018; 24: 2931-48 RESPONSE: Thank you for emphasizing the potentially crucial role of thromboelastometry/graphy in discerning hemostatic status. We acknowledge the complex nature of coagulation in many clinical situations, including liver resection with or without cancer and/or cirrhosis. However, TEG/ROTEM’s role in liver resection and neuraxial block is still not well established. This area is indeed ripe for more research endeavors but is not the goal of our project. Future research may very well show that TEG/ROTEM results can be important indicators as to whether neuraxial blocks should be contraindicated but at the present time, platelet count and INR remain the standard tests (however imperfect). As we are only using the platelet count and INR to exclude patients preoperatively as per industry standard and are not studying hemostatic changes associated with liver resection, we respectfully decline to include the Tripodi, Cerutti, and De Pietri references thoughtfully suggested. 3) 50 pts to be randomized: please provide the statistical justification of this number (enough power ??) RESPONSE: Please see the Protocol section (under Sample size, page 5) where it reads: “Non-inferiority trials typically require larger samples than superiority trials; 49,50 thus, we anticipate the need to include multiple centres to secure enough participants. Therefore, we propose a single-centre pilot study to generate the data needed to estimate the sample size required for a large, multi-centre trial. Based upon previous studies that compared TEA versus PVB for postoperative analgesia in patients undergoing thoracotomy, 45,51 we will aim for a convenience sample of 25 patients per group to generate pilot data upon which to base a larger, multi-centre trial.” 4) First lines of the "Discussion" seem to be to too dramatic" "Inadequate analgesia can lead to hypertension, tachycardia, pulmonary splinting, and inability to breathe deeply and cough. The result could be myocardial ischaemia, pneumonia, and/or the need for prolonged respiratory support.". I would be much more concerned for these complications (particularly for MACEs, respiratory complications) for the intraop anesthetic management CFR to be provided RESPONSE: We have shortened and softened the argument on the importance of good postoperative pain management without excessive reliance on opioids in the Discussion section (bottom page 10). We agree that intraoperative stable management is vital to avoid cardiorespiratory complications. We did not think it was necessary to explicitly mention that as such is the universal goal of all anesthetic management. Competing Interests: The authors have no conflicts of interest to declare Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 21 Jun 2024 Anthony Ho , Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada 21 Jun 2024 Author Response Dear Dr. De Gasperi, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript ... Continue reading Dear Dr. De Gasperi, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Postoperative hemostatic profile is not by default pro-hemorrhagic particularly in case of neoplastic diseases or in HCC in patients included in CHILD A / MELD < 11. RESPONSE: We acknowledge that preoperative liver functional status is one of several major factors influencing postoperative hemostatic function (please see 2 nd paragraph of Introduction). Viscoelastic tests should be strongly considered (TEG/ROTEM) to describe the pre/intra/post hemostatic profile.: to be considered the "rebalanced hemostasis " in cirrhotic patients (Tripodi et al Am J Gastroenterol, 2017; 112: 274-81 1 3) for the periop hemostatic profile in liver resection please consider also a) Cerutti et al Liver transplantation 2004; 10: 289-94 2 ---b) DePietri et al, World J Gastroenterol, 2018; 24: 2931-48 RESPONSE: Thank you for emphasizing the potentially crucial role of thromboelastometry/graphy in discerning hemostatic status. We acknowledge the complex nature of coagulation in many clinical situations, including liver resection with or without cancer and/or cirrhosis. However, TEG/ROTEM’s role in liver resection and neuraxial block is still not well established. This area is indeed ripe for more research endeavors but is not the goal of our project. Future research may very well show that TEG/ROTEM results can be important indicators as to whether neuraxial blocks should be contraindicated but at the present time, platelet count and INR remain the standard tests (however imperfect). As we are only using the platelet count and INR to exclude patients preoperatively as per industry standard and are not studying hemostatic changes associated with liver resection, we respectfully decline to include the Tripodi, Cerutti, and De Pietri references thoughtfully suggested. 3) 50 pts to be randomized: please provide the statistical justification of this number (enough power ??) RESPONSE: Please see the Protocol section (under Sample size, page 5) where it reads: “Non-inferiority trials typically require larger samples than superiority trials; 49,50 thus, we anticipate the need to include multiple centres to secure enough participants. Therefore, we propose a single-centre pilot study to generate the data needed to estimate the sample size required for a large, multi-centre trial. Based upon previous studies that compared TEA versus PVB for postoperative analgesia in patients undergoing thoracotomy, 45,51 we will aim for a convenience sample of 25 patients per group to generate pilot data upon which to base a larger, multi-centre trial.” 4) First lines of the "Discussion" seem to be to too dramatic" "Inadequate analgesia can lead to hypertension, tachycardia, pulmonary splinting, and inability to breathe deeply and cough. The result could be myocardial ischaemia, pneumonia, and/or the need for prolonged respiratory support.". I would be much more concerned for these complications (particularly for MACEs, respiratory complications) for the intraop anesthetic management CFR to be provided RESPONSE: We have shortened and softened the argument on the importance of good postoperative pain management without excessive reliance on opioids in the Discussion section (bottom page 10). We agree that intraoperative stable management is vital to avoid cardiorespiratory complications. We did not think it was necessary to explicitly mention that as such is the universal goal of all anesthetic management. Dear Dr. De Gasperi, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Postoperative hemostatic profile is not by default pro-hemorrhagic particularly in case of neoplastic diseases or in HCC in patients included in CHILD A / MELD < 11. RESPONSE: We acknowledge that preoperative liver functional status is one of several major factors influencing postoperative hemostatic function (please see 2 nd paragraph of Introduction). Viscoelastic tests should be strongly considered (TEG/ROTEM) to describe the pre/intra/post hemostatic profile.: to be considered the "rebalanced hemostasis " in cirrhotic patients (Tripodi et al Am J Gastroenterol, 2017; 112: 274-81 1 3) for the periop hemostatic profile in liver resection please consider also a) Cerutti et al Liver transplantation 2004; 10: 289-94 2 ---b) DePietri et al, World J Gastroenterol, 2018; 24: 2931-48 RESPONSE: Thank you for emphasizing the potentially crucial role of thromboelastometry/graphy in discerning hemostatic status. We acknowledge the complex nature of coagulation in many clinical situations, including liver resection with or without cancer and/or cirrhosis. However, TEG/ROTEM’s role in liver resection and neuraxial block is still not well established. This area is indeed ripe for more research endeavors but is not the goal of our project. Future research may very well show that TEG/ROTEM results can be important indicators as to whether neuraxial blocks should be contraindicated but at the present time, platelet count and INR remain the standard tests (however imperfect). As we are only using the platelet count and INR to exclude patients preoperatively as per industry standard and are not studying hemostatic changes associated with liver resection, we respectfully decline to include the Tripodi, Cerutti, and De Pietri references thoughtfully suggested. 3) 50 pts to be randomized: please provide the statistical justification of this number (enough power ??) RESPONSE: Please see the Protocol section (under Sample size, page 5) where it reads: “Non-inferiority trials typically require larger samples than superiority trials; 49,50 thus, we anticipate the need to include multiple centres to secure enough participants. Therefore, we propose a single-centre pilot study to generate the data needed to estimate the sample size required for a large, multi-centre trial. Based upon previous studies that compared TEA versus PVB for postoperative analgesia in patients undergoing thoracotomy, 45,51 we will aim for a convenience sample of 25 patients per group to generate pilot data upon which to base a larger, multi-centre trial.” 4) First lines of the "Discussion" seem to be to too dramatic" "Inadequate analgesia can lead to hypertension, tachycardia, pulmonary splinting, and inability to breathe deeply and cough. The result could be myocardial ischaemia, pneumonia, and/or the need for prolonged respiratory support.". I would be much more concerned for these complications (particularly for MACEs, respiratory complications) for the intraop anesthetic management CFR to be provided RESPONSE: We have shortened and softened the argument on the importance of good postoperative pain management without excessive reliance on opioids in the Discussion section (bottom page 10). We agree that intraoperative stable management is vital to avoid cardiorespiratory complications. We did not think it was necessary to explicitly mention that as such is the universal goal of all anesthetic management. Competing Interests: The authors have no conflicts of interest to declare Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Chelly J and Goel S. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.133913.r235498 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v1#referee-response-235498 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 13 Feb 2024 Jacques Chelly , Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Shiv Goel , Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.133913.r235498 The authors are proposing to compare thoracic epidural analgesia (TEA) to a right continuous Paravertebral block (PVB) in 50 patients undergoing hepatectomy using a subcostal approach. The hypothesis being that PVB may represent a safer alternative because it is established ... Continue reading READ ALL The authors are proposing to compare thoracic epidural analgesia (TEA) to a right continuous Paravertebral block (PVB) in 50 patients undergoing hepatectomy using a subcostal approach. The hypothesis being that PVB may represent a safer alternative because it is established that PVB provides hemodynamic stability, low failure rates, and low risk of spinal hematoma compared to TEA. This study will be conducted in 50 patients. This study will be a proof of concept and will allow to propose a multicentric study to include 450 patients, The authors are listing postoperative opioid consumption over 72 hours as the primary end point is. Secondary end points include opioid related side effects, hemodynamic stability, respiratory depression, complications (particularly spinal haematoma). In this study patients will be randomized to either TEA or PVB. The authors hypothesis is that opioid consumption, time to first analgesic request, and pain scores will be comparable between groups, but PVB patients will require fewer perioperative vasopressors/blood products, and have fewer adverse events and a shorter hospital stay. Critics The comparison of TEA and PVB is certainly interesting and clinically relevant especially in the context of a subcostal approach. However, if the authors want to conduct the study because they expect that the use of PVB would be safer than TEA, Why is opioid consumption used as the primary end point, There are a number of design questions? 