Therapeutic hypothermia, or targeted temperature management, has been shown to improve outcomes for patients who remain unconscious after resuscitation from cardiac arrest. Two key studies from 2002 demonstrated improved mortality and neurological function when patients' temperatures were cooled to 32-34°C for 12-24 hours after cardiac arrest. Subsequent meta-analyses and clinical guidelines have supported induced hypothermia for unconscious cardiac arrest survivors. However, the optimal target temperature range was still unclear. A 2013 randomized controlled trial compared outcomes between unconscious cardiac arrest survivors treated with targeted temperature management at 33°C versus 36°C and found no significant difference in mortality or neurological function between the two temperature targets.

2. Therapeutic Hypothermia
Fakhir Raza Haidri

3. Induced Hypothermia Post Cardiac Arrest
With ROSC
• In 2002, the New England Journal published two well designed
studies 1,2 showing dramatically improved outcomes when patients
are actively cooled after resuscitation from V. Fib or Pulseless V.
Tach. This led to an advisory statement by the ILCOR (International
Liaison Committee on Resuscitation) that such patients should be
cooled.
• 1. Bernard S. et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with
induced hypothermia. NEJM 2002, Feb 21; 346(8): 557-563.
• 2. The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to
improve the neurologic outcome after cardiac arrest. NEJM 2002, Feb 21; 346(8): 549-556.

4. What does “improved outcomes” mean?
• Both studies showed improved neurologic outcomes, not just
improved mortality.

5. A Meta analysis
• Meta-analysis including these two trials and another for patients
resuscitated from PEA or asystole and cooled for 4 hours 2 .
Neurologic recovery was improved and independent of method of
cooling. Number needed to treat 4 – 13. 1.
• Holzer M, et al. Hypothermia for neuroprotection after cardiac arrest: Systemic
review and individual patient data meta-analysis. Crit Care Med, 2005; 33(2): 414418.

6. ILCOR Advisory Statement
• “ Unconscious adult patients with spontaneous circulation after outof-hospital cardiac arrest should be cooled to 32° to 34°C for 12 to 24
hours when the initial rhythm was ventricular fibrillation.” “ Such
cooling may also be beneficial for other rhythms or in-hospital cardiac
arrest.”
• International Liaison Committee on Resuscitation. Therapeutic hypothermia after cardiac
arrest – An advisory statement by the Advanced Life Support Task Force of the
International Liaison Committee on Resuscitation. Circulation 2003; 108: 118-121.

7. Theoretical Basis for Hypothermia
• Slow cerebral metabolism
• Reduce apoptosis (programmed cell death)
• Blunt excitatory neurotoxicity
• Modulate immune response

8. Why does it work? Theoretical Basis:
• Slowed cerebral metabolism decreased 5 to 7% for each degree
Centigrade reduction in body temperature. Decrease core
temperature 4°C = 20-28% reduction in cerebral metabolism.
Protective effects appear to be much greater than explained by this
mechanism alone 1,2 .
1. Milde LN. Clinical use of mild hypothermia for brain protection: a dream revisited. J.
Neurosurg Anesth 1992; 4: 211-215.
2. Small DL, et al. Biology of ischemic cerebral cell death. Prog Cardiovasc Dis, 1999; 42:
185-207.

9. Why does it work? Theoretical Basis:
• Apoptosis:
• Apoptosis involves mitochondrial dysfunction and release of destructive
intracellular enzymes. Hypothermia can prevent these two processes leading
to apoptosis

10. Why does it work? Theoretical Basis:
• Excitatory neurotoxicity
• As neurons become ischemic, they cannot maintain membrane potential,
depolarize and release glutamate.
• Energy-requiring mechanisms of re-uptake are impaired.
• Surrounding neurons are stimulated longer than normal in an ischemic state,
causing more damage.
Hypothermia is believed to stabilize cell membranes and has been shown in
animals to slow excitatory neurotoxicity
• Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem, 1995; 65: 1704-1711. 4. Busto R, et al

11. Why does it work? Theoretical Basis:
• Modulation of immune response and edema
•
•
•
•
Hypothermia suppresses release of inflammatory cytokines (TNF- α and IL-1)
It also slows production of free radicals
Reduces disruptions of the blood-brain barrier, decreasing edema.
Moderate hypothermia delays proinflammatory cytokine production of
human peripheral blood mononuclear cells.
• Crit Care Med, 2002; 30: 1499-1502. 2. Globus M, et al.

