Lippincott Williams & Wilkins
1.????? Original protocol, final protocol, summary of changes.2.????? Original statistical analysis plan, final statistical analysis plan, summary of changesOriginal protocol, final protocol, summary of changes.The Original protocol has been published: BMJ Open 2018 Jun 30;8(6):e020873Final protocolINTRODUCTIONSince the 1960’s, intraoperative administration of opioids is considered a keystone of anaesthesia as well as hypnotics and muscle relaxants. Synthetic opioids were introduced to achieve hemodynamic stability during anaesthesia. They allow an inhibition of the sympathetic system without cardiovascular collapse and histamine release. Since then, anaesthesia has changed from inhalation to multimodal anaesthesia with lower doses of hypnotic. In 2017, the intraoperative objectives of hypnosis, hemodynamic stability, immobility and anticipation of postoperative analgesia can be achieved without opioids. Moreover, opioid administration consequences are neither scarce nor benign for the patient. Perioperative opioids areassociated with nausea and vomiting ADDIN EN.CITE <EndNote><Cite><Author>Apfel</Author><Year>1999</Year><RecNum>157</RecNum><DisplayText>[1]</DisplayText><record><rec-number>157</rec-number><foreign-keys><key app="EN" db-id="9zpdzfda6xszrke9er85ae9ie2vwfxstxevt">157</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Apfel, C. C.</author><author>Laara, E.</author><author>Koivuranta, M.</author><author>Greim, C. A.</author><author>Roewer, N.</author></authors></contributors><auth-address>Department of Anesthesiology, University of Wuerzburg, Germany. apfel@anaesthesie.uni-wuerzburg.de</auth-address><titles><title>A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers</title><secondary-title>Anesthesiology</secondary-title><alt-title>Anesthesiology</alt-title></titles><periodical><full-title>Anesthesiology</full-title><abbr-1>Anesthesiology</abbr-1></periodical><alt-periodical><full-title>Anesthesiology</full-title><abbr-1>Anesthesiology</abbr-1></alt-periodical><pages>693-700</pages><volume>91</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Analgesics, Opioid/adverse effects</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Postoperative Nausea and Vomiting/*etiology</keyword><keyword>Risk Factors</keyword><keyword>Sex Factors</keyword></keywords><dates><year>1999</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0003-3022 (Print)
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ADDIN EN.CITE.DATA [6], immunodepression ADDIN EN.CITE <EndNote><Cite><Author>Afsharimani</Author><Year>2011</Year><RecNum>167</RecNum><DisplayText>[7]</DisplayText><record><rec-number>167</rec-number><foreign-keys><key app="EN" db-id="9zpdzfda6xszrke9er85ae9ie2vwfxstxevt">167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Afsharimani, B.</author><author>Cabot, P.</author><author>Parat, M. O.</author></authors></contributors><auth-address>University of Queensland School of Pharmacy, 20 Cornwall Street, Woolloongabba, QLD 4012, Australia.</auth-address><titles><title>Morphine and tumor growth and metastasis</title><secondary-title>Cancer Metastasis Rev</secondary-title><alt-title>Cancer metastasis reviews</alt-title></titles><periodical><full-title>Cancer Metastasis Rev</full-title><abbr-1>Cancer metastasis reviews</abbr-1></periodical><alt-periodical><full-title>Cancer Metastasis Rev</full-title><abbr-1>Cancer metastasis reviews</abbr-1></alt-periodical><pages>225-38</pages><volume>30</volume><number>2</number><keywords><keyword>Analgesics, Opioid/pharmacology/therapeutic use</keyword><keyword>Animals</keyword><keyword>Cell Line, Tumor</keyword><keyword>Cell Proliferation/*drug effects</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>Morphine/pharmacology/*therapeutic use</keyword><keyword>Neoplasm Metastasis</keyword><keyword>Neoplasms/complications/*drug therapy/pathology</keyword><keyword>Pain/etiology/*prevention & control</keyword></keywords><dates><year>2011</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1573-7233 (Electronic)
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ADDIN EN.CITE.DATA [8 9]. Among these complications, hypoxemia, ileus and confusion/delirium are the most frequent. They are associated with a significant morbidity, can increase the length of stay and slow postoperative rehabilitation:- Postoperative hypoxemia is frequent in post anaesthesia care unit (PACU) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYW5ldDwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYW5ldDwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [10]. It appears within minutes after tracheal extubation and the incidence is maximal 30 minutes after the arrival in PACU. The incidence of postoperative arterial hypoxemia after abdominal surgery varies between 20 to 40 % in the literature PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdWU8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [11 12]. The residual effect of anaesthetic drugs plays a major role in the genesis of early postoperative hypoxemia, especially opioids ADDIN EN.CITE <EndNote><Cite><Author>Canet</Author><Year>1989</Year><RecNum>92</RecNum><DisplayText>[13]</DisplayText><record><rec-number>92</rec-number><foreign-keys><key app="EN" db-id="9zpdzfda6xszrke9er85ae9ie2vwfxstxevt">92</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Canet, J.</author><author>Ricos, M.</author><author>Vidal, F.</author></authors></contributors><auth-address>Servei d'Anestesiologia i Reanimacio, Hospital Germans Trias i Pujol, Barcelona, Spain.</auth-address><titles><title>Early postoperative arterial oxygen desaturation. Determining factors and response to oxygen therapy</title><secondary-title>Anesth Analg</secondary-title><alt-title>Anesthesia and analgesia</alt-title></titles><periodical><full-title>Anesth Analg</full-title><abbr-1>Anesthesia and analgesia</abbr-1></periodical><alt-periodical><full-title>Anesth Analg</full-title><abbr-1>Anesthesia and analgesia</abbr-1></alt-periodical><pages>207-12</pages><volume>69</volume><number>2</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Anesthesia Recovery Period</keyword><keyword>Anesthesia, Conduction</keyword><keyword>Anesthesia, General</keyword><keyword>Anoxia/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Oximetry</keyword><keyword>Oxygen/*blood</keyword><keyword>*Oxygen Inhalation Therapy</keyword><keyword>*Postoperative Period</keyword><keyword>Random Allocation</keyword></keywords><dates><year>1989</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0003-2999 (Print)
0003-2999 (Linking)</isbn><accession-num>2764289</accession-num><urls><related-urls><url>;[13]. Postoperative opioid-induced respiratory depression is a cause of death and brain damage. Amongst 357 acute pain claims registered in the USA between 1990 and 2009, 92 were respiratory depression of which 77% resulted in severe brain damage or death. The vast majority (88%) of respiratory depression occurred within 24 hours of surgery PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [16].Efficacious multimodal analgesia and anaesthesia are the basis of successful fast-track surgery. These multidrug regimens aim at decreasing postoperative pain, intra- and postoperative opioid requirements, and subsequently, opioid-related adverse effects and to fasten recovery. Opioid-free postoperative analgesia has been therefore recommended for more than 10 years ADDIN EN.CITE <EndNote><Cite><Author>Kehlet</Author><Year>2003</Year><RecNum>136</RecNum><DisplayText>[17]</DisplayText><record><rec-number>136</rec-number><foreign-keys><key app="EN" db-id="9zpdzfda6xszrke9er85ae9ie2vwfxstxevt">136</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kehlet, H.</author><author>Dahl, J. B.</author></authors></contributors><auth-address>Department of Surgical Gastroenterology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark. henrik.kehlet@hh.hosp.dk</auth-address><titles><title>Anaesthesia, surgery, and challenges in postoperative recovery</title><secondary-title>Lancet</secondary-title><alt-title>Lancet</alt-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1></periodical><alt-periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1></alt-periodical><pages>1921-8</pages><volume>362</volume><number>9399</number><keywords><keyword>Anesthesia/*methods</keyword><keyword>Convalescence</keyword><keyword>Forecasting</keyword><keyword>Humans</keyword><keyword>Intraoperative Care/methods</keyword><keyword>Outcome Assessment (Health Care)</keyword><keyword>Pain/prevention & control</keyword><keyword>Pain, Postoperative/prevention & control</keyword><keyword>Postoperative Care/*methods</keyword><keyword>Postoperative Complications/prevention & control</keyword><keyword>Professional Role</keyword><keyword>Surgical Procedures, Operative/*methods</keyword></keywords><dates><year>2003</year><pub-dates><date>Dec 06</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>14667752</accession-num><urls><related-urls><url>(03)14966-5</electronic-resource-num></record></Cite></EndNote>[17]. Based on the same principle of opioid sparing, opioid-free anaesthesia (OFA) is a multimodal anaesthesia associating hypnotics, NMDA antagonists, local anaesthetics, anti-inflammatory drugs and alpha-2 agonists. Hemodynamic stability can be achieved without opioids during anaesthesia in 2017. The first studies on OFA focused on bariatric surgery where respiratory complications are frequent. OFA with dexmedetomidine (Dex) significantly attenuated postoperative pain and reduced opioid requirements without causing respiratory depression in obese patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWxkPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [18 19]. OFA was then proposed for awake neurosurgery ADDIN EN.CITE <EndNote><Cite><Author>Goettel</Author><Year>2016</Year><RecNum>137</RecNum><DisplayText>[20]</DisplayText><record><rec-number>137</rec-number><foreign-keys><key app="EN" db-id="9zpdzfda6xszrke9er85ae9ie2vwfxstxevt">137</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goettel, N.</author><author>Bharadwaj, S.</author><author>Venkatraghavan, L.</author><author>Mehta, J.</author><author>Bernstein, M.</author><author>Manninen, P. H.</author></authors></contributors><auth-address>Department of Anesthesia, Toronto Western Hospital Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
Department of Anesthesia, Toronto Western Hospital.
