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Balanced Pilot Study - progress report & interim analysis May 2011

Balanced Pilot Study - progress report & interim analysis May 2011. 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,

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Balanced Pilot Study - progress report & interim analysis May 2011

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  1. Balanced Pilot Study-progress report & interim analysisMay 2011 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. Seven observational studiesSix show deep anaesthesia associated with increased risk of death‘Deep’ is BIS <45 for >1h

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

  4. The Balanced Study 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

  5. Primary Outcome • 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

  6. Secondary Outcomes • 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

  7. Pilot study of 120 patients • 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.

  8. Balanced Pilot Study -recruiting centres • Auckland City Hospital Auckland Tim Short Doug Campbell, Jack Hill, Martin Misur, Davina McAllister • Middlemore Hospital Auckland Francois Stapelberg • Prince of Wales Hospital Hong Kong Matthew Chan • Royal Melbourne Hospital Melbourne Kate Leslie • The Alfred Hospital Melbourne Paul Myles • Royal Perth Hospital Perth Thomas Corcoran • Freemantle Hospital Perth Ed O’Loughlin • Statistician Chris Frampton • Data Safety and Monitoring Board Prof Jamie Sleigh

  9. Results • 65 patients studied • 50 analysed

  10. Results –ability to achieve BIS targets

  11. Results –ability to achieve BIS targets

  12. MAC in the two groups

  13. MAC in the two groups

  14. DelitEffects of steroids, controlling blood sugar levels, and avoidance of deep anesthesia on patient outcomes after major vascular surgery. Dan Sessler & Bassem Abdelmalak, The Cleveland Clinic, USA • Targets 35 & 55 • Abandoned after 380 patients for futility (target 970) Prof Dan Sessler, personal communication

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

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

  17. Results so far • 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 … .. .

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

  19. Some handy hints for good targeting • 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 ?

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

  21. Thank you

  22. Vioxx 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-'0358000 demandes enregistréesUS$4.85 milliards règlement

  23. Optimal ‘brain’ depth for maintenance of anaesthesia is unknown Numerous studies compare techniques Few investigate levels of ‘depth’ Depth monitoring using EEG assumes ‘light’ is good Minimum to prevent awareness Hypnosis Analgesia PD PK Areflexia 100 Probability of adequate anesthesia 50 0 0 20 40 60 80 100 Drug Dose

  24. MonkAnesth Analg 2005,100:4-102003 Rovenstine LecturePostoperative Cognitive Dysfunction: The Next Challenge in Geriatric Anesthesia • 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% Table 4.  Multivariate Predictors of 1-yr Postoperative Mortality Predictor Relative 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 • 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

  25. LindholmAnesth Analg 2009;108:508-12 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

  26. LeslieAnesth Analg, 2009; in press 71% had >5min with BIS <40 PS=1.42 (1.04-1.93) at 4 yr if BIS <40 for >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

  27. SearlemanAnesthesiology 2008; 109 A1(Avidans group) 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 Relation beaucoup plus forte chez les patients cardiaques Chez tous les patients, une plus grande DHT ne semble pas correspondre à des doses plus élevées de l'anesthésique

  28. Saager ISAP 2009 A1-7 & A6 (Sesslers group) 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% Les patients qui sont sensibles à l'anesthésie font mal • 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

  29. Causality Is there a biological reason ? 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

  30. Prevalence of Anaesthesia • 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 • 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 Weiser Lancet 2008; 372,193-44

  31. Studies of survival in BIS-monitored patients and Mortality in the elderly [adapted from Leslie et al] Monk Lindholm Leslie Searleman Saager Number of patients 1064 4087 2463 1791 23,999 Age (years) 51 (37-65) 50 (36-65) 61 (46-71) 59 (14.6) Male sex (%) 37 38 62 53 ASA physical status ≥3 (%) 35 6 74 71 Cardiac surgery (%) 0 0 42 27 0 Duration of anesthesia (h) 3.1(2.3-4.3 ) 1.8(1.2-2.5 ) 3.1(1.4-4.4) - Volatile maintenance (%) 91 95 57 100 BIS monitoring (%) 100 100 50 100 100 Anaesthetist blind to BIS Yes No No 50% No Average BIS 49  9 37  7 45  7 43 9 Follow-up (years) 1 2 4 1 1+ 30-day mortality (%) 0.7 0.7 4.3 - 0.8 1-year mortality (%) 5.5 4.3 10.8 10.7 4.8 2-year mortality (%) - 6.5 14.6 - BIS mortality Prosp obs Prosp obs Prosp. obs Prosp. obs. Prosp. obs. BIS<45 blind BIS<40 BIS<45 BIS<45 BIS<45 for >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 yr at 1 yr 1 yr (1.08-1.29) 2yr Notes Monk 50% of mortality due to cancer24% increased risk of death per hour deep hypnosis Lindholm Deep hypnotic time not a predictor when pre-existing malignancy included in model >2hrs deep hypnosis had much higher mortality. Most patients rather fit Leslie Also decreased. risk of MI & CVA. Unable to calculate 1yr mortality Searleman Dead 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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