Cdn-links.lww.com
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)
0003-3022 (Linking)</isbn><accession-num>10485781</accession-num><urls><related-urls><url>;[1], sedation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXF1ZXJvbjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXF1ZXJvbjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE.DATA [2], ileus PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO
dW0+MTI3PC9SZWNOdW0+PERpc3BsYXlUZXh0PlszXTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVj
LW51bWJlcj4xMjc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk
PSI5enBkemZkYTZ4c3pya2U5ZXI4NWFlOWllMnZ3ZnhzdHhldnQiPjEyNzwva2V5PjwvZm9yZWln
bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u
dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+R2FuLCBULiBKLjwvYXV0aG9yPjxhdXRob3I+Um9i
aW5zb24sIFMuIEIuPC9hdXRob3I+PGF1dGhvcj5PZGVyZGEsIEcuIE0uPC9hdXRob3I+PGF1dGhv
cj5TY3JhbnRvbiwgUi48L2F1dGhvcj48YXV0aG9yPlBlcGluLCBKLjwvYXV0aG9yPjxhdXRob3I+
UmFtYW1vb3J0aHksIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk
ZHJlc3M+U3RvbnkgQnJvb2sgVW5pdmVyc2l0eSAsIFN0b255IEJyb29rLCBMb25nIElzbGFuZCwg
TlkgLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW1wYWN0IG9mIHBvc3RzdXJn
aWNhbCBvcGlvaWQgdXNlIGFuZCBpbGV1cyBvbiBlY29ub21pYyBvdXRjb21lcyBpbiBnYXN0cm9p
bnRlc3RpbmFsIHN1cmdlcmllczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DdXJyIE1lZCBSZXMg
T3Bpbjwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Q3VycmVudCBtZWRpY2FsIHJlc2VhcmNo
IGFuZCBvcGluaW9uPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+
Q3VyciBNZWQgUmVzIE9waW48L2Z1bGwtdGl0bGU+PGFiYnItMT5DdXJyZW50IG1lZGljYWwgcmVz
ZWFyY2ggYW5kIG9waW5pb248L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxm
dWxsLXRpdGxlPkN1cnIgTWVkIFJlcyBPcGluPC9mdWxsLXRpdGxlPjxhYmJyLTE+Q3VycmVudCBt
ZWRpY2FsIHJlc2VhcmNoIGFuZCBvcGluaW9uPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFn
ZXM+Njc3LTg2PC9wYWdlcz48dm9sdW1lPjMxPC92b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PGtl
eXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW5hbGdlc2ljcywgT3Bpb2lk
L2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8qYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxr
ZXl3b3JkPipDaG9sZWN5c3RlY3RvbXkvZWNvbm9taWNzL21ldGhvZHM8L2tleXdvcmQ+PGtleXdv
cmQ+KkNvbGVjdG9teS9lY29ub21pY3MvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5Db3N0cyBh
bmQgQ29zdCBBbmFseXNpczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdv
cmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPipJbGV1cy9lY29ub21pY3MvZXBpZGVtaW9sb2d5
L2V0aW9sb2d5L3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxr
ZXl3b3JkPipMYXBhcm9zY29weS9hZHZlcnNlIGVmZmVjdHMvbWV0aG9kczwva2V5d29yZD48a2V5
d29yZD4qTGFwYXJvdG9teS9hZHZlcnNlIGVmZmVjdHMvbWV0aG9kczwva2V5d29yZD48a2V5d29y
ZD5MZW5ndGggb2YgU3RheS9lY29ub21pY3Mvc3RhdGlzdGljcyAmYW1wOyBudW1lcmljYWwgZGF0
YTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9r
ZXl3b3JkPjxrZXl3b3JkPk91dGNvbWUgQXNzZXNzbWVudCAoSGVhbHRoIENhcmUpPC9rZXl3b3Jk
PjxrZXl3b3JkPlBhaW4sIFBvc3RvcGVyYXRpdmUvKmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5
d29yZD5QYXRpZW50IFJlYWRtaXNzaW9uL2Vjb25vbWljcy9zdGF0aXN0aWNzICZhbXA7IG51bWVy
aWNhbCBkYXRhPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29y
ZD48a2V5d29yZD5Vbml0ZWQgU3RhdGVzL2VwaWRlbWlvbG9neTwva2V5d29yZD48L2tleXdvcmRz
PjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHVi
LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ3My00ODc3IChFbGVjdHJvbmljKSYjeEQ7MDMwMC03OTk1
IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNTU4NjI5NjwvYWNjZXNzaW9uLW51bT48
dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1l
ZC8yNTU4NjI5NjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJj
ZS1udW0+MTAuMTE4NS8wMzAwNzk5NS4yMDE1LjEwMDU4MzM8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut
bnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA [3], confusion/delirium PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj
TnVtPjEzMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJl
Yy1udW1iZXI+MTMzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p
ZD0iOXpwZHpmZGE2eHN6cmtlOWVyODVhZTlpZTJ2d2Z4c3R4ZXZ0Ij4xMzM8L2tleT48L2ZvcmVp
Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv
bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldhbmcsIFkuPC9hdXRob3I+PGF1dGhvcj5TYW5k
cywgTC4gUC48L2F1dGhvcj48YXV0aG9yPlZhdXJpbywgTC48L2F1dGhvcj48YXV0aG9yPk11bGxl
biwgRS4gQS48L2F1dGhvcj48YXV0aG9yPkxldW5nLCBKLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48
L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgU3RhdGlzdGljcywgUHVy
ZHVlIFVuaXZlcnNpdHksIFdlc3QgTGFmYXlldHRlLCBJbmRpYW5hIDQ3OTA3LTIwNjksIFVTQS48
L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgZWZmZWN0cyBvZiBwb3N0b3BlcmF0aXZl
IHBhaW4gYW5kIGl0cyBtYW5hZ2VtZW50IG9uIHBvc3RvcGVyYXRpdmUgY29nbml0aXZlIGR5c2Z1
bmN0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogR2VyaWF0ciBQc3ljaGlhdHJ5PC9z
ZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaGUgQW1lcmljYW4gam91cm5hbCBvZiBnZXJpYXRy
aWMgcHN5Y2hpYXRyeSA6IG9mZmljaWFsIGpvdXJuYWwgb2YgdGhlIEFtZXJpY2FuIEFzc29jaWF0
aW9uIGZvciBHZXJpYXRyaWMgUHN5Y2hpYXRyeTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp
Y2FsPjxmdWxsLXRpdGxlPkFtIEogR2VyaWF0ciBQc3ljaGlhdHJ5PC9mdWxsLXRpdGxlPjxhYmJy
LTE+VGhlIEFtZXJpY2FuIGpvdXJuYWwgb2YgZ2VyaWF0cmljIHBzeWNoaWF0cnkgOiBvZmZpY2lh
bCBqb3VybmFsIG9mIHRoZSBBbWVyaWNhbiBBc3NvY2lhdGlvbiBmb3IgR2VyaWF0cmljIFBzeWNo
aWF0cnk8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFt
IEogR2VyaWF0ciBQc3ljaGlhdHJ5PC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIEFtZXJpY2FuIGpv
dXJuYWwgb2YgZ2VyaWF0cmljIHBzeWNoaWF0cnkgOiBvZmZpY2lhbCBqb3VybmFsIG9mIHRoZSBB
bWVyaWNhbiBBc3NvY2lhdGlvbiBmb3IgR2VyaWF0cmljIFBzeWNoaWF0cnk8L2FiYnItMT48L2Fs
dC1wZXJpb2RpY2FsPjxwYWdlcz41MC05PC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJl
cj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW5h
bGdlc2lhLCBQYXRpZW50LUNvbnRyb2xsZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW5hbGdlc2ljcywg
T3Bpb2lkL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8qYWR2ZXJzZSBlZmZlY3RzPC9rZXl3
b3JkPjxrZXl3b3JkPkFuZXN0aGVzaWEvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3Jk
PkNvZ25pdGlvbiBEaXNvcmRlcnMvY2hlbWljYWxseSBpbmR1Y2VkLypldGlvbG9neS9wcmV2ZW50
aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdv
cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5
d29yZD5Mb2dpc3RpYyBNb2RlbHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5
d29yZD5NdWx0aXZhcmlhdGUgQW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UGFpbiwgUG9zdG9w
ZXJhdGl2ZS8qZHJ1ZyB0aGVyYXB5Lypwc3ljaG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByb3Nw
ZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwv
a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2Rh
dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDY0LTc0ODEgKFByaW50KSYjeEQ7MTA2NC03
NDgxIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNzE5NDgxNTwvYWNjZXNzaW9uLW51
bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1
Ym1lZC8xNzE5NDgxNTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv
dXJjZS1udW0+MTAuMTA5Ny8wMS5KR1AuMDAwMDIyOTc5Mi4zMTAwOS5kYTwvZWxlY3Ryb25pYy1y
ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA [4], respiratory depression PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA [5], increased postoperative pain and morphine consumption PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GbGV0Y2hlcjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GbGV0Y2hlcjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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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)
0167-7659 (Linking)</isbn><accession-num>21267766</accession-num><urls><related-urls><url>;[7], hyperalgesia and chronic postoperative pain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb2x5PC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb2x5PC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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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 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 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA [5].- Postoperative ileus (POI) is a well-known consequence and complication of gastrointestinal, pelvic, and some non-abdominal surgeries (i.e. spine), resulting in significant morbidity and patient discomfort and dissatisfaction. More serious complications can include gastrointestinal perforation, nosocomial infections, malnourishment and muscular atrophy. These sequelae make POI one of the most important factors of prolonged hospitalization following abdominal surgery. The development and consequences of POI following abdominal surgery is further complicated by the need for opioids to manage moderate to severe pain. Opioids areassociated with bowel dysfunction, POI in non-abdominal procedures, and can exacerbate and prolong recovery from ileus following abdominal surgeries. A recent review revealed that, in selected surgeries, 10.3% of patients treated with opioids had ileus PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA [3]. Furthermore, higher doses of opioids were associated with higher incidence of POI.- Delirium and postoperative cognitive dysfunction (POCD) are extremely common ingeriatric surgical patient. After elective major joint replacement or other types of major surgery, about 5% to 15% of elders develop delirium and 25% to 40% and 12% to 15% develop, respectively, early or late POCD. Delirium and POCD are associated with prolonged length of stay, discharge to a place other than home and higher 1-year mortality. In addition, delirium is associated with an accelerated trajectory of cognitive decline to dementia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm9zYnk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm9zYnk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS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ADDIN EN.CITE.DATA [14 15]. Opioids are one of the risk factors of POCD. Patients receiving postoperative analgesia through a patient-controlled analgesia device that administer opioids intravenously were shown to be at significantly higher risk for the development of POCD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj
TnVtPjEzMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJl
Yy1udW1iZXI+MTMzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p
ZD0iOXpwZHpmZGE2eHN6cmtlOWVyODVhZTlpZTJ2d2Z4c3R4ZXZ0Ij4xMzM8L2tleT48L2ZvcmVp
Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv
bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPldhbmcsIFkuPC9hdXRob3I+PGF1dGhvcj5TYW5k
cywgTC4gUC48L2F1dGhvcj48YXV0aG9yPlZhdXJpbywgTC48L2F1dGhvcj48YXV0aG9yPk11bGxl
biwgRS4gQS48L2F1dGhvcj48YXV0aG9yPkxldW5nLCBKLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48
L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgU3RhdGlzdGljcywgUHVy
ZHVlIFVuaXZlcnNpdHksIFdlc3QgTGFmYXlldHRlLCBJbmRpYW5hIDQ3OTA3LTIwNjksIFVTQS48
L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgZWZmZWN0cyBvZiBwb3N0b3BlcmF0aXZl
IHBhaW4gYW5kIGl0cyBtYW5hZ2VtZW50IG9uIHBvc3RvcGVyYXRpdmUgY29nbml0aXZlIGR5c2Z1
bmN0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogR2VyaWF0ciBQc3ljaGlhdHJ5PC9z
ZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaGUgQW1lcmljYW4gam91cm5hbCBvZiBnZXJpYXRy
aWMgcHN5Y2hpYXRyeSA6IG9mZmljaWFsIGpvdXJuYWwgb2YgdGhlIEFtZXJpY2FuIEFzc29jaWF0
aW9uIGZvciBHZXJpYXRyaWMgUHN5Y2hpYXRyeTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp
Y2FsPjxmdWxsLXRpdGxlPkFtIEogR2VyaWF0ciBQc3ljaGlhdHJ5PC9mdWxsLXRpdGxlPjxhYmJy
LTE+VGhlIEFtZXJpY2FuIGpvdXJuYWwgb2YgZ2VyaWF0cmljIHBzeWNoaWF0cnkgOiBvZmZpY2lh
bCBqb3VybmFsIG9mIHRoZSBBbWVyaWNhbiBBc3NvY2lhdGlvbiBmb3IgR2VyaWF0cmljIFBzeWNo
aWF0cnk8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFt
IEogR2VyaWF0ciBQc3ljaGlhdHJ5PC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIEFtZXJpY2FuIGpv
dXJuYWwgb2YgZ2VyaWF0cmljIHBzeWNoaWF0cnkgOiBvZmZpY2lhbCBqb3VybmFsIG9mIHRoZSBB
bWVyaWNhbiBBc3NvY2lhdGlvbiBmb3IgR2VyaWF0cmljIFBzeWNoaWF0cnk8L2FiYnItMT48L2Fs
dC1wZXJpb2RpY2FsPjxwYWdlcz41MC05PC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJl
cj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW5h
bGdlc2lhLCBQYXRpZW50LUNvbnRyb2xsZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW5hbGdlc2ljcywg
T3Bpb2lkL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8qYWR2ZXJzZSBlZmZlY3RzPC9rZXl3
b3JkPjxrZXl3b3JkPkFuZXN0aGVzaWEvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3Jk
PkNvZ25pdGlvbiBEaXNvcmRlcnMvY2hlbWljYWxseSBpbmR1Y2VkLypldGlvbG9neS9wcmV2ZW50
aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdv
cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5
d29yZD5Mb2dpc3RpYyBNb2RlbHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5
d29yZD5NdWx0aXZhcmlhdGUgQW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UGFpbiwgUG9zdG9w
ZXJhdGl2ZS8qZHJ1ZyB0aGVyYXB5Lypwc3ljaG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlByb3Nw
ZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwv
a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2Rh
dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDY0LTc0ODEgKFByaW50KSYjeEQ7MTA2NC03
NDgxIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNzE5NDgxNTwvYWNjZXNzaW9uLW51
bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1
Ym1lZC8xNzE5NDgxNTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv
dXJjZS1udW0+MTAuMTA5Ny8wMS5KR1AuMDAwMDIyOTc5Mi4zMTAwOS5kYTwvZWxlY3Ryb25pYy1y
ZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA [4]. Moreover, fast-track set-up with multimodal opioid sparing analgesia is associated with a lack of delirium after elective hip and knee arthroplasty in elderly patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LcmVuazwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LcmVuazwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl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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 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)
0034-7094 (Linking)</isbn><accession-num>25990496</accession-num><urls><related-urls><url>;[21] or major surgeries PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaHRhbmk8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaHRhbmk8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS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ADDIN EN.CITE.DATA [22]. Two meta-analyses have concluded that intraoperative Dex reduced postoperative pain, opioid consumption PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbGF1ZHN6dW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbGF1ZHN6dW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy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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 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 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). The Confusion Assessment Method (CAM) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jbm91eWU8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jbm91eWU8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS
ZWNOdW0+MTQxPC9SZWNOdW0+PERpc3BsYXlUZXh0PlsyOCAyOV08L0Rpc3BsYXlUZXh0PjxyZWNv
cmQ+PHJlYy1udW1iZXI+MTQxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO
IiBkYi1pZD0iOXpwZHpmZGE2eHN6cmtlOWVyODVhZTlpZTJ2d2Z4c3R4ZXZ0Ij4xNDE8L2tleT48
L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5
cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPklub3V5ZSwgUy4gSy48L2F1dGhvcj48
YXV0aG9yPkxlby1TdW1tZXJzLCBMLjwvYXV0aG9yPjxhdXRob3I+WmhhbmcsIFkuPC9hdXRob3I+
PGF1dGhvcj5Cb2dhcmR1cywgUy4gVC4sIEpyLjwvYXV0aG9yPjxhdXRob3I+TGVzbGllLCBELiBM
LjwvYXV0aG9yPjxhdXRob3I+QWdvc3RpbmksIEouIFYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u
dHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+WWFsZSBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2lu
ZSwgRGVwYXJ0bWVudCBvZiBJbnRlcm5hbCBNZWRpY2luZSwgTmV3IEhhdmVuLCBDVCAwNjUyMCwg
VVNBLiBzaGFyb24uaW5vdXllQHlhbGUuZWR1ICZsdDtzaGFyb24uaW5vdXllQHlhbGUuZWR1Jmd0
OzwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkEgY2hhcnQtYmFzZWQgbWV0aG9kIGZvciBp
ZGVudGlmaWNhdGlvbiBvZiBkZWxpcml1bTogdmFsaWRhdGlvbiBjb21wYXJlZCB3aXRoIGludGVy
dmlld2VyIHJhdGluZ3MgdXNpbmcgdGhlIGNvbmZ1c2lvbiBhc3Nlc3NtZW50IG1ldGhvZDwvdGl0
bGU+PHNlY29uZGFyeS10aXRsZT5KIEFtIEdlcmlhdHIgU29jPC9zZWNvbmRhcnktdGl0bGU+PGFs
dC10aXRsZT5Kb3VybmFsIG9mIHRoZSBBbWVyaWNhbiBHZXJpYXRyaWNzIFNvY2lldHk8L2FsdC10
aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFtIEdlcmlhdHIgU29jPC9m
dWxsLXRpdGxlPjxhYmJyLTE+Sm91cm5hbCBvZiB0aGUgQW1lcmljYW4gR2VyaWF0cmljcyBTb2Np
ZXR5PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFt
IEdlcmlhdHIgU29jPC9mdWxsLXRpdGxlPjxhYmJyLTE+Sm91cm5hbCBvZiB0aGUgQW1lcmljYW4g
R2VyaWF0cmljcyBTb2NpZXR5PC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MzEyLTg8
L3BhZ2VzPjx2b2x1bWU+NTM8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48a2V5d29yZHM+PGtl
eXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48
a2V5d29yZD5EZWxpcml1bS8qZGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5
d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+KkludGVydmlldywgUHN5Y2hv
