Intraoperative Awareness

From Ether Day to THRIVE

George A. Mashour, M.D., Ph.D.

Robert B. Sweet Professor & Chair, Department of Anesthesiology

Professor of Neurosurgery & Pharmacology

Faculty, Neuroscience Graduate Program

University of Michigan Medical School, Ann Arbor

No conflicts of interest to declare

“Suffering so great as I

underwent cannot be

expressed in words… but

the blank whirlwind of

emotion, the horror of great

darkness, and the sense of

desertion by God and man,

which swept through my

mind, and overwhelmed my

heart, I can never forget.”

“During the operation the patient

muttered, as in a semi-conscious state,

and afterwards stated that the pain was

considerable though mitigated… There

was, probably, in this instance, some

defect in the process of inhalation…”

Outline

• Definition

• Incidence & risk factors

• Sequelae

• Prevention

Outline

• Definition

• Incidence & risk factors

• Sequelae

• Prevention

Defining the problem

“Awareness”

Defining the problem

“Awareness” = Consciousness + Memory

Defining the problem

“Awareness” = Consciousness + Memory

Consciousness = Arousal +

Defining the problem

“Awareness” = Consciousness + Memory

Consciousness = Arousal + Experience

Defining the problem

“Awareness” = Consciousness + Memory

Memory => Explicit Episodic Recall

4.6% (12/260 patients) had positive response

but no postoperative recall; inhaled anesthetic (after

induction, before intubation) appears protective

What does this mean for THRIVE?

• The group randomized to TIVA with no

post-induction inhaled agent might be

at higher risk of intraoperative

awareness without recall

Outline

• Definition

• Incidence & risk factors

• Sequelae

• Prevention

Incidence of the problem in the

United States

Incidence of 25/19,575 or 0.13%

Sebel et al, Anesth Analg, 2004;99:833

…consistent with a prospective

study in Sweden

Incidence of 19/11,785 or 0.16%

Sandin et al, Lancet, 2000;355:707

…consistent with a prospective

study in Sweden

Incidence of 19/11,785 or 0.16%

Note that incidence with NMB was higher

Sandin et al, Lancet, 2000;355:707

…not consistent with data from

another U.S. study

Incidence of 6/87,381 or 0.0068%

Pollard et al, Anesthesiology 2007:106:269

Comparing Brice interview to

quality assurance techniques

Mashour et al, Anesth Analg, 2013;116:889

Comparing Brice interview to

quality assurance techniques

Mashour et al, Anesth Analg, 2013;116:889

• Spontaneous patient reports are not

sufficient for an accurate incidence of

this outcome

• Any MPOG study including

intraoperative awareness will likely

have to involve enriched, prospective

data collection

What does this mean for THRIVE?

Mashour et al, Anesth Analg, 2010;110:813

Classifying awareness events

Mashour et al, Anesth Analg, 2010;110:813

Classifying awareness events

Pandit et al, Br J Anaesth, 2014;113:560

High-risk cases

• Cardiac

• Hemorrhagic trauma/surgery

• Cesarean section delivery

• Difficult airway

• Pediatric

• TIVA

High-risk cases

• Cardiac

• Hemorrhagic trauma/surgery

• Cesarean section delivery

• Difficult airway

• Pediatric

• TIVA

• TIVA is typically considered a high-risk

group for intraoperative awareness

with recall

• THRIVE will be the first study to

compare TIVA to inhaled anesthesia

with awareness as an outcome

What does this mean for THRIVE?

Risk factors and causes

Ghoneim et al, Anesth Analg, 2009;108:527

Risk factors and causes

Ghoneim et al, Anesth Analg, 2009;108:527

Are patients with a history of

awareness:

Are patients with a history of

awareness:

• At increased risk of awareness?

Are patients with a history of

awareness:

• At increased risk of awareness?

• Cared for differently by anesthesia

providers?

Are patients with a history of

awareness:

• At increased risk of awareness?

• Cared for differently by anesthesia

providers?

• Less responsive to the effects of

general anesthetics?

26,490 patients from three major trials

were screened for history of awareness

26,490 patients from three major trials

were screened for history of awareness

26,490 patients from three major trials

were screened for history of awareness

26,490 patients from three major trials

were screened for history of awareness

Control group

• Matched 5:1 for

– Age

– ASA physical status

– Comorbid conditions

– Risk factors for awareness

Increased incidence of awareness

with history of awareness

Aranake et al, Anesthesiology, 2013;119:1275

No difference in anesthetic care

Aranake et al, Anesthesiology, 2013;119:1275

0.4 0.80.6

1.0 1.2 1.4

Anesthetic concentration (aaMAC)

100

Bispectral Index

Altered MAC-BIS relationship

Controls

History of AWR

Controls

History of AWR

• A proportion of patients screened for

THRIVE will have a substantially higher

risk of awareness

• Clinicians are unlikely to change

practice as a result of that risk factor

What does this mean for THRIVE?

