Hypothermia in TBI for Neuroprotection.

1. HYPOTHERMIA IN TBI FOR
NEUROPROTECTION
Dr Sumit Sinha
Additional Professor
Deptt of Neurosurgery, AIIMS and
JNATC, New Delhi

2. Hypothermia in TBI
• TBI- leading cause of death and disabiity
worldwide
• Primary brain injury- shear and neuronal
damage at the time of impact
• Secondary brain injury- ischemia (impaired
autoregulation, ↑ICP, Hypoperfusion) and
reperfusion injury (cascade leading to
apoptosis)

3. Hypothermia in TBI
• First mentioned in Papyrus 5000 years ago
• Hippocrates- snow packing to stop bleeding
• Sir William Osler- reduction in mortality of
typhoid fever
• Temple Fay- invented cooling blanket- relief in
pain for terminal malignancy
• Rosomoff et al (1950’s)- beneficial effect on ICP in
TBI
• HTh after cardiac arrest trial- better outcomes
with HTh

4. Hypothermia in TBI
Mechanism
AcutePhase
Reduces the release
of excitatory AA
Down regulates
astrocytic glutamate
trasporter I- which
mediates reverse
transport of
glutamate
Prevents glutamate
induced NO synthesis
Suppresses NMDA rec
phosphorylation
SubacutePhase
Attenuation of
oxidative and
nitrosative stress
markers
Mitigates the
inflammatory response
by reducing astrocytic
and microglial
activation
Decreases expression
of inflammatory
cytokines
Attenuates release of
proapoptotic mediators
Preserves BBB
ChronicPhase
Decrease cerebral
metabolism
Attenuates reperfusion
injury, BBB
permeability, edema
Helps in neuronal
regeneration and
circuit repair

5. Hypothermia in TBI
CV Effects
Positive inotropic-
arrhytmias
↑ MAP,SVR; ↓HR, CO
↑ VR- ANP,↓ADH- cold
diuresis-
hypotension
Pulmonary Effects
↓PaCO2
↑PaO2/ FiO2
↑Wound infection
No difference in rate
of pneumonia
Hematologic
function
Affects
platelet count,
coagulation
cascade
↑aPTTRenal, Endocrine, GI
effects
Electrolyte disorders-
K,Mg ↓
↓Insulin sensitivity- HG
Ileus, DGE
Liver function/
drug
Metabolism
Affects tubular
secretion and
reabsorption
Reduction in
enzyme activity
↓cP450
Physiological Effects

6. Hypothermia in TBI
Therapeutic Hypothermia
• hTH started <24 hrs x 3-5 d/
till ↑ICP resolves
• 4/5 trials- ↓mortality/
↑outcome
★ Jiang et al. J Neurosurg 2000
★ Shiozaki et al. J Neurosurg 2003
★ Jiang et al. J Cereb Blood Flow Metab
2006
★ Qui et al. J Crit Care 2007
★ Yan et al. J Clin Neurosci 2010
Prophylactic Hypothermia
• 33-34° <10 hrs x 24-48 hrs
irresp of ICP
• All trials failed to show
improved outcome
✧ Clifton et al. N Engl J Med 2001
✧ Marion et al. N Engl J Med 1997
✧ Shiozaki et al. J Neurosurg 2001

7. Hypothermia in TBI
No. Target temp/
duration
Mortality Neurol
outcome
Clifton et al. (NABIS:H II Trial) Lancet 2011 97 33/48 No No
Hutchinson et al. (HiTBIC Trial). NEJM 2008. 225 32.5/24 No No
Qui et al. J Crit Care 2007 80 33/96 No Yes
Adelson et al (Cool Kids) HYPO I and II.
Neurosurgery 2005
48/26 32/48 No No
Qui et al.Clin J Traumatology 2005 86 33/103 Yes Yes
Smrcka et al. Acta Neurochirur 2005 72 34/72 No Yes
Zhi et al. Surg neurology 2003 396 34/62.4 Yes Yes
Clifton et al. (NABIS:H Trial) NEJM 2001 392 33/48 No No
Shiozaki et al. J Neurosurg 2001 91 34/48 No No
Jiang et al. J Neurosurg 2000 87 32/>72 Yes Yes
Clifton et al. J Neurotrauma 1993 46 32/48 No No
Marion et al. NEJM 1997 82 32/24 No No
SUMMARY OF DIFFERENT TRIALS ON HYPOTHERMIA

