Targeted Temperature Management in the Neuro-ICU: Who should be cooled

and why?

Fred Rincon, MD, MSc, MBE FACP, FCCP, FCCM

Associate Professor, Neurology and NeurosurgeryThomas Jefferson University

Division of Critical Care and NeurotraumaPhiladelphia, PA USA

Disclosures

• Financial

- Grant support (Current): Genentech, AHA CRP12050342

- Royalties: Elsevier

• Non-financial

- Research support: Cerner Corporation

• Unlabeled/Unapproved uses

- Most applications of cooling are off-label

My background

• I am a Critical Care Specialist with experience in different fields

• Extensive experience in implementing protocols for TTM in brain injured patients

• No personal experience in neonates

Outline

DefinitionsPathophysiologyEvidenceBench to bedside

From: 11th ICC SCCM. Puerto Rico 2008.

Targeted Temperature Management

NormothermiaHypothermia

Definitions

AUTHOR MILD MOD DEEP

Wong 32-35 26-31 20-25

Varnathan 32-35 26-31 20-25

Zeiner 34-36 28-33 17-27

Reuler 34-36 28-33 17-27

Hammer >32 28-32 20-28

Safar 33-36 28-32 11-27

Werner 34-36 29-33 17-28

From: Werner D. 11th ICC SCCM. Puerto Rico 2008.

Hypothermia

Definitions

STUDY INSULT TARGET TERM

Clifton TBI 33 Moderate

Bernard CA 33 Moderate

HACA CA 32-34 Mild

Todd Aneurysm 32.5-33.5 Mild

Shankaran Neonatal-Asphyxia 33.5 Not defined

Gluckman Neonatal-Asphyxia 33.5 Mild

From: Werner D. 11th ICC SCCM. Puerto Rico 2008.

Hypothermia

Consensus

•Clinical management issues

•Efficacy

•Basic science biology

Proposed Classification

• Normothermia (36-37)• Mild (35-36 C)

- Requires little intervention other than moderate sedation to control shivering

• Moderate (30-35 C)- Requires deep sedation, mechanical

ventilation, and/or neuromuscular blockade• Deep (<30 C)

- Requires extracorporeal circulatory support

Adapted from: Werner D. 11th ICC SCCM. Puerto Rico 2008.

TTM

Applications Neuro ICU

Neuroprotection ICP ControlCerebral edema

Hypothermia (30-35 C)Normothermia (36-37 C)

TTM

Experimental Brain Injury

Yamamoto et al. Infarct volume in focal cerebral ischemia in rats. Stroke 2001

Normo

Hypo

Kollmar et al. Stroke 2007

Buki et al. Axonal injury in TBI - rats. Exp Neurol 1999

Normo Hypo

CAMARADES. Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Stroke

Normo Hypo

Chopp et al. Neuronal death in global cerebral ischemia in rats. Stroke 1991

How does mild hypothermia attenuate neuronal death and improve neurological

outcomes when applied AFTER experimental brain injury?

Motor deficits in roedentsKakinohana. Anesthesiology 1999

Hypothermia

From: http://www.irmc.org. Accessed 10/1/10Michenfelder and Thiene. Anesthesiology, 1968

BEFORE injury ,deep and moderate hypothermia

have been used, and continued to be used, for preservation of cellular integrity, mithocondrial

function, and prevention of energy failure

Prevention of Brain InjuryHypothermia

Small differences in intra-ischemic brain temperature critically determine the extent of ischemic neuronal injury

Busto et al. J Cereb Blood Flow Metab 1987

20 min. of incomplete forebrainischemia

30 33 34 36 39

Measurement of energy

metabolites and hystopathology

at 3 days

MILD HYPOTHERMIA appeared to be neuroprotective by some other

mechanisms than simply preventing or reversing energy failure

Busto et al. J Cereb Blood Flow Metab 1987

50% reduction in neuronal death at 34 C

vs. 36 C, but no effect in striatal

levels of lactate, ATP, phosphocreatine, glycogen, glucose

Experimental Brain InjuryHypothermia

Therapeutic Hypothermia

Is it blocking secondary injury cascades?

Is it preventing loss of endogenous neuroprotectants?

Is it conferring benefits by increasing neuroprotectant levels?

Zhao H.Journal Cereb Blood Flow Metab 2007 & Kochaneck P. 11th ICC SCCM. Puerto Rico 2008.

1

2

3

Therapeutic Hypothermia

Zhao H.Journal Cereb Blood Flow Metab 2007

Therapeutic hypothermia blocks

NUMEROUS secondary injury mechanisms in

experimental brain injury relevant to

critical care medicine

SupressesGlutamate

release

Attenuatesoxidative

stress

Regulatesgene

expression

Attenuatesapoptosis

Blunts inflammatory

response

Limits energyfailure

Atennuatesnitrosative

stressLimits

cytoskeletaldamage Increases

levels ofneurotrop.

AtennuatesMMP

activation

Atennuatesanoxic

depolar.

AtennuatesBBB

injury

LimitsDephos-

phorilation

Mild Therapeutic Hypothermia

Adapted from: Kochaneck P. 11th ICC SCCM. Puerto Rico 2008.