bG9naWNhbDwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPipNZWRpY2Fs
IFJlY29yZHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48
a2V5d29yZD4qUHN5Y2hvbG9naWNhbCBUZXN0czwva2V5d29yZD48a2V5d29yZD5SZXByb2R1Y2li
aWxpdHkgb2YgUmVzdWx0czwva2V5d29yZD48a2V5d29yZD5TZW5zaXRpdml0eSBhbmQgU3BlY2lm
aWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29y
ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmVi
PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAwMi04NjE0IChQcmludCkmI3hEOzAw
MDItODYxNCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTU2NzMzNTg8L2FjY2Vzc2lv
bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv
di9wdWJtZWQvMTU2NzMzNTg8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMt
cmVzb3VyY2UtbnVtPjEwLjExMTEvai4xNTMyLTU0MTUuMjAwNS41MzEyMC54PC9lbGVjdHJvbmlj
LXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Jbm91eWU8L0F1dGhv
cj48WWVhcj4xOTkwPC9ZZWFyPjxSZWNOdW0+MTQyPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJl
cj4xNDI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI5enBk
emZkYTZ4c3pya2U5ZXI4NWFlOWllMnZ3ZnhzdHhldnQiPjE0Mjwva2V5PjwvZm9yZWlnbi1rZXlz
PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0
b3JzPjxhdXRob3JzPjxhdXRob3I+SW5vdXllLCBTLiBLLjwvYXV0aG9yPjxhdXRob3I+dmFuIER5
Y2ssIEMuIEguPC9hdXRob3I+PGF1dGhvcj5BbGVzc2ksIEMuIEEuPC9hdXRob3I+PGF1dGhvcj5C
YWxraW4sIFMuPC9hdXRob3I+PGF1dGhvcj5TaWVnYWwsIEEuIFAuPC9hdXRob3I+PGF1dGhvcj5I
b3J3aXR6LCBSLiBJLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy
ZXNzPllhbGUgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIE5ldyBIYXZlbiwgQ29ubmVj
dGljdXQuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2xhcmlmeWluZyBjb25mdXNpb246
IHRoZSBjb25mdXNpb24gYXNzZXNzbWVudCBtZXRob2QuIEEgbmV3IG1ldGhvZCBmb3IgZGV0ZWN0
aW9uIG9mIGRlbGlyaXVtPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFubiBJbnRlcm4gTWVkPC9z
ZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5Bbm5hbHMgb2YgaW50ZXJuYWwgbWVkaWNpbmU8L2Fs
dC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Bbm4gSW50ZXJuIE1lZDwv
ZnVsbC10aXRsZT48YWJici0xPkFubmFscyBvZiBpbnRlcm5hbCBtZWRpY2luZTwvYWJici0xPjwv
cGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uIEludGVybiBNZWQ8L2Z1
bGwtdGl0bGU+PGFiYnItMT5Bbm5hbHMgb2YgaW50ZXJuYWwgbWVkaWNpbmU8L2FiYnItMT48L2Fs
dC1wZXJpb2RpY2FsPjxwYWdlcz45NDEtODwvcGFnZXM+PHZvbHVtZT4xMTM8L3ZvbHVtZT48bnVt
YmVyPjEyPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+
QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QWxnb3JpdGhtczwva2V5d29yZD48
a2V5d29yZD5Db25mdXNpb24vKmRpYWdub3Npczwva2V5d29yZD48a2V5d29yZD5EZWxpcml1bS8q
ZGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1h
bnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5Qcm9zcGVjdGl2ZSBT
dHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPipQc3ljaGlhdHJpYyBTdGF0dXMgUmF0aW5nIFNjYWxl
czwva2V5d29yZD48a2V5d29yZD5SZXByb2R1Y2liaWxpdHkgb2YgUmVzdWx0czwva2V5d29yZD48
a2V5d29yZD5TZW5zaXRpdml0eSBhbmQgU3BlY2lmaWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+U3Vy
dmV5cyBhbmQgUXVlc3Rpb25uYWlyZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+
MTk5MDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYyAxNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh
dGVzPjxpc2JuPjAwMDMtNDgxOSAoUHJpbnQpJiN4RDswMDAzLTQ4MTkgKExpbmtpbmcpPC9pc2Ju
PjxhY2Nlc3Npb24tbnVtPjIyNDA5MTg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs
cz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjI0MDkxODwvdXJsPjwv
cmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
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 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYW5ldDwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE.DATA [10 11], 20% of postoperative hypoxemia (from 20% to 40% depending on the surgical site) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWVkZXI8L0F1dGhvcj48WWVhcj4xOTkyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWVkZXI8L0F1dGhvcj48WWVhcj4xOTkyPC9ZZWFyPjxS
ZWNOdW0+MTI1PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMiAxM108L0Rpc3BsYXlUZXh0PjxyZWNv
cmQ+PHJlYy1udW1iZXI+MTI1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO
IiBkYi1pZD0iOXpwZHpmZGE2eHN6cmtlOWVyODVhZTlpZTJ2d2Z4c3R4ZXZ0Ij4xMjU8L2tleT48
L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5
cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlJlZWRlciwgTS4gSy48L2F1dGhvcj48
YXV0aG9yPkdvbGRtYW4sIE0uIEQuPC9hdXRob3I+PGF1dGhvcj5Mb2gsIEwuPC9hdXRob3I+PGF1
dGhvcj5NdWlyLCBBLiBELjwvYXV0aG9yPjxhdXRob3I+Rm9leCwgUC48L2F1dGhvcj48YXV0aG9y
PkNhc2V5LCBLLiBSLjwvYXV0aG9yPjxhdXRob3I+TWNLZW56aWUsIFAuIEouPC9hdXRob3I+PC9h
dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TnVmZmllbGQgRGVwYXJ0bWVudCBv
ZiBBbmFlc3RoZXRpY3MsIEpvaG4gUmFkY2xpZmZlIEhvc3BpdGFsLCBIZWFkaW5ndG9uLCBPeGZv
cmQuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UG9zdG9wZXJhdGl2ZSBoeXBveGFlbWlh
IGFmdGVyIG1ham9yIGFiZG9taW5hbCB2YXNjdWxhciBzdXJnZXJ5PC90aXRsZT48c2Vjb25kYXJ5
LXRpdGxlPkJyIEogQW5hZXN0aDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QnJpdGlzaCBq
b3VybmFsIG9mIGFuYWVzdGhlc2lhPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1
bGwtdGl0bGU+QnIgSiBBbmFlc3RoPC9mdWxsLXRpdGxlPjxhYmJyLTE+QnJpdGlzaCBqb3VybmFs
IG9mIGFuYWVzdGhlc2lhPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVs
bC10aXRsZT5CciBKIEFuYWVzdGg8L2Z1bGwtdGl0bGU+PGFiYnItMT5Ccml0aXNoIGpvdXJuYWwg
b2YgYW5hZXN0aGVzaWE8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4yMy02PC9wYWdl
cz48dm9sdW1lPjY4PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3Jk
PkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAg
YW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QW9ydGEsIEFiZG9taW5hbC8qc3VyZ2VyeTwva2V5
d29yZD48a2V5d29yZD5Bb3J0aWMgQW5ldXJ5c20vKnN1cmdlcnk8L2tleXdvcmQ+PGtleXdvcmQ+
Qmxvb2QgVmVzc2VsIFByb3N0aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+RXZhbHVhdGlvbiBTdHVk
aWVzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5G
ZW1vcmFsIEFydGVyeS8qc3VyZ2VyeTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+
PGtleXdvcmQ+SHlwb3hpYS8qZXRpb2xvZ3kvcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3
b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+
PGtleXdvcmQ+T3h5Z2VuL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3JkPk94eWdlbiBJbmhhbGF0aW9u
IFRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+KlBvc3RvcGVyYXRpdmUgQ29tcGxpY2F0aW9ucy9w
cmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+UHJlb3BlcmF0aXZlIENh
cmU8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh
dGVzPjx5ZWFyPjE5OTI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0
ZXM+PC9kYXRlcz48aXNibj4wMDA3LTA5MTIgKFByaW50KSYjeEQ7MDAwNy0wOTEyIChMaW5raW5n
KTwvaXNibj48YWNjZXNzaW9uLW51bT4xNzM5NTYxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxh
dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE3Mzk1NjE8
L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+
