Prévention des nausées et vomissements post-opératoires Eve Charest Anesthésiologiste HDL 2 mai 2013

Plan !  Introduction !  Incidence ! Morbidité associée ! Facteurs de risque ! Pathophysiologie ! Pharmacothérapie ! Thérapie alternative ! Prophylaxie vs traitement ! Cas clinique

Introduction ! Nausée

!  Sensation de mal-être et d’inconfort accompagnant l’éventuelle approche des Vo

!  Varie en intensité et en durée !  Parfois associée avec hypersalivation, sudation, frisson, hypoTA,

perte d’appétit, etc. !  Méthode de mesure : VAS, NRS et VRS

! Vomissement !  Rejet actif d’une partie du contenu de l’estomac

! Efforts de vomissement

!  Similaire au vomissement mais sans que le contenu gastrique ne soit expulsé

Incidence Pédiatrie ! Rare chez enfants < 3 ans ! Augmentation du risque jusqu’à la puberté

! POV 40-73% post-amygdalectomie Adulte

! 20-30% ! 70-80% chez population à risque

Incidence ! Différencier

!  PACU : s.réveil + C1J !  «Postdischarge» : après la sortie de l’hôpital !  Haut pourcentage : No 17% et Vo 8% !  36% d’entre eux n’ont pas eu de NoVo au PACU !  L’efficacité de la pharmacothérapie serait la même pour les NoVo

«postdischarge»

Morbidité associée ! Admission post-op !  Insatisfaction ! Pneumonie d’aspiration ! Lacérations oesophagiennes ! Déhiscence de plaie ! Saignement ! Élévation de la pression oculaire et intracrânienne ! Élévation du pouls et de TA ! Déshydratation et désordres électrolytiques ! Douleur

Facteurs de risque ! Différencier «association» et «causalité» ! Par exemple

!  Est-ce qu’il y a plus de NoVo suite à une chirurgie gynécologique ???

!  «CAUSALITÉ» : Est-ce que l’intervention chirurgicale en soi cause plus de NoVo ??

!  «ASSOCIATION» : Est-ce le fait que ces interventions sont pratiquées que sur des femmes ??

! Facteurs de risque INDÉPENDANTS

Facteurs de risque – patient - ! Femme ! ATCD de PONV ou mal des transports

! Non fumeur ! Âge

! Obésité ! Cycle menstruel ! Anxiété

Facteurs de risque – anesthésie - ! Volatiles

! Des = Sevo = Iso ! N2O

!  Effet additif avec les volatiles ! Durée de l’anesthésie

!  Surtout vrai avec l’utilisation de volatiles !  Souvent associé avec des doses plus élevées d’opioïdes …

Facteurs de risque – anesthésie - ! Opioïdes intra-op et post-op

! Controversé !  La dose est importante mais pas le type !  Stratégies «opioids-sparing» sont efficaces

! Propofol !  Effet antiémétique ??

Facteurs de risque – chirurgie - ! La causalité est difficile à établir … ! Chirurgies abdominales et gynécologiques

!  «Associées» à un risque plus élevé !  Pas un facteur de risque indépendant !  Possibles exceptions : endocholécystectomie et hystérectomie

! Chirurgies de correction du strabisme !  Facteur de risque indépendant chez l’enfant

the history of PONV or motion sickness (2.32) and non-smoking status (1.78) (Supplementary Table S1). Unlike forPN/PONV, age (in decades) was not an independent predictorof PV. The history of migraine, history of motion sickness,high BMI, and low ASA physical status were not analysed(n,3). None of the 13 surgical categories reached the levelof significance as an independent predictor of PV.

For PN/PONV, heterogeneity was greatest in the surgery-related risk factors (mean I2¼70%), followed by a more mod-erate degree of heterogeneity in the anaesthesia-related riskfactors (mean I2¼58%). The lowest overall heterogeneitywas seen among the patient-specific predictors (meanI2¼46%; Table 3).

Funnel plots indicated an underlying publication biastowards positive results in the significant surgical categories(Fig. 3). In contrast, there was no funnel plot distortion for

any of the significant patient-specific (Supplementary FigsS6 and S7) or anaesthesia-related (Supplementary Fig. S8)risk factors.

DiscussionThis is the first systematic review and meta-analysis to iden-tify and quantify the impact of independent predictors inadults. Combining individual study results into the most ac-curate point estimate for each risk factor facilitated a directcomparison of the predictive strength of a comprehensivelist of predictors. The data suggest that PONV is mainly trig-gered by perioperative administration of emetogenic stimuli(volatile anaesthetics, prolonged duration of anaesthesia,nitrous oxide, postoperative opioids) to susceptible patients(women, patients with a history of PONV and/or motion

Table 3 PN/PONV: combined estimates for patient-, anaesthesia-, and surgery-related predictors. For each risk factor, the number of studies inwhich it was considered, the total number of patients, the ORs and respective 95% CIs, the degree of heterogeneity within the comparison, andthe number of outliers are given

Risk factors Studies (n) Participants (n) Combined estimate[OR (95% CI)]

P-value Heterogeneity, I2 Outliers (n)

Patient

Female gender 20 90 916 2.57 (2.32–2.84) ,0.001 69 —

History of PONV or MS 16 44 216 2.09 (1.90–2.29) ,0.001 54 —

Non-smoking 19 90 116 1.82 (1.68–1.98) ,0.001 45 —

Age (per decade) 9 70 562 0.88 (0.84–0.92) ,0.001 64 4

ASA 3 22 371 1.21 (0.88–1.67) 0.24 86 0

BMI 4 20 428 1.00 (0.98–1.02) 0.8 0 3

History of migraine 2 1778 1.77 (1.36–2.31) — — —

(mean¼46)

Anaesthesia

Volatile anaesthetics 7 58 557 1.82 (1.56–2.13) ,0.001 73 2

Duration (per hour) 12 64 168 1.46 (1.30–1.63) ,0.001 88 4

Opioids: postoperative 7 10294 1.39 (1.20–1.60) ,0.001 64 1

Nitrous oxide 4 40 071 1.45 (1.06–1.98) 0.02 89 0

Opioids: intraoperative 6 28 569 1.03 (0.94–1.13) 0.47 0 1

(mean¼58)