Division of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Canada.
Department of Anesthesia, Toronto Western Hospital pirjo.manninen@uhn.ca.</auth-address><titles><title>Dexmedetomidine vs propofol-remifentanil conscious sedation for awake craniotomy: a prospective randomized controlled trial</title><secondary-title>Br J Anaesth</secondary-title><alt-title>British journal of anaesthesia</alt-title></titles><periodical><full-title>Br J Anaesth</full-title><abbr-1>British journal of anaesthesia</abbr-1></periodical><alt-periodical><full-title>Br J Anaesth</full-title><abbr-1>British journal of anaesthesia</abbr-1></alt-periodical><pages>811-21</pages><volume>116</volume><number>6</number><dates><year>2016</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1471-6771 (Electronic)
0007-0912 (Linking)</isbn><accession-num>27099154</accession-num><urls><related-urls><url>;[20] and various minor ADDIN EN.CITE <EndNote><Cite><Author>Bakan</Author><Year>2015</Year><RecNum>154</RecNum><DisplayText>[21]</DisplayText><record><rec-number>154</rec-number><foreign-keys><key app="EN" db-id="9zpdzfda6xszrke9er85ae9ie2vwfxstxevt">154</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bakan, M.</author><author>Umutoglu, T.</author><author>Topuz, U.</author><author>Uysal, H.</author><author>Bayram, M.</author><author>Kadioglu, H.</author><author>Salihoglu, Z.</author></authors></contributors><auth-address>Departamento de Anestesiologia e Reanimacao, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turquia. Electronic address: mefkur@.
Departamento de Anestesiologia e Reanimacao, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turquia.
Departamento de Medicina Pulmonar, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turquia.
Departamento de Cirurgia Geral, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turquia.</auth-address><titles><title>[Opioid-free total intravenous anesthesia with propofol, dexmedetomidine and lidocaine infusions for laparoscopic cholecystectomy: a prospective, randomized, double-blinded study]</title><secondary-title>Rev Bras Anestesiol</secondary-title><alt-title>Revista brasileira de anestesiologia</alt-title></titles><periodical><full-title>Rev Bras Anestesiol</full-title></periodical><pages>191-9</pages><volume>65</volume><number>3</number><dates><year>2015</year><pub-dates><date>May-Jun</date></pub-dates></dates><orig-pub>Anestesia venosa total livre de opioides, com infusoes de propofol, dexmedetomidina e lidocaina para colecistectomia laparoscopica: estudo prospectivo, randomizado e duplo-cego.</orig-pub><isbn>1806-907X (Electronic)
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ADDIN EN.CITE.DATA [23 24]. One study showed a reduction of postoperative nausea and vomiting PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaWVtYW5uLUdpbW1lbDwvQXV0aG9yPjxZZWFyPjIwMTQ8
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ADDIN EN.CITE.DATA [25]. Adverse effects were hypotension and bradycardia. Proofs of the effect of OFA on reducing opioid-related adverse events after major or intermediate non-cardiac surgery are still scarce. We hypothesized that the reduced opioid used during and after surgery allowed by OFA compared with standard of care will be associated with a reduction of postoperative opioid-related adverse events.METHODS AND ANALYSIS Trial designThe POFA study is an investigator initiated, national, multicentre, randomized, single-blind, parallel-group clinical trial with concealed allocation of patients scheduled to undergo elective intermediate or major non-cardiac surgery 1:1 to receive either a standard anaesthesia protocol or OFA. The trial will be conducted at 11 university and non-university centres. The study started in December 2017 and the recruiting period will be 24 months.Participant eligibility and consentTrial site investigators will identify consecutive eligible patients from the listed criteria. Eligible patients will receive written and oral information and will be included after investigators have obtained informed written consent.Inclusion criteriaAdult (18 years or older) patients admitted to the participating centreUndergoing a scheduled major or intermediate non-cardiac surgery PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LcmlzdGVuc2VuPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh
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ADDIN EN.CITE.DATA [26]Benefiting from the health insurance systemHaving signed an informed consentNon-inclusion criteriaPregnant or breast-feeding womenAllergy to dexmedetomidine or one of its excipientsAllergy to one of the drugs used for anaesthesia or one of their excipientsUrgent surgeryIntracranial surgeryTransplant surgery or transplanted patients Surgery with planned regional anaesthesiaOutpatient surgeryAtrioventricular block, intraventricular or sinoatrial blockAdam-Stokes syndromePatients chronically treated with beta blockers and HR < 50 bpmCardiac insufficiency with a LVEF <40% Epilepsy or seizures, Acute cerebral pathology Obstructive sleep apnoea syndrome Severe hepatic insufficiency (Prothrombin Ratio < 15%) Adults legally protected (under judicial protection, guardianship, or supervision), persons deprived of their libertyPatients in whom the CAM-ICU cannot be performed (i.e. deaf patients) Uncontrolled hypotension,Allocation and blindingPatients will be randomized in two groups (control group and Dex group). In order to ensure group comparability, a plan of randomization will be used. Randomization will be done by investigators as close as possible to the surgery. Each patient will be given a unique patient-number and a randomization number (patient code) will be computer generated. It will be a block-randomization. Randomization will be stratified on the centre and on the type of surgery: abdominal (digestive, urological, gynaecological) or non-abdominal. The primary evaluation criterion will be assessed blinded to the randomization group. During the study period, patients and outcome assessors will be kept blind to the randomization group. Nurses evaluating outcomes in PACU and in the ward will not participate to the anaesthesia and will not be aware of the randomization group. They will be blind to the treatment. The anaesthesiologist and the nurse anaesthesiologist (care providers) will be the only ones not blinded. They will not participate in the assessment of the patients at any time.At each participating centre, data will be collected and entered into the electronic web-based case report form (eCRF) by trial or clinical trained personal (clinical research associate), blinded to the allocation group, under the supervision of the trial site investigators.InterventionsAll included patients will be allocated to one of the following two study groups:Control group: patients will receive a standardized anaesthesia protocol with remifentanilDex group: patients will receive a standard anaesthesia protocol with dexmedetomidineStandardized intravenous induction of general anaesthesia will include: Propofol: 1.5 - 2 mg/kg, Lidocaine: 1.5 mg/kg (IV bolus), Ketamine: 0.5 mg/kg (IV bolus), Cisatracurium: 0.15 mg/kg (IV bolus before tracheal intubation), Dexamethasone: 8 mg (IV bolus) and target-controlled infusion (TCI) of remifentanil (3 - 5 ng/ml) (Control group) or IV dexmedetomidine 0.4-1.4 μg/kg IV (Dex group).Standardized maintenance of general anaesthesia will include: Desflurane, IV Lidocaine: 1.5 mg/kg/h , IV Ketamine: 0.25 mg/kg/h, IV Cisatracurium as needed and TCI remifentanil (2 - 5 ng/ml) (Control group) or IV dexmedetomidine 0.4-1.4 μg/kg/h IV (Dex group). At the end of surgery, IV morphine (0.05 mg/kg) will be administered in the Control group. In both groups, intraoperative dose changes will be left to the anaesthesiologist in charge of the patient. Depth of anaesthesia (BISTM, Covidien, France) and analgesia (ANITM, Métrodoloris, France) will be monitored. The target of BISTM will range between 40 and 60 and ANITM between 50 and 70.Standardized postoperative protocol will include:Extubation after verification of standard criteria: Spontaneous breathing with VTe ≥ 5-8 ml/kg, respiratory rate of 12 to 25 c/min, absence of residual curarisation defined by T4/T1 ≥ 90% (train-of-four), SpO2 ≥ 95% with FiO2 ≤ 50%, verbal and motor response to simple orders, temperature ≥ 36°C. Extubation defines the H0 for assessment of the primary and secondary criteria events.Postoperative treatment: IV Lidocaine 1.5 mg/kg/h for 12 hours, Paracetamol (1g/6h IV and then oral), Nefopam (20mg/6h IV and then oral), Morphine titration in PACU according to routine standard of care, Morphine IV PCA according to routine standard