Mechanistic evidence

1 Is it blocking secondary injury cascades?

Mordecai G. J. Neurochem. 65, 1704-1711 (1995)

Hypothermia 30 C

2 Is it preventing loss of endogenous neuroprotectants?

Zhao H. The Journal of Neuroscience, 2005 • 25(42):9794 –9806

AKT= protein kinase B (PKB)

8 min. of asphyxial CAHypothermia 33 C 60 minutes after

ROSC12-24 hr

Measurement of BDNF(Prevents neuronal death)

3 Is it conferring benefits by increasing neuroprotectant levels?

DCruz J et al. Journal of Cerebral Blood Flow & Metabolism 2002; 22:843–851.

MILD-MOD HYPOTHERMIA blocks numerous secondary injury pathways but

has complex mechanistic effects

Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc 1964; 54:629–635

Cardiac Arrest

Holzer M. N Engl J Med 2002;346:549-56.

Cardiac Arrest

Holzer M. Crit Care Med 2005; 33:414–418.

Hypothermia

Cardiac ArrestHypothermia

Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. N Engl J Med. 2013 Nov 17.

Traumatic Brain Injury

Traumatic Brain InjuryHypothermia

Traumatic Brain Injury

• No effect on outcome

• Significantly reduced ICP

• Increased rate of complications and LOS

N Engl J Med, Vol. 344, No. 8 · February 22, 2001

Hypothermia

Traumatic Brain Injury

Tukotomi T et al. Neurosurgery 52:102-112, 2003

Hypothermia

Traumatic Brain Injury

Polar RCT

Spinal Cord Injury

Spinal Cord Injury

Motor deficits in roedentsKakinohana. Anesthesiology 1999

Hypothermia

Ischemic Stroke

Ischemic stroke

Kollmar and Schwab. JOURNAL OF NEUROTRAUMA 26:377–386 (March 2009)Den Hertog Cochrane Review 2009.

Hypothermia

HypothermiaMalignant MCA Stroke

Schwab S et al. Stroke. 1998;29:2461-2466.

StrokeHypothermia

Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, et al. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke. 2010 Oct;41(10):2265–70.

Ischemic StrokeFever

Saini M et al. Stroke. 2009;40:00-00.

Ischemic Stroke

http://www.eurohyp.org

RECCLAIM STUDY: Endovascular Management and Cooling

ICH

ICHHypothermia

Kollmar R. Stroke 2010; 41:1684-1689

35 oC mRS 9 daysHematoma growthPerihematma edemaSide effects hypothermia

12 patientssICH

> 25cc

ICH

Schwarz S. Neurology 2000; 54: 354-361

Fever

ICHFever

Rincon F, Lyden P, Mayer SA. Relationship Between Temperature, Hematoma Growth, and Functional Outcome After Intracerebral Hemorrhage. Neurocrit Care. 2012 Sep 22;18(1):45–53.

ICH

CINCH

TTM-ICHhttp://clinicaltrials.gov/ct2/show/NCT01607151

http://www.controlled-trials.com/ISRCTN28699995

SAH

SAH

Todd MM et al. N Engl J Med 2005;352:135-45.

SAHFever

Fernandez A. Neurology.2007; 68: 1013-1019

• Jalan et al (Lancet 1999)

- 7 patients with ALF and intracranial hypertension + cerebral edema

- Moderate hypothermia

- ICP decreased from 45 to 16mmHg

- CPP increased from 45 to 70mmHg

- 3 patients bridged to transplant and all survived

Hepatic Encephalopathy

Hepatic Encephalopathy

Stravitz RT, Larsen FS. Therapeutic hypothermia for acute liver failure. Crit Care Med. 2009 Jul 1;37(Supplement):S258–64.

Status Epilepticus

Status Epilepticus

HYBERNATUS

http://clinicaltrials.gov/show/NCT01359332

Other applications

• Severe sepsis / septic shock

• ARDS

• Radio-contrast nephropathy

• Meningo-encephalitis

• Post-Cardiac surgery shock

• ACS/AMI

Brain InjuryFever

Greer DM. Stroke. 2008;39: 000

14,431

Brain InjuryFever

Rincon F et al. (Unpublished data)

Effect of Early Hyperthermia on Hospital Mortality in Critically-ill Neurological Patients

Brain InjuryFever

Rincon F et al. Significance of admission temperature and impact on mortality in critically-ill neurological patients. Critical Care 2011; 15(Suppl 1): P320 (11 March 2011).

Recommendations

• Neuroprotection

- Cardiac Arrest

- SCI

- MCA Infarction

- SAH - Aneurysm, TBI

Hypothermia

Recommendations

• ICP and mass effect

- TBI?, Hepatic encephalopathy

- MCA infarction

Hypothermia

RecommendationsNormothermia

• Neuroprotection

- All brain injuries

Summary

• Experimental models suggest that hypothermia modulates multiple mechanisms in models of CCM related insults

• Clinical studies mainly in CA, SCI, and TBI (mainly animal) have shown some or clear evidence in clinical outcomes

• Survival after brain injury may depend on the brain remaining “Cool”

Acknowledgements

• Slide segments / portions

• D. Werner, Duke Medical Center

• P. Kochaneck, UPMC

• Sergio Zanotti, Cooper

• SCCM