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Dr Timothy Short Auckland City Hospital adhb.govt.nz Disclosure of interest: I have done clinical research and/or consulted for Johnson and Johnson,

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Presentation on theme: "Dr Timothy Short Auckland City Hospital adhb.govt.nz Disclosure of interest: I have done clinical research and/or consulted for Johnson and Johnson,"— Presentation transcript:

1 Dr Timothy Short Auckland City Hospital tims @ adhb.govt.nz Disclosure of interest: I have done clinical research and/or consulted for Johnson and Johnson, Purdue, MSD, Novo Nordisc, Astra-Zeneca, Roche, Klein Medical, Safer-Sleep & The USA Ministry of Defence.

2 NASA 3&4Mortality % ↑ risk if ‘deep’ Monk 20051064 35%5.5 1 yrRR = 1.24 Lindholm 20094087 6%4.3 2 yrHR = 1.18 Leslie 20102463 74%10.8 4 yrPS = 1.42 Searleman 20091791 71%10.7 1 yrOR = 1.25/h Saager 200923,999~30%4.8 1 yrRR= ~1.18 Kertai 2010 cardiac460100%17.8 3 yrHR = 1.29 Kertai 2011 non-cardiac1473~60%24.3 3 yrMHR = 1.03

3 Association does not imply causality 协会并不意味着因果关系 Google translator

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5 Does anaesthetic depth influence post-operative mortality ? Prospective, randomized, double blind (patients & investigators), intention to treat Patients Age 60+ ASA 3 & 4 Surgery lasting 2+ h General Anaesthesia, + major regional block, + TIVA a priori BP target BIS guided either BIS = 35 or BIS = 50

6 1 year mortality Power 20% increase in 1 yr mortality if p1=0.08, p2=0.10, then N=6564 3300 in each group N=6600

7 Volatile use (MAC) Arterial pressure Post-operative Pain, PONV & Satisfaction Post op morbidity DVT, MI, PE, CVA, Sepsis, etc… Duration of hospital stay Cancer recurrence Chronic Pain

8 Refine and test the protocol for a major study Ensure: BIS targets can be met Blood pressure is not a confounding factor Separation of volatile anaesthetic dose Show anaesthetics are in other respects similar Cost analysis Acceptability of trial to our patients Assess adverse event rates Acceptability of protocol to our colleagues Assess alternative trial designs eg using a composite adverse event rate score as the primary outcome variable.

9 Auckland City Hospital AucklandTim Short Doug Campbell, Jack Hill, Martin Misur, Davina McAllister Middlemore Hospital Auckland Francois Stapelberg Prince of Wales Hospital Hong KongMatthew Chan Royal Melbourne Hospital MelbourneKate Leslie The Alfred Hospital MelbournePaul Myles Royal Perth Hospital PerthThomas Corcoran Freemantle Hospital PerthEd O’Loughlin StatisticianChris Frampton Data Safety and Monitoring BoardProf Jamie Sleigh

10 65 patients studied 50 analysed

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13 AllBIS 50N=27 BIS 35N=20 meanmaxminstdevmeanmaxminstdev Duration of Data21635128871803508076 BIS -mean of medians48593533947334

14 Results – ability to achieve BIS targets AllBIS 50N=27 BIS 35N=20 meanmaxminstdevmeanmaxminstdev Duration of Data21635128871803508076 BIS -mean of medians48593533947334

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16 AllBIS 50N=18 BIS 35N=11 meanmaxminstdevmeanmaxminstdev Duration of Data2122521414118832613275 MAC mean of medians0.631.30.320.230.781.340.30.30

17 AllBIS 50N=18 BIS 35N=11 meanmaxminstdevmeanmaxminstdev Duration of Data2122521414118832613275 MAC mean of medians0.631.30.320.230.781.340.30.30

18 Targets 35 & 55 Abandoned after 380 patients for futility (target 970) Prof Dan Sessler, personal communication

19 Delit or Balanced ?? Prof Dan Sessler, personal communication Sequential Patients Target 50, Mean 48 Target 35, Mean 38

20 Delit or Balanced ?? Sequential Patients Target 50, Mean 48 Target 35, Mean 38

21 Insufficient BIS separation 48 VS 39 Too many protocol violations 15% median on wrong side of BIS=45 Little MAC separation 0.63 vs 0.78 Data analysis time consuming Recruitment behind target This looks like a repeat of the DeLiT study …...

