10 avril 2018 transfusion de produits sanguins chez le
TRANSCRIPT
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DESC Réanimation Ile de France Réanimation en traumatologie
10 avril 2018
Transfusion de produits sanguins chez le polytraumatisé
Dr Mathieu Boutonnet Réanimation – Hôpital d’Instruction des Armées Percy
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Revuedelali*érature22études1980-2008
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Revuedelali*érature22études1980-2008
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De quoi meurent les traumatisés?
Du*onRP,etal.1997-2008.JTrauma2010;69:620–6.
30,0%18,5%
46,7%
0%10%20%30%40%50%60%70%80%90%100%
Autres
SDMV
Traumacranien
Hémorragie
65454traumaNsésadultessurvivant>15mnaprèsl’admissionde1997à2008
5500traumaNsésparan 3,4%dedécès
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Causedudécès(%)
Délaiavantdécès(médiane)
Traumacrânien 51% 24h
Hémorragie 30% 2h
Sepsis/SDMV 10% 15jours
5500paNentsparanBalNmore,USA
Médianedesurviedeshémorragiques:2heures
Du*onRP,etal.1997-2008.JTrauma2010;69:620–6.
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Triade létale
HypothermieT°<34°C
CoagulopathieTTetTCA>2N
AcidosepH<7,2
Lactate>5mM
MooreEE.etal.Americanjournalofsurgery1996;172:405-10
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Hémorragie
Etatdechoc
Hypothermie
MooreEE.etal.Americanjournalofsurgery1996;172:405-10
Chirurgie
Anesthésie
Remplissage
Transfusion
Catécholamines
AgentshémostaNques
miracles
Réchauffer
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Transfusion de CGR en urgence
• Risques:
• Hémolyseaiguë• IncompaAbilitéABO• Existenced’unanNcorpsirrégulier
• Allo-immunisaNon
BoisenML,etal.Anesthesiology2015;122:191–5.
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Transfusion de CGR en urgence
• Risques:
• Hémolyseaiguë• UAlisaAond’ungroupecompaAble+++• IdenNficaNond’unanNcorpsirrégulier
• Allo-immunisaNon
BoisenML,etal.Anesthesiology2015;122:191–5.
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Transfusion de CGR en urgence:
• Risques:• Hémolyseaigüe
• UNlisaNond’ungroupecompaNble• IdenNficaNond’unanNcorpsirrégulier
• Allo-immunisaNon
BoisenML,etal.Anesthesiology2015;122:191–5.
CGRO
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Transfusion de CGR en urgence
• Risques:• Hémolyseaiguë
• Allo-immunisaNon• RespectduphénotypeRh-Kell• 5anNgènesRhprincipaux:D,C,E,cete
• Risqued’alloimmunisaNonRh1:50%ensituaNon«stable»,10-33%ensituaNon«clinique»
BoisenML,etal.Anesthesiology2015;122:191–5.
CGRO
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Transfusion de CGR en urgence
• Risques:• Hémolyseaiguë
• Allo-immunisaNon• RespectduphénotypeRh-Kell• 5anNgènesRhprincipaux:D,C,E,cete
• Risqued’alloimmunisaNonRh1:50%ensituaNon«stable»,10-33%ensituaNon«clinique»
BoisenML,etal.Anesthesiology2015;122:191–5.
CGRO
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Transfusion de CGR en urgence
• Risques:• Hémolyseaiguë
• Allo-immunisaNon• RespectduphénotypeRh-Kell• 5anNgènesRhprincipaux:D,C,E,cete
DeuxdéterminaAons:CGRisogroupesCGRO
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Transfusion de CGR en urgence
RESEARCH Open Access
Management of bleeding and coagulopathyfollowing major trauma: an updated EuropeanguidelineDonat R Spahn1, Bertil Bouillon2, Vladimir Cerny3,4, Timothy J Coats5, Jacques Duranteau6,Enrique Fernández-Mondéjar7, Daniela Filipescu8, Beverley J Hunt9, Radko Komadina10, Giuseppe Nardi11,Edmund Neugebauer12, Yves Ozier13, Louis Riddez14, Arthur Schultz15, Jean-Louis Vincent16 and Rolf Rossaint17*
Abstract
Introduction: Evidence-based recommendations are needed to guide the acute management of the bleedingtrauma patient. When these recommendations are implemented patient outcomes may be improved.