8. Hypothermia in TBI
NABIS:H trial
• 392 pts- terminated for futility
• 33° x 48 hrs at a mean of 8.4 hrs
• hTH didn’t improve outcome+ more
hypotension
• Weak evidence of better outcome in pts
hypothermic at admission
Clifton GL et al. Lack of effect of induction of hypothermia after
acute brain injury. N Engl J Med 2001;344:556-63

9. Hypothermia in TBI
NABIS:H trial- Lessons learned!!!
• Pts hypothermic at admission and then
rewarmed- did worse
• >45 yrs- worse with hTH
• <45 yrs presenting with hTH not rewarmed
did well- suggests that there may be a narrow
therapeutic window

10. Hypothermia in TBI
• 13 Trials- Level II (6) and Level III (7)
• Overall, no difference in mortality, but 46% ↑
chance of good outcome
• hTH >48 hrs has ↓mortality
• level III recommendation for the use of hTH in
TBI
The brain trauma Foundation. Guidelines for the management of
severe traumatic brain injury. J Neurotrauma 2007;24:S21-25

11. Hypothermia in TBI
• Pts enrolled within 2-2.5 hrs- 33°x 48 hrs
• 232 pts- 119 (hTH)/113 (NT)
• No difference in outcome and mortality
• No utility of hypothermia
Clifton GL et al. Very early hypothermia induction in patients
with severe brain injury (the National Acute Brain Injury Study:
Hypothermia II): a randomised trial. Lancet Neurol 2011;10:131-
39

12. Hypothermia in TBI
• 77 pts- Terminated for futility
• hTH x 48 hrs- no difference after pediatric
severe traumatic brain injury
Adelson et al. Comparison of hypothermia and normothermia
after severe traumatic brain injury (Cool kids): A phase III
randomised controlled trial. Lancet Neurol 2013;12(6):546-53

13. Hypothermia in TBI
• 23 RCT- 1614 pts
• Significant benefit- only in low quality trials
• High quality trials- no decrease in death with hTH-
play of chance.
• hTH should not be used except in the context of a
high quality RCT with good allocation concealment
No evidence that
hypothermia is beneficial

14. Hypothermia in TBI
8 Metanalysis since
2002
Trials No. Mortality Neurological
outcome
Fox et al. CJEM. 2010;12:355-64 12 1327 Y Y
Sydenham et al. The Cochrane databse of systematic reviews
2009
21 1587 Y Y
Peterson et al. J Neurotrauma 2008;25:62-71 13 1339 Y Y
AANS BTF. J Neurotrauma 2007;24:S1-106
Alderson et al. . The Cochrane databse of systematic reviews
2004
Henderson et al. Intens Care Med 2003;29:1637-44 8 748 Y Y
McIntyre et al. JAMA 2003;289:2992-2999
Harris et al. Arch Neurol 2002;59:1077-1083 7 668 Y

15. Hypothermia in TBI
• 18 RCT (1851 Pts)- GRADE recommendations
• Overall RR of mortality and poor neurologic
outcome with hTH vs controls- 0.84 and 0.81
• High quality trials- RR 1.28
• hTH a/w ↓CPP on rewarming and pneumonia
• No benefit of hTH on mortality or neurologic
outcome
Georgiou et al. Role of Therapeutic hypothemria in improving
outcome after traumatic Brain injury: a systematic review.
Br J Anaesthesia 2013;110(3):357-67

16. Hypothermia in TBI
Forest Plot of all trials- effect of hTH vs NT on mortality

17. Hypothermia in TBI
Forest Plot of all trials- effect of hTH vs NT on poor neurological outcome

18. Hypothermia in TBI
Forest Plot of high quality trials- effect of hTH vs NT on mortality
Forest Plot of high quality trials- effect of hTH vs NT on poor neurological outcome

19. Hypothermia in TBI
Why lack of evidence so far???
• TBI- heterogenous disease- no study adequately
powered to study effect of hTH
• Peak ICP ↑ occurs >48 hrs- when several trials
have started rewarming
• Peak neuronal death occurs hrs after TBI- target
temp achieved <8 hrs only in some trials
• GOS is a crude assessment measure- subtle
outcome differences missed- GOSE better

