Kees H. PoldermanThe Essex Cardiothoracic Centre, Basildon and

Thurrock University Hospitals; Anglia Ruskin School of Medicine, London-Essex, United Kingdom; and

United General Hospital, Houston, USA

Targeted temperature management to treat post-

ischemic injuries

Napa Valley, September 27TH 2019

First: Thanks for inviting me here!

DisclosuresMy trip here is being sponsored by BD

medical.A honorarium will be paid to a research

foundation.The slides and opinions presented here are

my own.

Topics of my lecture:1: Introduction2: (Briefly): physiology/underlying mechanisms3. Fever4: Cardiac arrest – which temperature target?5: Perspective & conclusions

Temperature is an important physiological parameter in critically ill patients.It should be regarded in the same way as

blood pressure, heart rate, etc. So you should have a core temperature

target for each patient, and a range that you are willing to accept; and if the temperature is outside that range you should react just as aggressively as you would for hypo/hypertension, or hyper/hypocapnia, or hypoxia/hyperoxia.

Production of free radicals (O2, NO2, H2O2, OH-)

Reperfusion injury

Immune response, neuroinflammation

Ion pump dysfunction, influx of

calcium into cell, neuroexcitotoxicity

Cell membrane leakage, formation of

cytotoxic edema, intracellular acidosis

Mitochondrial injury and

dysfunction

Increased vascular permeability,

edema formation

“Cerebral thermo-pooling” and local

hyperthermia

Coagulation activation,

formation of micro-thrombi

Harmful changes in

cerebral metabolism

Permeability of the blood-brain barrier, edema formation

Epileptic activity & seizures

Apoptosis, calpain-mediated proteolysis,

DNA injury

Local generation of endothelin & TxA2;

generation of prostaglandins

Decreased tolerance for

ischemia

Spreading depression-like depolarizations

Activation of protective

“Early genes”

Destructive processes following ischemia/reperfusion. that can be prevented or significantly mitigated .Blue lettering = early mechanisms Red lettering = late mechanisms

Adapted from: Polderman KH. Mechanisms of action, physiologic effects and complications of hypothermia. Crit Care Med 2009; 37[Suppl.]:S186 –S202

Decrease in cerebral repair mechanisms;

acidosis, production of toxic metabolites

Production of free radicals (O2, NO2, H2O2, OH-)

Reperfusion injury

Immune response, neuroinflammation

Ion pump dysfunction, influx of calcium into cell,

decreased neuroexcitotoxicity

Cell membrane leakage, formation of cytotoxic edema, intracellular acidosis

Mitochondrial injury and

dysfunction

Decreased vascular permeability, edema formation

“Cerebral thermo-pooling” and local

hyperthermia

Coagulation activation, formation of micro-thrombi

Cerebral metabolism

(increase 6-10% per oC below

37oC)

Permeability of the blood-brain

barrier, edema formation

More depressed cerebral repair, acidosis, production of toxic

metabolites

Increase of epileptic activity &

seizures

Apoptosis, calpain-mediated proteolysis,

DNA injury

Local generation of endothelin & TxA2; generation of prostaglandins

Decreased tolerance for

ischemia

Spreading depression-like depolarizations

Activation of protective

“Early genes”

They are allstimulatedby fever…

Production of free radicals (O2, NO2, H2O2, OH-)

Reperfusion injury

Immune response, neuroinflammation

Ion pump dysfunction, influx of calcium into cell,

decreased neuroexcitotoxicity

Cell membrane leakage, formation of cytotoxic edema, intracellular acidosis

Mitochondrial injury and

dysfunction

Decreased vascular permeability, edema formation

“Cerebral thermo-pooling” and local

hyperthermia

Coagulation activation, formation of micro-thrombi

Cerebral metabolism (decrease 6-10% per oC below 37oC)

Permeability of the blood-brain

barrier, edema formation

Improved cerebral repair, acidosis, production

of toxic metabolites

Suppression of epileptic activity &

seizures

Apoptosis, calpain-mediated proteolysis,

DNA injury

Local generation of endothelin & TxA2; generation of prostaglandins

Improved tolerance for ischemia

Spreading depression-like depolarizations

Activation of protective

“Early genes”

...and inhibitedby hypothermia!