of care, Ondansetron as a rescue medication in case of PONV. Patients will leave the PACU when Aldrete score > 9. Decisions about all other aspects of patient care will be performed according to the expertise of the staff at each centre and to routine clinical practice to minimize interference with the trial intervention. Nevertheless, to avoid extremes of clinical practice, trial investigators will be strongly encouraged to apply intraoperative normothermia, multimodal postoperative analgesia (without regional anaesthesia) and prevention of postoperative nausea and vomiting (PONV) based on Apfel score. Early postoperative resumption of fluids and solids will be encouraged.Outcome measuresPrimary composite outcome The primary composite outcome will be the occurrence of a severe postoperative opioid-related adverse event within the first 48 hours after extubation defined as: postoperative hypoxemia or postoperative ileus (POI) or postoperative cognitive dysfunction (POCD). The onset of an opioid-related adverse event will be assessed blinded to the randomization groupPostoperative hypoxemia is defined as therapeutic oxygen supplementation to maintain SpO2 > 95% within the first 48h after extubation; the duration of oxygen treatment will also be recorded ADDIN EN.CITE <EndNote><Cite><Author>Abbott</Author><Year>2018</Year><RecNum>173</RecNum><DisplayText>[27]</DisplayText><record><rec-number>173</rec-number><foreign-keys><key app="EN" db-id="9zpdzfda6xszrke9er85ae9ie2vwfxstxevt">173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abbott, T.E.F</author><author>Fowler, A.J.</author><author>Pelosi, P.</author><author>Gama de Abreu, M.</author><author>Moller, A.M.</author><author>Canet, J.</author><author>Creagh-Brown, B.</author><author>Mythen, M.</author><author>Gin, T.</author><author>Lalu, M.</author><author>Futier, E.</author><author>Grocott, M.P.</author><author>Schutz, M.J.</author><author>Pearse, R.M. and the StEP-COMPAC group</author></authors></contributors><titles><title>A systematic review and consensus definitions for standardised end-points in perioperative medicine: pulmonary complications.</title><secondary-title>Br J Anaesth</secondary-title></titles><periodical><full-title>Br J Anaesth</full-title><abbr-1>British journal of anaesthesia</abbr-1></periodical><volume>In Press</volume><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote>[27].Postoperative ileus (POI) is defined as an absence of flatus or stools within the first 48h after extubation.Postoperative cognitive dysfunction (POCD) will be evaluated using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) by a care provider (either anaesthesiologist or nurse). 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ADDIN EN.CITE.DATA [28 29] has been validated in multiple settings and is a widely used standardized method for identifying delirium with a high sensitivity of 94% (95% CI, 91%-97%), high specificity of 89% (95%CI, 85%-94%). The CAM algorithm consists of 4 items: 1. Acute Onset or Fluctuating Course. 2. Inattention 3. Disorganized thinking. 4. Altered Level of consciousness. The diagnosis of delirium by CAM/CAM-ICU requires a positive response to features 1 and 2 plus either 3 or 4; in these cases, the patients will be considered as presenting a POCD.Secondary outcomes Each component of the primary outcome measure will be analysed separately. Number of episodes of postoperative pain (numeric rating scale (NPS) ≥ 3) within 48 hours after extubation and at restOpioid consumption during the 48 hours following extubationTime between the end of remifentanil or dexmedetomidine administration and an Aldrete score > 9 (when applicable)Time between the end of remifentanil or dexmedetomidine administration and extubationRate of unscheduled admission in intensive care unitNumber of PONV episodes during the 48 hours following extubation. Need for rescue antiemetic medication will be recordedHospital length of stay (max 28 days) defined as the number of days after extubation before first hospital dischargeNumber of cardiac events during surgery (bradycardia defined as the number of episodes with atropine administration, hypotension defined as PAM < 65 mmHg, hypertension defined as PAM > 90 mmHg) and rescue medicationSample size estimation196 patients per group will be needed to have 80% power, at a two-sided alpha level of 0.05, to show a relative between-group difference of 40% in the composite primary outcome measure (30% to 18%), under the assumption of an overall incidence of 5% of postoperative ileus (from 5% to 20.6% after major or intermediate non-abdominal and abdominal surgery, respectively) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYW5ldDwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [3 5 14], thus 30% for the primary outcome measure. A total of 400 patients will be included to take into account non-evaluable patients. Patients undergoing a second surgery or dying within 48 hours without presenting the primary evaluation criteria will be kept considered as success in the analysis. Statistical analysis (cf. plan of statistics)Missing valuesMissing data will not be replaced. Mixed models can be used in analysis of repeated data to avoid deleting subjects with any missing values.Data RegistrationData will be entered into the web- based electronic case report form (eCRF) by trial or clinical personnel under the supervision of the trial site investigators at each participating centre. From the eCRF the trial database will be established. Data collection will be monitored by trained research coordinators.The following data will be registered:Baseline characteristics at randomization: Demographic data (age, height, weight, gender and body mass index); American Society of Anaesthesiologists (ASA) physical status; type of surgery; significant comorbidities (cardio-vascular, respiratory, neurologic, psychiatric and /or abdominal disease, cancer, preoperative chemotherapy or radiotherapy).Intraoperative data:Date of surgery, total doses of anaesthesia medications, doses of rescue medication (atropine, norepinephrine, adrenaline, ephedrine, anti-hypertensive medications), BISTM and ANITM values, Ventilation data at the beginning and the end of the surgery (Vt, RR, Peep, inspired fraction of oxygen), duration of surgery and anaesthesia, intraoperative complications (episode of bradycardia with atropine administration, hypotension (MAP < 65 mmHg), hypertension (MAP < 90 mmHg), shock (haemorrhagic, septic, cardiac, anaphylactic), clamping of a major vessel (aorta, vena cava), cardiac arrest, death, oxygen desaturation (SpO2 < 90% during more than 5 minutes), necessity to interrupt the procedure).Postoperative data:Patients will be assessed once daily during until the end of day 2 (48 hours).The following data will be collected:Post OR care pathway (PACU, scheduled intensive care unit (ICU) admission, unscheduled ICU admission)Duration to obtain Aldrete score ≥ 9Extubation timePost PACU care pathway (surgical ward, scheduled intensive care unit (ICU) admission, unscheduled ICU admission)Duration of stay in PACUEpisodes of oxygen desaturation defined by SPO2 < 95 % with oxygen requirement during the first 48 hours after extubationTime to first flatus and first stoolCAM-ICU daily during the first 48 hours after extubationEpisodes of PONVPresence of a postoperative naso gastric tube. If yes, date and hour if withdrawal Postoperative pain: episodes of NRS ≥ 3Total morphine consumption during the first 24 and 48 hours after extubationLength of stay (max 28 days)Death (until day 28)Patient withdrawalA participant who no longer agrees to participate in the clinical trial can withdraw the informed consent at any time without need of further explanation. Participants who will withdraw from the study will be followed up, according to routine clinical practice in each participating centre. In order to conduct intention-to-treat analyses with as little missing data as possible, the investigator may ask the participant which aspects of the trial he/she wishes to withdraw from (participation in the remaining follow-up assessments, use of already collected data). Whenever possible, the participant will be asked for permission to obtain data for the primary outcome measure. All randomised patients will be reported, and all data available with consent will be used in the analyses. If appropriate, missing data will be handled in accordance with multiple imputation procedures if missing data are greater than 5%.SafetyEvery serious adverse event related to the studied treatment or not, expected or unexpected, must be reported within 24 hours by the investigator to the sponsor on