22 Get pilot study completed and analysed for Palm Cove Discussion about viability of study If a suitable design is found –joint applications in 2012

23 Use a relaxant infusion More opioid helps stabilise BIS variability Don’t be afraid of low volatile levels But do such alterations to practice alter the study ? Should we raise ‘light’ BIS target to 55 ? Look for an alternative protocol ? We need a feasible trial design ! Is this it ?

24 Roni Horn quoting Flannery O’Connor, Good Country People HER EYES ICEY BLUE WITH THE LOOK OF SOMEONE WHO HAS ACHIEVED BLINDNESS BY AN ACT OF WILL AND MEANS TO KEEP IT

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27 Rofecoxib observational studies of MI Levesque 2005, RR 1.24 low dose, 1.73 high dose Kaiser Permanente 1.47 low dose, 3.58 high dose Questionable significance APPROVe study 25mg daily for 3 yr Stopped at 2587 patients 32 vs 12 deaths in placebo grp, RR = 1.92 92,8 millions prescriptions 27785 décès par '99-'03 58000 demandes enregistrées US$4.85 milliards règlement

28 Numerous studies compare techniques Few investigate levels of ‘depth’ Depth monitoring using EEG assumes ‘light’ is good Minimum to prevent awareness HypnosisAnalgesia Areflexia 806040201000 Probability of adequate anesthesia 100 Drug Dose PDPK 0 50

29 Table 4. Multivariate Predictors of 1-yr Postoperative Mortality PredictorRelative risk (odds ratio) [95% CI] P value Charleston Co-morbidity Score (3+ vs 0-2) 16.1 (10.1-33.7) <0.0001 Cumulative deep hypnotic time (per h) 1.24 (1.06-1.74) 0.012 Systolic blood pressure <80 mmHg (per min) 1.04 (1.01-1.07) 0.013 Prospective observational study 1064 patients Age 51 (IQR 37-65) 35% ASA 3-4 Major non-cardiac surgery, 2-4hr BIS 49 (sd 9), Anesthetist blind to BIS 1 yr mortality 5.5% BIS < 45 increased mortality 52% deaths cancer and 17% CVS Ces associations donnent à penser que la gestion anesthésique peropératoire mai affecter les résultats sur des périodes de temps plus longue que précédemment appréciée

30 HR=1.13 at 1yr if BIS<45 HR=1.18 (1.08-1.29) at 2yr if BIS<45 Deep hypnotic time not a predictor when pre-existing malignancy included in model, P=0.08 >2hrs deep hypnosis had much higher mortality Prospective observational study 4087 patients Age 50 (IQR 36-65) 6% ASA 3-4 Major non-cardiac surgery, 1.2-2.5 hr BIS 37 (sd 7) (target 40-60) 1 yr mortality 4.3% 75% deaths cancer and 17% CVS patients rather fit, deep and terminal Le lien du BIS <45 à la mortalité postopératoire est très faible en comparaison avec la co-morbidité telle qu'elle est évaluée par le score ASA, le statut de malignité, et de l'âge et une relation de causalité, le cas échéant, ne peut être évaluée dans un essai prospectif randomisé

31 71% had >5min with BIS <40 PS=1.42 (1.04-1.93) at 4 yr if BIS 5 min* Also risk of MI 1.7 & Stroke 2.8 in ‘deep’ patients Unable to calculate 1yr mortality Retrospective audit of patients studied for risk of awareness 2463 patients, 1064 BIS monitored and studied Age 61 (46-71) 74% ASA 3-4 Major surgery, 42% cardiac, mean 3.1 h BIS 45 (sd 7), target 40–60 1 yr mortality 10.8% 40% deaths cancer, 26% CVS, included emergency surgery Patients rather old, CVS, not as deep Relation beaucoup plus forte chez les patients cardiaques