Methods: The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with theaim of developing a guideline for the management of bleeding following severe injury. This document representsan updated version of the guideline published by the group in 2007 and updated in 2010. Recommendationswere formulated using a nominal group process, the Grading of Recommendations Assessment, Development andEvaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.
Results: Key changes encompassed in this version of the guideline include new recommendations on theappropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patientsin the population at large treated with antiplatelet agents and/or oral anticoagulants. The current guideline alsoincludes recommendations and a discussion of thromboprophylactic strategies for all patients following traumaticinjury. The most significant addition is a new section that discusses the need for every institution to develop,implement and adhere to an evidence-based clinical protocol to manage traumatically injured patients. Theremaining recommendations have been re-evaluated and graded based on literature published since the lastedition of the guideline. Consideration was also given to changes in clinical practice that have taken place duringthis time period as a result of both new evidence and changes in the general availability of relevant agents andtechnologies.
Conclusions: A comprehensive, multidisciplinary approach to trauma care and mechanisms with which to ensurethat established protocols are consistently implemented will ensure a uniform and high standard of care acrossEurope and beyond.
IntroductionSevere trauma is one of the major health care issuesfaced by modern society, resulting in the annual deathof more than five million people worldwide, and thisnumber is expected to increase to more than eight mil-lion by 2020 [1]. Uncontrolled post-traumatic bleedingis the leading cause of potentially preventable death
among these patients [2,3]. Appropriate management ofthe massively bleeding trauma patient includes the earlyidentification of bleeding sources followed by promptmeasures to minimise blood loss, restore tissue perfu-sion and achieve haemodynamic stability.An awareness of the specific pathophysiology asso-
ciated with bleeding following traumatic injury by treat-ing physicians is essential. About one-third of allbleeding trauma patients present with a coagulopathyupon hospital admission [4-7]. This subset of patientshas a significantly increased incidence of multiple organ
* Correspondence: [email protected] of Anaesthesiology, University Hospital Aachen, RWTH AachenUniversity, Pauwelsstrasse 30, D-52074 Aachen, GermanyFull list of author information is available at the end of the article
Spahn et al. Critical Care 2013, 17:R76http://ccforum.com/content/17/2/R76
© 2013 Spahn et al.; licensee BioMed Central Ltd This is an open access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
QuelobjecNfd’hémoglobinémie?
7à9g/dL
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Stratégie transfusionnelle classique (avant 2005)
2,52,01,51,00,50,00
20
40
60
80
100 CGR
VolumeplasmaAque
Volumeérythrocytaire
Massesanguine
%
Massesanguine
%FacteursdecoagulaAon
2,52,01,51,00,50,00
20
40
60
80
100
DiaposiNve:ProfYvesOzier
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Stratégie : Le déclic
5293blessésdeguerreNov2003-Sept2005àBagdad246(4.6%)TM
BorgmanMA,JTrauma2007;63:805–13.
MortalitéglobaledesTM:28%
n=31
n=53
n=162
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Stratégie - Haut ratio Plasma/CGR
22civiles4militaires
17enfaveurdeshautsraNos
5nonconcluantes
HoAM,etal.Anesthesiology2012
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Stratégie transfusionnelle
BhanguA,etal.Injury.2013;44(12):1693–1699.
⬇50%delamortalité
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DuranteauJ,etal.RecommandaNonssurlaréanimaNonduchochémorragique.Anesthésie&Réanima8on.2015;1(1):62–74.