a “Serious adverse event” form on which will be indicated the date of occurrence, criterion of severity, intensity, relationship with the treatment (or the study) evaluated, and the outcome. The period in which serious adverse events should be reported begins from the day of the written informed consent to the end of the follow-up (48 hours). Whenever a serious adverse event persists at the end of the study, the investigator must follow the patient until the event is considered resolved. The following events: postoperative hypoxemia, postoperative ileus and postoperativecognitive dysfunction will be recorded as primary evaluation criterion in the case report form. In order to avoid collection duplication, they will not be reported on the “adverse event” page of the case report form. As planned in the study, they will be analysed at the time of interim analyses (two interim analyses after inclusion of 1/3 and 2/3 of the patients) which will permit to show potential difference between the two groups during the study.In addition, serious adverse events will be submitted to the data monitoring and safety committee (DMSC). The DMSC is independent of the trial investigators and will perform an ongoing review of safety parameters and overall study conduct. The DMSC is comprised of three independent clinicians (anaesthesiologists), a physician pharmacologist and a methodologist. The DMSC will be responsible for safeguarding the interests of trial participants, assessing the safety and efficacy of the interventions during the trial, and for monitoring the overall conduct of the clinical trial. To contribute to enhancing the integrity of the trial, the DMSC may also formulate recommendations relating to the recruitment/retention of participants, their management, improving adherence to protocol-specified regimens and retention of participants, and the procedures for data management and quality control. Recommendations for pausing or stopping the study will be made by the DMSC in case of serious adverse reactions and suspected unexpected serious adverse reaction.All adverse events for which the investigator or the sponsor considers that a causal relationship with the investigational medicinal products can be reasonably considered, will be considered as suspected adverse reactions. If they are unexpected, they are qualified as being Suspected Unexpected SAR (SUSAR) and will be notified in a report by the sponsor to Eudravigilance (European pharmacovigilance database) and to local regulatory agency within the regulatory time periods for reporting: Immediate declaration if seriousness criteria is death or life-threatening condition, declaration within 15 days for other seriousness criteria.Data handling and retentionData will be handled according to French law. All original records (including consent forms, reports of suspected unexpected serious adverse reactions and relevant correspondences) will be archived at trial sites for 15 years. The clean trial database file will be anonymised and maintained for 15 years.Patient and public involvementPatient and public were not involved in any of the phases of this studyETHICS AND DISSEMINATIONEthical and legislative approvalsPOFA trial was approved by the French National Safety and Drug Agency (Agence Nationale de Sécurité du Médicament (July, 11th, 2017). By September 4, 2017, the study has been approved for all centres by a central ethics committee (Comité de Protection des Personnes Ile-de-France II, Paris, France). The POFA trial is registered in the European Clinical Trials Database (EudraCT 2017-001907-61) and at with the trial identification number NCT03316339. Trial methods and results will be reported according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 guidelines ADDIN EN.CITE <EndNote><Cite><Author>Schulz</Author><Year>2010</Year><RecNum>40</RecNum><DisplayText>[31]</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="v09d255eis099aepzxppdretvvxwe5adzfvx" timestamp="1500645455">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schulz, K. F.</author><author>Altman, D. G.</author><author>Moher, D.</author><author>Consort Group</author></authors></contributors><auth-address>Family Health International, Research Triangle Park, NC 27709, USA. kschulz@</auth-address><titles><title>CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>BMJ</full-title></periodical><pages>c332</pages><volume>340</volume><keywords><keyword>Publishing/*standards</keyword><keyword>Randomized Controlled Trials as Topic/methods/*standards</keyword><keyword>Research Design/standards</keyword></keywords><dates><year>2010</year><pub-dates><date>Mar 23</date></pub-dates></dates><isbn>1756-1833 (Electronic)
0959-535X (Linking)</isbn><accession-num>20332509</accession-num><urls><related-urls><url>;[31].Publication planScientific presentations and reports corresponding to the study will be written under the responsibility of the coordinating investigator of the study with the agreement of the principal investigators and the methodologist. The co-authors of the report and of publications will be the investigators and clinicians involved, on a pro rata basis of their contribution in the study, as well as the biostatistician and associated researchers. All trial sites will be acknowledged, and all investigators at these sites will appear with their names under ‘the POFA investigators’ in an Appendix to the final manuscript. Rules on publication will follow international recommendations ADDIN EN.CITE <EndNote><Cite><Author>International Committee of Medical Journal</Author><Year>1997</Year><RecNum>150</RecNum><DisplayText>[32]</DisplayText><record><rec-number>150</rec-number><foreign-keys><key app="EN" db-id="9zpdzfda6xszrke9er85ae9ie2vwfxstxevt">150</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>International Committee of Medical Journal, Editors</author></authors></contributors><titles><title>Uniform requirements for manuscripts submitted to biomedical journals</title><secondary-title>N Engl J Med</secondary-title><alt-title>The New England journal of medicine</alt-title></titles><periodical><full-title>N Engl J Med</full-title><abbr-1>The New England journal of medicine</abbr-1></periodical><alt-periodical><full-title>N Engl J Med</full-title><abbr-1>The New England journal of medicine</abbr-1></alt-periodical><pages>309-15</pages><volume>336</volume><number>4</number><keywords><keyword>Authorship</keyword><keyword>Periodicals as Topic/*standards</keyword><keyword>Publishing/*standards</keyword></keywords><dates><year>1997</year><pub-dates><date>Jan 23</date></pub-dates></dates><isbn>0028-4793 (Print)
0028-4793 (Linking)</isbn><accession-num>8995096</accession-num><urls><related-urls><url>;[32].ConclusionThe POFA trial is the first prospective, randomized, parallel, single-blind, multicentre study evaluating the effect of OFA on severe postoperative opioid-related adverse events. If POFA yields positive results, it would bring strong data to promote OFA. Showing a benefit of OFA in terms of reduction of opioid-related adverse events, reduction of global morbidity, reduction of the economic burden associated with opioid-related adverse events and reduction in length of stay would result in a collective benefit for future patients and could lead to significant changes in the standard of care in anaesthesia. DMSC: Prof Patricia Lavand’homme (Brussels, Belgium), Dr Emmanuel Marret (Paris, France), Prof Jean Joris (Liège, Belgium), Dr Theodora Bejan-Angoulvant (Tours, France), Marina Nguon (Lyon, France).Scientific committee: Prof Emmnanuel Futier (Clermont-Ferrand, France), Prof Gerald Chanques (Montpellier, France), Prof Bruno Laviolle (Rennes, france), Prof Helene Beloeil (Rennes, France).Funding: POFA trial is supported by funding from French Ministry of Health (Programme Hospitalier de Recherché Clinique National (PHRC) 2016).The funding sources had no role in the trial design, trial conduct, data handling, data analysis or writing and publication of the manuscript.Trial sponsor: CHU de Rennes, Direction de la recherche Clinique, 2 avenue Henri le Guilloux, 35033 Rennes Cedex, France. The sponsor had no role in the trial design, trial conduct, data handling, data analysis or writing and publication of the manuscript.References ADDIN EN.REFLIST 1. Apfel CC, Laara E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology 1999;91(3):693-700 2. Paqueron X, Lumbroso A, Mergoni P, et al. Is morphine-induced sedation synonymous with analgesia during intravenous morphine titration? British journal of anaesthesia 2002;89(5):697-701 3. Gan TJ, Robinson SB, Oderda GM, et al. Impact of postsurgical opioid use and ileus on economic outcomes in gastrointestinal surgeries. Current medical research and opinion 2015;31(4):677-86 4. Wang Y, Sands LP, Vaurio L, et al. The effects of postoperative pain and its management on postoperative cognitive dysfunction. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2007;15(1):50-9 5. Lee LA, Caplan RA, Stephens LS, et al. Postoperative opioid-induced respiratory depression: a closed claims analysis. Anesthesiology 2015;122(3):659-65 6. Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. British journal of anaesthesia 2014;112(6):991-1004 7. Afsharimani B, Cabot P, Parat MO. Morphine and tumor growth and metastasis. Cancer metastasis reviews 2011;30(2):225-38 8. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005;103(1):147-55 9. van Gulik L, Ahlers SJ, van de Garde EM, et al. Remifentanil during cardiac surgery is associated with chronic thoracic pain 1 yr after sternotomy. British journal of anaesthesia 2012;109(4):616-22 10. Canet J, Gallart L, Gomar C, et al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology 2010;113(6):1338-50 11. Xue FS, Li BW, Zhang GS, et al. The influence of surgical sites on early postoperative hypoxemia in adults undergoing elective surgery. Anesthesia and analgesia 1999;88(1):213-9 12. Reeder MK, Goldman MD, Loh L, et al. Postoperative hypoxaemia after major abdominal vascular surgery. British journal of anaesthesia 1992;68(1):23-6 13. Canet J, Ricos M, Vidal F. Early postoperative arterial oxygen desaturation. Determining factors and response to oxygen therapy. Anesthesia and analgesia 1989;69(2):207-12 14. Crosby G, Culley DJ, Dexter F. Cognitive outcome of surgery: is there no place like home? Anesthesia and analgesia 2014;118(5):898-900 15. Card E, Pandharipande P, Tomes C, et al. Emergence from general anaesthesia and evolution of delirium signs in the post-anaesthesia care unit. British journal of anaesthesia 2015;115(3):411-7 16. Krenk L, Kehlet H, Baek Hansen T, et al. Cognitive dysfunction after fast-track hip and knee replacement. Anesthesia and analgesia 2014;118(5):1034-40 17. Kehlet H, Dahl JB. Anaesthesia, surgery, and challenges in postoperative recovery. Lancet 2003;362(9399):1921-8 18. Feld JM, Hoffman WE, Stechert MM, et al. Fentanyl or dexmedetomidine combined with desflurane for bariatric surgery. Journal of clinical anesthesia 2006;18(1):24-8 19. Hofer RE, Sprung J, Sarr MG, et al. Anesthesia for a patient with morbid obesity using dexmedetomidine without narcotics. Canadian journal of anaesthesia = Journal canadien d'anesthesie 2005;52(2):176-80 20. Goettel N, Bharadwaj S, Venkatraghavan L, et al. Dexmedetomidine vs propofol-remifentanil conscious sedation for awake craniotomy: a prospective randomized controlled trial. British journal of anaesthesia 2016;116(6):811-21 21. Bakan M, Umutoglu T, Topuz U, et al. [Opioid-free total intravenous anesthesia with propofol, dexmedetomidine and lidocaine infusions for laparoscopic cholecystectomy: a prospective, randomized, double-blinded study]. Rev Bras Anestesiol 2015;65(3):191-9 22. Ohtani N, Yasui Y, Watanabe D, et al. Perioperative infusion of dexmedetomidine at a high dose reduces postoperative analgesic requirements: a randomized control trial. Journal of anesthesia 2011;25(6):872-8 23. Blaudszun G, Lysakowski C, Elia N, et al. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology 2012;116(6):1312-22 24. Schnabel A, Meyer-Friessem CH, Reichl SU, et al. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain 2013;154(7):1140-9 25. Ziemann-Gimmel P, Goldfarb AA, Koppman J, et al. Opioid-free total intravenous anaesthesia reduces postoperative nausea and vomiting in bariatric surgery beyond triple prophylaxis. British journal of anaesthesia 2014;112(5):906-11 26. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). European heart journal 2014;35(35):2383-431 27. Abbott TEF, Fowler AJ, Pelosi P, et al. A systematic review and consensus definitions for standardised end-points in perioperative medicine: pulmonary complications. British journal of anaesthesia 2018;In Press 28. Inouye SK, Leo-Summers L, Zhang Y, et al. A chart-based method for identification of delirium: validation compared with interviewer ratings using the confusion assessment method. Journal of the American Geriatrics Society 2005;53(2):312-8 29. Inouye SK, van Dyck CH, Alessi CA, et al. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Annals of internal medicine 1990;113(12):941-8 30. Sacerdote P, Franchi S, Panerai AE. Non-analgesic effects of opioids: mechanisms and potential clinical relevance of opioid-induced immunodepression. Current pharmaceutical design 2012;18(37):6034-42 31. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332 32. International Committee of Medical Journal E. Uniform requirements for manuscripts submitted to biomedical journals. The New England journal of medicine 1997;336(4):309-15 Summary of changes DateversionmodificationsApproval by promotorApproval by ECApproval by ANSM05/15/2017V1.005/17/201707/11/201705/22/201709/27/2017V2.0Answers to EC’s questions09/04/201710/06/2017V3.02 centres added10/06/201711/06/201711/20/210711/20/2017V4.0New version sent to the centres03/06/2018V5.0Adding ancillary study on chronic pain03/07/201805/14/2018NA06/14/2018V6.0New version sent to the centres11/19/2018V7.0Modification of the dosage of dexmedetomidine11/19/201812/17/201812/14/201812/28/2018V8.0New version sent to the centres01/18/2019V9.0Recruitment suspended01/18/2019Non-authorizedNon-authorizedANSM= agence nationale de la sécurité du médicament = National agency for drug safety, EC = ethics committeeOriginal statistical analysis plan, final statistical analysis plan, summary of changesOriginal statistical analysis plan Writter?: Maxime EsvanStatistical analysis plan is written according to protocol V8.0 (December 28, 2018).It follows discussions and e-mail exchanges on September 6, 2018; January 10, 2019; June 4,5 and 6, 2019.Methodologist?: Coordinating Investigator:Pr. Bruno LaviolleTelephone?: 02 99 28 96 68Mail: bruno.laviolle@chu-rennes.frPr. Hélène BeloeilTelephone: 02.99.28.24.22 Mail: helene.beloeil@chu-rennes.frReminder on the protocolStudy objectivesThe primary objective is to compare the effects of an intraoperative opioid-free analgesia strategy with that of standard clinical practice on postoperative opioid-related severe adverse events after major or intermediate non-cardiac surgery.The secondary objectives are described below:Determine if OFA is associated with a better postoperative analgesia;Determine if OFA can reduce postoperative opioid consumption;Determine if OFA can reduce the delay to obtain an Aldrete score ≥ 9 and the delay to extubation;Determine if OFA reduces postoperative rate of unscheduled admission in ICU;Determine if OFA reduces postoperative nausea and vomiting (PONV);Determine if OFA reduces the length of stay in the hospital;Evaluate the tolerance to Dexmedetomidine in OFA.Evaluation criteriaPrimary evaluation criteriaThe primary outcome measure will be the occurrence of a severe postoperative opioid-related adverse event within the first 48 hours after extubation defined as: postoperative hypoxemia or postoperative ileus (POI) or postoperative cognitive dysfunction (POCD).In addition, each?component of the primary outcome measure will be analysed separately.The onset of an opioid-related adverse event will be assessed blinded to the randomization group.Postoperative hypoxemia is defined as a SpO2 < 95% with a need for oxygen supplementation within the first 48h after extubation; the duration of oxygen treatment will also be recorded.Postoperative ileus is defined as an absence of flatus or stools within the first 48h after extubation.Postoperative cognitive dysfunction will be evaluated using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) by a care provider (either anaesthesiologist or nurse). The Confusion Assessment Method (CAM), has been validated in multiple settings and is a widely used standardized method for identifying delirium with a high sensitivity of 94% (95% CI, 91%-97%), high specificity of 89% (95%CI, 85%-94%).The CAM algorithm consists of 4 items: 1. Acute Onset or Fluctuating Course. 2. Inattention 3. Disorganized thinking. 