Surgery

Cholecystectomy 4 11 433 1.90 (1.36–2.68) ,0.001 49 —

Laparoscopic 8 29 614 1.37 (1.07–1.77) 0.01 62 —

Gynaecology 7 56 158 1.24 (1.02–1.52) 0.03 60 3

Ear, nose and throat 11 72 472 1.19 (1.00–1.42) 0.05 56 —

Orthopaedics 9 33 571 1.23 (0.99–1.52) 0.06 72 —

Neurology 3 29 367 2.98 (0.75–11.86) 0.12 93 0

Thyroid 3 8829 1.46 (0.90–2.37) 0.13 65 —

Ophthalmology 8 51 968 1.19 (0.95–1.50) 0.13 68 3

Plastics 3 18 837 2.45 (0.66–9.10) 0.18 80 0

Head and neck 3 33 458 1.50 (0.79–2.84) 0.21 83 0

Abdominal 9 59 326 1.08 (0.90–1.28) 0.42 64 2

Urology 2 28 297 2.71 (0.35–20.94) — — —

Breast 2 5689 0.71 (0.46–1.10) — — —

(mean¼70)

OR, odds ratio; CI, confidence interval; MS, motion sickness; PN, postoperative nausea; PONV, postoperative nausea and/or vomiting; ‘—’ denotes ‘not applicable’.

Systematic review of PONV risk factors BJA

7

at Bibliotheque de l'U

niversite Laval on May 1, 2013

http://bja.oxfordjournals.org/D

ownloaded from

Score de Koivuranta Prédicteurs indépendants ! Sexe féminin ! ATCD NVPO ! ATCD de mal des transport ! Non fumeur ! Durée de la chirurgie supérieure à 60 minutes

! Si 0, 1, 2, 3, 4 ou 5 prédicteurs présents : risque de NVPO de 17%, 18%, 42%, 54% et 87%.

Si facteurs de risque de 0, 1 ,2, 3 ou 4 points ➔ risque de NVPO de 10%, 20%, 40%, 60% ou 80%

the use of postoperative opioids. The emetogeniceffect of the inhaled anesthetics and opioids appears tobe dose related (13,15). Longer procedures undergeneral volatile anesthetic with concomitantly longerexposure to the volatile anesthetics and increasedpostoperative opioid consumption are associated withan increased incidence of PONV (4,11).

It is appreciated that some types of surgery areassociated with a higher incidence of PONV thanothers. However, no agreement could be reachedabout whether the association between type of surgeryand increased PONV risk is causal. Numerous studiessuggest that the higher incidences are due to otherindependent risk factors associated with the type ofsurgery (3,10,14,22,26,27,32), while other analyses sug-gest that certain types of surgery are independent riskfactors (4,9,11,12,23,28,30) (Table 1).

Many factors commonly believed to augment riskare not actually independent factors. These includeobesity, anxiety, antagonizing neuromuscular block-ade (10,22,26,30,32–35). However, no single patient- oranesthetic-related risk factor is sufficiently sensitive orspecific enough to provide a useful risk assessment forPONV. Several risk models have therefore been devel-oped (30). The simplified models of Apfel et al. andKoivuranta et al. have shown some usefulness for theprediction of the PONV baseline risk in a variety ofsituations (Fig. 1) (10,24,27,28). It is important to notethat no risk model can accurately predict the likeli-hood of an individual having PONV; risk models onlyallow clinicians to estimate the risk for PONV amongpatient groups (32).

In children, a number of papers have been pub-lished citing a variety of risk factors associated withPOV (36–38). However, evidence is lacking to supportthese associations. More recently, Eberhart et al. (39)published a study of a large series of pediatric patientsin which a multivariable analysis was applied toidentify POV risk factors in children. Four indepen-dent predictors of POV were identified, includingduration of surgery !30 min, age !3 yr, strabismussurgery, and a positive history of POV in the patient,parent or sibling (Fig. 2). They demonstrated that therisk for POV was 9%, 10%, 30%, 55%, and 70% when0, 1, 2, 3, or 4 of those independent predictors werepresent.

Use of prophylactic antiemetics should be based onvalid assessment of the patient’s risk for POV orPONV. In other words, antiemetic prophylaxis shouldbe used only when the patient’s individual risk issufficiently high. This can be estimated by multiplyingthe expected incidence (baseline risk) by the relativerisk reduction resulting from prophylaxis. This ap-proach produces a clinically meaningful decrease inthe risk of PONV (2,40). However, more liberal pro-phylaxis is appropriate for patients in whom vomitingposes a particular medical risk, including those withwired jaws, increased intracranial pressure, gastric oresophageal surgery, and when the anesthesia careprovider determines the need or the patient has astrong preference to avoid PONV.

Guideline 2: Reduce Baseline Risk Factors for PONVApproaches for decreasing baseline risk factors are

presented in Table 2.

0%

20%

40%

60%

80%

100%

0 1 2 3 4# of Risk Factors

PO

NV

-Ris

k

Risk Factors PointsFemale Gender 1Non-Smoker 1History of PONV 1Postoperative Opioids 1

Sum = 0 ... 4

0%

20%

40%

60%

80%

100%

0 1 2 3 4# of Risk Factors

-

Risk Factors PointsFemale Gender 1Non-Smoker 1History of PONVPostoperative Opioids 1

Sum = 0 ... 4

Figure 1. Simplified risk score for PONV in adults (3).Simplified risk score from Apfel et al. (3) to predict thepatients risk for PONV. When 0, 1, 2, 3, or 4 of the depictedindependent predictors are present, the corresponding riskfor PONV is approximately 10%, 20%, 40%, 60%, or 80%.

0 . . . 4Sum =

1History ofPOV orPONV inrelatives

1Strabismussurgery

1Age > 3years

1Surgery > 30min.

PointsRisk Factors

0

20

40

60

80

0 1 2 3 4Number of Risk Factors

PO

VR

isk

(%)

Figure 2. Simplified risk score for POV in children (39).Simplified risk score from Eberhart et al. (39) to predict therisk for POV in children. When 0, 1, 2, 3, or 4 of the depictedindependent predictors are present, the corresponding riskfor PONV is approximately 10%, 10%, 30%, 55%, or 70%.