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S’affranchir du biais de survie Analyse au fil du temps
deBiasiAR,etal.Transfusion2011;51:1925-32
835paNentstransfusésenextrêmeurgence(SAUV)
TransfusionmassiveanNcipéeProtocole(packdeTM):délaimédianduplasma=40mn
TM(≥10CGR/24h):307(36,8%)
Mortalité:36%(301/835)49%d’hémorragieincontrolée
33%demortcérébrale9%deSDMV
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deBiasiAR,etal.Transfusion2011;51:1925-32
Lowplasmadeficit CGR–plasma<2Moderateplasmadeficit
Highplasmadeficit CGR–plasma>6
835paNentstransfusésenextrêmeurgence(SAUV)
TransfusionmassiveanNcipéeProtocole(packdeTM):délaimédianduplasma=40mn
S’affranchir du biais de survie Analyse au fil du temps
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DuranteauJ,etal.RecommandaNonssurlaréanimaNonduchochémorragique.Anesthésie&Réanima8on.2015;1(1):62–74.
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Stratégie transfusionnelle - Plaquettes?
CapAP,etal.JTraumaAcuteCareSurg2012;73:S89-94
8618blessésdeguerre–414TM(10CGRen24h)avecuNlisaNondeplaque*esdebanque
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JohanssonPI,etal.JEmergTraumaShock2012;5:120-5
10études–3602paNentsBénéficeglobal(moyen)del’ordrede20%à
l’apport«important»deplaque*es
Stratégie transfusionnelle - Plaquettes?
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Synergie+++avecl’apportde
plasma
Holcombetal.AnnSurg2008;248:447-458
466TMdetraumatologiecivile16levelItraumacenterJuillet2005–Juin2006
îPltîPlasma
ìPltìPlasma
ìPltîPlasma
îPltìPlasma
Stratégie transfusionnelle - Plaquettes?
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DuranteauJ,etal.RecommandaNonssurlaréanimaNonduchochémorragique.Anesthésie&Réanima8on.2015;1(1):62–74.
Stratégie transfusionnelle - Plaquettes?
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905traumaNsésadultessurvivant>30mnaprèsl’admissionayantreçu≥1CGRdansles6premièresheureset≥3PSL(CGR,plasma,plaque*es)dansles24premièresheures25%dedécès
ns
Plaque*esPlasma
EtudedecohorteprospecNve10traumacenters34362traumaNsés1245recevant≥1CGRdansles6premièresheures21%dedécès
ns
Holcomb,J.B.JAMASurg2013;148(2):127-36.
The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study
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RéducNondelamortalitéhospitalièreet
praNquetransfusionnelledes6premièresheures
The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study
RaAo Faible<1/2 Modéré>1/2à1/1 Elevé>1/1
Min31–6h HR p HR p
Plasma:CGR 1 Réf 0,42 <0,001 0,23 <0,001
Plq:CGR 1 Réf 0,66 0,16 0,37 0,04
Holcomb,J.B.JAMASurg2013;148(2):127-36.
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Holcomb,J.B.JAMASurg2013;148(2):127-36.
Plasma Plaque*es
➡94%desdécèsdecausehémorragique<24h➡81%<6h,60%<3h➡médianede2,6heuresaprèsl’admission
The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study
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De quoi meurent les polytraumatisés?
Holcomb,J.B.JAMASurg2013;148(2):127-36.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Autre
Cardiaque
SDMV
Sepsis
Défaillancerespiratoire
Traumacranien
Hémorragie
905traumaNsésadultessurvivant>30mnaprèsl’admissionayantreçu≥1CGRdansles6premièresheureset≥3PSL(CGR,plasma,plaque*es)dansles24premièresheures25%dedécès
95 37 88 226n=
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The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial
HolcombJB,etal.JAMA2015;313:471–82.
12traumacenters2stratégiesraNo1:1:1ou1:1:2
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The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial
HolcombJB,etal.JAMA2015;313:471–82.