4. Altered Level of consciousness. The diagnosis of delirium by CAM/CAM-ICU requires a positive response to features 1 and 2 plus either 3 or 4; in these cases, the patients will be considered as presenting a POCD.Secondary evaluation criteriaNumber of episodes of postoperative pain (numeric rating scale ≥ 3) within 48 hours after extubation, at rest;Opioid consumption during the 48 hours following extubation;Time between the end of remifentanil or dexmedetomidine administration and an Aldrete score ≥ 9 (when applicable);Time between the end of remifentanil or dexmedetomidine administration and extubation;Rate of unscheduled admission in intensive care unit;Number of PONV episodes during the 48 hours following extubation. Need for rescue antiemetic medication will be recorded;Hospital length of stay (max 28 days) defined as the number of days after extubation before first hospital discharge;Number of cardiac events (bradycardia defined as the number of episodes with atropine administration, hypotension defined as PAM < 65 mmHg, hypertension defined as PAM > 90 mmHg) and rescue medication, during surgery.DesignThis is a multicentre, prospective, randomized, controlled, simple-blind, parallel group trial. Patients will be randomized in two groups:Control group: Standard anaesthesia protocol with remifentanil. Dex group: Standard anaesthesia protocol with dexmedetomidine (OFA).Conduct of the studyD-30 to D-1D-1 to D0D0SurgeryH0extubationH48D2D7 (or hospital discharge if < D7)Preoperative consultation / InformationXWritten informed consent XSelection criteriaXRandomizationXAdministration of the treatmentXMorphine consumption NRS ≥ 3Cardiac events: bradycardia (episodes with atropine)hypotension (PAM<65 mmHg) hypertension (PAM>90 mmHg)PONVOpioid-related adverse events: hypoxemia, ileus, POCD (CAM-ICU)Ancillary study : 3 tubes of 5 ml of blood on agar-free lithium heparinate (green top)X* (morning before surgery)X* (morning)X* (morning)Expected duration of participation of personsRecruitment period : 24 monthsDuration of patient follow-up : maximum 28 daysDuration of data analysis : 6 monthsEstimated total duration of study : 31 months Starting with inclusion of the first patient, the sponsor has to inform without delay the local health agency and the ethics committee of the actual date of start-up of the study. The actual date of start-up = date of signature of consent form by the first person who is a subject in the study.The date of end of the study will be transmitted by the sponsor to the ethics committee and to the local health agency within 90 days or earlier according to local regulations. The date of end of the study corresponds to the last visit of the last person participating in the study.RandomizationPatients will be randomized in two groups (control group and Dex group). In order to ensure group comparability, a plan of randomization will be used. Randomization will be done online by investigators as close as possible to the surgery (D-1 or D0). Each patient will be allocated a unique randomization number (patient code). Randomization will be stratified on the centre and on the type of surgery: abdominal (digestive, urological, gynaecological) or non-abdominal.Methods of blinding The primary evaluation criterion will be assessed blinded to the randomization group. During the study period, patients and outcome assessors will be kept blind to the randomization group. Nurses evaluating outcomes in PACU and in the ward will not participate to the anaesthesia and will not be aware of the randomization group. They will be blind to the treatment. The anaesthesiologist and the nurse anaesthesiologist (care providers) will be the only ones not blinded. They will not participate in the assessment of the patients at any time. Sample size196 patients per group will be needed to have 80% power,?at a two-sided alpha level of 0.05, to show a relative between-group difference of 40% in the composite primary outcome measure?(30% to 18%), under the assumption of an overall incidence of 5% of postoperative ileus (from 5% to 20.6% after major or intermediate non-abdominal and abdominal surgery, respectively),, 20% of postoperative hypoxemia (from 20% to 40% depending on the surgical site),?and 5% of postoperative delirium (from 3.6% to 30% after elective surgery and abdominal surgery, respectively),,?, thus 30% for the primary outcome measure.A total of 400 patients will be included to take into account non-evaluable patients. Patients undergoing a second surgery or dying within 48 hours without presenting the primary evaluation criteria will be kept considered as success in the analysis.Planned analysisStatistical analysis will be performed on all randomized and evaluated patients (intention to treat analysis).Descriptive analysisA first overall descriptive analysis and analysis by group will be performed. This consists of separate estimates, numbers and percentages for qualitative variables, means, standard error, medians and interquartile intervals for quantitative variables. The normal feature of the distribution of quantitative variables is parison of groups at baselineStudent’s t test or a Mann-Whitney test if necessary will be used to compare quantitative variables, and a Chi? or Fisher’s exact test if necessary will be used to compare qualitative variables between two groups at inclusion.Analysis of the primary criteriaThe primary endpoint (composite endpoint) will be compared between the two groups with the Chi? test.Two interim analyses after inclusion of 1/3 and 2/3 of the patients, and one final analysis are planned. Stopping rules will use the alpha spending function with the O’Brien-Fleming boundary. The cumulative values of alpha for each analysis are: 0.00021 at the first analysis, 0.01202 at the second analysis and 0.04626 at the final analysis (nTerim, V1.1, Statistical solutions Ltd, Cork, Ireland). The trial will be stopped early if the significance of the Chi? test is below these alpha values.Analysis of other criteriaFor the analysis of the other endpoints, the same strategy as for baseline comparisons will be used.In addition, censored endpoints (time to achieve an Aldrete score ≥ 9) will be compared using the log-rank test.Continuous endpoints repeatedly measured during the study will be compared using a repeated measure two-way (time, group) analysis of variance.For all these analyses, adjustments can be made in case of heterogeneity at inclusion.Analysis of adverse eventsPossible adverse events are coded according to the MedDRA classification and are the subject of a descriptive analysis.Planned degree of statistical significanceExcept for the interim analyses described above, a p value <0.05 will be considered as significant for all analyses.Method of management of missing, unused or invalid dataMissing data will not be replaced. Mixed models can be used in analysis of repeated data to avoid deleting subjects with any missing values.Choice of persons to include in the analysisThis trial is an intention to treat study, that is all randomized and evaluated patients will be analysed in their randomization group.Changes to the protocolPrimary evaluation criteriaPatients with a surgical recovery within 48 hours after extubation are evaluable and considered successful if they have not met the primary endpoint.Patients whose resumption of transit is not notified in the file are "not assessable for transit" if the hospital discharge takes place from D3 onwards.The systematic administration of O2 before desaturation should be noted as a deviation. An episode of hypoxemia will be reported if and only if SpO2 < 95%.If CAM-ICU H48 is not performed because the patient is discharged before H48 post-extubation and has no other component of the primary endpoint, it will be considered successful for the primary endpoint.Patients with absence of two components of the primary endpoint will be considered successful for the primary endpoint if hospital discharge takes place on D3.Secondary evaluation criteriaTime between the end of remifentanil or dexmedetomidine administration and an Aldrete score ≥ 9 (when applicable): if time when Aldrete score ≥ 9 is missing, it will be replaced with time when patients leave the PACU.End of the studyAt the request of the sponsor and the ANSM (French National Agency for Medicines and Health Products Safety) on 10/01/2019, inclusions were suspended for urgent safety measures to the new fact that the information of bradycardia cases represents. Patient addition and randomization rights were removed on 11/01/2019. No inclusion and randomization took place between 10 and 11 January 2019.Analysed populationsNumber of subjects included316 patients were included and randomized: 158 in the control group and 158 in the Dex group. Populations314 patients are included in intent-to-treat population: 157 in the control group and 157 in the Dex group 312 patients have met the primary endpoint: 156 in the control group and 156 in the Dex group.Flow-diagram of the POFA trial:240030114301 Discontinued intervention1 Logistic reason (04008)1 Discontinued intervention1 Adverse