1-If the authors interested is to compare TEA to PVB which make sense for this reviewer why is the local anesthetics protocol different for TEA or PVB. Patients in the TEA group are schedule to receive bupivacaine 0.1% with hydromorphone 10 μg/mL will be infused at 6-10 mL/h and five mL boluses will be allowed at 30 min intervals at the discretion of the anaesthesiologist. Upon admission to the PACU, patient-controlled epidural analgesia (PCEA) will be initiated. The PCEA bolus of the same solution will be set at three mL with a lockout period of 30 min, and the epidural infusion of the same solution will be set at six mL/h and adjusted in two mL/h increments (or decrements) up to 10 mL/h depending upon pain scores and sensory block tested with ice in the PACU. Whereas patients in the PVB group will be scheduled to receive An infusion of ropivacaine 0.25% at a rate of 0.1 mL/kg/h will be started shortly after induction of GA. In addition, five mL boluses of ropivacaine 0.25% will be allowed at 30 min intervals intraoperatively at the discretion of the anesthesiologist. Upon transfer to the PACU, patient-controlled paravertebral analgesia (PCPA) will be started. The PCPA bolus will be five mL ropivacaine 0.25% with a lockout period of two hours, and an infusion of ropivacaine 0.25% will be continued at 0.1 mL/kg/h and increased in two mL/h increments up to 10 mL/h, depending on the pain scores and sensory block to ice tested in the PACU. This initial infusion will be continued for the first 24 h after surgery, and then reduced by 25% on postoperative day (POD) two, and further reduced another 25% on POD3. This means that the authors are not comparing TEA vs PVB but rather TEA + specific infusion solution vs PVB + a different infusion solution. Why not use the same solution for both TEA and PVB? Also please consider eliminating opioid in the TEA solution. This is adding 1.2 to 2,4 or more mg of hydromorphone in the TEA group 2- Why are the authors administrating IV hydromorphone at a dose of 0.5 to 1 mg every hour without any reference to the pain of the patient? Can these administration be q 2 or 3 hrs and the among establish according to the pain level of the patient? 3-The authors provide a long list of variables that they are going to monitor, but do not provide any details on they intend to qualify these variables? Example hypotensive episode define as MPA < 50 mh requiring intervention ? urinary retention? At the very least they need to refer to articles if they don’t want to include a definition in their protocol. 4- Including both a blind or US approach to perform PVB is a design problem. Please chose one or the other It is important that the technique used for the placement of a catheter in the PVB space is consistent and reliable. In contrast of what is stated by the authors, placing a catheter in the PVB space is difficult and required both expertise and the use of an ultrasound. Without the use of ultrasound, it is really possible to establish is what is being performed is a true PVB or an ESP block. In this reviewer experience, in most cases a blind technique doesn’t result in the catheter being placed in PVB space. However, in the past a blind approach has being used. Therefore, the recommendation of this reviewer would be for the authors to use either a blind or an ultrasound approach but not both. Other requests. a-Please provide details of the PVB technique either blind or with US. b- the authors use 20% as their inferiority margin for cumulative opioid consumption at 72 hours postoperatively, because they consider that 20% is not clinically significant ? Although, this reviewer would prefer 10% instead of 20%, the confounding variable is the excessive among of opioid expected to be administered. Please consider eliminating opioid from the TEA solution and consider a PRN administration according to the pain level instead of a systematic administration of 0.5-1 mg of hydromorphone q1hr. In addition this is incredibly time. Please consider, q 2 or 3 hr interval. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? No Are sufficient details of the methods provided to allow replication by others? No Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Regioaal Anesthesia and Pain We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Chelly J and Goel S. Reviewer Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.133913.r235498 ) The direct URL for this report is: https://f1000research.com/articles/11-1067/v1#referee-response-235498 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 21 Jun 2024 Anthony Ho , Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada 21 Jun 2024 Author Response Dear Drs. Chelly and Goel, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the ... Continue reading Dear Drs. Chelly and Goel, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Dr Chelly’s summary: The authors are proposing to compare thoracic epidural analgesia (TEA) to a right continuous paravertebral block (PVB) in 50 patients undergoing hepatectomy using a subcostal approach. The hypothesis being that PVB may represent a safer alternative because it is established that PVB provides hemodynamic stability, low failure rates, and low risk of spinal hematoma compared to TEA. This study will be conducted in 50 patients. This study will be a proof of concept and will allow to propose a multicentric study to include 450 patients. The authors are listing postoperative opioid consumption over 72 hours as the primary end point is. Secondary end points include opioid related side effects, hemodynamic stability, respiratory depression, complications (particularly spinal haematoma). In this study patients will be randomized to either TEA or PVB. The author’s hypothesis is that opioid consumption, time to first analgesic request, and pain scores will be comparable between groups, but PVB patients will require fewer perioperative vasopressors/blood products, and have fewer adverse events and a shorter hospital stay. Critics The comparison of TEA and PVB is certainly interesting and clinically relevant especially in the context of a subcostal approach. However, if the authors want to conduct the study because they expect that the use of PVB would be safer than TEA, why is opioid consumption used as the primary end point, There are a number of design questions?1 - If the authors interest is to compare TEA to PVB which make sense for this reviewer why is the local anesthetics protocol different for TEA or PVB. Patients in the TEA group are schedule to receive bupivacaine 0.1% with hydromorphone 10 μg/mL will be infused at 6-10 mL/h and five mL boluses will be allowed at 30 min intervals at the discretion of the anaesthesiologist. Upon admission to the PACU, patient-controlled epidural analgesia (PCEA) will be initiated. The PCEA bolus of the same solution will be set at three mL with a lockout period of 30 min, and the epidural infusion of the same solution will be set at six mL/h and adjusted in two mL/h increments (or decrements) up to 10 mL/h depending upon pain scores and sensory block tested with ice in the PACU. Whereas patients in the PVB group will be scheduled to receive an infusion of ropivacaine 0.25% at a rate of 0.1 mL/kg/h will be started shortly after induction of GA. In addition, five mL boluses of ropivacaine 0.25% will be allowed at 30 min intervals intraoperatively at the discretion of the anesthesiologist. Upon transfer to the PACU, patient-controlled paravertebral analgesia (PCPA) will be started. The PCPA bolus will be five mL ropivacaine 0.25% with a lockout period of two hours, and an infusion of ropivacaine 0.25% will be continued at 0.1 mL/kg/h and increased in two mL/h increments up to 10 mL/h, depending on the pain scores and sensory block to ice tested in the PACU. This initial infusion will be continued for the first 24 h after surgery, and then reduced by 25% on postoperative day (POD) two, and further reduced another 25% on POD3. This means that the authors are not comparing TEA vs PVB but rather TEA + specific infusion solution vs PVB + a different infusion solution. Why not use the same solution for both TEA and PVB? RESPONSE: The reason for setting opioid consumption as a primary end point is that the major complications (neuraxial hematoma, pneumothorax, total spinal) associated with TEA and PVB are rare. Furthermore, opioid consumption comparison is almost universal when comparing any 2 or more analgesic regimens. As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” Also please consider eliminating opioid in the TEA solution. This adds 1.2 to 2.4 more mg of hydromorphone in the TEA group. RESPONSE: We acknowledge the systemic and some central analgesic effect of the opioid in the epidural group. The amount of epidural opioid, however, is small. For an infusion of 7 mL/h, for example, the hydromorphone infused is 0.07 mg/h, or 1.68 mg/24 h. Adding opioid to PVB, as stated earlier, is not standard practice. 2. Why are the authors administrating IV hydromorphone at a dose of 0.5 to 1 mg every hour without any reference to the pain of the patient? Can the administration be a q2 or 3 hrs and the amount established according to the pain level of the patient? RESPONSE: Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency. 3 -The authors provide a long list of variables that they are going to monitor, but do not provide any details on they intend to qualify these variables? Example hypotensive episode define as MPA < 50 mh requiring intervention? urinary retention? At the very least they need to refer to articles if they don’t want to include a definition in their protocol. RESPONSE: The authors are not totally certain about what the reviewer means by this comment; however, our intention in collecting these variables is simply descriptive, i.e., to determine whether their incidence would be similar/vary according to the treatment (i.e., TEA vs. PVB) modality. The differences between TEA and PVB need to be highlighted. Among these differences, TEA almost always cause a drop in blood pressure and thoracic PVB almost never. Likewise, TEA commonly causes urinary retention whereas PVB simply does not. We use MAP<50 mmHg as qualifying for hypotension and the need for urinary bladder catheterization as a surrogate for retention. These are rather well-defined markers. Similarly, the Ramsay score is a validated metric for sedation. The other outcomes such as vasopressor use, fluid requirement, urine output, and length of stay are all well defined endpoints that we quantify. 