Table 1. Risk Factors for Postoperative Nausea and Vomiting(PONV) in Adults

Patient-specific risk factors (3,9,10–14)The most important being:

Female gender (RCT)Nonsmoking status (RCT)History of PONV/motion sickness (RCT)

Anesthetic risk factors (3,12–20)The most important being:

Use of volatile anesthetics (RCT)Nitrous oxide systematic review (SR)Use of intraoperative (SR) and postoperative opioids

(RCT)Surgical risk factors (11,12,14)

Duration of surgery (each 30-min increase in durationincreases PONV risk by 60%, so that a baseline riskof 10% is increased by 16% after 30 min)(Prospective observational study)

Type of surgery (laparoscopy, laparotomy, breast,strabismus, plastic surgery, maxillofacial,gynecological, abdominal, neurologic,ophthalmologic, urologic) (Prospective observationalstudy)

RCT ! randomized controlled trial; SR ! systematic review.

Vol. 105, No. 6, December 2007 © 2007 International Anesthesia Research Society 1617

Score de Eberhart pour VPO chez l’enfant Prédicteurs ! Durée de chirurgie ≥ 30 minutes ! Âge ≥ 3 ans ! Chirurgie pour correction du strabisme ! ATCD de VPO chez l’enfant ou de NVPO dans sa famille

immédiate

! Si 0, 1, 2, 3 ou 4 prédicteurs présents : risque de VPO de 9%, 10%, 30%, 55% et 70%

the use of postoperative opioids. The emetogeniceffect of the inhaled anesthetics and opioids appears tobe dose related (13,15). Longer procedures undergeneral volatile anesthetic with concomitantly longerexposure to the volatile anesthetics and increasedpostoperative opioid consumption are associated withan increased incidence of PONV (4,11).

It is appreciated that some types of surgery areassociated with a higher incidence of PONV thanothers. However, no agreement could be reachedabout whether the association between type of surgeryand increased PONV risk is causal. Numerous studiessuggest that the higher incidences are due to otherindependent risk factors associated with the type ofsurgery (3,10,14,22,26,27,32), while other analyses sug-gest that certain types of surgery are independent riskfactors (4,9,11,12,23,28,30) (Table 1).

Many factors commonly believed to augment riskare not actually independent factors. These includeobesity, anxiety, antagonizing neuromuscular block-ade (10,22,26,30,32–35). However, no single patient- oranesthetic-related risk factor is sufficiently sensitive orspecific enough to provide a useful risk assessment forPONV. Several risk models have therefore been devel-oped (30). The simplified models of Apfel et al. andKoivuranta et al. have shown some usefulness for theprediction of the PONV baseline risk in a variety ofsituations (Fig. 1) (10,24,27,28). It is important to notethat no risk model can accurately predict the likeli-hood of an individual having PONV; risk models onlyallow clinicians to estimate the risk for PONV amongpatient groups (32).

In children, a number of papers have been pub-lished citing a variety of risk factors associated withPOV (36–38). However, evidence is lacking to supportthese associations. More recently, Eberhart et al. (39)published a study of a large series of pediatric patientsin which a multivariable analysis was applied toidentify POV risk factors in children. Four indepen-dent predictors of POV were identified, includingduration of surgery !30 min, age !3 yr, strabismussurgery, and a positive history of POV in the patient,parent or sibling (Fig. 2). They demonstrated that therisk for POV was 9%, 10%, 30%, 55%, and 70% when0, 1, 2, 3, or 4 of those independent predictors werepresent.

Use of prophylactic antiemetics should be based onvalid assessment of the patient’s risk for POV orPONV. In other words, antiemetic prophylaxis shouldbe used only when the patient’s individual risk issufficiently high. This can be estimated by multiplyingthe expected incidence (baseline risk) by the relativerisk reduction resulting from prophylaxis. This ap-proach produces a clinically meaningful decrease inthe risk of PONV (2,40). However, more liberal pro-phylaxis is appropriate for patients in whom vomitingposes a particular medical risk, including those withwired jaws, increased intracranial pressure, gastric oresophageal surgery, and when the anesthesia careprovider determines the need or the patient has astrong preference to avoid PONV.

Guideline 2: Reduce Baseline Risk Factors for PONVApproaches for decreasing baseline risk factors are

presented in Table 2.

0%

20%

40%

60%

80%

100%

0 1 2 3 4# of Risk Factors

PON

V-R

isk

Risk Factors PointsFemale Gender 1Non-Smoker 1History of PONV 1Postoperative Opioids 1

Sum = 0 ... 4

0%

20%

40%

60%

80%

100%

0 1 2 3 4# of Risk Factors

-

Risk Factors PointsFemale Gender 1Non-Smoker 1History of PONVPostoperative Opioids 1

Sum = 0 ... 4

Figure 1. Simplified risk score for PONV in adults (3).Simplified risk score from Apfel et al. (3) to predict thepatients risk for PONV. When 0, 1, 2, 3, or 4 of the depictedindependent predictors are present, the corresponding riskfor PONV is approximately 10%, 20%, 40%, 60%, or 80%.

0 . . . 4Sum =

1History ofPOV orPONV inrelatives

1Strabismussurgery

1Age > 3years

1Surgery > 30min.

PointsRisk Factors

0

20

40

60

80

0 1 2 3 4Number of Risk Factors

PO

VR

isk

(%)

Figure 2. Simplified risk score for POV in children (39).Simplified risk score from Eberhart et al. (39) to predict therisk for POV in children. When 0, 1, 2, 3, or 4 of the depictedindependent predictors are present, the corresponding riskfor PONV is approximately 10%, 10%, 30%, 55%, or 70%.

Table 1. Risk Factors for Postoperative Nausea and Vomiting(PONV) in Adults

Patient-specific risk factors (3,9,10–14)The most important being:

Female gender (RCT)Nonsmoking status (RCT)History of PONV/motion sickness (RCT)

Anesthetic risk factors (3,12–20)The most important being:

Use of volatile anesthetics (RCT)Nitrous oxide systematic review (SR)Use of intraoperative (SR) and postoperative opioids

(RCT)Surgical risk factors (11,12,14)

Duration of surgery (each 30-min increase in durationincreases PONV risk by 60%, so that a baseline riskof 10% is increased by 16% after 30 min)(Prospective observational study)

Type of surgery (laparoscopy, laparotomy, breast,strabismus, plastic surgery, maxillofacial,gynecological, abdominal, neurologic,ophthalmologic, urologic) (Prospective observationalstudy)

RCT ! randomized controlled trial; SR ! systematic review.

