ttm and prognostication after cardiac arrest on tt… · n=16,252 patients post ohca. 36° = sloppy...

TTM and Prognostication

after Cardiac ArrestDamon Scales MD PhD

Sunnybrook Health Sciences Centre, University of Toronto

Objectives

• Review evidence supporting TTM

after cardiac arrest

• Recommendations for neurological

prognostication after cardiac arrest

Rationale for Therapeutic

Hypothermia After Anoxic Injury

Animal Studies Show Benefits of

Hypothermia after Anoxic Insults

Animal Studies Show Benefits of

Hypothermia after Anoxic Insults

Metabolic Chain of Events

After Cardiac Arrest

Cardiac

ArrestNo Blood Flow Ischemia

Cell Damage

Metabolic Chain of Events

After Cardiac Arrest

Cardiac

ArrestNo Blood Flow Ischemia

O2 ReperfusionFree Radicals

Edema, Cell Death

and Cerebral injury CPR /

Pulse

Cell Damage

Metabolic Chain of Events

After Cardiac Arrest

Cardiac

ArrestNo Blood Flow Ischemia

O2 ReperfusionFree Radicals

Edema, Cell Death

and Cerebral injury CPR /

Pulse

Cell Damage

COOLING

Cooling

interrupts

apoptotic

pathways

Yenari, Soo Han. Nat Rev

Neurosci. 2012. 22;13:267.

Positive effects

of cooling

APOPTOSIS

ICH

EDEMA

NECROSIS Yenari, Soo Han. Nat Rev

Neurosci. 2012. 22;13:267.

Practice-Changing RCTs

Demonstrating Clinical Benefit

[1] Holzer et al, NEJM 2002; 0.3C/hr cooling with cold air and ice packs

[2] Bernard et al, NEJM 2002; 0.9C/hr cooling with ice packs

0%

20%

40%

60%

HACA [1] Bernard et al [2]

Normothermia

Hypothermia

26% 49%39% 55%

NNT ~ 6 NNT ~ 4

Practice-Changing RCTs

Demonstrating Clinical Benefit

[1] Holzer et al, NEJM 2002; 0.3C/hr cooling with cold air and ice packs

[2] Bernard et al, NEJM 2002; 0.9C/hr cooling with ice packs

0%

20%

40%

60%

HACA [1] Bernard et al [2]

Normothermia

Hypothermia

26% 49%39% 55%

NNT ~ 6 NNT ~ 4

Number needed to treat to have one

more patient survive with good

neurological outcome (NNT) = 5

Practice-Changing RCTs

Demonstrating Clinical Benefit

Compelling Stories:

Protective Effects of Cooling

Compelling Stories:

Protective Effects of Cooling

Problems with Earlier Trials

• Relatively small RCTs and quasi-RCTs

• Control arm: Usual care (no pyrexia avoidance)

• Implausible effect size

• Unblinded intervention – potential bias

The Targeted Temperature

Management (TTM) Trial

The Targeted Temperature

Management (TTM) Trial

• 939 patients, all rhythms

– ~ 75%-80% VT/VF

• Randomized to receive in hospital:

– Controlled normothermia: target

36 degrees

– Controlled hypothermia: target 33

degrees

The Targeted Temperature

Management (TTM) Trial

The Targeted Temperature

Management (TTM) Trial

The Targeted Temperature

Management (TTM) Trial

• No difference long-term outcomes

• No differences in adverse events

• More shivering in 36°C group

The TTM Trial in Animals

Che et al. Crit Care Med 2011; 39:1423.

HYPOTHERMIA

NORMOTHERMIA

Che et al. Crit Care Med 2011; 39:1423.

• Higher neuron counts

after cooling to 33°C

The TTM Trial in Animals

Inadequate group separation to be

biologically important?