4 - Including both a blind or US approach to perform PVB is a design problem. Please chose one or the other It is important that the technique used for the placement of a catheter in the PVB space is consistent and reliable. In contrast of what is stated by the authors, placing a catheter in the PVB space is difficult and required both expertise and the use of an ultrasound. Without the use of ultrasound, it is really possible to establish is what is being performed is a true PVB or an ESP block. In this reviewer experience, in most cases a blind technique doesn’t result in the catheter being placed in PVB space. However, in the past a blind approach has being used. Therefore, the recommendation of this reviewer would be for the authors to use either a blind or an ultrasound approach but not both. RESPONSE: US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice. Other requests. a-Please provide details of the PVB technique either blind or with US. RESPONSE: The blind technique is now well described as follows: “In the landmark technique, once the appropriate thoracic level is identified, the needle is inserted at 2.5-3 cm lateral to the most cephalad aspect of the spinous process and advanced perpendicular to the skin in all planes to contact the transverse process of the vertebra below. The needle is then walked above the transverse process and gradually advanced until a loss of resistance to saline is felt as the needle tip traverses the thin superior costotransverse ligament. 52 ” (page 8, 3 rd paragraph, Ref: Karmakar MK, Ho AMH. Thoracic and lumbar paravertebral block. In: Modern Regional Anesthesia. Ed. Hadzic A, McGraw-Hill 2007, New York: Chapter 43: pp. 583-97.) The US-guided technique is as follows: a high-frequency linear US transducer is placed 2.5-3 cm lateral to the most cephalad aspect of the spinous process and oriented vertically at the target thoracic level. Once the transverse process is identified as a “squared” bony structure (note, the identification of a “round” bony structure is usually consistent with the rib, indicating that the probe should be slowly moved medially), the superior/cephalad aspect of the probe is maintained static, while its inferior/caudal aspect is slightly (~30 o ) rotated counterclockwise until the costotransverse ligament (usually ~0.5 cm superficial to the pleura) is brought into view. The block needle is carefully advanced in plane with the probe in a cephalad direction until it pierces the costotransverse ligament. Correct LA deposition is evidenced by the inferior displacement of the pleura under direct US visualization. b- the authors use 20% as their inferiority margin for cumulative opioid consumption at 72 hours postoperatively, because they consider that 20% is not clinically significant? Although this reviewer would prefer 10% instead of 20%, the confounding variable is the excessive among of opioid expected to be administered. Please consider eliminating opioid from the TEA solution RESPONSE: We respectfully disagree as adding a small amount of opioid in the epidural solution is a common practice - and an industry-wide and our institutional standard of care - since it allows the use of a diluted local anesthetic solution thereby decreasing the incidence of motor block while still providing adequate, or even enhanced, analgesia) and consider a PRN administration according to the pain level instead of a systematic administration of 0.5-1 mg of hydromorphone q1hr. In addition, this is incredibly time. Please consider, q 2 or 3 hr interval. RESPONSE: Please refer to our response question #2 above where we indicate that the sentence pertaining to postoperative hydromorphone administration is indeed inconsistent with our practice as we routinely offered subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request (i.e., on a PRN basis) as we expected some breakthrough pain from the epidural (which has a diluted LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision), page 9, 2 nd paragraph). Dear Drs. Chelly and Goel, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Dr Chelly’s summary: The authors are proposing to compare thoracic epidural analgesia (TEA) to a right continuous paravertebral block (PVB) in 50 patients undergoing hepatectomy using a subcostal approach. The hypothesis being that PVB may represent a safer alternative because it is established that PVB provides hemodynamic stability, low failure rates, and low risk of spinal hematoma compared to TEA. This study will be conducted in 50 patients. This study will be a proof of concept and will allow to propose a multicentric study to include 450 patients. The authors are listing postoperative opioid consumption over 72 hours as the primary end point is. Secondary end points include opioid related side effects, hemodynamic stability, respiratory depression, complications (particularly spinal haematoma). In this study patients will be randomized to either TEA or PVB. The author’s hypothesis is that opioid consumption, time to first analgesic request, and pain scores will be comparable between groups, but PVB patients will require fewer perioperative vasopressors/blood products, and have fewer adverse events and a shorter hospital stay. Critics The comparison of TEA and PVB is certainly interesting and clinically relevant especially in the context of a subcostal approach. However, if the authors want to conduct the study because they expect that the use of PVB would be safer than TEA, why is opioid consumption used as the primary end point, There are a number of design questions?1 - If the authors interest is to compare TEA to PVB which make sense for this reviewer why is the local anesthetics protocol different for TEA or PVB. Patients in the TEA group are schedule to receive bupivacaine 0.1% with hydromorphone 10 μg/mL will be infused at 6-10 mL/h and five mL boluses will be allowed at 30 min intervals at the discretion of the anaesthesiologist. Upon admission to the PACU, patient-controlled epidural analgesia (PCEA) will be initiated. The PCEA bolus of the same solution will be set at three mL with a lockout period of 30 min, and the epidural infusion of the same solution will be set at six mL/h and adjusted in two mL/h increments (or decrements) up to 10 mL/h depending upon pain scores and sensory block tested with ice in the PACU. Whereas patients in the PVB group will be scheduled to receive an infusion of ropivacaine 0.25% at a rate of 0.1 mL/kg/h will be started shortly after induction of GA. In addition, five mL boluses of ropivacaine 0.25% will be allowed at 30 min intervals intraoperatively at the discretion of the anesthesiologist. Upon transfer to the PACU, patient-controlled paravertebral analgesia (PCPA) will be started. The PCPA bolus will be five mL ropivacaine 0.25% with a lockout period of two hours, and an infusion of ropivacaine 0.25% will be continued at 0.1 mL/kg/h and increased in two mL/h increments up to 10 mL/h, depending on the pain scores and sensory block to ice tested in the PACU. This initial infusion will be continued for the first 24 h after surgery, and then reduced by 25% on postoperative day (POD) two, and further reduced another 25% on POD3. This means that the authors are not comparing TEA vs PVB but rather TEA + specific infusion solution vs PVB + a different infusion solution. Why not use the same solution for both TEA and PVB? RESPONSE: The reason for setting opioid consumption as a primary end point is that the major complications (neuraxial hematoma, pneumothorax, total spinal) associated with TEA and PVB are rare. Furthermore, opioid consumption comparison is almost universal when comparing any 2 or more analgesic regimens. As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” Also please consider eliminating opioid in the TEA solution. This adds 1.2 to 2.4 more mg of hydromorphone in the TEA group. RESPONSE: We acknowledge the systemic and some central analgesic effect of the opioid in the epidural group. The amount of epidural opioid, however, is small. For an infusion of 7 mL/h, for example, the hydromorphone infused is 0.07 mg/h, or 1.68 mg/24 h. Adding opioid to PVB, as stated earlier, is not standard practice. 2. Why are the authors administrating IV hydromorphone at a dose of 0.5 to 1 mg every hour without any reference to the pain of the patient? Can the administration be a q2 or 3 hrs and the amount established according to the pain level of the patient? RESPONSE: Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency. 3 -The authors provide a long list of variables that they are going to monitor, but do not provide any details on they intend to qualify these variables? Example hypotensive episode define as MPA < 50 mh requiring intervention? urinary retention? At the very least they need to refer to articles if they don’t want to include a definition in their protocol. RESPONSE: The authors are not totally certain about what the reviewer means by this comment; however, our intention in collecting these variables is simply descriptive, i.e., to determine whether their incidence would be similar/vary according to the treatment (i.e., TEA vs. PVB) modality. The differences between TEA and PVB need to be highlighted. Among these differences, TEA almost always cause a drop in blood pressure and thoracic PVB almost never. Likewise, TEA commonly causes urinary retention whereas PVB simply does not. We use MAP<50 mmHg as qualifying for hypotension and the need for urinary bladder catheterization as a surrogate for retention. These are rather well-defined markers. Similarly, the Ramsay score is a validated metric for sedation. The other outcomes such as vasopressor use, fluid requirement, urine output, and length of stay are all well defined endpoints that we quantify. 4 - Including both a blind or US approach to perform PVB is a design problem. Please chose one or the other It is important that the technique used for the placement of a catheter in the PVB space is consistent and reliable. In contrast of what is stated by the authors, placing a catheter in the PVB space is difficult and required both expertise and the use of an ultrasound. Without the use of ultrasound, it is really possible to establish is what is being performed is a true PVB or an ESP block. In this reviewer experience, in most cases a blind technique doesn’t result in the catheter being placed in PVB space. However, in the past a blind approach has being used. Therefore, the recommendation of this reviewer would be for the authors to use either a blind or an ultrasound approach but not both. RESPONSE: US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice. Other requests. a-Please provide details of the PVB technique either blind or with US. RESPONSE: The blind technique is now well described as follows: “In the landmark technique, once the appropriate thoracic level is identified, the needle is inserted at 2.5-3 cm lateral to the most cephalad aspect of the spinous process and advanced perpendicular to the skin in all planes to contact the transverse process of the vertebra below. The needle is then walked above the transverse process and gradually advanced until a loss of resistance to saline is felt as the needle tip traverses the thin superior costotransverse ligament. 