Vol. 105, No. 6, December 2007 © 2007 International Anesthesia Research Society 1617

Pathophysiologie

Pharmacothérapie

Antagonistes 5-HT3 Récepteurs 5-HT3

! GABA récepteurs ! Localisés dans les neurones du tractus g-i et du cerveau Sérotonine ! Libérée par les cellules entérochromaffines du petit intestin ! Stimule les afférences vagales par les récepteurs 5-HT3 !  Initie le réflexe de vomissement Antagonistes 5-HT3 ! Sélectifs pour le récepteur 5-HT3

Antagonistes 5-HT3 ! Bloque l’afférence vagale vers le centre du vomissement a/n

medulla oblongata ! Plus efficace pour prévenir les Vo que les No ! Peu efficace contre le mal des transports

Antagonistes 5-HT3 ! Ondansetron Zofran ® ! Granisetron Kytril ® ! Tropisetron Navoban ® ! Palonosetron Aloxi ® ! Dolasetron Anzemet ® ! Ramosetron

Ondansetron Zofran® ! Dosage :

!  Prophylaxie 4 mg IV à la fin de la chirurgie Pédiatrie 0,05-0,15mg/kg IV ou 0,15mg/kg PO

!  Traitement 1-8 mg IV q6h Pédiatrie 0,1mg/kg ad 4mg IV

! T1/2 : 3-4 heures ! Métabolisme via plusieurs Cyt P450 2D6

! Excrétion rénale

Ondansetron ! Aurait plus d’effet anti-Vo que anti-No

! No : NNT = 7 et RR = 0,68 !  Vo : NNT = 6 et RR = 0,54

! Effets secondaires ! Céphalée : NNH = 36 après une dose unique et RR = 1.16

! Diarrhée !  Élévation des transaminases

!  Prolongation QT

Granisetron Kytril® ! Plus sélectif que l’ondansetron ! Dosage :

!  0,02-0,04mg/kg IV à la fin de l’intervention ! T1/2 : 9 heures ! Métabolisme hépatique ! Excrétion rénale dont 10% sous forme active

Granisetron ! Aurait aussi plus d’effet anti-Vo qu’anti-No

! No : RR = 0.67 !  Vo : RR = 0.42

! Effets secondaires !  Plus légers que l’ondansetron ! Céphalée !  Sédation ! Diarrhée

Tropisetron Navoban® ! Très sélectif ! Dosage

!  2 mg IV à la fin de la chirurgie ! T1/2 : 7,3 heures ! Métabolisme hépatique par Cyt P450 ! Traitement expérimental de la fibromyalgie … ! Ne semble pas encore approuvé au Canada …

Dolasetron Anzemet® Dolasetron ! Très puissant

! Dolasetron 1.8mg = ondansetron 32mg =granisetron 3mg ! Dosage

!  Prophylaxie 12,5 mg IV à la fin de la chirurgie vs « timing » peu important

! T1/2 : 8 heures ! Métabolisme hépatique via Cyt P-450 ! Excrétion rénale ! Effets secondaires : céphalée, étourdissement, augmentation de

l’appétit ! Retrait de la solution injectable en raison du risque d’arythmie !!

Palonosetron Aloxi® ! Très puissant ! Dosage

!  0,25mg IV à la fin de l’intervention ! T ½ = 40 heures ! Métabolisme hépatique ! Excrétion rénale : 80% dont 49% sous forme inchangée ! Approuvé au Canada depuis août 2012

! Études de palonosetron vs ondansetron : effet semblable durant les deux premières heures post-op puis nette différence en faveur du palonostron de 2-24h

Antagonistes dopaminergiques ! Dropéridol Inapsine® ! Metoclopramide Maxeran® ! Alizapride ! Perphenazine Trilafon® ! Prochlorperazine Stemetil®

Droperidol Inapsine® ! Neuroleptique : classe des butyrophénones ! Antagoniste dopaminergique D2 ! À dose élevée

!  Anti-sérotoninergique !  Anti-histaminique

Droperidol ! Dosage

!  0,625-1,25 mg à donner à la fin de l’intervention !  Pédiatrie 0,01-0,015 mg/kg

! T ½ = 104 min ! Métabolisme hépatique ! Excrétion rénale (75%)

! Serait aussi efficace pour prévenir les nausées que les vomissements

! Plus efficace sur NoVo précoces

Droperidol Effets secondaires ! SNC

! Dysphorie !  Akathisie !  Syndrome neuroleptique malin ! Réactions extrapyramidales ! C-I : Parkinson !  Vasoconstricteur cérébral, sans diminution des besoins

métaboliques en O2

Droperidol Effets secondaires ! Cardiovasculaires

! Diminution légère de la TA ! HyperTA possible en présence d’un phéochromocytome ! Diminution de la conduction cardiaque par les voies accessoires

responsables de tachyarythmies chez WPW

!  Prolongation du QTc et torsade de pointes ! Mort subite

FDA décembre 2001 WARNING Cases of QT prolongation and/or torsades de pointes have been reported in patients receiving INAPSINE at doses at or below recommended doses. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.

Due to its potential for serious proarrhythmic effects and death, INAPSINE should be reserved for use in the treatment of patients who fail to show an acceptable response to other adequate treatments, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs (see Warnings, Adverse Reactions, Contraindications, and Precautions).

Cases of QT prolongation and serious arrhythmias (e.g., torsades de pointes) have been reported in patients treated with INAPSINE. Based on these reports, all patients should undergo a 12-lead ECG prior to administration of INAPSINE to determine if a prolonged QT interval (i.e., QTc greater than 440 msec for males or 450 msec for females) is present. If there is a prolonged QT interval, INAPSINE should NOT be administered. For patients in whom the potential benefit of INAPSINE treatment is felt to outweigh the risks of potentially serious arrhythmias, ECG monitoring should be performed prior to treatment and continued for 2-3 hours after completing treatment to monitor for arrhythmias.

INAPSINE is contraindicated in patients with known or suspected QT prolongation, including patients with congenital long QT syndrome.

INAPSINE should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g., congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia, hypomagnesemia, or administration of other drugs known to increase the QT interval). Other risk factors may include age over 65 years, alcohol abuse, and use of agents such as benzodiazepines, volatile anesthetics, and IV opiates. Droperidol should be initiated at a low dose and adjusted upward, with caution, as needed to achieve the desired effect.