36.0°C 37.6°C

TTM Trial

HACA Trial

33.0°C

33.0°C

Overall Summary of Evidence

All-cause mortality after TTM – including the Nielsen TTM Trial

Overall Summary of Evidence

All-cause mortality after TTM – excluding the Nielsen TTM Trial

Canadian NCS Guidelines

Patients Enrolled in TTM trials

HACA Bernard TTM

Patients 275 77 939

Age 18-75 >18 >18

Rhythm VT/ VF VF 80% VT/VF

Collapse to ROSC ~23 min ~25 min ~25 min

Bystander CPR 46% 45% 73%

Start of BLS N/A N/A 1 min

Start of ALS N/A 11 min 9 min

Patients Enrolled in TTM trials

HACA Bernard TTM

Patients 275 77 939

Age 18-75 >18 >18

Rhythm VT/ VF VF 80% VT/VF

Collapse to ROSC ~23 min ~25 min ~25 min

Bystander CPR 46% 45% 73%

Start of BLS N/A N/A 1 min

Start of ALS N/A 11 min 9 min

Patients Enrolled in TTM trials

HACA Bernard TTM

Patients 275 77 939

Age 18-75 >18 >18

Rhythm VT/ VF VF 80% VT/VF

Collapse to ROSC ~23 min ~25 min ~25 min

Bystander CPR 46% 45% 73%

Start of BLS N/A N/A 1 min

Start of ALS N/A 11 min 9 min

Bystander CPR - Toronto: 39%

• Patients with no cerebral ischemia (i.e. early CPR) will

survive regardless of what we do

• Patients with extensive ischemia will die regardless of

what we do

• Hypothermia is MOST LIKELY to help those who

have moderate cerebral ischemia

Cooling will only HELP when there

has been cerebral ischemia

Most benefit:

Patients with longer down-times

Testori et al. Resuscitation 2012.

Testori et al. Resuscitation 2012.

Most benefit:

Patients with longer down-times

36° = SLOPPY COOLING

33 degrees

36 degrees

% in target

range

36° = SLOPPY COOLING

36° = SLOPPY COOLING

36° = SLOPPY COOLING

Crit Care Med 2018

Trends before-after TTM trial

ANZICS 2005-2016

n=16,252 patients post OHCA

36° = SLOPPY COOLING

Crit Care Med 2018

Trends before-after TTM trial

ANZICS 2005-2016

n=16,252 patients post OHCA

TTM for non-shockable rhythms

• 581 patients, non-shockable OHCA

• 33°C vs 37°C

• Primary outcome survival with good

outcome at 90 days

TTM for non-shockable rhythms

Good outcome (CPC 1 or 2):

- 10.2% in 33°C group

- 5.7% in 37°C group

- ARR: 4.5% 95%CI 0.1-8.9, p=0.04

Does the duration of TTM matter?

355 OHCA patients, all rhythms:

- TTM 33°C x 24 hours, vs

- TTM 33°C x 48 hours

Primary outcome: good neuro outcome

at 6 months (CPC 1 or 2)

Does the duration of TTM matter?

Good outcome:

- 24 hours: 64%

- 48 hours: 69%

RR: 1.08 (0.93-1.25), p=0.33

Adverse events: 97% vs 91%, p=0.04

Does the duration of TTM matter?

Cognitive impairment:

• Non-impaired: ≤2 test scores below cut-off

• Impaired: ≥3 test scores below cut-off

1. TTM improves good neurological outcomes after cardiac arrest

2. Targeting 33°may be better to improve protocol adherence (and avoid sloppy hypothermia)

3. If it was YOUR brain, what temperature would you choose?

SUMMARY

1. TTM improves good neurological outcomes after cardiac arrest

2. Targeting 33°may be better to improve protocol adherence (and avoid sloppy hypothermia)

3. If it was YOUR brain, what temperature would you choose?

SUMMARY

Neurological prognostication

in the cooling era

A Typical Case

▪ 35 year old woman

▪ Found unresponsive by family

(unwitnessed)

▪ CPR by paramedics

▪ Initial rhythm PEA

▪ ROSC after 2 rounds CPR/epi

▪ Intubated

▪ Initial ABG:

▪ pH 6.87 / pCO2 80 / pO2 152 / HCO3 14

▪ GCS 3T, pupils dilated and unreactive

bilaterally

▪ Toxicology screen: opiates

▪ TTM started in ER

A Typical Case

CT brain:

▪ loss of grey-white differentiation

▪ “consistent with diffuse anoxic brain injury”

MRI brain:

▪ Appearance consistent with “global ischemic insult”

A Typical Case

CT brain:

▪ loss of grey-white differentiation

▪ “consistent with diffuse anoxic brain injury”

MRI brain:

▪ Appearance consistent with “global ischemic insult”

