Continuous wound infusion of local anesthetic and steroid after major abdominal surgery: study protocol for a randomized controlled trial.
BACKGROUND
Inflammatory response is one of the key components of pain perception. Continuous infusion (CWI) of local anesthetics has been shown to be effective in controlling pain and reducing postoperative morphine consumption, but the effect of adding a potent anti-inflammatory drug (such as a steroid) has never been addressed. In our study, we want to investigate the effect of CWI with local anesthetic + methylprednisolone on acute and persistent pain, correlating clinical data with biomarkers of inflammation and genetic background.


METHODS
After approval by their institutional review board, three hospitals will enroll 120 patients undergoing major abdominal surgery in a randomized, double-blind, phase III study. After a 24-h CWI of ropivacaine 0.2 % + methylprednisolone 1 mg/kg, patients will be randomly assigned to receive either ropivacaine + steroid or placebo for the next 24 h. Then, patient-controlled CWI with only ropivacaine 0.2 % or placebo (according to the group of randomization) is planned after 48 h up to 7 days (bolus 10 ml, lock-out 1 h, maximum dose of 40 ml in 4 h). Morphine equivalent consumption up to 7 days will be analyzed, together with any catheter- or drug-related side effect. Persistent post-surgical pain (PPSP) incidence will also be investigated. Our primary endpoint is analgesic consumption in the first 7 days after surgery; we will evaluate, as secondary endpoints, any catheter- or drug-related side effect, genotype/phenotype correlations between some polymorphisms and postoperative outcome in terms of morphine consumption, development of the inflammatory response, and incidence of PPSP. Finally, we will collect, in a subgroup of patients, wound exudate samples by micro-dialysis, blood samples, and urine samples up to 72 h to investigate local and systemic inflammation and oxidative stress.


CONCLUSIONS
This is a phase III trial to evaluate the safety and efficacy of wound infusion with steroid and local anesthetic. The study is aimed also to evaluate how long this infusion has to be maintained in order to maximize effectiveness. Our data are intended to quantify the amount of ropivacaine and methylprednisolone needed by patients undergoing major abdominal surgery, to be stored in a new nanotechnology device for sustained pain treatment after surgery. We also aim to clarify the roles of inflammatory response, oxidative stress, and genetic background on postoperative and persistent pain after major abdominal surgery.