12. Inclusion Criteria
Exclusion Criteria
• Non-Traumatic cardiac
arrest with return of
circulation
• TH initiated within 6 hours
of arrest
• Systolic BP > 90 or MAP >
60 after fluid resuscitation
with or without pressors
• > 12 years old
• GCS > 8
• Greater than 6 hours since
arrest
• DNR
• Non-mechanically ventilated
patient
• Pregnancy
• Active bleeding
• Arrest secondary to sepsis

13. Internal Method

14. External Method

15. Complications of Cooling
• hypovolemia (hypothermia induced dieresis)
• coagulopathy (impaired coagulation cascade and
thrombocytopenia
• electrolyte disorders (hypothermia induced dieresis, K+, Mg++,
Ca++)
• insulin resistance
• changes in drugs effects and metabolism (altered clearance of
fentanyl, midazolam, and atracurium)

16. Complications of Rewarming
• worsening cerebral edema
• further changes in electrolyte abnormalities (especially
hyperkalemia)
• hyperthermia (induced fever)

17. Goal
• CPC 1 and CPC 2

18. Clinical Performance Category
• CPC 5. Brain death: apnea, areflexia, EEG silence, etc.
• CPC 4 . Coma or vegetative state: any degree of coma without the presence of
all brain death criteria. Unawareness, even if appears awake (vegetative state)
without interaction with environment; may have spontaneous eye opening
and sleep/awake cycles. Cerebral unresponsiveness.
• CPC 3. Severe cerebral disability: conscious, dependent on others for daily
support because of impaired brain function. Ranges from ambulatory state to
severe dementia or paralysis
• CPC 2. Moderate cerebral disability: conscious, sufficient cerebral function
for independent activities of daily life. Able to work in sheltered
environment
• CPC 1. Good cerebral performance: conscious, alert, able to work, might
have mild neurologic or psychologic deficit
• Lancet 1975. 1(7905):480-4

19. Hypothermia in Comatose Survivors From
Out-of-Hospital Cardiac Arrest: Pilot Trial
Comparing 2 Levels of Target Temperature
• Circulation. published online November 6, 2012;

20. Methods and Results
• Patients were eligible if they had a witnessed out-of-hospital cardiac
arrest from March 2008 to August 2011.
• Target temperature was randomly assigned to 32°C or 34°C.
• The primary outcome was survival free from severe dependence
(Barthel Index score 60 points) at 6 months.
• Thirty-six patients were enrolled in the trial (26 shockable rhythm, 10
asystole), with 18 assigned to 34°C and 18 to 32°C.
• Eight of 18 patients in the 32°C group (44.4%) met the primary end
point compared with 2 of 18 in the 34°C group (11.1%) (log-rank
P0.12).

21. Conclusions
• The findings of this pilot trial suggest that a lower cooling level may
be associated with a better outcome in patients surviving out-ofhospital cardiac arrest secondary to a shockable rhythm. The
benefits observed here merit further investigation in a larger trial in
out-of-hospital cardiac arrest patients with different presenting
rhythms.

22. Original Article
Targeted Temperature Management at
33°C versus 36°C after Cardiac Arrest
• N Engl J Med 2013; 369:2197-2206, December 5, 2013

23. Background
• Unconscious survivors of out-of-hospital cardiac arrest have a high
risk of death or poor neurologic function. Therapeutic hypothermia is
recommended by international guidelines, but the supporting
evidence is limited, and the target temperature associated with the
best outcome is unknown.
• Our objective was to compare two target temperatures, both
intended to prevent fever.

24. Methods
• International trial
• randomly assigned 950 unconscious adults after out-of-hospital
cardiac arrest of presumed cardiac cause to targeted temperature
management at either 33°C or 36°C.
• The primary outcome was all-cause mortality through the end of the
trial.
• Secondary outcomes included a composite of poor neurologic
function or death at 180 days, as evaluated with the Cerebral
Performance Category (CPC) scale and the modified Rankin scale.

25. Results
• 50% of the patients in the 33°C group (235 of 473 patients) had
died, as compared with 48% of the patients in the 36°C group (225 of
466 patients) (P=0.51).
• At the 180-day follow-up, 54% of the patients in the 33°C group had
died or had poor neurologic function according to the CPC, as
compared with 52% of patients in the 36°C (P=0.78).
• In the analysis using the modified Rankin scale, the comparable rate
was 52% in both groups (P=0.87).
• The results of analyses adjusted for known prognostic factors were similar.

26. Conclusions
• In unconscious survivors of out-of-hospital cardiac arrest of presumed
cardiac cause, hypothermia at a targeted temperature of 33°C did not
confer a benefit as compared with a targeted temperature of 36°C.

27. Any
Questions