20. Hypothermia in TBI
Future hTH trials should consider !!!!
• Initiation of hTH in prehospital setting
• Maintainence of hTH >48 hrs
• Rewarming acc to physiological rather than
time based criteria
• FU using GOSE

21. Hypothermia in TBI
Ongoing trials- Results Awaited Eagerly !!!
*Cooper J
*Andrews et al. Trials 2011;12:8
POLAR- RCT
Eurotherm

22. Hypothermia in TBI
AIIMS JPNATC Experience

23. PG ± HTh in severe TBI
FINANCIAL DISCLOSURES
Research grant funded by Department
of Biotechnology (DBT) New Delhi,
India

24. PG ± HTh in severe TBI
Aims and Objectives
• To examine the efficacy of Progesterone drug
and hypothermia, alone or in combination, in
improving neurological outcome in Severe
Traumatic Brain Injury.
• To study the difference in the levels of various
serum biomarkers after treatment and their
correlation with outcome

25. PG ± HTh in severe TBI
Materials and Methods
• Data Collected-
– Daily- vitals, ICP, CPP, BP, Intake/ Output, GCS score, ABG(pH , K+ , pCO2
,pO2,Hco3)
– Lab Test for 7 days.(Biochemistry,Haematology,Coagulation)
– CT Scan- at admission and Day 6
– Biochemical markers of STBI- (S100,NSE, Progesterone, Estrogen, IL 6, GFAP)-
at admission and 1st Week
INCLUSION CRITERIA EXCLUSION CRITERIA
• 18-65 years. • Any investigational drugs 30 days prior to
enrollment.
• GCS score 4-8 • Severe anoxic intracerebral damage or brain
death.
• <8 hours of injury. • Spinal Cord Injury
• Pregnancy
Type of study: Randomized Placebo controlled study

26. PG ± HTh in severe TBI
Study groups
Normal
temperature
Progesterone +
Normal
temperature
Hypothermia
Hypothermia
+Progesterone
Follow up at 1 and 6 moths
Primary endpoints:-
i. Glasgow Outcome Score
(GOS)
Secondary endpoints: --
i. Functional Independence
Measure (FIM).
ii. Mortality

27. PG ± HTh in severe TBI
Materials and Methods (Contd.)
• Injn. Progesterone- 1mg/kg I/M BD X 5 days
• Hypothermia- (surface cooling by blankets-
Blanketrol II, Cincinnati Sub-Zero, Cincinnati)
– 34 degree C X 24 hrs
– Rewarming- 0.5 degree/ 2hrs
• Placebo- 5 ml distilled water I/M BDX 5 days

28. PG ± HTh in severe TBI
Results
• Total Patients recruited- 107(27 in each A ,C &
D groups and 26 in Group B )
• Mean Age- 32 ± 11.27
• Sex- 90 males and 17 females
• Mean GCS- 6 ± 1.0
• Average time to recruitment- 5.0 ± 1.2 hrs
• Average time to desired temperature (34° C)- 45
± 12 minutes
• Mean ICP-10.21 ± 5.6

29. Group A
(Control )
Group B
(PG)
Group C
(HTh)
Group D
(HTh+PG)
Mean Age-
(years)
33.96 33.73 31.44 31.25
Sex- M/F 23/4 20/6 24/3 23/4
Mean GCS 6 6 6 6
Mean ICP 7.60 10.75 11.21 10.47
Base-line characteristics of patients with severe TBI
PG ± HTh in severe TBI
Results contd.

30. PG ± HTh in severe TBI
Results (Contd.)
Primary Endpoints-
GOS at 1 month
(n=90)
GOS at 6 month
(n=81)

31. PG ± HTh in severe TBI
Results (Contd.)
SECONDARY ENDPOINTS
Overall mortality-20.6%

32. PG ± HTh in severe TBI
CONCLUSIONS
• Good outcome at 6th month- best in Hypothermia group
(83%), followed by PG group (77%).
• Highest mortality found in Control (26%); Lowest (15%)
in Hypothermia group .
• PRG- shows more (76%) functionally independent pts at
6th month, followed by Hypothermia group (66.5%)
• PG + hTH does not confer any additional advantage

33. Hypothermia in TBI
TAKE HOME MESSAGE
• hTH should logically be useful in improving
the mortality and neurologic outcome
• Requires well designed large multicentric
RCT’s to prove association
• Presently, no definite Level I or II evidence-
BTF proposes Level III guideline

34. THANK YOU