Droperidol ! Recommandations FDA

!  Obtenir un ECG 12 dérivations avant l’administration !  À éviter si QTc > 440 msec chez l’homme et QTc > 450 msec chez la

femme !  Monitoring ECG x 2-3 heures !  À éviter chez patient à risque de prolongation du QTc : insuf.

cardiaque, bradycardie, hypokaliémie, personnes âgées !  À éviter si prise concomitante de médication augmentant le QTc :

BCC, antifongique, ISRS, macrolide, quinolone, antirétroviraux et amiodarone

! Prolongation de QTc est maximal 2-3 min après l’administration, mais peut durer quelques heures

Droperidol ! Review récent

!  20 000 patients !  500 patients ayant un QTc prolongé !  Plus de 35 000 doses de droperidol 0,625 mg !  Aucun cas de tachycardie ventriculaire polymorphique

Metoclopramide Maxeran® !  Action centrale : ! Antagoniste dopaminergique D2 : effet central sur CTZ ! Antagoniste sérotoninergique à haute dose

! Action périphérique : ! Augmente le tonus du sphincter eosophagien inférieur ! Stimule la motilité du tractus GI supérieur

! Dosage !  10 mg IV ou 0,15 mg/kg

! T ½ : 2-4 heures

Metoclopramide ! Effets secondaires

! Réactions extra-pyramidales ! HypoTA lors d’injection rapide

! Efficacité questionnable !  Probablement inefficace pour le traitement des nausées

(NNT=16) !  Peu efficace pour les vomissements (NNT=9)

Prochlorperazine Stemetil® ! Phénothiazine ! Mécanisme d’action

!  Antagoniste dopaminergique D2 !  Antagoniste muscarinique !  Antagoniste histaminique !  Antagoniste alpha

! Dosage !  2,5-10 mg (max 40 mg/24h) à la fin de l’intervention

! Effets secondaires !  Somnolence ! Réactions extra-pyramidales

Dexamethasone Decadron® ! Corticostéroïde ! Mécanisme d’action : pas très bien compris!! ! Possibles mécanismes d’action

!  Inhibition centrale du nucleus tractus solitarii sans inhibition de l’area postrema

!  Inhibition des prostaglandines ! Diminution de la synthèse de sérotonine par déplétion du

tryptophan ! Diminution de libération de sérotonine a/n intestin !  Libération d’endorphines…ce qui augmente l’appétit et améliore

l’humeur

Dexamethasone ! Dosage

!  4-8 mg IV à l’induction ! Dose minimale efficace = 2.5-5mg !  Pédiatrie 0,1-0,15 mg/kg ! Dose minimale efficace en pédiatrie = 0,0625mg/kg

! T ½ = 3,5 – 5 heures ! Métabolisme hépatique ! Excrétion rénale de métabolites inactifs

Dexamethasone ! C-I relatives

! Diabète mal contrôlé !  Patients immunosupprimés !  Tuberculose récente !  ATCD ulcération digestive !  Pas d’évidence d’augmentation des infections périopératoires

! Effets secondaires !  Prurit périnéal

Dexamethasone ! Amygdalectomie en pédiatrie ! Revue systématique de Jennifer Plante

!  Pas davantage de saignements en post-op ! Davantage de réinterventions pour hémostase !  Possible augmentation de la sévérité des saignements

Dimenhydrinate Gravol® ! Mécanisme d’action

!  Antagoniste histaminique H1

!  Anti-muscarinique faible ! Dosage

!  50 mg IV q6h !  Pédiatrie 0,5 – 1,0 mg/kg

! Effets secondaires !  Sédation

Scopolamine ! Anticholinergique, amine tertiaire ! Mécanisme d’action

!  Antiagoniste muscarinique !  Antagoniste histaminergique !  Antagoniste dopaminergique

! Dosage : 0,1-0,2mg SC/IV avant l’induction 1,5mg/patch au moins 4 heures avant la chirurgie

! Très courte T1/2 (environ 1h IM/IV et 3,5h SC) d’où application transdermique

! En transdermique, délai d’action de 4h suite à l’application ! Métabolisme hépatique et excrétion rénale ! Efficace contre le mal des transports

Scopolamine ! Effets secondaires

!  Sédation ! Mydriase !  Sécheresse buccale !  Augmentation rythme cardiaque légère !  Syndrome cholinergique central

Aprepitant Emend® ! Antagoniste de la substance P ! Mécanisme d’action

!  Antagoniste du récepteur NK1 ! Dosage

!  Formulation po seulement !  PONV : 40 mg po le matin de la chirurgie !  Chimiotx : 125 mg id à J1 puis 80 mg id à J2 et J3

! Effets secondaires !  Céphalée !  Hoquet !  Constipation

Aprepitant ! Aussi efficace que les autres anti-émétiques pour la

prévention des No ! Grandement plus efficace pour les Vo

Mirtazapine Remeron® ! Antidépresseur ISRS, antagoniste des 5HT2A ! RCT de 100 patients ! Mirtazapine 30 mg vs placebo 1 heure pré-op ! Morphine 200 mcg intrathécale !  Incidence de No et Vo : 26,5% vs 56,3% ! « Mean onset time » des No et Vo retardé : 9,4 vs 5,2 h ! Sévérité diminuée à 3-6h et 6-12h ! À suivre …

«Traitements» autres

Gestion de la douleur ! Anesthésie locale ou régionale diminue le risque de NVPO

!  Locale vs spinale vs générale = 7% vs 12% vs 62% NVPO ! Régionale vs générale = 8% vs 30% !  Spinale vs générale = 5% vs 15%

! AINS !  Par diminution des besoins en opioïdes !  Égal à ondansetron 4mg

Hydratation IV ! Apfel 2012 : Revue de 15 RCT portant sur l’hydratation avec

cristalloïdes IV vs hydratation conservatrice ! Hydratation conservatrice 0-2 ml/kg et supplémentaire 15-30 ml/

kg ! 1570 patients ! Réduction

!  Risque de NPO précoce et tardif !  VPO total !  Traitement antiémétique de secours

! Aucun effet sur !  VPO précoce et tardif

! Hydratation IV améliore plusieurs issues NVPO

Thérapie alternative

Acupuncture et acupression P6 ! Stimulation du point P6 (Neiguan)