52 ” (page 8, 3 rd paragraph, Ref: Karmakar MK, Ho AMH. Thoracic and lumbar paravertebral block. In: Modern Regional Anesthesia. Ed. Hadzic A, McGraw-Hill 2007, New York: Chapter 43: pp. 583-97.) The US-guided technique is as follows: a high-frequency linear US transducer is placed 2.5-3 cm lateral to the most cephalad aspect of the spinous process and oriented vertically at the target thoracic level. Once the transverse process is identified as a “squared” bony structure (note, the identification of a “round” bony structure is usually consistent with the rib, indicating that the probe should be slowly moved medially), the superior/cephalad aspect of the probe is maintained static, while its inferior/caudal aspect is slightly (~30 o ) rotated counterclockwise until the costotransverse ligament (usually ~0.5 cm superficial to the pleura) is brought into view. The block needle is carefully advanced in plane with the probe in a cephalad direction until it pierces the costotransverse ligament. Correct LA deposition is evidenced by the inferior displacement of the pleura under direct US visualization. b- the authors use 20% as their inferiority margin for cumulative opioid consumption at 72 hours postoperatively, because they consider that 20% is not clinically significant? Although this reviewer would prefer 10% instead of 20%, the confounding variable is the excessive among of opioid expected to be administered. Please consider eliminating opioid from the TEA solution RESPONSE: We respectfully disagree as adding a small amount of opioid in the epidural solution is a common practice - and an industry-wide and our institutional standard of care - since it allows the use of a diluted local anesthetic solution thereby decreasing the incidence of motor block while still providing adequate, or even enhanced, analgesia) and consider a PRN administration according to the pain level instead of a systematic administration of 0.5-1 mg of hydromorphone q1hr. In addition, this is incredibly time. Please consider, q 2 or 3 hr interval. RESPONSE: Please refer to our response question #2 above where we indicate that the sentence pertaining to postoperative hydromorphone administration is indeed inconsistent with our practice as we routinely offered subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request (i.e., on a PRN basis) as we expected some breakthrough pain from the epidural (which has a diluted LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision), page 9, 2 nd paragraph). Competing Interests: The authors have no competing interests to declare Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 21 Jun 2024 Anthony Ho , Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada 21 Jun 2024 Author Response Dear Drs. Chelly and Goel, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the ... Continue reading Dear Drs. Chelly and Goel, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Dr Chelly’s summary: The authors are proposing to compare thoracic epidural analgesia (TEA) to a right continuous paravertebral block (PVB) in 50 patients undergoing hepatectomy using a subcostal approach. The hypothesis being that PVB may represent a safer alternative because it is established that PVB provides hemodynamic stability, low failure rates, and low risk of spinal hematoma compared to TEA. This study will be conducted in 50 patients. This study will be a proof of concept and will allow to propose a multicentric study to include 450 patients. The authors are listing postoperative opioid consumption over 72 hours as the primary end point is. Secondary end points include opioid related side effects, hemodynamic stability, respiratory depression, complications (particularly spinal haematoma). In this study patients will be randomized to either TEA or PVB. The author’s hypothesis is that opioid consumption, time to first analgesic request, and pain scores will be comparable between groups, but PVB patients will require fewer perioperative vasopressors/blood products, and have fewer adverse events and a shorter hospital stay. Critics The comparison of TEA and PVB is certainly interesting and clinically relevant especially in the context of a subcostal approach. However, if the authors want to conduct the study because they expect that the use of PVB would be safer than TEA, why is opioid consumption used as the primary end point, There are a number of design questions?1 - If the authors interest is to compare TEA to PVB which make sense for this reviewer why is the local anesthetics protocol different for TEA or PVB. Patients in the TEA group are schedule to receive bupivacaine 0.1% with hydromorphone 10 μg/mL will be infused at 6-10 mL/h and five mL boluses will be allowed at 30 min intervals at the discretion of the anaesthesiologist. Upon admission to the PACU, patient-controlled epidural analgesia (PCEA) will be initiated. The PCEA bolus of the same solution will be set at three mL with a lockout period of 30 min, and the epidural infusion of the same solution will be set at six mL/h and adjusted in two mL/h increments (or decrements) up to 10 mL/h depending upon pain scores and sensory block tested with ice in the PACU. Whereas patients in the PVB group will be scheduled to receive an infusion of ropivacaine 0.25% at a rate of 0.1 mL/kg/h will be started shortly after induction of GA. In addition, five mL boluses of ropivacaine 0.25% will be allowed at 30 min intervals intraoperatively at the discretion of the anesthesiologist. Upon transfer to the PACU, patient-controlled paravertebral analgesia (PCPA) will be started. The PCPA bolus will be five mL ropivacaine 0.25% with a lockout period of two hours, and an infusion of ropivacaine 0.25% will be continued at 0.1 mL/kg/h and increased in two mL/h increments up to 10 mL/h, depending on the pain scores and sensory block to ice tested in the PACU. This initial infusion will be continued for the first 24 h after surgery, and then reduced by 25% on postoperative day (POD) two, and further reduced another 25% on POD3. This means that the authors are not comparing TEA vs PVB but rather TEA + specific infusion solution vs PVB + a different infusion solution. Why not use the same solution for both TEA and PVB? RESPONSE: The reason for setting opioid consumption as a primary end point is that the major complications (neuraxial hematoma, pneumothorax, total spinal) associated with TEA and PVB are rare. Furthermore, opioid consumption comparison is almost universal when comparing any 2 or more analgesic regimens. As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” Also please consider eliminating opioid in the TEA solution. This adds 1.2 to 2.4 more mg of hydromorphone in the TEA group. RESPONSE: We acknowledge the systemic and some central analgesic effect of the opioid in the epidural group. The amount of epidural opioid, however, is small. For an infusion of 7 mL/h, for example, the hydromorphone infused is 0.07 mg/h, or 1.68 mg/24 h. Adding opioid to PVB, as stated earlier, is not standard practice. 2. Why are the authors administrating IV hydromorphone at a dose of 0.5 to 1 mg every hour without any reference to the pain of the patient? Can the administration be a q2 or 3 hrs and the amount established according to the pain level of the patient? RESPONSE: Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency. 3 -The authors provide a long list of variables that they are going to monitor, but do not provide any details on they intend to qualify these variables? Example hypotensive episode define as MPA < 50 mh requiring intervention? urinary retention? At the very least they need to refer to articles if they don’t want to include a definition in their protocol. RESPONSE: The authors are not totally certain about what the reviewer means by this comment; however, our intention in collecting these variables is simply descriptive, i.e., to determine whether their incidence would be similar/vary according to the treatment (i.e., TEA vs. PVB) modality. The differences between TEA and PVB need to be highlighted. Among these differences, TEA almost always cause a drop in blood pressure and thoracic PVB almost never. Likewise, TEA commonly causes urinary retention whereas PVB simply does not. We use MAP<50 mmHg as qualifying for hypotension and the need for urinary bladder catheterization as a surrogate for retention. These are rather well-defined markers. Similarly, the Ramsay score is a validated metric for sedation. The other outcomes such as vasopressor use, fluid requirement, urine output, and length of stay are all well defined endpoints that we quantify. 4 - Including both a blind or US approach to perform PVB is a design problem. Please chose one or the other It is important that the technique used for the placement of a catheter in the PVB space is consistent and reliable. In contrast of what is stated by the authors, placing a catheter in the PVB space is difficult and required both expertise and the use of an ultrasound. Without the use of ultrasound, it is really possible to establish is what is being performed is a true PVB or an ESP block. In this reviewer experience, in most cases a blind technique doesn’t result in the catheter being placed in PVB space. However, in the past a blind approach has being used. Therefore, the recommendation of this reviewer would be for the authors to use either a blind or an ultrasound approach but not both. RESPONSE: US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice. Other requests. a-Please provide details of the PVB technique either blind or with US. RESPONSE: The blind technique is now well described as follows: “In the landmark technique, once the appropriate thoracic level is identified, the needle is inserted at 2.5-3 cm lateral to the most cephalad aspect of the spinous process and advanced perpendicular to the skin in all planes to contact the transverse process of the vertebra below. The needle is then walked above the transverse process and gradually advanced until a loss of resistance to saline is felt as the needle tip traverses the thin superior costotransverse ligament. 52 ” (page 8, 3 rd paragraph, Ref: Karmakar MK, Ho AMH. Thoracic and lumbar paravertebral block. In: Modern Regional Anesthesia. Ed. Hadzic A, McGraw-Hill 2007, New York: Chapter 43: pp. 583-97.) The US-guided technique is as follows: a high-frequency linear US transducer is placed 2.5-3 cm lateral to the most cephalad aspect of the spinous process and oriented vertically at the target thoracic level. Once the transverse process is identified as a “squared” bony structure (note, the identification of a “round” bony structure is usually consistent with the rib, indicating that the probe should be slowly moved medially), the superior/cephalad aspect of the probe is maintained static, while its inferior/caudal aspect is slightly (~30 o ) rotated counterclockwise until the costotransverse ligament (usually ~0.5 cm superficial to the pleura) is brought into view. The block needle is carefully advanced in plane with the probe in a cephalad direction until it pierces the costotransverse ligament. Correct LA deposition is evidenced by the inferior displacement of the pleura under direct US visualization. b- the authors use 20% as their inferiority margin for cumulative opioid consumption at 72 hours postoperatively, because they consider that 20% is not clinically significant? Although this reviewer would prefer 10% instead of 20%, the confounding variable is the excessive among of opioid expected to be administered. Please consider eliminating opioid from the TEA solution RESPONSE: We respectfully disagree as adding a small amount of opioid in the epidural solution is a common practice - and an industry-wide and our institutional standard of care - since it allows the use of a diluted local anesthetic solution thereby decreasing the incidence of motor block while still providing adequate, or even enhanced, analgesia) and consider a PRN administration according to the pain level instead of a systematic administration of 0.5-1 mg of hydromorphone q1hr. In addition, this