Plasmadécongeléàl’avancepourêtredisponibleenmoinsde10mn:
Délaiadmission-demande:9mnDélaidemande-arrivéeauxurgences:8mn
Accompagnéed’unecarteplasNfiéeindiquant“transfuserlesplaque*esenpremier”
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The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial
12,7%(1:1:1)vs17%(1:1:2) 22,4%(1:1:1)vs26,1%(1:1:2)
Mortalitéà24h Mortalitéà30jours
MortparexsanguinaNon9.2%vs14.6%
HolcombJB,etal.JAMA2015;313:471–82.
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Causes des décès dans PROPPR
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Agents hémostatiques miracles ? FVIIa
BoffardKD,RiouB,WarrenB,etal.RecombinantfactorVIIaasadjuncAvetherapyforbleedingcontrolinseverelyinjuredtraumapaAents:twoparallelrandomized,placebo-controlled,double-blindclinicaltrials.J Trauma 2005;59:8.Intérêtdansletraumafermé?RéducNondunombredeCGRtransfusésPasdedifférencedemortalité
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Facteur VIIa
• Expérienceaméricaineenmédecinedeguerre• 18638blessésdeguerreenregistrésde2003à2009• 2050transfusés(11%)• 506reçoiventduFVIIa(1/4)
Wade,C.E.JTrauma.2010;69:353–359
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Facteur VIIa • Traumatologiecivile• EtudeCONTROL
• 100hôpitaux/20pays• 573paNents 481traumafermés 92traumapénétrants
HauserCJ,etal.JTrauma.2010;69:489-500
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Agents hémostatiques miracles ?
Lancet2010
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Lancet2010
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Acide tranexamique
ShakurH,etal.Effectsoftranexamicacidondeath,vascularocclusiveevents,andbloodtransfusionintraumapaNentswithsignificanthaemorrhage(CRASH-2):arandomised,placebo-controlledtrial.Lancet2010;376:23-32
+de20000paNents274centres40pays
îDelamortalitéde10%
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Données Françaises IDF
Critèresd’inclusion2011–2015Adultes(>16ans)6994admissionsprimairesTraumaCenterIDFGravité:4CGR<6hCGRenSAUVNADàl’admission
Boutonnetetal.JTraumaAcuteCareSurg.2018Mar12.
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Données Françaises IDF
Boutonnetetal.JTraumaAcuteCareSurg.2018Mar12.
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• Acidetranexamique• Urgence+++àPréhospitalier• Moinsde3heuresaprèsletraumaNsme• 1gen10minpuis1gsur8h
RESEARCH Open Access
Management of bleeding and coagulopathyfollowing major trauma: an updated EuropeanguidelineDonat R Spahn1, Bertil Bouillon2, Vladimir Cerny3,4, Timothy J Coats5, Jacques Duranteau6,Enrique Fernández-Mondéjar7, Daniela Filipescu8, Beverley J Hunt9, Radko Komadina10, Giuseppe Nardi11,Edmund Neugebauer12, Yves Ozier13, Louis Riddez14, Arthur Schultz15, Jean-Louis Vincent16 and Rolf Rossaint17*
Abstract
Introduction: Evidence-based recommendations are needed to guide the acute management of the bleedingtrauma patient. When these recommendations are implemented patient outcomes may be improved.
Methods: The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with theaim of developing a guideline for the management of bleeding following severe injury. This document representsan updated version of the guideline published by the group in 2007 and updated in 2010. Recommendationswere formulated using a nominal group process, the Grading of Recommendations Assessment, Development andEvaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.
Results: Key changes encompassed in this version of the guideline include new recommendations on theappropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patientsin the population at large treated with antiplatelet agents and/or oral anticoagulants. The current guideline alsoincludes recommendations and a discussion of thromboprophylactic strategies for all patients following traumaticinjury. The most significant addition is a new section that discusses the need for every institution to develop,implement and adhere to an evidence-based clinical protocol to manage traumatically injured patients. Theremaining recommendations have been re-evaluated and graded based on literature published since the lastedition of the guideline. Consideration was also given to changes in clinical practice that have taken place duringthis time period as a result of both new evidence and changes in the general availability of relevant agents andtechnologies.