Outline

• Definition

• Incidence & risk factors

• Sequelae

• Prevention

Post-traumatic stress disorder

• Elevated autonomic arousal and

generalized anxiety

• Intrusive and distressing thoughts or

images recalling the trauma

• Behavioral avoidance of physical cues

that prompt memory of the trauma

Incidence of post-awareness PTSD

Mashour, Anesth Analg, 2010;110:668

PTSD in 71%

Incidence of post-awareness PTSD

Mashour, Anesth Analg, 2010;110:668

Psychological Sequelae of

Surgery (Psych SOS) study

• Awareness patients and matched controls

taken from B-Unaware, BAG-RECALL and

MACS trials

• PCL-S self-report administered

• 43% with awareness met a screening

threshold for PTSD

• Dissociation appeared to be a mediating

factor

Whitlock et al, Anesth Analg, 2015;120:87

• Trial participants reporting awareness

should be made aware of the risk for

syndromal or subsyndromal PTSD

What does this mean for THRIVE?

Outline

• Definition

• Incidence & risk factors

• Sequelae

• Prevention

Major randomized controlled trials

 B-Aware trial (2004)

 B-Unaware trial (2008)

 BAG-RECALL trial (2011)

 BIS-TIVA trial (2011)

 MACS (2012)

B-Aware trial

High-risk population, multicenter

Randomized to routine care or BIS

40-60

Confirmed awareness 0.17% (n=2) in

BIS compared to 0.91% (n=11) in

control (p=0.02)

Myles et al, Lancet, 2004;363:1757

B-Unaware trial

High-risk population, single center

Compared BIS 40-60 to MAC 0.7-1.3

2 cases of definite awareness in each

group (overall incidence of 0.21%)

Avidan et al, NEJM, 2008;358:1097

BAG-RECALL trial

High-risk population, multicenter

Elimination of “minor criteria”

Compared BIS 40-60 to age-adjusted

MAC 0.7-1.3

Avidan et al, NEJM, 2011;365:591

Outcomes

Avidan et al, NEJM, 2011;365:591

BIS-TIVA trial

High-risk population, multicenter

2919 TIVA cases randomized to BIS 40-

60, 2309 TIVA cases randomized to

routine care

Confirmed awareness 0.14% (n=4) in

BIS compared to 0.65% (n=15) in

control (p=0.002)

Zhang et al, Chin Med J, 2011;124:3664

MACS

All risk levels, multihospital, single

center

Randomized to real-time decision

support with alarms for BIS>60 or

“effective” MAC<0.5

Study terminated for futility after interim

analysis and recruitment of >20,000

patients

Mashour et al, Anesthesiology;2012:117:717

Primary outcome

Mashour et al, Anesthesiology;2012:117:717

Secondary outcome

Mashour et al, Anesthesiology;2012:117:717

Synthesizing the Trials

BIS is effective in reducing awareness

compared to routine care

and in patients

receiving TIVA

(B-Aware, 2004; Zhang-TIVA trial, 2011;

MACS, 2012)

BIS not superior compared to a MAC-

guided protocol

(B-Unaware, 2008; BAG-RECALL, 2011;

MACS 2012)

Avidan & Mashour, Anesthesiology, 2013;118:449

Mashour & Avidan, Br J Anaesth, 2015;115:i20

2014, 2019

• Patients randomized to the TIVA group

would likely benefit from intraoperative

EEG monitoring to reduce risk of

intraoperative awareness with recall

What does this mean for THRIVE?

Summary

• “Awareness” refers to arousal, experience,

and explicit episodic recall

• Awareness occurs in approximately 1-2

cases/1000

• Risk factors include high-risk anesthetics

and a history of awareness

• PTSD occurs in a significant proportion of

patients experiencing awareness

• BIS monitor is likely effective in

reducing awareness compared to

routine care and during TIVA

• MAC protocol is a cost-effective

alternative in patients receiving volatile

anesthetics

Summary

• Neural inertia

• Emergence trajectories

• EEG oscillations

• Coherence, cross-frequency coupling,

connectivity

• Cortical dynamics

Current Directions

Acknowledgments