Acupuncture et acupression P6 ! Étude de Liu 2008 : 96 patients, stimulation à l’aiguille par

TOF vs sham : réduction de l’incidence et de la sévérité des NoVo et réduction de la douleur post-op

! Étude Arnberger 2007 : 220 patientes, stimulation P6 par électrode vs sham : diminution NoVo, surtout précoces (< 6h)

! Étude de Majholm 2011 : 134 patientes, acupression de P6 par bracelet au poignet vs sham : aucune différence sauf effets secondaires du bracelet, soit rougeur, œdème et douleur

Acupuncture P6 ! Revue systématique Cochrane 2009 ! 40 études, 4858 patient ! Acupuncture vs sham

! Réduction des No (RR=0,71) ! Réduction des Vo (RR=0,70) ! Réduction des besoins en traitements de secours (RR 0,69)

! Efficacité idem adultes vs pédiatrie ! Acupuncture vs pharmacothérapie

!  Efficacité idem entre l’acupuncture de P6 et la pharmacothérapie ! Effets secondaires rares

Acupuncture et acupression P6 ! Probables effets physiologiques de l’acupuncture

!  Effet sur les neurotransmetteurs responsables de NoVo ! Modulation vagale ! Relaxation gastrique

! Acupuncture serait supérieure à l’acupression ! Complément à la pharmacothérapie ?

Prophylaxie vs Traitement

n engl j med

350;24

www.nejm.org june

10, 2004

2441

The

new englandjournal

of

medicine

established in 1812

june

10

,

2004

vol. 350 no. 24

A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and Vomiting

Christian C. Apfel, M.D., Kari Korttila, F.R.C.A., Ph.D., Mona Abdalla, Ph.D., Heinz Kerger, M.D., Alparslan Turan, M.D., Ina Vedder, M.D., Carmen Zernak, M.D., Klaus Danner, M.D., Ritva Jokela, M.D., Ph.D.,

Stuart J. Pocock, Ph.D., Stefan Trenkler, M.D., Markus Kredel, M.D., Andreas Biedler, M.D., Daniel I. Sessler, M.D., and Norbert Roewer, M.D., for the IMPACT Investigators*

abstract

From Julius-Maximilians Universität,Würzburg, Germany (C.C.A., M.K., N.R.);the University of Louisville, Louisville, Ky.(C.C.A., D.I.S.); Helsinki University Cen-tral Hospital, Helsinki, Finland (K.K., R.J.);the London School of Hygiene and Tropi-cal Medicine, London (M.A., S.J.P.); theUniversitätsklinik Mannheim, Mannheim,Germany (H.K.); Trakya University Hospital,Edirne, Turkey (A.T.); von Bodelschwing-sche Anstalten Bethel, Bielefeld, Germany(I.V.); Kreiskrankenhaus Garmisch-Parten-kirchen, Garmisch-Partenkirchen, Germany(C.Z.); Westpfalz-Klinikum, Kaiserslaut-ern, Germany (K.D.); Reiman UniversityHospital, Presov, Slovakia (S.T.); and theUniversitätskliniken des Saarlandes, Hom-burg, Germany (A.B.). Address reprint re-quests to Dr. Apfel at Outcomes ResearchInstitute, 501 East Broadway, Suite 210,Louisville, KY 40202, or at apfel@ponv.org.

*The International Multicenter Protocolto Assess the Single and Combined Ben-efits of Antiemetic Interventions in a Con-trolled Clinical Trial of a 2¬2¬2¬2¬2¬2Factorial Design (IMPACT) Investigatorsare listed in the Appendix.

N Engl J Med 2004;350:2441-51.

Copyright © 2004 Massachusetts Medical Society.

background

Untreated, one third of patients who undergo surgery will have postoperative nauseaand vomiting. Although many trials have been conducted, the relative benefits of pro-phylactic antiemetic interventions given alone or in combination remain unknown.

methods

We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a ran-domized, controlled trial of factorial design that was powered to evaluate interactionsamong as many as three antiemetic interventions. Of these patients, 4123 were ran-domly assigned to 1 of 64 possible combinations of six prophylactic interventions:4 mg of ondansetron or no ondansetron; 4 mg of dexamethasone or no dexamethasone;1.25 mg of droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen ornitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly as-signed with respect to the first four interventions. The primary outcome was nauseaand vomiting within 24 hours after surgery, which was evaluated blindly.

results

Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperativenausea and vomiting by about 26 percent. Propofol reduced the risk by 19 percent, andnitrogen by 12 percent; the risk reduction with both of these agents (i.e., total intrave-nous anesthesia) was thus similar to that observed with each of the antiemetics. All theinterventions acted independently of one another and independently of the patients’baseline risk. Consequently, the relative risks associated with the combined interventionscould be estimated by multiplying the relative risks associated with each intervention.Absolute risk reduction, though, was a critical function of patients’ baseline risk.

conclusions

Because antiemetic interventions are similarly effective and act independently, the safestor least expensive should be used first. Prophylaxis is rarely warranted in low-risk pa-tients, moderate-risk patients may benefit from a single intervention, and multiple in-terventions should be reserved for high-risk patients.

The New England Journal of Medicine Downloaded from nejm.org on February 18, 2013. For personal use only. No other uses without permission.

Copyright © 2004 Massachusetts Medical Society. All rights reserved.

! 5199 patients à haut risque de NVPO ! 6 interventions

! Ondansetron 4mg ou non ! Dexamethasone 4mg ou non ! Droperidol 1,25mg ou non !  Propofol ou volatiles ! N2O ou air ! Remifentanil ou fentanyl

! 64 combinaisons possibles !  Issue primaire : No et Vo pendant 24h suivant la chirurgie

n engl j med

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2004

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those given propofol and nitrogen. Figure 3 showsthese incidences broken down according to thenumber of antiemetics. There was no significantinteraction between propofol and nitrogen (chi-square=0.94, 2 df, by the likelihood ratio test;P=0.33). Although the type of volatile anesthetic(isoflurane, sevoflurane, or desflurane) was not arandomized factor, it had no significant effect onthe incidence of postoperative nausea and vomitingin a multivariate model (P=0.30). The incidence ofpostoperative nausea and vomiting was 31 percentamong the patients who received 80 percent oxygenin nitrogen and 24 percent among those who re-ceived 30 percent oxygen in nitrogen (P=0.07).

