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Hypothermia in TbI

Hypothermia in TBI for Neuroprotection.

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Hypothermia in TbI

  1. 1. HYPOTHERMIA IN TBI FOR NEUROPROTECTION Dr Sumit Sinha Additional Professor Deptt of Neurosurgery, AIIMS and JNATC, New Delhi
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 16. Hypothermia in TBI Forest Plot of all trials- effect of hTH vs NT on mortality
  17. 17. Hypothermia in TBI Forest Plot of all trials- effect of hTH vs NT on poor neurological outcome
  18. 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. 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. 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. 21. Hypothermia in TBI Ongoing trials- Results Awaited Eagerly !!! *Cooper J *Andrews et al. Trials 2011;12:8 POLAR- RCT Eurotherm
  22. 22. Hypothermia in TBI AIIMS JPNATC Experience
  23. 23. PG ± HTh in severe TBI FINANCIAL DISCLOSURES Research grant funded by Department of Biotechnology (DBT) New Delhi, India
  24. 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. 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. 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. 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. 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. 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. 30. PG ± HTh in severe TBI Results (Contd.) Primary Endpoints- GOS at 1 month (n=90) GOS at 6 month (n=81)
  31. 31. PG ± HTh in severe TBI Results (Contd.) SECONDARY ENDPOINTS Overall mortality-20.6%
  32. 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. 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. 34. THANK YOU