Balanced Pilot Study-progress report & interim analysis

May 2011

Dr Timothy Short

Auckland City Hospital

tims @ adhb.govt.nzDisclosure 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.

Seven observational studiesSix show deep anaesthesia associated with increased risk of death‘Deep’ is BIS <45 for >1h

N ASA 3&4 Mortality % ↑risk if ‘deep’

Monk 2005 1064 35% 5.5 1 yr RR = 1.24

Lindholm 2009 4087 6% 4.3 2 yr HR = 1.18

Leslie 2010 2463 74% 10.8 4 yr PS = 1.42

Searleman 2009 1791 71% 10.7 1 yr OR = 1.25/h

Saager 2009 23,999 ~30% 4.8 1 yr RR= ~1.18

Kertai 2010 cardiac 460 100% 17.8 3 yr HR = 1.29

Kertai 2011 non-cardiac 1473 ~60% 24.3 3 yr MHR = 1.03

Association does not imply causalityAssociation does not imply causalityAssociation does not imply causalityAssociation does not imply causalityAssociation does not imply causalityAssociation does not imply causalityAssociation does not imply causalityAssociation does not imply causalityAssociation does not imply causality 协会并不意味着因果关系

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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

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

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

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.

Balanced Pilot Study -recruiting centres

• Auckland City Hospital Auckland Tim ShortDoug 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

Results

• 65 patients studied• 50 analysed

Results –ability to achieve BIS targets

All BIS 50 N=27 BIS 35 N=20

mean max min stdev mean max min stdev

Duration of Data 216 351 28 87 180 350 80 76

BIS -mean of medians 48 59 35 3 39 47 33 4

Results –ability to achieve BIS targets

All BIS 50 N=27 BIS 35 N=20

mean max min stdev mean max min stdev

Duration of Data 216 351 28 87 180 350 80 76

BIS -mean of medians 48 59 35 3 39 47 33 4

MAC in the two groups

All BIS 50 N=18 BIS 35 N=11

mean max min stdev mean max min stdev

Duration of Data 212 252 141 41 188 326 132 75

MAC mean of medians 0.63 1.3 0.32 0.23 0.78 1.34 0.3 0.30

MAC in the two groups

All BIS 50 N=18 BIS 35 N=11

mean max min stdev mean max min stdev

Duration of Data 212 252 141 41 188 326 132 75

MAC mean of medians 0.63 1.3 0.32 0.23 0.78 1.34 0.3 0.30

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

Delit or Balanced ??

Prof Dan Sessler, personal communication

20

30

40

50

60

70

80

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46

Q3

Q1

Median

Sequential Patients

Target 50, Mean 48 Target 35, Mean 38

Delit or Balanced ??

20

30

40

50

60

70

80

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46

Q3

Q1

Median

Sequential Patients

Target 50, Mean 48 Target 35, Mean 38

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 … .. .

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

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 ?

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

Thank you

VioxxRofecoxib observational studies of MILevesque 2005, RR 1.24 low dose, 1.73 high doseKaiser Permanente 1.47 low dose, 3.58 high doseQuestionable significance

APPROVe study 25mg daily for 3 yrStopped at 2587 patients32 vs 12 deaths in placebo grp, RR = 1.92

92,8 millions prescriptions 27785 décès par '99-'0358000 demandes enregistréesUS$4.85 milliards règlement

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

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Monk Anesth Analg 2005,100:4-10 2003 Rovenstine LecturePostoperative Cognitive Dysfunction: The Next Challenge in Geriatric Anesthesia

Table 4.  Multivariate Predictors of 1-yr Postoperative MortalityPredictor Relative risk (odds ratio) [95% CI] P valueCharleston Co-morbidity Score (3+ vs 0-2) 16.1 (10.1-33.7) <0.0001Cumulative deep hypnotic time (per h) 1.24 (1.06-1.74) 0.012Systolic 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

Lindholm Anesth 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

Leslie Anesth 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

Searleman Anesthesiology 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

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

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%

• 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

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

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

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

Studies of survival in BIS-monitored patients and Mortality in the elderly [adapted from Leslie et al]

Monk Lindholm Leslie Searleman SaagerNumber of patients 1064 4087 2463 1791 23,999Age (years) 51 (37-65) 50 (36-65) 61 (46-71) 59 (14.6)Male sex (%) 37 38 62 53ASA physical status ≥3 (%) 35 6 74 71Cardiac surgery (%) 0 0 42 27 0Duration 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 100BIS monitoring (%) 100 100 50 100 100Anaesthetist blind to BIS Yes No No 50% NoAverage BIS 49 9 37 7 45 7 43 9Follow-up (years) 1 2 4 1 1+30-day mortality (%) 0.7 0.7 4.3 - 0.81-year mortality (%) 5.5 4.3 10.8 10.7 4.82-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 lowor 1.24/h HR=1.18 at 4 yr at 1 yr1 yr (1.08-1.29)

2yr NotesMonk 50% of mortality due to cancer24% increased risk of death per hour deep hypnosisLindholm Deep hypnotic time not a predictor when pre-existing malignancy included in model

>2hrs deep hypnosis had much higher mortality. Most patients rather fitLeslie Also decreased. risk of MI & CVA. Unable to calculate 1yr mortalitySearleman 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)