Multivariate logistic analyses of data from all5161 patients and of data from the 4086 patientsassigned with respect to all six treatments are shownin Table 2. This analysis found no significant inter-actions among the treatments. When the interac-tions between treatments and potentially confound-ing factors (e.g., the type of surgery) were analyzed,only one significant interaction was detected: an in-teraction between droperidol and sex (P=0.003).Droperidol significantly reduced the risk of post-operative nausea and vomiting among women, butnot among men: 910 of the 2106 women who didnot receive droperidol had nausea or vomiting (43percent), as compared with 662 of the 2101 womenwho did receive this agent (32 percent) (odds ratio,0.61; 95 percent confidence interval, 0.53 to 0.69;P<0.001), and the effect was independent of men-strual-cycle phase or whether menopause had oc-

curred; in contrast, 79 of the 482 men who did notreceive droperidol had nausea or vomiting (16 per-cent), as compared with 80 of the 472 men who didreceive this agent (17 percent) (odds ratio, 1.04; 95percent confidence interval, 0.74 to 1.46; P=0.82).

The results based on analyses of data from 4086patients remained essentially unchanged when datafrom all 5161 patients were considered or when po-tential confounders were included in the statisticalmodels (Table 2). Detailed results for the 4086 pa-tients in the 64 groups are given in Table S2 of theSupplementary Appendix. Given the finding that to-tal intravenous anesthesia or the use of any anti-emetic independently reduced the risk of postoper-ative nausea and vomiting by about 26 percent, theincidence of postoperative nausea and vomiting forfive different initial risks was calculated for as manyas four interventions (Table 3).

The large enrollment and the factorial design of ourtrial allowed simultaneous evaluation of the anti-emetic efficacy of three antiemetic interventions andthree anesthetic interventions and of all possiblecombinations of two or three interventions. All thetested antiemetics appeared to be similarly effective.Ondansetron and other 5-hydroxytryptamine type 3antagonists are considered relatively safe, but theyare more expensive than droperidol and dexameth-asone. However, low-dose droperidol can cause dys-phoria,

28,29

and the Food and Drug Administration

discussion

* CI denotes confidence interval.† P values were calculated by the chi-square test.‡ The numbers shown are the numbers of patients who had postoperative nausea, vomiting, or both (PONV) divided by

the total numbers of patients randomly assigned to the specified intervention for whom complete outcome data could be analyzed. The data are based on all 5161 randomly assigned patients who completed the study, with the exceptions of

the data for carrier gas (4277 patients) and for remifentanil versus fentanyl (4789 patients).

Table 1. Risk of Postoperative Nausea and Vomiting According to Patients’ Randomly Assigned Interventions.

Intervention Received InterventionPercent RelativeRisk (95% CI)*

PValue†

Yes No

no. with PONV/total no. (%)

‡

Ondansetron (vs. no ondansetron) 735/2576 (28.5) 996/2585 (38.5) ¡26.0 (¡31.5 to ¡19.9) <0.001

Dexamethasone (vs. no dexamethasone) 739/2596 (28.5) 992/2565 (38.7) ¡26.4 (¡31.9 to ¡20.4) <0.001

Droperidol (vs. no droperidol) 742/2573 (28.8) 989/2588 (38.2) ¡24.5 (¡30.2 to ¡18.4) <0.001

Propofol (vs. inhalational anesthetic) 1066/3427 (31.1) 665/1734 (38.4) ¡18.9 (¡25.0 to ¡12.3) <0.001

Nitrogen as carrier gas (vs. nitrous oxide) 668/2146 (31.1) 755/2131 (35.4) ¡12.1 (¡19.3 to ¡4.3) 0.003

Remifentanil (vs. fentanyl) 827/2386 (34.7) 792/2403 (33.0) 5.2 (¡2.9 to 13.8) 0.21

The New England Journal of Medicine Downloaded from nejm.org on February 18, 2013. For personal use only. No other uses without permission.

Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Conclusion ! Puisque les différents antiémétiques sont tout aussi efficaces

et agissent indépendamment, le plus sécuritaire et le moins coûteux devrait être choisi en premier

! Patients à bas risque : aucune prophylaxie nécessaire ! Patienst à risque moyen : une seule intervention ! Patients à risque élevé : intervention multiple

Prévention ou non ?? ! Selon certains auteurs, les données montrent peu de

différences quand une prophylaxie est administrée vs le traitement des symptômes lorsqu’ils se présentent …

! Outre l’inconfort des patients … ! Et le fait que lorsqu’il y a NVPO malgré prophylaxie ou non,

la probabilité que ces NVPO persistent ou recommencent est de 65% …

! Et le fait que parfois les Sx peuvent apparaître que suite à la sortie de l’hôpital …

Prévention ou non ?? ! Plusieurs aspects à considérer

!  Facteurs de risque du patient, de l’anesthésie et de la chirurgie !  Les comorbidités associées !  Les complications délétères des NVPO !  Les coûts de prévenir ou non les NVPO

prophylaxis, although a systematic review shows thatsome of the data on granisetron may be less reliablethan others (61,68–70,80–83). Tropisetron, 2 mg IV,shows significant efficacy for reducing risk for nausea

and vomiting and is recommended for PONV prophy-laxis (79,84). The 5-HT3 antagonists have a favorableside effect profile and are considered equally safe. Thenumber-needed-to-harm (NNH) with a single dose of

Dexa-methasone

5-HT3antagonist

Non-pharma-cological:Acupuncture

Scopolamine

Ephedrine Dimen-hydrinate

Propofol inPACU

(rescue only)

PromethazineProchlorperazinePerphenazine

Droperidol†or Haloperidol

RegionalAnesthesia

PropofolAnesthesia

Portfolio ofprophylaxisand treatment

Adult Risk Factors Children Risk FactorsPatient Related Environmental Surgery > 30 minHistory of PONV/motion sickness Postop opioids Age > 3 yearsFemale gender Emetogenic surgery Strabismus surgeryNon-smoker (type and duration) History of POV/relative with PONV

Cost-effectiveness

Level of Risk0 RF = 10%1 RF = 10% - 20%2 RF = 30% - 40%3 RF = 50% - 60%4 RF = 70% - 80%

Consider

Patient risk

LowWait and See

High> 2 Interventions/Multimodal Approach

Treatment OptionsIf prophylaxis fails or was not received: use antiemeticfrom different class than prophylactic agentReadminister only if > 6 hours after PACU; do notreadminister dexamethasone or scopolamine

† Use droperidol in children onlyif other therapy has failed andpatient is being admitted tohospitalSome of the drugs may not havebeen studied or approved by theFDA for use in children.