Q2FuZXQ8L0F1dGhvcj48WWVhcj4xOTg5PC9ZZWFyPjxSZWNOdW0+OTI8L1JlY051bT48cmVjb3Jk
PjxyZWMtbnVtYmVyPjkyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk
Yi1pZD0iOXpwZHpmZGE2eHN6cmtlOWVyODVhZTlpZTJ2d2Z4c3R4ZXZ0Ij45Mjwva2V5PjwvZm9y
ZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48
Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q2FuZXQsIEouPC9hdXRob3I+PGF1dGhvcj5S
aWNvcywgTS48L2F1dGhvcj48YXV0aG9yPlZpZGFsLCBGLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv
bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNlcnZlaSBkJmFwb3M7QW5lc3Rlc2lvbG9naWEgaSBS
ZWFuaW1hY2lvLCBIb3NwaXRhbCBHZXJtYW5zIFRyaWFzIGkgUHVqb2wsIEJhcmNlbG9uYSwgU3Bh
aW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RWFybHkgcG9zdG9wZXJhdGl2ZSBhcnRl
cmlhbCBveHlnZW4gZGVzYXR1cmF0aW9uLiBEZXRlcm1pbmluZyBmYWN0b3JzIGFuZCByZXNwb25z
ZSB0byBveHlnZW4gdGhlcmFweTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbmVzdGggQW5hbGc8
L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkFuZXN0aGVzaWEgYW5kIGFuYWxnZXNpYTwvYWx0
LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFuZXN0aCBBbmFsZzwvZnVs
bC10aXRsZT48YWJici0xPkFuZXN0aGVzaWEgYW5kIGFuYWxnZXNpYTwvYWJici0xPjwvcGVyaW9k
aWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5lc3RoIEFuYWxnPC9mdWxsLXRpdGxl
PjxhYmJyLTE+QW5lc3RoZXNpYSBhbmQgYW5hbGdlc2lhPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNh
bD48cGFnZXM+MjA3LTEyPC9wYWdlcz48dm9sdW1lPjY5PC92b2x1bWU+PG51bWJlcj4yPC9udW1i
ZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xlc2NlbnQ8L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8
L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zl
cjwva2V5d29yZD48a2V5d29yZD4qQW5lc3RoZXNpYSBSZWNvdmVyeSBQZXJpb2Q8L2tleXdvcmQ+
PGtleXdvcmQ+QW5lc3RoZXNpYSwgQ29uZHVjdGlvbjwva2V5d29yZD48a2V5d29yZD5BbmVzdGhl
c2lhLCBHZW5lcmFsPC9rZXl3b3JkPjxrZXl3b3JkPkFub3hpYS9ibG9vZDwva2V5d29yZD48a2V5
d29yZD5DaGlsZDwva2V5d29yZD48a2V5d29yZD5DaGlsZCwgUHJlc2Nob29sPC9rZXl3b3JkPjxr
ZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+
TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5PeGlt
ZXRyeTwva2V5d29yZD48a2V5d29yZD5PeHlnZW4vKmJsb29kPC9rZXl3b3JkPjxrZXl3b3JkPipP
eHlnZW4gSW5oYWxhdGlvbiBUaGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPipQb3N0b3BlcmF0aXZl
IFBlcmlvZDwva2V5d29yZD48a2V5d29yZD5SYW5kb20gQWxsb2NhdGlvbjwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4xOTg5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRl
PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAwMy0yOTk5IChQcmludCkmI3hEOzAwMDMtMjk5
OSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc2NDI4OTwvYWNjZXNzaW9uLW51bT48
dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1l
ZC8yNzY0Mjg5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu
ZE5vdGU+
ADDIN EN.CITE.DATA [12 13] and 5% of postoperative delirium (from 3.6% to 30% after elective surgery and abdominal surgery, respectively) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO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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 ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related searches
- posting links for companies
- promote links for free
- make money posting links online
- fda links to dog food
- companies that need links posted
- posting links online scam
- legitimate posting links from home
- jobs posting links for companies
- how to cite links in mla format
- no fee posting links jobs
- posting links online jobs
- what is posting links job