Production of free radicals (O2, NO2, H2O2, OH-)

Reperfusion injury

Immune response, neuroinflammation

Ion pump dysfunction, influx of

calcium into cell, neuroexcitotoxicity

Cell membrane leakage, formation of

cytotoxic edema, intracellular acidosis

Mitochondrial injury and

dysfunction

Increased vascular permeability,

edema formation

“Cerebral thermo-pooling” and local

hyperthermia

Coagulation activation,

formation of micro-thrombi

Harmful changes in

cerebral metabolism

Permeability of the blood-brain barrier, edema formation

Epileptic activity & seizures

Apoptosis, calpain-mediated proteolysis,

DNA injury

Local generation of endothelin & TxA2;

generation of prostaglandins

Decreased tolerance for

ischemia

Spreading depression-like depolarizations

Activation of protective

“Early genes”

Some of these processes

GENERATE HEAT.

Decrease in cerebral repair mechanisms;

acidosis, production of toxic metabolites

Romano et al., Brain temperature exceeds systemic temperature in head-injured patients. Critical Care Medicine 1998;562-567

Brain-, blood- and rectal temperature in TBI:

Blood

Brain

BloodRectum

Brain

Brain and bladder temperature in stroke

Schwab S et al. Neurology 1997; 48:762-7.

In cardiac arrest patients:N=11 patients with severe injuryBrain temperature compared to esophageal or

rectalOn average brain temperature was 0.34C°

higher than core temperature. The difference varied, and brain temperature

exceeded measured core temperature by ≥1°C for 7% of the time.

OF NOTE, these patients were all being cooled to 32-33oC, which decreases the brain-core gradient!

Coppler PJ et al. Ther Hypothermia Temp Manag 2016;6:194-197

Infectious Infectious

√ Pneumonia

√ Central lines infection

√ (Urinary Tract Infection)

√ NG Tubes

√ etc.

Sources of fever in neuro patientsNon-Infectious

Neurogenic or Central√ Activation of the

inflammatory cascade

√ Damage to the

thermoregulatory center in

the hypothalamus

√ Trauma or intracranial

lesions

√ Presence of ICP monitor

Miscellaneous√ Drugs, medications

Infectious Infectious

√ Pneumonia

√ Central lines infection

√ (Urinary Tract Infection)

√ NG Tubes

√ etc.

Non-infectious√ Drugs, medications

Sources of fever in neuro patientsNon-Infectious

Neurogenic or Central√ Activation of the inflammatory

cascade

√ Damage to the thermoregulatory

center in the hypothalamus

√ Trauma or intracranial lesions

√ Presence of ICP monitor

Miscellaneous√ Drugs, medications

In addition, patients with acute brain injury have immune dysfunction, mediated through the vagal nerve and cytokine release. This has been

shown for TBI but likely also occurs in other types of brain injury.

Fever in neurological injury:In all animal models for stroke, global ischemia, TBI and intracranial haemorrhage: Active warming is harmful (even a little warming, say

1oC above normal);Spontaneous development of hyperthermia is

harmful;Maintaining normothermia is protective;And mild hypothermia significantly decreases

the extent of injury

Azzimondi G et al, Stroke 1995; 26:2040–2043; Dávalos A. Cerebrovasc Dis 1997; 7:64–69; Hajat C et al. Stroke 2000; 31:410-14; Kammersgaard LP et al. Stroke 2002; 33:1759-6; etc.

Fever in neurological injury:In all animal models for stroke, global ischemia, TBI and intracranial haemorrhage: Active warming is harmful (even a little warming, say

1oC above normal);Spontaneous development of hyperthermia is

harmful;Maintaining normothermia is protective;And mild hypothermia significantly decreases

the extent of injuryHyperthermia is especially harmful during periods of ischemia (i.e., during secondary injury)

Azzimondi G et al, Stroke 1995; 26:2040–2043; Dávalos A. Cerebrovasc Dis 1997; 7:64–69; Hajat C et al. Stroke 2000; 31:410-14; Kammersgaard LP et al. Stroke 2002; 33:1759-6; etc.

37oC

38oC

39oC

Wass CT et al. Anesthesiology 1995;83:325-35

Neurologic function

Poor outcome when fever develops after hypothermia treatment after CA….

Zeiner A et al. Arch Int Med 2001;161:2007-12

Fever following out-of-hospital cardiac arrest (OHCA):

Suffoletto B et al. Resusciatation 2009; 80:1365-70.

Fever following in-hospital cardiac arrest (IHCA):

Douds GL et al. Neurol Res Int2012;479865.

Greer DM et al. Stroke 2008;39:3029-35.

This is not really new….