32 OR=1.25/h (1.13-1.37) if BIS <45, of mortality within one year DHT 6 min in cardiac deaths & 51 min in non-cardiac (n.s.) Dead received a median of 0.07 MAC less volatile than survivors Prospective observational study (ETAG study) 1791 patients Age 59 (sd 14.6) 71% ASA 3-4 Major surgery, 27% cardiac 2-4hr BIS 43 (sd 9) anaesthetist blind to BIS 1 yr mortality 10.7% Patients rather old, sick Chez tous les patients, une plus grande DHT ne semble pas correspondre à des doses plus élevées de l'anesthésique Relation beaucoup plus forte chez les patients cardiaques

33 Categorisation of patients MAC 0.72 0.57 0.39 MAP 96 86 78 BIS 52 45 38 BIS <45, RR=1.63 mortality at 1 yr Triple low RR=1.89, MAC=0.4, MAP<80, BIS<40 Treating low MAP in <5 min improved survival (RR 0.99 vs 1.57) >20 min triple low tripled mortality Retrospective audit 23,999 patients Age adult (~33% over 60) ASA ? Surgery all BIS mean ? ~45 1 yr mortality 4.8% Triple low very bad Low MAP worse then low BIS Early treatment of low MAP reduced mortality Interventional trial of early treatment of low MAP commenced Les patients qui sont sensibles à l'anesthésie font mal

34 Anaesthesia is probably bad for you Anaesthesia, surgery & inflammation Volatiles & Alzheimers Anaesthesia & neuronal apoptosis Opioids and angiogenesis Post-operative cognitive dysfunction Post-operative delirium Low BP Si l'une de ces causes possibles sont à l'en croire, le problème devient celui de la dose - réponse

35 234,200,000 (CI 187m - 281m) surgical procedures/year world wide 11,110/100,000 population in well developed countries 295/100,000 in less developed countries Weiser Lancet 2008; 372,193-44 Le volume mondial de la chirurgie est importante. Compte tenu de la mortalité élevés et les taux de complication des procédures chirurgicales majeures, la sécurité chirurgical doit être maintenant une importante préoccupation mondiale de la santé publique

36 MonkLindholmLeslieSearlemanSaager Number of patients106440872463179123,999 Age (years) 51 (37-65)50 (36-65)61 (46-71)59 (14.6) Male sex (%)37386253 ASA physical status ≥3 (%) 3567471 Cardiac surgery (%)0042270 Duration of anesthesia (h) 3.1(2.3-4.3 ) 1.8(1.2-2.5 ) 3.1(1.4-4.4) - Volatile maintenance (%)919557100 BIS monitoring (%)10010050100100 Anaesthetist blind to BISYesNoNo50%No Average BIS49  937  745  743  9 Follow-up (years)1 2 4 11+ 30-day mortality (%)0.70.74.3-0.8 1-year mortality (%)5.54.310.810.74.8 2-year mortality (%)-6.514.6- BIS mortalityProsp obsProsp obs Prosp. obs Prosp. obs. Prosp. obs. BIS<45 blind BIS<40BIS<45 BIS<45 BIS 5 min Statistic(CI95)RR=1.34 HR=1.04 1yr PS=1.42 OR=1.25/h RR=1.63 (1.06-1.41) (0.92-1.16) (1.04-1.93)(1.13-1.37)NB triple low or 1.24/h HR=1.18 at 4 yrat 1 yr 1 yr (1.08-1.29) 2yr Notes Monk50% of mortality due to cancer24% increased risk of death per hour deep hypnosis LindholmDeep hypnotic time not a predictor when pre-existing malignancy included in model >2hrs deep hypnosis had much higher mortality. Most patients rather fit LeslieAlso decreased. risk of MI & CVA. Unable to calculate 1yr mortality SearlemanDead received a median of 0.07 MAC less volatile than survivors DHT 51 min in cardiac deaths & 6 min in non-cardiac (non sign)


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