A Typical Case

The Bad• Unwitnessed

• No bystander CPR

• Non-shockable initial rhythm

• ? Long down-time

• Unreactive pupils, GCS 3

• Anoxic injury on neuroimaging

The Good• Successful ROSC

• Young patient

• CPR by paramedics

Early Outcome Prediction

The Bad• Unwitnessed

• No bystander CPR

• Non-shockable initial rhythm

• ? Long down-time

• Unreactive pupils, GCS 3

• Anoxic injury on neuroimaging

The Good• Successful ROSC

• Young patient

• CPR by paramedics

• ? Confounding by opiates

Early Outcome Prediction

Avoid

prematurely

terminating life

support in

patients who will

survive

Avoid continuing

life support in

patients who will

have poor

neurological

outcomes

Competing Goals

▪ 213 out of hospital arrests / 100,000 adults

▪ Overall survival about 8%

▪ Alive at ED: survival about 40 – 50%

Cardiac arrest can be

a devastating event

Sayre et al. Part 5: Adult Basic Life Support. Circulation 2010;122:S298-

324.

Aufderheide T et al. NEJM 2011;365:798-806

Most survivors have good

neurological outcomes

Mortality ~ 50%

Most survivors have good

neurological outcomes

90% of Survivors

• Woke up Day 5

• Extubated – Discharge from ICU at day 8

• Mild memory impairment at time of

hospital discharge

A Typical Case:

Follow-Up

Outcome Prediction

After Cardiac Arrest

• N=210 patients

• Serial assessments

Outcome Prediction

After Cardiac Arrest

Outcome Prediction

After Cardiac Arrest

Outcome Prediction

After Cardiac Arrest

Outcome Prediction

After Cardiac Arrest

• Medications used to induce and maintain hypothermia

• TTM may attenuate degree of brain injury, alter accuracy of exam findings

TTM may change accuracy

of clinical predictors

GCS ≤ 2: 24% FP rate GCS ≤ 2: 10% FP rate

▪ “A 55-yr-old man presented with cardiac

arrest… spontaneous perfusion restored,

and therapeutic hypothermia provided”

▪ “Death was pronounced and the family

consented to organ donation.”

Webb and Samuels, CCM 2011.

Webb and Samuels, CCM 2011.

▪ “24 hrs after brain death, on

arrival to the operating room for

organ procurement, the patient

was found to have regained

corneal reflexes, cough reflex,

and spontaneous respirations.”

Predicting Outcome After TTM

• 20 studies – post TTM neuroprognostication

• 1845 patients

Crit Care Med 2014;42:1919

Predicting Outcome After TTM

Predicting Outcome After TTM

Predicting Outcome After TTM

Predicting Outcome After TTM

Predicting Outcome After TTM

Predicting Outcome After TTM

Predicting Outcome After TTM

Predicting Outcome After TTM

CT Scan - GWR

Gray-white ratio (20 studies, n=2327)

Sensitivity: 0.44 (0.29-0.60)

Specificity: 0.97 (0.93-0.99)

FPR: 0.03 (0.01-0.07)

CT Scan - GWR

SENS SPEC

MRI – DWI and FLAIR

Good

Outcome

Bad Outcome

Acta Neurol Scand 2004: 110: 361

DWI (16 studies, n=805)

Sensitivity: 0.77 (0.65-0.85)

Specificity: 0.92 (0.85-0.96)

FPR: 0.08 (0.04-0.15)

MRI – DWI and FLAIR

SENS SPEC

Do we stop too early?

• 16,875 OHCA cases

• 4265 (25%) survived to 60 min after hospital arrival

• 919 (33% of deaths) occurred following WLST <72 hours

Do we stop too early?

WLST Based on

Neurological Prognosis

72 hours

Do we stop too early?

Do we stop too early?

▪ Delay neurological prognostication until at least 72 hours after

rewarming

▪ Emphasis on clinical exam:

▪ Lack of pupillary reflexes, corneal reflexes, SSEP responses, +/- poor

motor exam (7 days)

▪ If none present – explain prognostic uncertainty

▪ Avoid long-acting sedatives, if possible

▪ Avoid pessimism about outcomes for these patients – and

premature decisions to WLST

My approach

damon.scales@sunnybrook.ca