Greer et. al. (2008)

Meta-analysis in 14,431 patients

Fever was significantly

associated with worse

outcomes

Elevated body temperature was associated with a dose-dependent: ICU & Hospital LOSMortality rate

Diringer M et al. Crit Care Med 2004; 32;1489-93

4,295 patients with LOS >1 day

Elevated body temperature was associated with 3.2 additional ICU days and 4.3 additional hospital days

ICU LOS was predicted by the number of complications and elevated body temperature

Fever in a mixed neuro-ICU:Diringer M et al. Crit Care Med 2004; 32;1489-93

Subarachnoid Hemorrhage Fever burden is independently associated with

mortality and poor functional outcomeFernandez A et al., Neurology 2007;68:1013-19

Intracerebral Hemorrhage Duration of fever (>37.5° C!) within the first 72

hours is independently associated with poor outcomeSchwarz S et al., Neurology 2000;54:354-61

Fever in hemorrhagic stroke:

Does controlling fever improve outcome?

Badjatia N et al. Neurosurgery 2010;66:696-700

Badjatia N et al. Neurosurgery 2010;66:696-700

But don’t we need a febrile response to fight infections?

Schortgen F et al. Am J Respir Crit Care Med 2012;185:1088–1095

Schortgen F et al. Am J Respir Crit Care Med 2012;185:1088–1095

Schortgen F et al. Am J Respir Crit Care Med 2012;185:1088–1095

N=436 patients. Age >50. Septic shock. Routine thermal.

management vs. 24 hours of TH 32-34°C.

No benefit: 0-day mortality 44.2% vs. 35·8% (p=0.07).

OK. So, how can we control fever?

Overview of Cooling MethodsConventional

– Antipyretic drugs

– Evaporation:• Water sprays, sponge bath

– Conduction• Ice, water circulation, water blanket, immersion

– Convection• Fans, air circulating cooling blanket

– Radiation • Exposure 1. Bader, MK. & Littlejohn, LR. (2009). AANN Core Curriculum for Neuroscience Nursing. St. Louis, MO: Saunders. pp. 237-246.

2. Mehta, S. (2010). PA: HMP Communications. pp. 603-612.3. Lee, K. (2012). The NeuroICU Book. New York: McGraw Hill

Companies, Inc. p. 192.4. Badjatia, N. (2012). The NeuroICU Book. New York, NY: McGraw

Hill. pp. 342-357.5. Guanci, MM. & Mathiesen, C. (2009). Foundations of Neuroscience

Nursing. pp. 237-246.

Advanced– Non-invasive core cooling

– Intravascular

Ok. So we start by giving Tylenol, or NSAID’s.

Efficacy of oral (or IV) antipyretics:

1. Dippel DW et al. Stroke 2001; 32:1607-12; 2. Dippel DW et al. BMC Cardiovasc Disord 2003;3:2; 3. Kasner SE et al. Stroke 2002; 33:130-4; 4. Gozzoli V et al. Intensive Care Med 2004; 30:401-7; 5. Henker R et al. Am J Crit Care 2001; 10:276-80; 6. Bachert C et al. Clin Ther 2005; 27:993-1003; 7. Walson PD et al. Clin Pharmacol Ther 1989; 46:9-17; 8. Latest study Dippel

The effectiveness of these drugs is very limited, especially in patients with neurological (central) fever.

In large studies the average decrease in temperature during treatment with high doses (4000-6000 mg/day) of acetaminophen is only 0.3-0.4oC.1-8

Similar results have been reported in smaller studies using high doses of aspirin, Ibuprofen and metamizole.5-7

Shivering ManagementCounter warming is the first line therapy for

shivering treatment1

Sedation prevents increased metabolism1

Paralytic agents affect shivering1-3 Precautions: difficult to identify seizures, select agent with anticonvulsant

properties, continuous EEG may be utilized, drug metabolism is affected, appropriate dosing must be tailored to the specific conditions of the patients and must be tightly monitored

1. Mehta, S. (2010). PA: HMP Communications. pp. 603-612.2. Nunnally, ME. (2010). Mount Prospect: SCCM. pp. 21-27.3. Lee, K (2012). The NeuroICU Book. New York: McGraw Hill

Companies, Inc. p. 192.