BACKGROUND
The trial was registered on ClinicalTrials.gov ( NCT02002663 ) on 24 Oct. 2013.
Department of Surgical Sciences, University of Parma, Via Gramsci, 14, 43100, Parma, Italy. dariobugada@gmail.com.|SIMPAR Group (Study in Multidisciplinary Pain Research), Parma, Italy. dariobugada@gmail.com.
Dario
D
Bugada
SIMPAR Group (Study in Multidisciplinary Pain Research), Parma, Italy. manuela.degregori@unipv.it.|Pain Therapy Service, IRCCS Foundation Policlinico S. Matteo, Pavia, P.le Golgi 19, 27100, Pavia, Italy. manuela.degregori@unipv.it.
Manuela
M
De Gregori
SIMPAR Group (Study in Multidisciplinary Pain Research), Parma, Italy. ccompagnone@parmanesthesia.com.|Department of Anesthesia, ICU and Pain Therapy, University Hospital of Parma, Via Gramsci, 14, 43100, Parma, Italy. ccompagnone@parmanesthesia.com.
Christian
C
Compagnone
Department of Health Science, Interregional Research Center for Food Safety & Health (IRC-FSH), University "Magna Graecia" of Catanzaro, Complesso "Ninì Barbieri", 88021, Roccelletta di Borgia, Italy. muscoli@unicz.it.|IRCCS San Raffaele Pisana, Via di Val Cannuta, 247, 00166, Rome, Italy. muscoli@unicz.it.
Carolina
C
Muscoli
Department of Anesthesia, IRCCS Humanitas Research Center, Via Alessandro Manzoni, 56, 20089, Rozzano, Milano, Italy. ferdinando.raimondi@humanitas.it.
Ferdinando
F
Raimondi
Department of Anesthesia and ICU, IRCCS Foundation Policlinico S. Matteo, Pavia, P.le Golgi 19, 27100, Pavia, Italy. s.bettinelli@smatteo.pv.it.
Silvia
S
Bettinelli
Laboratory of Transplant Immunology/Cell Factory, IRCCS Foundation Policlinico "San Matteo", P.le Golgi 19, 27100, Pavia, Italy. ma.avanzini@smatteo.pv.it.
Maria Antonietta
MA
Avanzini
Department of Surgical Sciences, IRCCS Foundation Policlinico S. Matteo, Pavia, P.le Golgi 19, 27100, Pavia, Italy. l.cobianchi@smatteo.pv.it.
Lorenzo
L
Cobianchi
Department of Surgical Sciences, IRCCS Foundation Policlinico S. Matteo, Pavia, P.le Golgi 19, 27100, Pavia, Italy. andreapeloso@hotmail.it.
Andrea
A
Peloso
SIMPAR Group (Study in Multidisciplinary Pain Research), Parma, Italy. mbaciarello@parmanesthesia.com.|Department of Anesthesia, ICU and Pain Therapy, University Hospital of Parma, Via Gramsci, 14, 43100, Parma, Italy. mbaciarello@parmanesthesia.com.
Marco
M
Baciarello
SIMPAR Group (Study in Multidisciplinary Pain Research), Parma, Italy. cdagostino@parmanesthesia.com.|Department of Health Science, Interregional Research Center for Food Safety & Health (IRC-FSH), University "Magna Graecia" of Catanzaro, Complesso "Ninì Barbieri", 88021, Roccelletta di Borgia, Italy. cdagostino@parmanesthesia.com.
Concetta
C
Dagostino
Department of Health Science, Interregional Research Center for Food Safety & Health (IRC-FSH), University "Magna Graecia" of Catanzaro, Complesso "Ninì Barbieri", 88021, Roccelletta di Borgia, Italy. luigi.giancotti@unicz.it.
Luigino A
LA
Giancotti
IRCCS San Raffaele Pisana, Via di Val Cannuta, 247, 00166, Rome, Italy. sara.ilari@sanraffaele.it.
Sara
S
Ilari
Department of Health Science, Interregional Research Center for Food Safety & Health (IRC-FSH), University "Magna Graecia" of Catanzaro, Complesso "Ninì Barbieri", 88021, Roccelletta di Borgia, Italy. milena.lauro@unicz.it.
Filomena
F
Lauro
Department of Anesthesia, IRCCS Humanitas Research Center, Via Alessandro Manzoni, 56, 20089, Rozzano, Milano, Italy. stefania.grimaldi@humanitas.it.
Stefania
S
Grimaldi
Department of Nanomedicine, The Methodist Hospital Research Institute, 6670 Bertner Avenue Suite R10-116, Houston, TX, 77030, USA. etasciotti@tmhs.org.
Ennio
E
Tasciotti
IRCCS San Raffaele Pisana, Via di Val Cannuta, 247, 00166, Rome, Italy. massimo.fini@sanraffaele.it.
Massimo
M
Fini
Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T), University of Parma, Faculty of Medicine, Via Volturno, 39, 43121, Parma, Italy. gloria.saccani@unipr.it.
Gloria M R
GM
Saccani Jotti
Department of Clinical and Experimental Medicine, University of Parma, Via A. Gramsci, 14, 43100, Parma, Italy. tiziana.meschi@unipr.it.
Tiziana
T
Meschi
Department of Surgical Sciences, University of Parma, Via Gramsci, 14, 43100, Parma, Italy. segreteria@parmanesthesia.com.|Department of Anesthesia, ICU and Pain Therapy, University Hospital of Parma, Via Gramsci, 14, 43100, Parma, Italy. segreteria@parmanesthesia.com.
Guido
G
Fanelli
Department of Surgical Sciences, University of Parma, Via Gramsci, 14, 43100, Parma, Italy. mallegri@parmanesthesia.com.|SIMPAR Group (Study in Multidisciplinary Pain Research), Parma, Italy. mallegri@parmanesthesia.com.|Department of Anesthesia, ICU and Pain Therapy, University Hospital of Parma, Via Gramsci, 14, 43100, Parma, Italy. mallegri@parmanesthesia.com.
Massimo
M
Allegri
D000005:Abdomen / Q000601:surgery*; D059787:Acute Pain / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D000577:Amides / Q000008:administration & dosage* / Q000009:adverse effects; D000701:Analgesics, Opioid / Q000627:therapeutic use; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000009:adverse effects; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D002985:Clinical Protocols; D004311:Double-Blind Method; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood; D007263:Infusions, Parenteral; D007558:Italy; D008775:Methylprednisolone / Q000008:administration & dosage* / Q000009:adverse effects; D018384:Oxidative Stress / Q000187:drug effects; D010149:Postoperative Pain / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D010641:Phenotype; D011446:Prospective Studies; D012107:Research Design; D000077212:Ropivacaine; D013256:Steroids / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome
D000577:Amides; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D018836:Inflammation Mediators; D013256:Steroids; D000077212:Ropivacaine; D008775:Methylprednisolone