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