Patient preferencesFear of PONVFrequency ofPONV causingheadaches/migraine

Reducing baseline risksAvoidance/minimization of:Nitrous oxideVolatile anestheticsHigh-dose neostigminePost-op opioids

MediumPick 1 or 2 Interventions for adultsPick > 2 Interventions for children

Figure 3. Algorithm for managementof postoperative nausea and vomiting(PONV).

Table 3. Antiemetic Doses and Timing for Prevention of Postoperative Nausea and Vomiting (PONV) in Adults

Drugs Dose Evidence Timing EvidenceDexamethasone 4–5 mg IV SR (55–57) At induction RCT (57)Dimenhydrinate 1 mg/kg IV SR (58) RCT (59,60)Dolasetron 12.5 mg IV RCT (61) End of surgery; timing

may not affect efficacyRCT (61)

Droperidola 0.625–1.25 mg IV RCT (62,63) End of surgery SR (64)Ephedrine 0.5 mg/kg IM RCT (65,66) End of surgery RCT (65,66)Granisetron 0.35–1.5 mg IV RCT (67–71) End of surgery RCT (68–70)Haloperidol 0.5–2 mg IM/IV SR (72)Prochlorperazine 5–10 mg IM/IV RCT (73) End of surgery RCT (73)Promethazineb 6.25–25 mg IV RCT (74,75) At induction RCT (74,75)Ondansetron 4 mg IV RCT (76) End of surgery SR (67)Scopolamine Transdermal patch SR (77,78) Prior evening or 4 h

before surgeryRCT (78)

Tropisetron 2 mg IV RCT (79) End of surgery Expert opinionNote: These recommendations are evidence-based and not all the drugs have a FDA indication for PONV.Drugs are listed alphabetically.a See Food and Drug Administration (FDA) !black box! warning.b FDA Alert: Should not be used in children less than 2 years old.RCT " randomized, controlled trial; SR " systematic review.

Vol. 105, No. 6, December 2007 © 2007 International Anesthesia Research Society 1619

prophylaxis, although a systematic review shows thatsome of the data on granisetron may be less reliablethan others (61,68–70,80–83). Tropisetron, 2 mg IV,shows significant efficacy for reducing risk for nausea

and vomiting and is recommended for PONV prophy-laxis (79,84). The 5-HT3 antagonists have a favorableside effect profile and are considered equally safe. Thenumber-needed-to-harm (NNH) with a single dose of

Dexa-methasone

5-HT3antagonist

Non-pharma-cological:Acupuncture

Scopolamine

Ephedrine Dimen-hydrinate

Propofol inPACU

(rescue only)

PromethazineProchlorperazinePerphenazine

Droperidol†or Haloperidol

RegionalAnesthesia

PropofolAnesthesia

Portfolio ofprophylaxisand treatment

Adult Risk Factors Children Risk FactorsPatient Related Environmental Surgery > 30 minHistory of PONV/motion sickness Postop opioids Age > 3 yearsFemale gender Emetogenic surgery Strabismus surgeryNon-smoker (type and duration) History of POV/relative with PONV

Cost-effectiveness

Level of Risk0 RF = 10%1 RF = 10% - 20%2 RF = 30% - 40%3 RF = 50% - 60%4 RF = 70% - 80%

Consider

Patient risk

LowWait and See

High> 2 Interventions/Multimodal Approach

Treatment OptionsIf prophylaxis fails or was not received: use antiemeticfrom different class than prophylactic agentReadminister only if > 6 hours after PACU; do notreadminister dexamethasone or scopolamine

† Use droperidol in children onlyif other therapy has failed andpatient is being admitted tohospitalSome of the drugs may not havebeen studied or approved by theFDA for use in children.

Patient preferencesFear of PONVFrequency ofPONV causingheadaches/migraine

Reducing baseline risksAvoidance/minimization of:Nitrous oxideVolatile anestheticsHigh-dose neostigminePost-op opioids

MediumPick 1 or 2 Interventions for adultsPick > 2 Interventions for children

Figure 3. Algorithm for managementof postoperative nausea and vomiting(PONV).

Table 3. Antiemetic Doses and Timing for Prevention of Postoperative Nausea and Vomiting (PONV) in Adults

Drugs Dose Evidence Timing EvidenceDexamethasone 4–5 mg IV SR (55–57) At induction RCT (57)Dimenhydrinate 1 mg/kg IV SR (58) RCT (59,60)Dolasetron 12.5 mg IV RCT (61) End of surgery; timing

may not affect efficacyRCT (61)

Droperidola 0.625–1.25 mg IV RCT (62,63) End of surgery SR (64)Ephedrine 0.5 mg/kg IM RCT (65,66) End of surgery RCT (65,66)Granisetron 0.35–1.5 mg IV RCT (67–71) End of surgery RCT (68–70)Haloperidol 0.5–2 mg IM/IV SR (72)Prochlorperazine 5–10 mg IM/IV RCT (73) End of surgery RCT (73)Promethazineb 6.25–25 mg IV RCT (74,75) At induction RCT (74,75)Ondansetron 4 mg IV RCT (76) End of surgery SR (67)Scopolamine Transdermal patch SR (77,78) Prior evening or 4 h

before surgeryRCT (78)

Tropisetron 2 mg IV RCT (79) End of surgery Expert opinionNote: These recommendations are evidence-based and not all the drugs have a FDA indication for PONV.Drugs are listed alphabetically.a See Food and Drug Administration (FDA) !black box! warning.b FDA Alert: Should not be used in children less than 2 years old.RCT " randomized, controlled trial; SR " systematic review.

Vol. 105, No. 6, December 2007 © 2007 International Anesthesia Research Society 1619

Cas clinique ! Dame de 65 ans ! Chirurgie d’urgence pour œil ouvert ! Estomac plein ! Connue pour parkinson ! Allergie probable au Gravol

! L’ophtalmologiste vous demande de réduire le plus possible les efforts de toux ou de Vo post-op

! Quelles sont vos options ??