ttm and prognostication after cardiac arrest on tt… · n=16,252 patients post ohca. 36° = sloppy...
TRANSCRIPT
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TTM and Prognostication
after Cardiac ArrestDamon Scales MD PhD
Sunnybrook Health Sciences Centre, University of Toronto
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Objectives
• Review evidence supporting TTM
after cardiac arrest
• Recommendations for neurological
prognostication after cardiac arrest
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Rationale for Therapeutic
Hypothermia After Anoxic Injury
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Animal Studies Show Benefits of
Hypothermia after Anoxic Insults
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Animal Studies Show Benefits of
Hypothermia after Anoxic Insults
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Metabolic Chain of Events
After Cardiac Arrest
Cardiac
ArrestNo Blood Flow Ischemia
Cell Damage
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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
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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
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Cooling
interrupts
apoptotic
pathways
Yenari, Soo Han. Nat Rev
Neurosci. 2012. 22;13:267.
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Positive effects
of cooling
APOPTOSIS
ICH
EDEMA
NECROSIS Yenari, Soo Han. Nat Rev
Neurosci. 2012. 22;13:267.
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Practice-Changing RCTs
Demonstrating Clinical Benefit
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[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
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[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
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Compelling Stories:
Protective Effects of Cooling
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Compelling Stories:
Protective Effects of Cooling
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Problems with Earlier Trials
• Relatively small RCTs and quasi-RCTs
• Control arm: Usual care (no pyrexia avoidance)
• Implausible effect size
• Unblinded intervention – potential bias
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The Targeted Temperature
Management (TTM) Trial
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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
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The Targeted Temperature
Management (TTM) Trial
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The Targeted Temperature
Management (TTM) Trial
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The Targeted Temperature
Management (TTM) Trial
• No difference long-term outcomes
• No differences in adverse events
• More shivering in 36°C group
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The TTM Trial in Animals
Che et al. Crit Care Med 2011; 39:1423.
HYPOTHERMIA
NORMOTHERMIA
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Che et al. Crit Care Med 2011; 39:1423.
• Higher neuron counts
after cooling to 33°C
The TTM Trial in Animals
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Inadequate group separation to be
biologically important?
36.0°C 37.6°C
TTM Trial
HACA Trial
33.0°C
33.0°C
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Overall Summary of Evidence
All-cause mortality after TTM – including the Nielsen TTM Trial
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Overall Summary of Evidence
All-cause mortality after TTM – excluding the Nielsen TTM Trial
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Canadian NCS Guidelines
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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
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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
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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%
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• 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
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Most benefit:
Patients with longer down-times
Testori et al. Resuscitation 2012.
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Testori et al. Resuscitation 2012.
Most benefit:
Patients with longer down-times
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36° = SLOPPY COOLING
33 degrees
36 degrees
% in target
range
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36° = SLOPPY COOLING
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36° = SLOPPY COOLING
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36° = SLOPPY COOLING
Crit Care Med 2018
Trends before-after TTM trial
ANZICS 2005-2016
n=16,252 patients post OHCA
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36° = SLOPPY COOLING
Crit Care Med 2018
Trends before-after TTM trial
ANZICS 2005-2016
n=16,252 patients post OHCA
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TTM for non-shockable rhythms
• 581 patients, non-shockable OHCA
• 33°C vs 37°C
• Primary outcome survival with good
outcome at 90 days
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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
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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)
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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
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Does the duration of TTM matter?
Cognitive impairment:
• Non-impaired: ≤2 test scores below cut-off
• Impaired: ≥3 test scores below cut-off
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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
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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
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Neurological prognostication
in the cooling era
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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
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▪ 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
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CT brain:
▪ loss of grey-white differentiation
▪ “consistent with diffuse anoxic brain injury”
MRI brain:
▪ Appearance consistent with “global ischemic insult”
A Typical Case
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CT brain:
▪ loss of grey-white differentiation
▪ “consistent with diffuse anoxic brain injury”
MRI brain:
▪ Appearance consistent with “global ischemic insult”
A Typical Case
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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
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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
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Avoid
prematurely
terminating life
support in
patients who will
survive
Avoid continuing
life support in
patients who will
have poor
neurological
outcomes
Competing Goals
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▪ 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
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Most survivors have good
neurological outcomes
Mortality ~ 50%
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Most survivors have good
neurological outcomes
90% of Survivors
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• Woke up Day 5
• Extubated – Discharge from ICU at day 8
• Mild memory impairment at time of
hospital discharge
A Typical Case:
Follow-Up
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Outcome Prediction
After Cardiac Arrest
• N=210 patients
• Serial assessments
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Outcome Prediction
After Cardiac Arrest
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Outcome Prediction
After Cardiac Arrest
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Outcome Prediction
After Cardiac Arrest
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Outcome Prediction
After Cardiac Arrest
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• 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
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▪ “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.
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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.”
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Predicting Outcome After TTM
• 20 studies – post TTM neuroprognostication
• 1845 patients
Crit Care Med 2014;42:1919
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Predicting Outcome After TTM
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Predicting Outcome After TTM
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Predicting Outcome After TTM
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Predicting Outcome After TTM
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Predicting Outcome After TTM
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Predicting Outcome After TTM
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Predicting Outcome After TTM
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Predicting Outcome After TTM
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CT Scan - GWR
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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
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MRI – DWI and FLAIR
Good
Outcome
Bad Outcome
Acta Neurol Scand 2004: 110: 361
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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
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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
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Do we stop too early?
WLST Based on
Neurological Prognosis
72 hours
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Do we stop too early?
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Do we stop too early?
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▪ 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