event (01081)157 Included in intent-to-treat analysisa1 Excluded from intent-to-treat analysis1 Consent withdrawal (09005)157 Included in intent-to-treat analysisb1 Excluded from intent-to-treat analysis1 Consent withdrawal (06020)158 randomized to receive remifentanil (Control Group)157 Received remifentanil as randomized1 Did not received remifentanil as randomized 1 Randomization mail not received (09005)158 randomized to receive dexmedetomidine (Dex Group)154 received dexmedetomidine as randomized4 Did not received dexmedetomidine as randomized 1 Failure to comply with randomization for administration of clonidine (treatment contraindicated with dexmedetomidine but not indicated in the protocol) (06007)1 Randomization mail not received (06020)2 Anesthesiologist did not know that the patient was including (10006, 10010)316 randomizedAllocationFollow-upAnalysis1 Discontinued intervention1 Logistic reason (04008)1 Discontinued intervention1 Adverse event (01081)157 Included in intent-to-treat analysisa1 Excluded from intent-to-treat analysis1 Consent withdrawal (09005)157 Included in intent-to-treat analysisb1 Excluded from intent-to-treat analysis1 Consent withdrawal (06020)158 randomized to receive remifentanil (Control Group)157 Received remifentanil as randomized1 Did not received remifentanil as randomized 1 Randomization mail not received (09005)158 randomized to receive dexmedetomidine (Dex Group)154 received dexmedetomidine as randomized4 Did not received dexmedetomidine as randomized 1 Failure to comply with randomization for administration of clonidine (treatment contraindicated with dexmedetomidine but not indicated in the protocol) (06007)1 Randomization mail not received (06020)2 Anesthesiologist did not know that the patient was including (10006, 10010)316 randomizedAllocationFollow-upAnalysisa One patient does not meet the primary criteria (04008)b One patient does not meet the primary criteria (01081)General informationStatistical analysis will be performed with SAS software V9.4 (SAS Institute, Cary, North Carolina, USA).Presentation will be performed by treatment group (control group and Dex group).The first interim analysis was performed on November 2, 2018 and the second on January 31, 2019.Analysis of the evaluation criteriaPrimary evaluation criteriaSee 1.2, 1.4 and 2Secondary evaluation criteriaSee 1.2, 1.4 and 2. Final statistical analysis plan (September, 17, 2019)Writter?: Maxime EsvanStatistical analysis plan is written according to protocol V8.0 (December 28, 2018).It follows discussions and e-mail exchanges on September 6, 2018; January 10, 2019; June 4,5 and 6, 2019; August 5 and 21, 2019; September 4 and 6, 2019.Methodologist?: Coordinating Investigator:Pr. Bruno LaviollePhone?: 02 99 28 96 68EMail: bruno.laviolle@chu-rennes.frProf Hélène BeloeilPhone: 02.99.28.24.22 EMail: helene.beloeil@chu-rennes.frReminder on the protocolStudy objectivesThe primary objective is to compare the effects of an intraoperative opioid-free analgesia strategy with that of standard clinical practice on postoperative opioid-related severe adverse events after major or intermediate non-cardiac surgery.The secondary objectives are described below:Determine if OFA is associated with a better postoperative analgesia;Determine if OFA can reduce postoperative opioid consumption;Determine if OFA can reduce the delay to obtain an Aldrete score ≥ 9 and the delay to extubation;Determine if OFA reduces postoperative rate of unscheduled admission in ICU;Determine if OFA reduces postoperative nausea and vomiting (PONV);Determine if OFA reduces the length of stay in the hospital;Evaluate the tolerance to Dexmedetomidine in OFA.Evaluation criteriaPrimary evaluation criteriaThe primary outcome measure will be the occurrence of a severe postoperative opioid-related adverse event within the first 48 hours after extubation defined as: postoperative hypoxemia or postoperative ileus (POI) or postoperative cognitive dysfunction (POCD).In addition, each?component of the primary outcome measure will be analysed separately.The onset of an opioid-related adverse event will be assessed blinded to the randomization group.Postoperative hypoxemia is defined as a SpO2 < 95% with a need for oxygen supplementation within the first 48h after extubation; the duration of oxygen treatment will also be recorded.Postoperative ileus is defined as an absence of flatus or stools within the first 48h after extubation.Postoperative cognitive dysfunction will be evaluated using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) by a care provider (either anaesthesiologist or nurse). The Confusion Assessment Method (CAM), has been validated in multiple settings and is a widely used standardized method for identifying delirium with a high sensitivity of 94% (95% CI, 91%-97%), high specificity of 89% (95%CI, 85%-94%).The CAM algorithm consists of 4 items: 1. Acute Onset or Fluctuating Course. 2. Inattention 3. Disorganized thinking. 4. Altered Level of consciousness. The diagnosis of delirium by CAM/CAM-ICU requires a positive response to features 1 and 2 plus either 3 or 4; in these cases, the patients will be considered as presenting a POCD.Secondary evaluation criteriaNumber of episodes of postoperative pain (numeric rating scale ≥ 3) within 48 hours after extubation, at rest;Opioid consumption during the 48 hours following extubation;Time between the end of remifentanil or dexmedetomidine administration and an Aldrete score ≥ 9 (when applicable);Time between the end of remifentanil or dexmedetomidine administration and extubation;Rate of unscheduled admission in intensive care unit;Number of PONV episodes during the 48 hours following extubation. Need for rescue antiemetic medication will be recorded;Hospital length of stay (max 28 days) defined as the number of days after extubation before first hospital discharge;Number of cardiac events (bradycardia defined as the number of episodes with atropine administration, hypotension defined as PAM < 65 mmHg, hypertension defined as PAM > 90 mmHg) and rescue medication, during surgery.DesignThis is a multicentre, prospective, randomized, controlled, simple-blind, parallel group trial. Patients will be randomized in two groups:Control group: Standard anaesthesia protocol with remifentanil. Dex group: Standard anaesthesia protocol with dexmedetomidine (OFA).Conduct of the studyD-30 to D-1D-1 to D0D0SurgeryH0extubationH48D2D7 (or hospital discharge if < D7)Preoperative consultation / InformationXWritten informed consent XSelection criteriaXRandomizationXAdministration of the treatmentXMorphine consumption NRS ≥ 3Cardiac events: bradycardia (episodes with atropine)hypotension (PAM<65 mmHg) hypertension (PAM>90 mmHg)PONVOpioid-related adverse events: hypoxemia, ileus, POCD (CAM-ICU)Ancillary study : 3 tubes of 5 ml of blood on agar-free lithium heparinate (green top)X* (morning before surgery)X* (morning)X* (morning)Expected duration of participation of personsRecruitment period : 24 monthsDuration of patient follow-up : maximum 28 daysDuration of data analysis : 6 monthsEstimated total duration of study : 31 months Starting with inclusion of the first patient, the sponsor has to inform without delay the local health agency and the ethics committee of the actual date of start-up of the study. The actual date of start-up = date of signature of consent form by the first person who is a subject in the study.The date of end of the study will be transmitted by the sponsor to the ethics committee and to the local health agency within 90 days or earlier according to local regulations. The date of end of the study corresponds to the last visit of the last person participating in the study.RandomizationPatients will be randomized in two groups (control group and Dex group). In order to ensure group comparability, a plan of randomization will be used. Randomization will be done online by investigators as close as possible to the surgery (D-1 or D0). Each patient will be allocated a unique randomization number (patient code). Randomization will be stratified on the centre and on the type of surgery: abdominal (digestive, urological, gynaecological) or non-abdominal.Methods of blinding The primary evaluation criterion will be assessed blinded to the randomization group. During the study period, patients and outcome assessors will be kept blind to the randomization group. Nurses evaluating outcomes in PACU and in the ward will not participate to the anaesthesia and will not be aware of the randomization group. They will be blind to the treatment. The anaesthesiologist and the nurse anaesthesiologist (care providers) will be the only ones not blinded. They will not participate in the assessment of the patients at any time. Sample size196 patients per group will be needed to have 80% power,?at a two-sided alpha level of 0.05, to show a relative between-group difference of 40% in the composite primary outcome measure?