is incredibly time. Please consider, q 2 or 3 hr interval. RESPONSE: Please refer to our response question #2 above where we indicate that the sentence pertaining to postoperative hydromorphone administration is indeed inconsistent with our practice as we routinely offered subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request (i.e., on a PRN basis) as we expected some breakthrough pain from the epidural (which has a diluted LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision), page 9, 2 nd paragraph). Dear Drs. Chelly and Goel, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Dr Chelly’s summary: The authors are proposing to compare thoracic epidural analgesia (TEA) to a right continuous paravertebral block (PVB) in 50 patients undergoing hepatectomy using a subcostal approach. The hypothesis being that PVB may represent a safer alternative because it is established that PVB provides hemodynamic stability, low failure rates, and low risk of spinal hematoma compared to TEA. This study will be conducted in 50 patients. This study will be a proof of concept and will allow to propose a multicentric study to include 450 patients. The authors are listing postoperative opioid consumption over 72 hours as the primary end point is. Secondary end points include opioid related side effects, hemodynamic stability, respiratory depression, complications (particularly spinal haematoma). In this study patients will be randomized to either TEA or PVB. The author’s hypothesis is that opioid consumption, time to first analgesic request, and pain scores will be comparable between groups, but PVB patients will require fewer perioperative vasopressors/blood products, and have fewer adverse events and a shorter hospital stay. Critics The comparison of TEA and PVB is certainly interesting and clinically relevant especially in the context of a subcostal approach. However, if the authors want to conduct the study because they expect that the use of PVB would be safer than TEA, why is opioid consumption used as the primary end point, There are a number of design questions?1 - If the authors interest is to compare TEA to PVB which make sense for this reviewer why is the local anesthetics protocol different for TEA or PVB. Patients in the TEA group are schedule to receive bupivacaine 0.1% with hydromorphone 10 μg/mL will be infused at 6-10 mL/h and five mL boluses will be allowed at 30 min intervals at the discretion of the anaesthesiologist. Upon admission to the PACU, patient-controlled epidural analgesia (PCEA) will be initiated. The PCEA bolus of the same solution will be set at three mL with a lockout period of 30 min, and the epidural infusion of the same solution will be set at six mL/h and adjusted in two mL/h increments (or decrements) up to 10 mL/h depending upon pain scores and sensory block tested with ice in the PACU. Whereas patients in the PVB group will be scheduled to receive an infusion of ropivacaine 0.25% at a rate of 0.1 mL/kg/h will be started shortly after induction of GA. In addition, five mL boluses of ropivacaine 0.25% will be allowed at 30 min intervals intraoperatively at the discretion of the anesthesiologist. Upon transfer to the PACU, patient-controlled paravertebral analgesia (PCPA) will be started. The PCPA bolus will be five mL ropivacaine 0.25% with a lockout period of two hours, and an infusion of ropivacaine 0.25% will be continued at 0.1 mL/kg/h and increased in two mL/h increments up to 10 mL/h, depending on the pain scores and sensory block to ice tested in the PACU. This initial infusion will be continued for the first 24 h after surgery, and then reduced by 25% on postoperative day (POD) two, and further reduced another 25% on POD3. This means that the authors are not comparing TEA vs PVB but rather TEA + specific infusion solution vs PVB + a different infusion solution. Why not use the same solution for both TEA and PVB? RESPONSE: The reason for setting opioid consumption as a primary end point is that the major complications (neuraxial hematoma, pneumothorax, total spinal) associated with TEA and PVB are rare. Furthermore, opioid consumption comparison is almost universal when comparing any 2 or more analgesic regimens. As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” Also please consider eliminating opioid in the TEA solution. This adds 1.2 to 2.4 more mg of hydromorphone in the TEA group. RESPONSE: We acknowledge the systemic and some central analgesic effect of the opioid in the epidural group. The amount of epidural opioid, however, is small. For an infusion of 7 mL/h, for example, the hydromorphone infused is 0.07 mg/h, or 1.68 mg/24 h. Adding opioid to PVB, as stated earlier, is not standard practice. 2. Why are the authors administrating IV hydromorphone at a dose of 0.5 to 1 mg every hour without any reference to the pain of the patient? Can the administration be a q2 or 3 hrs and the amount established according to the pain level of the patient? RESPONSE: Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency. 3 -The authors provide a long list of variables that they are going to monitor, but do not provide any details on they intend to qualify these variables? Example hypotensive episode define as MPA < 50 mh requiring intervention? urinary retention? At the very least they need to refer to articles if they don’t want to include a definition in their protocol. RESPONSE: The authors are not totally certain about what the reviewer means by this comment; however, our intention in collecting these variables is simply descriptive, i.e., to determine whether their incidence would be similar/vary according to the treatment (i.e., TEA vs. PVB) modality. The differences between TEA and PVB need to be highlighted. Among these differences, TEA almost always cause a drop in blood pressure and thoracic PVB almost never. Likewise, TEA commonly causes urinary retention whereas PVB simply does not. We use MAP<50 mmHg as qualifying for hypotension and the need for urinary bladder catheterization as a surrogate for retention. These are rather well-defined markers. Similarly, the Ramsay score is a validated metric for sedation. The other outcomes such as vasopressor use, fluid requirement, urine output, and length of stay are all well defined endpoints that we quantify. 4 - Including both a blind or US approach to perform PVB is a design problem. Please chose one or the other It is important that the technique used for the placement of a catheter in the PVB space is consistent and reliable. In contrast of what is stated by the authors, placing a catheter in the PVB space is difficult and required both expertise and the use of an ultrasound. Without the use of ultrasound, it is really possible to establish is what is being performed is a true PVB or an ESP block. In this reviewer experience, in most cases a blind technique doesn’t result in the catheter being placed in PVB space. However, in the past a blind approach has being used. Therefore, the recommendation of this reviewer would be for the authors to use either a blind or an ultrasound approach but not both. RESPONSE: US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice. Other requests. a-Please provide details of the PVB technique either blind or with US. RESPONSE: The blind technique is now well described as follows: “In the landmark technique, once the appropriate thoracic level is identified, the needle is inserted at 2.5-3 cm lateral to the most cephalad aspect of the spinous process and advanced perpendicular to the skin in all planes to contact the transverse process of the vertebra below. The needle is then walked above the transverse process and gradually advanced until a loss of resistance to saline is felt as the needle tip traverses the thin superior costotransverse ligament. 52 ” (page 8, 3 rd paragraph, Ref: Karmakar MK, Ho AMH. Thoracic and lumbar paravertebral block. In: Modern Regional Anesthesia. Ed. Hadzic A, McGraw-Hill 2007, New York: Chapter 43: pp. 583-97.) The US-guided technique is as follows: a high-frequency linear US transducer is placed 2.5-3 cm lateral to the most cephalad aspect of the spinous process and oriented vertically at the target thoracic level. Once the transverse process is identified as a “squared” bony structure (note, the identification of a “round” bony structure is usually consistent with the rib, indicating that the probe should be slowly moved medially), the superior/cephalad aspect of the probe is maintained static, while its inferior/caudal aspect is slightly (~30 o ) rotated counterclockwise until the costotransverse ligament (usually ~0.5 cm superficial to the pleura) is brought into view. The block needle is carefully advanced in plane with the probe in a cephalad direction until it pierces the costotransverse ligament. Correct LA deposition is evidenced by the inferior displacement of the pleura under direct US visualization. b- the authors use 20% as their inferiority margin for cumulative opioid consumption at 72 hours postoperatively, because they consider that 20% is not clinically significant? Although this reviewer would prefer 10% instead of 20%, the confounding variable is the excessive among of opioid expected to be administered. Please consider eliminating opioid from the TEA solution RESPONSE: We respectfully disagree as adding a small amount of opioid in the epidural solution is a common practice - and an industry-wide and our institutional standard of care - since it allows the use of a diluted local anesthetic solution thereby decreasing the incidence of motor block while still providing adequate, or even enhanced, analgesia) and consider a PRN administration according to the pain level instead of a systematic administration of 0.5-1 mg of hydromorphone q1hr. In addition, this is incredibly time. Please consider, q 2 or 3 hr interval. RESPONSE: Please refer to our response question #2 above where we indicate that the sentence pertaining to postoperative hydromorphone administration is indeed inconsistent with our practice as we routinely offered subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request (i.e., on a PRN basis) as we expected some breakthrough pain from the epidural (which has a diluted LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision), page 9, 2 nd paragraph). Competing Interests: The authors have no competing interests to declare Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 20 Sep 2022 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 3 (revision) 28 Jun 24 read Version 2 (revision) 03 Jun 24 read read Version 1 20 Sep 22 read read read Jacques Chelly , University of Pittsburgh Medical Center, Pittsburgh, USA Shiv Goel , University of Pittsburgh Medical Center, Pittsburgh, USA Andrea De Gasperi , ASST Great Metropolitan Niguarda, Milan, Italy Heitor J S Medeiros , Massachussets General Hospital, Boston, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 De Gasperi A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 08 Jul 2024 | for Version 3 Andrea De Gasperi , [Retired], ASST Great Metropolitan Niguarda, Milan, Italy 0 Views copyright © 2024 De Gasperi A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I am not full convinced of the answers I had from the Authors' revisions and response. Since this is an ongoing trial still recruiting patients as assessed by the authors, I dare suggest to wait for the results to study the completed series and to submit a proof of concept article and not only a project. Then, my suggestion is "Not to Accept" the