Conclusions: A comprehensive, multidisciplinary approach to trauma care and mechanisms with which to ensurethat established protocols are consistently implemented will ensure a uniform and high standard of care acrossEurope and beyond.
IntroductionSevere trauma is one of the major health care issuesfaced by modern society, resulting in the annual deathof more than five million people worldwide, and thisnumber is expected to increase to more than eight mil-lion by 2020 [1]. Uncontrolled post-traumatic bleedingis the leading cause of potentially preventable death
among these patients [2,3]. Appropriate management ofthe massively bleeding trauma patient includes the earlyidentification of bleeding sources followed by promptmeasures to minimise blood loss, restore tissue perfu-sion and achieve haemodynamic stability.An awareness of the specific pathophysiology asso-
ciated with bleeding following traumatic injury by treat-ing physicians is essential. About one-third of allbleeding trauma patients present with a coagulopathyupon hospital admission [4-7]. This subset of patientshas a significantly increased incidence of multiple organ
* Correspondence: [email protected] of Anaesthesiology, University Hospital Aachen, RWTH AachenUniversity, Pauwelsstrasse 30, D-52074 Aachen, GermanyFull list of author information is available at the end of the article
Spahn et al. Critical Care 2013, 17:R76http://ccforum.com/content/17/2/R76
© 2013 Spahn et al.; licensee BioMed Central Ltd This is an open access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
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L’hémorragie d’origine traumatique L’anémie qui tue vite
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• Traitementprécocedelacoagulopathie:PFC:CGR=Aumoins1:2Plaquekesprécoces(dèsle4èmeCGR)Fibrinogène
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• Nécessitédeme*reenplacedesprotocolesdetransfusionmassive46
RESEARCH Open Access
Management of bleeding and coagulopathyfollowing major trauma: an updated EuropeanguidelineDonat R Spahn1, Bertil Bouillon2, Vladimir Cerny3,4, Timothy J Coats5, Jacques Duranteau6,Enrique Fernández-Mondéjar7, Daniela Filipescu8, Beverley J Hunt9, Radko Komadina10, Giuseppe Nardi11,Edmund Neugebauer12, Yves Ozier13, Louis Riddez14, Arthur Schultz15, Jean-Louis Vincent16 and Rolf Rossaint17*
Abstract
Introduction: Evidence-based recommendations are needed to guide the acute management of the bleedingtrauma patient. When these recommendations are implemented patient outcomes may be improved.
Methods: The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with theaim of developing a guideline for the management of bleeding following severe injury. This document representsan updated version of the guideline published by the group in 2007 and updated in 2010. Recommendationswere formulated using a nominal group process, the Grading of Recommendations Assessment, Development andEvaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.
Results: Key changes encompassed in this version of the guideline include new recommendations on theappropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patientsin the population at large treated with antiplatelet agents and/or oral anticoagulants. The current guideline alsoincludes recommendations and a discussion of thromboprophylactic strategies for all patients following traumaticinjury. The most significant addition is a new section that discusses the need for every institution to develop,implement and adhere to an evidence-based clinical protocol to manage traumatically injured patients. Theremaining recommendations have been re-evaluated and graded based on literature published since the lastedition of the guideline. Consideration was also given to changes in clinical practice that have taken place duringthis time period as a result of both new evidence and changes in the general availability of relevant agents andtechnologies.
Conclusions: A comprehensive, multidisciplinary approach to trauma care and mechanisms with which to ensurethat established protocols are consistently implemented will ensure a uniform and high standard of care acrossEurope and beyond.