(30% to 18%), under the assumption of an overall incidence of 5% of postoperative ileus (from 5% to 20.6% after major or intermediate non-abdominal and abdominal surgery, respectively),, 20% of postoperative hypoxemia (from 20% to 40% depending on the surgical site),?and 5% of postoperative delirium (from 3.6% to 30% after elective surgery and abdominal surgery, respectively),,?, thus 30% for the primary outcome measure.A total of 400 patients will be included to take into account non-evaluable patients. Patients undergoing a second surgery or dying within 48 hours without presenting the primary evaluation criteria will be kept considered as success in the analysis.Planned analysisStatistical analysis will be performed on all randomized and evaluated patients (intention to treat analysis).Descriptive analysisA first overall descriptive analysis and analysis by group will be performed. This consists of separate estimates, numbers and percentages for qualitative variables, means, standard error, medians and interquartile intervals for quantitative variables. The normal feature of the distribution of quantitative variables is parison of groups at baselineStudent’s t test or a Mann-Whitney test if necessary will be used to compare quantitative variables, and a Chi? or Fisher’s exact test if necessary will be used to compare qualitative variables between two groups at inclusion.Analysis of the primary criteriaThe primary endpoint (composite endpoint) will be compared between the two groups with the Chi? test.Two interim analyses after inclusion of 1/3 and 2/3 of the patients, and one final analysis are planned. Stopping rules will use the alpha spending function with the O’Brien-Fleming boundary. The cumulative values of alpha for each analysis are: 0.00021 at the first analysis, 0.01202 at the second analysis and 0.04626 at the final analysis (nTerim, V1.1, Statistical solutions Ltd, Cork, Ireland). The trial will be stopped early if the significance of the Chi? test is below these alpha values.Analysis of other criteriaFor the analysis of the other endpoints, the same strategy as for baseline comparisons will be used.In addition, censored endpoints (time to achieve an Aldrete score ≥ 9) will be compared using the log-rank test.Continuous endpoints repeatedly measured during the study will be compared using a repeated measure two-way (time, group) analysis of variance.For all these analyses, adjustments can be made in case of heterogeneity at inclusion.Analysis of adverse eventsPossible adverse events are coded according to the MedDRA classification and are the subject of a descriptive analysis.Planned degree of statistical significanceExcept for the interim analyses described above, a p value <0.05 will be considered as significant for all analyses.Method of management of missing, unused or invalid dataMissing data will not be replaced. Mixed models can be used in analysis of repeated data to avoid deleting subjects with any missing values.Choice of persons to include in the analysisThis trial is an intention to treat study, that is all randomized and evaluated patients will be analysed in their randomization group.Changes to the protocolPrimary evaluation criteriaPatients with a surgical recovery within 48 hours after extubation are evaluable and considered successful if they have not met the primary endpoint.Patients whose resumption of transit is not notified in the file are "not assessable for transit" if the hospital discharge takes place from D3 onwards.The systematic administration of O2 before desaturation should be noted as a deviation. An episode of hypoxemia will be reported if and only if SpO2 < 95%.If CAM-ICU H48 is not performed because the patient is discharged before H48 post-extubation and has no other component of the primary endpoint, it will be considered successful for the primary endpoint.Patients with absence of two components of the primary endpoint will be considered successful for the primary endpoint if hospital discharge takes place on D3.RR and IC95% will be performed.Secondary evaluation criteriaTime between the end of remifentanil or dexmedetomidine administration and an Aldrete score ≥ 9 (when applicable): if time when Aldrete score ≥ 9 is missing, it will be replaced with time when patients leave the PACU.End of the studyAt the request of the sponsor and the ANSM (French National Agency for Medicines and Health Products Safety) on 10/01/2019, inclusions were suspended for urgent safety measures to the new fact that the information of bradycardia cases represents. Patient addition and randomization rights were removed on 11/01/2019. No inclusion and randomization took place between 10 and 11 January 2019.Missing dataBecause of missing data for the primary endpoint, we will use multiple imputation by chained equation.Subgroup analysisSubgroup analyses will be performed on the primary evaluation criteria according to the type of surgery: abdominal (digestive, urological, gynaecological) or non-abdominal.The primary evaluation criteria and bradycardia will be analysed by separating patients in the dex group according to the median dose of dexmedetomidine received.Analysed populationsNumber of subjects included316 patients were included and randomized: 158 in the control group and 158 in the Dex group. Populations314 patients are included in intent-to-treat population: 157 in the control group and 157 in the Dex group 312 patients have met the primary endpoint: 156 in the control group and 156 in the Dex group.Flow-diagram of the POFA trial:240030114301 Discontinued intervention1 Logistic reason (04008)1 Discontinued intervention1 Adverse event (01081)157 Included in intent-to-treat analysisa1 Excluded from intent-to-treat analysis1 Consent withdrawal (09005)157 Included in intent-to-treat analysisb1 Excluded from intent-to-treat analysis1 Consent withdrawal (06020)158 randomized to receive remifentanil (Control Group)157 Received remifentanil as randomized1 Did not received remifentanil as randomized 1 Randomization mail not received (09005)158 randomized to receive dexmedetomidine (Dex Group)154 received dexmedetomidine as randomized4 Did not received dexmedetomidine as randomized 1 Failure to comply with randomization for administration of clonidine (treatment contraindicated with dexmedetomidine but not indicated in the protocol) (06007)1 Randomization mail not received (06020)2 Anesthesiologist did not know that the patient was including (10006, 10010)316 randomizedAllocationFollow-upAnalysis1 Discontinued intervention1 Logistic reason (04008)1 Discontinued intervention1 Adverse event (01081)157 Included in intent-to-treat analysisa1 Excluded from intent-to-treat analysis1 Consent withdrawal (09005)157 Included in intent-to-treat analysisb1 Excluded from intent-to-treat analysis1 Consent withdrawal (06020)158 randomized to receive remifentanil (Control Group)157 Received remifentanil as randomized1 Did not received remifentanil as randomized 1 Randomization mail not received (09005)158 randomized to receive dexmedetomidine (Dex Group)154 received dexmedetomidine as randomized4 Did not received dexmedetomidine as randomized 1 Failure to comply with randomization for administration of clonidine (treatment contraindicated with dexmedetomidine but not indicated in the protocol) (06007)1 Randomization mail not received (06020)2 Anesthesiologist did not know that the patient was including (10006, 10010)316 randomizedAllocationFollow-upAnalysisa One patient does not meet the primary criteria (04008)b One patient does not meet the primary criteria (01081)General informationStatistical analysis will be performed with SAS software V9.4 (SAS Institute, Cary, North Carolina, USA).Presentation will be performed by treatment group (control group and Dex group).The first interim analysis was performed on November 2, 2018 and the second on January 31, 2019.Analysis of the evaluation criteriaPrimary evaluation criteriaSee 1.2, 1.4 and 2Secondary evaluation criteriaSee 1.2, 1.4 and 2.Change historyDateDocument nameVersionModification/Context06/06/19PAS_POFA_190606_V1V1First version01/07/19PAS_POFA_190701_V2V2Management of missing data updated17/09/19PAS_POFA_190917_V3V3Primary evaluation criteria updated (RR and IC95%)Addition of subgroup analysis26/09/2019PAS_POFA_190924_V4V4Subgroup analysis updated ................
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