article as it is. Competing Interests No competing interests were disclosed. Reviewer Expertise anesthesia , intensive care, abdominal organ transplants, infections I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) De Gasperi A. Peer Review Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.168365.r296648) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-1067/v3#referee-response-296648 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Medeiros H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 18 Jun 2024 | for Version 2 Heitor J S Medeiros , DACCPM, Massachussets General Hospital, Boston, MA, USA 0 Views copyright © 2024 Medeiros H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors comments sufficiently address my previous concerns. Competing Interests No competing interests were disclosed. Reviewer Expertise Anesthesiology, regional anesthesia I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Medeiros HJS. Peer Review Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.166251.r285904) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-1067/v2#referee-response-285904 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Chelly J et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 08 Jun 2024 | for Version 2 Jacques Chelly , Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Shiv Goel , Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA 0 Views copyright © 2024 Chelly J et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The proposed solution to be infused following a PVB block or an epidural remain the same as in the original version. They authors really need to understand that it is not possible to compare the efficacy of these 2 techniques when one technique (Epidural is infused with opioid) and the other only receive local anesthetics (PVB). In these conditions, the authors give me no choice but to again recommend that this not be approved unless it is clearly stated in the background that the proposed protocol is based on the standard technique being used in your institution and that the goal of the study is to compare an Epidural infused with a solution of ............ to a continuous PVB infused with ............ in term of a/ b/ .......... It is understood that the proposed protocol is not to compare the use of epidural vs continuous PVB because our standard of care is based of using different solutions for Epidural and PVB. Basically the authors have not addressed my comment about the use of 2 different solutions one specific to the epidural with opioid and the second got PVB containing no opioids. Competing Interests No competing interests were disclosed. Reviewer Expertise Regioaal Anesthesia and Pain We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 29 Jun 2024 Anthony Ho, Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada Dear Drs. Chelly and Goel, Thank you for taking the time to review the second version of our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Comments from Drs Chelly and Goal and authors responses NOT APPROVED The proposed solution to be infused following a PVB block or an epidural remain the same as in the original version. They authors really need to understand that it is not possible to compare the efficacy of these 2 techniques when one technique (Epidural is infused with opioid) and the other only receive local anesthetics (PVB). In these conditions, the authors give me no choice but to again recommend that this not be approved unless it is clearly stated in the background that the proposed protocol is based on the standard technique being used in your institution and that the goal of the study is to compare an Epidural infused with a solution of ............ to a continuous PVB infused with ............ in term of a/b/ Apologies that we did not previously make this clear. In fact, our objective is to compare two standard of care anesthesia practices used for postoperative pain control in hepatectomy patients. The whole reason we hypothesise that PVB will have comparable analgesia but with reduced side-effects is because there is LA in the PVB to provide pain relief but no opioid infusion to cause adverse side effects and prolong the length of hospital stay. .......... It is understood that the proposed protocol is not to compare the use of epidural vs continuous PVB because our standard of care is based of using different solutions for Epidural and PVB. Basically the authors have not addressed my comment about the use of 2 different solutions one specific to the epidural with opioid and the second got PVB containing no opioids. Our intention was never to compare the “techniques” in isolation which would definitely require equal solutions and we never stated this as our aim. However, we have now better clarified what our aim was both in the Abstract and the end of the Introduction. We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. View more View less Competing Interests No competing interests reply Respond Report a concern Chelly J and Goel S. Peer Review Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.166251.r285905) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-1067/v2#referee-response-285905 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Medeiros H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 23 May 2024 | for Version 1 Heitor J S Medeiros , DACCPM, Massachussets General Hospital, Boston, MA, USA 0 Views copyright © 2024 Medeiros H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The study's purpose and goals are clearly explained. It addresses the risks and downsides of TEA and explores if PVB can provide the same pain relief with fewer complications. Design flaws: Different drugs are used for TEA and PVB, which could affect the results - Is the result coming from technique or simply by drug differences? This needs to be well adressed in discussion. Using the same anesthetic for both groups would provide a clearer comparison. The study uses both blind and ultrasound-guided PVB, which adds variability. Sticking to one method (eg ultrasound) would have improved consistency. The protocol for intravenous hydromorphone administration is not ideal as it doesn’t consider patient pain levels - why is this done this way? institutional protocol? please clarify and adress accordingly . Adjusting doses based on pain levels would be more effective? Are the datasets clearly presented in a usable and accessible format? Partly : While data storage and recording are described, the format isn't clear. This could impact external validity. Providing examples as supplementary material or templates of the datasets would improve clarity. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Anesthesiology, regional anesthesia I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 05 Jun 2024 Anthony Ho, Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada Dear Dr. Medeiros, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revisions made to the second version of the manuscript uploaded to F1000. Best Regards, Anthony Ho Dr. Medeiros’ comments and the authors responses: NOT APPROVED The study's purpose and goals are clearly explained. It addresses the risks and downsides of TEA and explores if PVB can provide the same pain relief with fewer complications. Response: Thank you. Design flaws: Different drugs are used for TEA and PVB, which could affect the results - Is the result coming from technique or simply by drug differences? This needs to be well adressed in discussion. Using the same anesthetic for both groups would provide a clearer comparison. Response: Your comment is very similar to one asked by Chelly and Goel in the first review to which we responded: “As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” The study uses both blind and ultrasound-guided PVB, which adds variability. Sticking to one method (eg ultrasound) would have improved consistency. RESPONSE: Once again your concern is virtually the same as one noted by previous reviewers to which we responded: “US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice.” We have now described both the blind and US-guided methods within the text (page 8). The protocol for intravenous hydromorphone administration is not ideal as it doesn’t consider patient pain levels - why is this done this way? institutional protocol? please clarify and adress accordingly . Adjusting doses based on pain levels would be more effective? Response: Once again, your comment is very similar to one made by Drs. Chelly and Goel to which we responded: “Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency.” Are the datasets clearly presented in a usable and accessible format? Partly : While data storage and recording are described, the format isn't clear. This could impact external validity. Providing examples as supplementary material or templates of the datasets would improve clarity. Response: Given that this is a protocol manuscript and not a final manuscript with results, the authors believe the data collection processes are adequately described. As stated previously, final data may be placed into a public depository although no identifiable information will be used. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Anesthesiology, Regional anesthesia I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. View more View less Competing Interests The authors have no competing interests to declare. reply Respond Report a concern Medeiros HJS. Peer Review Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.133913.r249114) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-1067/v1#referee-response-249114 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 De Gasperi A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 04 Mar 2024 | for Version 1 Andrea De Gasperi , [Retired], ASST Great Metropolitan Niguarda, Milan, Italy 0 Views copyright © 2024 De Gasperi A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 1) Postoperative hemostatic profile is not by default pro-hemorrhagic particularly in case of neoplastic diseases or in HCC in patients included in CHILD A / MELD < 11. 2) Viscoelastic tests should be strongly considered (TEG/ROTEM) to describe the pre/intra/post hemostatic profile.: to be considered the "rebalanced hemostasis " in cirrhotic patiens (Tripodi et al Am J Gastroenterol, 2017; 112: 274-81 1 3) for the periop hemostatic profile in liver resection please consider also a) Cerutti et al Liver transplantation 2004; 10: 289-94 2 ---b) DePietri et al, World J Gastroenterol, 2018; 24: 2931-48 3 4) 50 pts to be randomized : please provide the statistical justification of this number (enough power ??) 5) First lines of the "Discussion" seem to be to too dramatic" "Inadequate analgesia can lead to hypertension, tachycardia, pulmonary splinting, and inability to breathe deeply and cough. The result could be myocardial ischaemia, pneumonia, and/or the need for prolonged respiratory support.". I would be much more concerned for these complications (particularly for MACEs, respiratory complications ) for the intraop anesthetic management 6) CFR to be provided Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Partly References 1. Tripodi A, Primignani M, Mannucci PM, Caldwell SH: Changing Concepts of Cirrhotic Coagulopathy. Am J Gastroenterol . 2017; 112 (2): 274-281 PubMed Abstract | Publisher Full Text 2. Cerutti E, Stratta C, Romagnoli R, Schellino MM, et al.: Thromboelastogram monitoring in the perioperative period of hepatectomy for adult living liver donation. Liver Transpl . 