1) Therapeutic hypothermia after cardiac arrest and ischemic stroke has been shown to improve outcomes by reducing neurological injury through several mechanisms such as preventing blood-brain barrier disruption and reducing excitotoxic neurotransmitter release. 2) Two randomized controlled trials found that inducing mild hypothermia (32-34°C) for 24 hours in comatose cardiac arrest survivors improved survival and neurological outcomes with a number needed to treat of 6-7 to see benefit. 3) Methods to induce and maintain therapeutic hypothermia include surface cooling blankets, intravenous cold saline, endovascular cooling catheters, and cooling helmets. Careful rewarming is also important to avoid rebound injury.

1. Hypothermic Resuscitation
Sombat Muengtaweepongsa M D
Muengtaweepongsa, M.D.
Division of Neurology
Faculty of Medicine
Thammasat University

2. Scope
• Therapeutic hypothermia after cardiac arrest
• Therapeutic hypothermia in ischemic stroke
• Fever control in critical care neurology

4. 2005 ILCOR
• There seems to be good evidence (level
1) to recommend the use of induced
)
mild hypothermia in comatose
survivors of out hospital cardiac arrest
of-out-hospital
caused by VF.
Level 1 evidence indicates one or more randomized clinical trials in which
benefit was shown

5. Therapeutic Hypothermia after Cardiac
Arrest
(N Engl J Med 2002;346:557-63.)

6. The
Th RCT of TH after cardiac arrest
f ft di t
HACA (European) Bernard trial (Australia)
Sample N=275 N=77
Cooled verses 137 cooled 43 cooled
normothermia 138 normothermia 34 normothermia
Intervention Cooling blankets Ice packs
and ice packs
Target temperature 32-34 degrees 33 degrees
Initiation Prehospital
p ER
Duration 24 hours 12 hours
Follow up 6 months 30 days

7. Benefit
• NNT of 7 to prevent 1 death with TH
• NNT of 6 to reduce neurologic
impairment with TH
The NNT is the number of patients who need to be treated in order to
prevent one additional bad outcome

8. HACA study group, 2002. New England Journal of
Medicine 346(8).
Adverse E
Ad Events
t
• Bleeding, pneumonia, sepsis, pancreatitis,
renal failure, pulmonary edema, seizures,
,p y , ,
arrhythmias and pressure sores were
g
recorded in both trials with no significant
adverse events.
“ Sepsis was more likely to develop in the patients
with h pothermia than those in normothermia
ith hypothermia normothermia,
although this difference was not statistically
significant
significant” (HACA study group 2002)
group,

9. Side ff t f
Sid effects of moderate hypothermia on
d t h th i
various organ systems
Variable Normothermia Hypothermia After-rewarming
Plt count
t 183 (145-310) 110 (20-180) 160 (50-210)
aPTT 27 (20-45) 34 (25-50) 30 (20-55)
lipase 140 (60-190) 250 (140-1200) 200 (135-1000)
K+ 4.1 (3.5-4.7)
(3.5 4.7) 3.4 (3.1-3.9)
(3.1 3.9) 4.4 (4.0-5.2)
(4.0 5.2)
Na+ 139 (134-145) 140 (138-150) 145 (139-155)
Cr Clearance
C Cl 81 (60-100) 65 (45-90) 70 (45-95)
Norepinephrine 0 0.32 (0.0-0.45) 0.08 (0.0-0.24)

10. What is the purpose of TH?
• Aimed at minimizing the effects of
anoxic neurologic injury following
g j y g
cardiac arrest
• Other than supportive care TH it is the
only identified measure to improve
quality of life post resuscitation
f f

11. So why is TH not
done more often?
Both of these studies involved a highly selected group of
patients, excluding up to 92% of patients with out-of-hospital
cardiac arrest initially assessed for eligibility

12. Suggested Inclusion Criteria
gg
• TH is indicated if the patient meets all of the
following criteria:
1. Witnessed arrest
2. Initial rhythm VF or pulseless VT…. But
3. Time to ACLS was less than 15 minutes and total
of ACLS time less than 60 minutes
4. GCS of 8 or below
5. SBP of > 90 with or without vasopressors
6.
6 Less than 8 hours have elapsed since return of
spontaneous circulation (ROSC)

13. Suggested Exclusion Criteria
gg
1. Pregnancy
2. GCS 10 and improving
3. Down time of > 30 minutes
4. ACLS preformed for > 60 minutes
5.
5 Known terminal illness
6. Comatose state prior to cardiac arrest
7.
7 Prolonged hypotension (ie MAP < 60 f >30
P l dh t i (i for 30
minutes)
8. Evidence of hypoxemia for > 15 min following
ROSC
9. Known coagulopathy that cannot be reversed

14. Mechanisms of neuroprotection by
M h i f t ti b
hypothermia
• counteract ischemic brain damage by
several mechanisms
– prevention of the blood–brain-barrier
disruption
– oxygen-based free-radical production
–  excitotoxicneurotransmitter release
– anti-inflammatory action
– delayed apoptosis

15. Historical Observations
• Not Dead till Warm and Dead
– Cold patients would wake up in the Morgue
p p g
• Kids / Hockey Players- fall through ice,
long rescue times but good recovery
times,
• Hibernation: state of low oxygen, acidosis,
yg
low energy supply

16. Ideal temperature curve
Induction
erature
Rewarming
Tempe
Sustainment
Time
e

17. Methods to Control Brain
Temperature in Stroke
Patients

18. Methods of Cooling
• Selective head cooling
– Cooling helmet: ineffective in adult
g
• Internal cooling by intravenous and
intraarterial ice-cold saline
ice cold
– Need large volume
• Surface cooling
• Endovascular cooling