IntroductionSevere trauma is one of the major health care issuesfaced by modern society, resulting in the annual deathof more than five million people worldwide, and thisnumber is expected to increase to more than eight mil-lion by 2020 [1]. Uncontrolled post-traumatic bleedingis the leading cause of potentially preventable death
among these patients [2,3]. Appropriate management ofthe massively bleeding trauma patient includes the earlyidentification of bleeding sources followed by promptmeasures to minimise blood loss, restore tissue perfu-sion and achieve haemodynamic stability.An awareness of the specific pathophysiology asso-
ciated with bleeding following traumatic injury by treat-ing physicians is essential. About one-third of allbleeding trauma patients present with a coagulopathyupon hospital admission [4-7]. This subset of patientshas a significantly increased incidence of multiple organ
* Correspondence: [email protected] of Anaesthesiology, University Hospital Aachen, RWTH AachenUniversity, Pauwelsstrasse 30, D-52074 Aachen, GermanyFull list of author information is available at the end of the article
Spahn et al. Critical Care 2013, 17:R76http://ccforum.com/content/17/2/R76
© 2013 Spahn et al.; licensee BioMed Central Ltd This is an open access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
![Page 47: 10 avril 2018 Transfusion de produits sanguins chez le](https://reader035.vdocuments.pub/reader035/viewer/2022062501/62af9150be45d554de05bc29/html5/thumbnails/47.jpg)
Bibliographie
RESEARCH Open Access
Management of bleeding and coagulopathyfollowing major trauma: an updated EuropeanguidelineDonat R Spahn1, Bertil Bouillon2, Vladimir Cerny3,4, Timothy J Coats5, Jacques Duranteau6,Enrique Fernández-Mondéjar7, Daniela Filipescu8, Beverley J Hunt9, Radko Komadina10, Giuseppe Nardi11,Edmund Neugebauer12, Yves Ozier13, Louis Riddez14, Arthur Schultz15, Jean-Louis Vincent16 and Rolf Rossaint17*
Abstract
Introduction: Evidence-based recommendations are needed to guide the acute management of the bleedingtrauma patient. When these recommendations are implemented patient outcomes may be improved.
Methods: The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with theaim of developing a guideline for the management of bleeding following severe injury. This document representsan updated version of the guideline published by the group in 2007 and updated in 2010. Recommendationswere formulated using a nominal group process, the Grading of Recommendations Assessment, Development andEvaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.
Results: Key changes encompassed in this version of the guideline include new recommendations on theappropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patientsin the population at large treated with antiplatelet agents and/or oral anticoagulants. The current guideline alsoincludes recommendations and a discussion of thromboprophylactic strategies for all patients following traumaticinjury. The most significant addition is a new section that discusses the need for every institution to develop,implement and adhere to an evidence-based clinical protocol to manage traumatically injured patients. Theremaining recommendations have been re-evaluated and graded based on literature published since the lastedition of the guideline. Consideration was also given to changes in clinical practice that have taken place duringthis time period as a result of both new evidence and changes in the general availability of relevant agents andtechnologies.
Conclusions: A comprehensive, multidisciplinary approach to trauma care and mechanisms with which to ensurethat established protocols are consistently implemented will ensure a uniform and high standard of care acrossEurope and beyond.
IntroductionSevere trauma is one of the major health care issuesfaced by modern society, resulting in the annual deathof more than five million people worldwide, and thisnumber is expected to increase to more than eight mil-lion by 2020 [1]. Uncontrolled post-traumatic bleedingis the leading cause of potentially preventable death
among these patients [2,3]. Appropriate management ofthe massively bleeding trauma patient includes the earlyidentification of bleeding sources followed by promptmeasures to minimise blood loss, restore tissue perfu-sion and achieve haemodynamic stability.An awareness of the specific pathophysiology asso-
ciated with bleeding following traumatic injury by treat-ing physicians is essential. About one-third of allbleeding trauma patients present with a coagulopathyupon hospital admission [4-7]. This subset of patientshas a significantly increased incidence of multiple organ
* Correspondence: [email protected] of Anaesthesiology, University Hospital Aachen, RWTH AachenUniversity, Pauwelsstrasse 30, D-52074 Aachen, GermanyFull list of author information is available at the end of the article
Spahn et al. Critical Care 2013, 17:R76http://ccforum.com/content/17/2/R76
© 2013 Spahn et al.; licensee BioMed Central Ltd This is an open access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
JAMA2015;313:471–82