2004; 10 (2): 289-94 PubMed Abstract | Publisher Full Text 3. De Pietri L, Montalti R, Nicolini D, Troisi RI, et al.: Perioperative thromboprophylaxis in liver transplant patients. World J Gastroenterol . 2018; 24 (27): 2931-2948 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise anesthesia , intensive care, abdominal organ transplants, infections I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 21 Jun 2024 Anthony Ho, Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada Dear Dr. De Gasperi, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Postoperative hemostatic profile is not by default pro-hemorrhagic particularly in case of neoplastic diseases or in HCC in patients included in CHILD A / MELD < 11. RESPONSE: We acknowledge that preoperative liver functional status is one of several major factors influencing postoperative hemostatic function (please see 2 nd paragraph of Introduction). Viscoelastic tests should be strongly considered (TEG/ROTEM) to describe the pre/intra/post hemostatic profile.: to be considered the "rebalanced hemostasis " in cirrhotic patients (Tripodi et al Am J Gastroenterol, 2017; 112: 274-81 1 3) for the periop hemostatic profile in liver resection please consider also a) Cerutti et al Liver transplantation 2004; 10: 289-94 2 ---b) DePietri et al, World J Gastroenterol, 2018; 24: 2931-48 RESPONSE: Thank you for emphasizing the potentially crucial role of thromboelastometry/graphy in discerning hemostatic status. We acknowledge the complex nature of coagulation in many clinical situations, including liver resection with or without cancer and/or cirrhosis. However, TEG/ROTEM’s role in liver resection and neuraxial block is still not well established. This area is indeed ripe for more research endeavors but is not the goal of our project. Future research may very well show that TEG/ROTEM results can be important indicators as to whether neuraxial blocks should be contraindicated but at the present time, platelet count and INR remain the standard tests (however imperfect). As we are only using the platelet count and INR to exclude patients preoperatively as per industry standard and are not studying hemostatic changes associated with liver resection, we respectfully decline to include the Tripodi, Cerutti, and De Pietri references thoughtfully suggested. 3) 50 pts to be randomized: please provide the statistical justification of this number (enough power ??) RESPONSE: Please see the Protocol section (under Sample size, page 5) where it reads: “Non-inferiority trials typically require larger samples than superiority trials; 49,50 thus, we anticipate the need to include multiple centres to secure enough participants. Therefore, we propose a single-centre pilot study to generate the data needed to estimate the sample size required for a large, multi-centre trial. Based upon previous studies that compared TEA versus PVB for postoperative analgesia in patients undergoing thoracotomy, 45,51 we will aim for a convenience sample of 25 patients per group to generate pilot data upon which to base a larger, multi-centre trial.” 4) First lines of the "Discussion" seem to be to too dramatic" "Inadequate analgesia can lead to hypertension, tachycardia, pulmonary splinting, and inability to breathe deeply and cough. The result could be myocardial ischaemia, pneumonia, and/or the need for prolonged respiratory support.". I would be much more concerned for these complications (particularly for MACEs, respiratory complications) for the intraop anesthetic management CFR to be provided RESPONSE: We have shortened and softened the argument on the importance of good postoperative pain management without excessive reliance on opioids in the Discussion section (bottom page 10). We agree that intraoperative stable management is vital to avoid cardiorespiratory complications. We did not think it was necessary to explicitly mention that as such is the universal goal of all anesthetic management. View more View less Competing Interests The authors have no conflicts of interest to declare reply Respond Report a concern De Gasperi A. Peer Review Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . F1000Research 2024, 11 :1067 ( https://doi.org/10.5256/f1000research.133913.r235497) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-1067/v1#referee-response-235497 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Chelly J et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 13 Feb 2024 | for Version 1 Jacques Chelly , Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Shiv Goel , Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA 0 Views copyright © 2024 Chelly J et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors are proposing to compare thoracic epidural analgesia (TEA) to a right continuous Paravertebral block (PVB) in 50 patients undergoing hepatectomy using a subcostal approach. The hypothesis being that PVB may represent a safer alternative because it is established that PVB provides hemodynamic stability, low failure rates, and low risk of spinal hematoma compared to TEA. This study will be conducted in 50 patients. This study will be a proof of concept and will allow to propose a multicentric study to include 450 patients, The authors are listing postoperative opioid consumption over 72 hours as the primary end point is. Secondary end points include opioid related side effects, hemodynamic stability, respiratory depression, complications (particularly spinal haematoma). In this study patients will be randomized to either TEA or PVB. The authors hypothesis is that opioid consumption, time to first analgesic request, and pain scores will be comparable between groups, but PVB patients will require fewer perioperative vasopressors/blood products, and have fewer adverse events and a shorter hospital stay. Critics The comparison of TEA and PVB is certainly interesting and clinically relevant especially in the context of a subcostal approach. However, if the authors want to conduct the study because they expect that the use of PVB would be safer than TEA, Why is opioid consumption used as the primary end point, There are a number of design questions? 1-If the authors interested is to compare TEA to PVB which make sense for this reviewer why is the local anesthetics protocol different for TEA or PVB. Patients in the TEA group are schedule to receive bupivacaine 0.1% with hydromorphone 10 μg/mL will be infused at 6-10 mL/h and five mL boluses will be allowed at 30 min intervals at the discretion of the anaesthesiologist. Upon admission to the PACU, patient-controlled epidural analgesia (PCEA) will be initiated. The PCEA bolus of the same solution will be set at three mL with a lockout period of 30 min, and the epidural infusion of the same solution will be set at six mL/h and adjusted in two mL/h increments (or decrements) up to 10 mL/h depending upon pain scores and sensory block tested with ice in the PACU. Whereas patients in the PVB group will be scheduled to receive An infusion of ropivacaine 0.25% at a rate of 0.1 mL/kg/h will be started shortly after induction of GA. In addition, five mL boluses of ropivacaine 0.25% will be allowed at 30 min intervals intraoperatively at the discretion of the anesthesiologist. Upon transfer to the PACU, patient-controlled paravertebral analgesia (PCPA) will be started. The PCPA bolus will be five mL ropivacaine 0.25% with a lockout period of two hours, and an infusion of ropivacaine 0.25% will be continued at 0.1 mL/kg/h and increased in two mL/h increments up to 10 mL/h, depending on the pain scores and sensory block to ice tested in the PACU. This initial infusion will be continued for the first 24 h after surgery, and then reduced by 25% on postoperative day (POD) two, and further reduced another 25% on POD3. This means that the authors are not comparing TEA vs PVB but rather TEA + specific infusion solution vs PVB + a different infusion solution. Why not use the same solution for both TEA and PVB? Also please consider eliminating opioid in the TEA solution. This is adding 1.2 to 2,4 or more mg of hydromorphone in the TEA group 2- Why are the authors administrating IV hydromorphone at a dose of 0.5 to 1 mg every hour without any reference to the pain of the patient? Can these administration be q 2 or 3 hrs and the among establish according to the pain level of the patient? 3-The authors provide a long list of variables that they are going to monitor, but do not provide any details on they intend to qualify these variables? Example hypotensive episode define as MPA < 50 mh requiring intervention ? urinary retention? At the very least they need to refer to articles if they don’t want to include a definition in their protocol. 4- Including both a blind or US approach to perform PVB is a design problem. Please chose one or the other It is important that the technique used for the placement of a catheter in the PVB space is consistent and reliable. In contrast of what is stated by the authors, placing a catheter in the PVB space is difficult and required both expertise and the use of an ultrasound. Without the use of ultrasound, it is really possible to establish is what is being performed is a true PVB or an ESP block. In this reviewer experience, in most cases a blind technique doesn’t result in the catheter being placed in PVB space. However, in the past a blind approach has being used. Therefore, the recommendation of this reviewer would be for the authors to use either a blind or an ultrasound approach but not both. Other requests. a-Please provide details of the PVB technique either blind or with US. b- the authors use 20% as their inferiority margin for cumulative opioid consumption at 72 hours postoperatively, because they consider that 20% is not clinically significant ? Although, this reviewer would prefer 10% instead of 20%, the confounding variable is the excessive among of opioid expected to be administered. Please consider eliminating opioid from the TEA solution and consider a PRN administration according to the pain level instead of a systematic administration of 0.5-1 mg of hydromorphone q1hr. In addition this is incredibly time. Please consider, q 2 or 3 hr interval. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? No Are sufficient details of the methods provided to allow replication by others? No Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Regioaal Anesthesia and Pain We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 21 Jun 2024 Anthony Ho, Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, K7L2V7, Canada Dear Drs. Chelly and Goel, Thank you for taking the time to review our protocol. Please see our responses to your comments below and the revised version of the manuscript uploaded to F1000. Dr Chelly’s summary: The authors are proposing to compare thoracic epidural analgesia (TEA) to a right continuous paravertebral block (PVB) in 50 patients undergoing hepatectomy using a subcostal approach. The hypothesis being that PVB may represent a safer alternative because it is established that PVB provides hemodynamic stability, low failure rates, and low risk of spinal hematoma compared to TEA. This study will be conducted in 50 patients. This study will be a proof of concept and will allow to propose a multicentric study to include 450 patients. The authors are listing postoperative opioid consumption over 72 hours as the primary end point is. Secondary end points include opioid related side effects, hemodynamic stability, respiratory depression, complications (particularly spinal haematoma). In this study patients will be randomized to either TEA or PVB. The author’s hypothesis is that opioid consumption, time to first analgesic request, and pain scores will be comparable between groups, but PVB patients will require fewer perioperative vasopressors/blood products, and have fewer adverse events and a shorter hospital stay. Critics The comparison of TEA and PVB is certainly interesting and clinically relevant especially in the context of a subcostal approach. However, if the authors want to conduct the study because they expect that the use of PVB would be safer than TEA, why is opioid consumption used as the primary end point, There are a number of design questions?1 - If the authors interest is to compare TEA to PVB which make sense for this reviewer why is the local anesthetics protocol different for TEA or PVB. Patients in the TEA group are schedule to receive bupivacaine 0.1% with hydromorphone 10 μg/mL will be infused at 6-10 mL/h and five mL boluses will be allowed at 30 min intervals at the discretion of the anaesthesiologist. Upon admission to the PACU, patient-controlled epidural analgesia (PCEA) will be initiated. The PCEA bolus of the same solution will be set at three mL with a lockout period of 30 min, and the epidural infusion of the same solution will be set at six mL/h and adjusted in two mL/h increments (or decrements) up to 10 mL/h depending upon pain scores and sensory block tested with ice in the PACU. Whereas patients in the PVB group will be scheduled to receive an infusion of ropivacaine 0.25% at a rate of 0.1 mL/kg/h will be started shortly after induction of GA. In addition, five mL boluses of ropivacaine 0.25% will be allowed at 30 min intervals intraoperatively at the discretion of the anesthesiologist. Upon transfer to the PACU, patient-controlled paravertebral analgesia (PCPA) will be started. The PCPA bolus will be five mL ropivacaine 0.25% with a lockout period of two hours, and an infusion of ropivacaine 0.25% will be continued at 0.1 mL/kg/h and increased in two mL/h increments up to 10 mL/h, depending on the pain scores and sensory block to ice tested in the PACU. This initial infusion will be continued for the first 24 h after surgery, and then reduced by 25% on postoperative day (POD) two, and further reduced another 25% on POD3. This means that the authors are not comparing TEA vs PVB but rather TEA + specific infusion solution vs PVB + a different infusion solution. Why not use the same solution for both TEA and PVB? RESPONSE: The reason for setting opioid consumption as a primary end point is that the major complications (neuraxial hematoma, pneumothorax, total spinal) associated with TEA and PVB are rare. Furthermore, opioid consumption comparison is almost universal when comparing any 2 or more analgesic regimens. As for why the differences in the blocking solutions, (a very valid question), we are trying to adhere to industry (as well as local) standards of using a motor-sparing LA concentration supplemented by a very small amount of opioids in epidural infusions, and a higher LA concentration without opioids in thoracic PVB. Hence, to answer the reviewer’s question (“Why not use the same solution for both TEA and PVB?”), using a similar solution for both groups would completely deviate from industry (and local) standard practice and render our study irrelevant. We have added the following to clarify this point (see bottom of page 8): “Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 mcg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.” Also please consider eliminating opioid in the TEA solution. This adds 1.2 to 2.4 more mg of hydromorphone in the TEA group. RESPONSE: We acknowledge the systemic and some central analgesic effect of the opioid in the epidural group. The amount of epidural opioid, however, is small. For an infusion of 7 mL/h, for example, the hydromorphone infused is 0.07 mg/h, or 1.68 mg/24 h. Adding opioid to PVB, as stated earlier, is not standard practice. 2. Why are the authors administrating IV hydromorphone at a dose of 0.5 to 1 mg every hour without any reference to the pain of the patient? Can the administration be a q2 or 3 hrs and the amount established according to the pain level of the patient? RESPONSE: Thank you for pointing this out. In fact, this sentence is indeed inconsistent with our practice as we routinely offer subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request as we expected some breakthrough pain from the epidural (which has a diluted motor-sparing LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision of ~5 cm). This has now been corrected (page 9, 2 nd paragraph). We apologize for not picking up this inconsistency prior to the initial publication of our protocol, and sincerely thank the reviewer for pointing out this inconsistency. 3 -The authors provide a long list of variables that they are going to monitor, but do not provide any details on they intend to qualify these variables? Example hypotensive episode define as MPA < 50 mh requiring intervention? urinary retention? At the very least they need to refer to articles if they don’t want to include a definition in their protocol. RESPONSE: The authors are not totally certain about what the reviewer means by this comment; however, our intention in collecting these variables is simply descriptive, i.e., to determine whether their incidence would be similar/vary according to the treatment (i.e., TEA vs. PVB) modality. The differences between TEA and PVB need to be highlighted. Among these differences, TEA almost always cause a drop in blood pressure and thoracic PVB almost never. Likewise, TEA commonly causes urinary retention whereas PVB simply does not. We use MAP<50 mmHg as qualifying for hypotension and the need for urinary bladder catheterization as a surrogate for retention. These are rather well-defined markers. Similarly, the Ramsay score is a validated metric for sedation. The other outcomes such as vasopressor use, fluid requirement, urine output, and length of stay are all well defined endpoints that we quantify. 4 - Including both a blind or US approach to perform PVB is a design problem. Please chose one or the other It is important that the technique used for the placement of a catheter in the PVB space is consistent and reliable. In contrast of what is stated by the authors, placing a catheter in the PVB space is difficult and required both expertise and the use of an ultrasound. Without the use of ultrasound, it is really possible to establish is what is being performed is a true PVB or an ESP block. In this reviewer experience, in most cases a blind technique doesn’t result in the catheter being placed in PVB space. However, in the past a blind approach has being used. Therefore, the recommendation of this reviewer would be for the authors to use either a blind or an ultrasound approach but not both. RESPONSE: US-guided paravertebral block was not commonplace at our institution when the protocol was written, and some experienced anesthesiologists were actually more comfortable with the landmark “blind” technique. In the end, we decided to let anesthesiologists choose the technique with which they were most comfortable. We usually aim for a “true” PVB by seeking a loss of resistance upon piercing the superior costotransverse ligament. This loss of resistance is more subtle than that in an epidural block. Therefore, we agree that sometimes a block akin to an erector spinae plane (ESP) block may be the result if a loss of resistance is not discerned after walking off the transverse process and advancing the needle by ~1 cm or slightly more (depending on the needle angle). In the end, this represents reality as ultrasound guided thoracic PVB can be challenging, and resorting to blindly advancing the needle beyond the transverse process is still practiced by some. Whether the resulting block is an ESP block or a true PVB, while important, is simply a reflection of actual clinical practice. Other requests. a-Please provide details of the PVB technique either blind or with US. RESPONSE: The blind technique is now well described as follows: “In the landmark technique, once the appropriate thoracic level is identified, the needle is inserted at 2.5-3 cm lateral to the most cephalad aspect of the spinous process and advanced perpendicular to the skin in all planes to contact the transverse process of the vertebra below. The needle is then walked above the transverse process and gradually advanced until a loss of resistance to saline is felt as the needle tip traverses the thin superior costotransverse ligament. 52 ” (page 8, 3 rd paragraph, Ref: Karmakar MK, Ho AMH. Thoracic and lumbar paravertebral block. In: Modern Regional Anesthesia. Ed. Hadzic A, McGraw-Hill 2007, New York: Chapter 43: pp. 583-97.) The US-guided technique is as follows: a high-frequency linear US transducer is placed 2.5-3 cm lateral to the most cephalad aspect of the spinous process and oriented vertically at the target thoracic level. Once the transverse process is identified as a “squared” bony structure (note, the identification of a “round” bony structure is usually consistent with the rib, indicating that the probe should be slowly moved medially), the superior/cephalad aspect of the probe is maintained static, while its inferior/caudal aspect is slightly (~30 o ) rotated counterclockwise until the costotransverse ligament (usually ~0.5 cm superficial to the pleura) is brought into view. The block needle is carefully advanced in plane with the probe in a cephalad direction until it pierces the costotransverse ligament. Correct LA deposition is evidenced by the inferior displacement of the pleura under direct US visualization. b- the authors use 20% as their inferiority margin for cumulative opioid consumption at 72 hours postoperatively, because they consider that 20% is not clinically significant? Although this reviewer would prefer 10% instead of 20%, the confounding variable is the excessive among of opioid expected to be administered. Please consider eliminating opioid from the TEA solution RESPONSE: We respectfully disagree as adding a small amount of opioid in the epidural solution is a common practice - and an industry-wide and our institutional standard of care - since it allows the use of a diluted local anesthetic solution thereby decreasing the incidence of motor block while still providing adequate, or even enhanced, analgesia) and consider a PRN administration according to the pain level instead of a systematic administration of 0.5-1 mg of hydromorphone q1hr. In addition, this is incredibly time. Please consider, q 2 or 3 hr interval. RESPONSE: Please refer to our response question #2 above where we indicate that the sentence pertaining to postoperative hydromorphone administration is indeed inconsistent with our practice as we routinely offered subcutaneous hydromorphone 0.5-1 mg every 1-2 hours and upon patient request (i.e., on a PRN basis) as we expected some breakthrough pain from the epidural (which has a diluted LA concentration), and from the PVB (which may not cover the medial/midline portion of the surgical incision), page 9, 2 nd paragraph). View more View less Competing Interests The authors have no competing interests to declare reply Respond Report a concern Chelly J and Goel S. Peer Review Report For: Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study [version 3; peer review: 1 approved, 2 not approved] . 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