19. Surface blanket

20. Surface cooling

21. Surface cooling

22. Figure 1. The Reprieve Endovascular Temperature Management System
De Georgia, M. A. et al. Neurology 2004;63:312-317

23. Endovascular catheter

24. Intravascular Hypothermic
Machine

25. Intravascular Hypothermic
Catheter

26. Thermoregulatory Defenses
Against Hypothermia
• Vasoconstriction
– Primary autonomic defenses
y
– Threshold: 36.5o C
• Shivering
– “last resort” response
– Threshold: 35.5o C

27. Introduction of thermoregulatory
tolerance
• Nonpharmacological treatments
– Whole body surface warming
y g
• Pharmacological treatments
–AAnesthetics and M
th ti d Muscle relaxants
l l t
– Meperidine
– Drug combination
• Meperidine and Buspirone
p p
• Meperidine and Dexmedetomidine

29. Reductions in the shivering threshold (compared with the control day) for the
dexmedetomidine (Dex), meperidine (Mep), and 2-drug combination (Combo) days
Doufas, A. G. et al. Stroke 2003;34:1218-1223
Copyright ©2003 American Heart Association

31. Rewarming
• Th most critical period of risk related t
The t iti l i d f i k l t d to
therapeutic hypothermia
• Vasodilation
• Hypermetabolic response
– Systemic inflammatory response syndrome
(SIRS)
• Passive controlled rewarming
Stepwise rewarming rate: 0 1 0 5 oC per h
– St i i t 0.1-0.5 hr

32. Rewarming
• C b l side effects
Cerebral id ff t
– Rebound edema and ICP elevation
• E
Extracerebral side effects
b l id ff
– Infection
• P
Pneumonia
i
• Sepsis
– Cardiopulmonary
• Elevation of catecholamines: arrhythmia
– Hematologic
• Induced thrombosis

33. Therapeutic Hypothermia
for
Ischemic Stroke

34. A case scenario
69 y/o woman presented to an outside
hospital with sudden onset of right sided
h it l ith dd t f i ht id d
weakness and speech impairment. She
arrived at the OSH at 20 minutes after
onset. CT brain was negative. TPA was
CT-brain
started at 90 minutes after the onset
before she was transferred to SLUH
SLUH.

35. A case scenario (cont )
(cont.)
She
Sh was alert and awake, b t aphasic.
l t d k but h i
NIHSS was 8 with:
LOCb 2,
partial hemianopia
hemianopia,
right arm drifting,
some effort against gravity on right leg
leg,
partial sensory loss on the left side
moderate aphasia.
aphasia

36. A case scenario (cont )
(cont.)
Without ith i t b ti
With t either intubation or sedation,
d ti
therapeutic hypothermia with
endovascular cooling technique was
started at 5 hours after onset. Target core
temperature of 33oC was reached within 3
hrs. Shivering was under control with
combination of surface warming and
meperidine p
p plus buspirone. Gradual
p
rewarming was applied after target
temperature was maintained for 24 hrs.

38. Temperature and stroke

39. For each 1 degrees C increase in
body temperature the relative risk
of poor outcome rose by 2.2 (95
percent CI 1.4-3.5) (p less than
0.002).

41. She was discharged to a rehab after 5 days
of admission with NIHSS of 5 and mRS of
3.
At day 30 She walked by herself to follow
30,
up at DOB. NIHSS was only 3 including
hemianopia and partial sensory loss. mRSS
was 2.

42. Hypothermia for Malignant
MCA Infarction

45. Fever-related Brain Injury in the
Neuro-ICU
• C b l I f ti
Cerebral Infarction
• Elevated temperature is associated with
poor outcome after stroke
t ft t k
Hajat et al, Stroke 2000;31:410
• Subarachnoid Hemorrhage
• Fever burden independently associated with
mortality & poor functional outcome.
y p
Mayer et al, Crit Care Med 2003 (Suppl);30:A5
• Intracerebral Hemorrhage
• D ti of f
Duration f fever (>37.5° C) within th fi t
( 37 5° ithi the first
72 hours is independently associated with
poor outcome
Schwarz et al, Neurology 2000;54:354

46. Treatment of fever in the neurologic intensive care unit with a
catheter-based heat exchange system
th t b dh t h t
Diringer MN, CCM 2204;32:559
• 296 patients with T ≥38° C for at least 2
occasions
i
– SAH, TBI, ICH and cerebral infarction
• Alsius Cool Line endovascular heat exchange
catheter plus standard surface cooling
• Fever Burden >38 °C
38 C
– 7.92 °C-hours 64% relative reduction (P<0.01)
– 2.87 °C-hours
• Shivering “of concern” in four patients (3.7%)

47. Clinical Trial of a Novel Surface Cooling System
for Fever Control in Neurocritical Care Patients
Mayer, et al, Crit Care Med 2004
• 47 patients with T ≥38.3° C for >2 consecutive
hours after receiving acetaminophen
– Median GCS 8 0 8.0
– SAH, ICH, infarction, TBI
– Mean 42 hours >38 3° C prior to
>38.3
randomization
• Interventions
– Standard SubZero cooling blanket
– Medivance Artcic Sun surface cooling
system
• Main outcome measure
– 24 h hour f
fever b d
burden

48. Clinical Trial of a Novel Surface Cooling System
for Fever Control in Neurocritical Care Patients
P=0.001

49. Change in Glasgow Coma Scale
P=.038, GEE model

50. Conclusion
• TH is a standard treatment in selected
patients after cardiac arrest.
p
• TH should be benefit for penumbra
salvaging in acute ischemic stroke
stroke.
• TH is one of treatments for increase ICP.
• Fever control is essential, particularly in
conditions.
such a bad neurological conditions

51. Take home message
“ No evidence”
doesn t
doesn’t mean
“Evidence does not exist”.

52. Thank you for your attention