Skin counterwarming

• May reduce incidence of shivering

• Tricks skin receptors into believing the body is warm

• Warm air circulating may be used to cover these areas

1. Bader MK, Littlejohn LR. AANN Core Curriculum for Neuroscience Nursing. St. Louis, MO: Saunders 2009 page 237-246.

2. Guanci MM, Mathiesen C. Foundations of Neuroscience Nursing 2009;237-246.

Magnesium (MgSO4, MgCl2) Buspirone Ondansetron Nefopam Clonidine Ketanserin Urapidil Physostigmine Doxapram

Paralytic agents

Medications to combat shivering:

Adapted from: Polderman KH et al. Critical Care Med 2009; 37:1101-20

Meperidine/pethidine Opiates quick-acting: fentanyl,

remi-fentanyl; or slow-acting, e.g.tramadol or morphine)

Propofol Benzodiazepines

(midazolam, temazepam, diazepam, etc. )

Dexmedetomidine Ketamine

Non-sedating Sedating

So, cooling for cardiac arrest….

3 major changes compared to 2010: 1. Recommendation for strict fever management after initial period of hypothermia; 2. Recommendation to treat all CA arrest patients with TTM (strong recommendation for shockable rhythms, weak recommendation for non-shockable rhythms and IHCA);3. Widening of temperature range for hypothermia from 32-34oC to 32-36oC.

AAN guidelines 2017: TTM 32-34oC recommended

ENLS guidelines update 2015 and 2017: no change in recommended target temperature, remains at 32-34oC

Disclosure:

No significant difference between 36 and 33 degree group….

46.5% 47.8%

Nielsen N et al. N Engl J Med 2013;369:2197-206.

The only difference in favor of 33oC compared to 36oC…..

So, why do I feel that this study doesn´t settle the case?

Production of free radicals (O2, NO2, H2O2, OH-)

Reperfusion injury

Immune response, neuroinflammation

Ion pump dysfunction, influx of

calcium into cell, neuroexcitotoxicity

Cell membrane leakage, formation of

cytotoxic edema, intracellular acidosis

Mitochondrial injury and

dysfunction

Increased vascular permeability,

edema formation

“Cerebral thermo-pooling” and local

hyperthermia

Coagulation activation,

formation of micro-thrombi

Harmful changes in

cerebral metabolism

Permeability of the blood-brain barrier, edema formation

Epileptic activity & seizures

Apoptosis, calpain-mediated proteolysis,

DNA injury

Local generation of endothelin & TxA2;

generation of prostaglandins

Decreased tolerance for

ischemia

Spreading depression-like depolarizations

Activation of protective

“Early genes”

Argument 1: physiology.

Destructive processes following ischemia/reperfusion. that can be

Blue lettering = early mechanisms Red lettering = late mechanisms

Adapted from: Polderman KH. Mechanisms of action, physiologic effects and complications of hypothermia. Crit Care Med 2009; 37[Suppl.]:S186 –S202

Decrease in cerebral repair mechanisms;

acidosis, production of toxic metabolites

Production of free radicals (O2, NO2, H2O2, OH-)

Reperfusion injury

Immune response, neuroinflammation

Ion pump dysfunction, influx of calcium into cell,

decreased neuroexcitotoxicity

Cell membrane leakage, formation of cytotoxic edema, intracellular acidosis

Mitochondrial injury and

dysfunction

Decreased vascular permeability, edema formation

“Cerebral thermo-pooling” and local

hyperthermia

Coagulation activation, formation of micro-thrombi

Cerebral metabolism

(increase 6-10% per oC below

37oC)

Permeability of the blood-brain

barrier, edema formation

More depressed cerebral repair, acidosis, production of toxic

metabolites

Increase of epileptic activity &

seizures

Apoptosis, calpain-mediated proteolysis,

DNA injury

Local generation of endothelin & TxA2; generation of prostaglandins

Decreased tolerance for

ischemia

Spreading depression-like depolarizations

Activation of protective

“Early genes”

They are allstimulatedby fever…

Production of free radicals (O2, NO2, H2O2, OH-)

Reperfusion injury

Immune response, neuroinflammation

Ion pump dysfunction, influx of calcium into cell,

decreased neuroexcitotoxicity

Cell membrane leakage, formation of cytotoxic edema, intracellular acidosis

Mitochondrial injury and

dysfunction

Decreased vascular permeability, edema formation

“Cerebral thermo-pooling” and local

hyperthermia

Coagulation activation, formation of micro-thrombi

Cerebral metabolism (decrease 6-10% per oC below 37oC)

Permeability of the blood-brain

barrier, edema formation

Improved cerebral repair, acidosis, production

of toxic metabolites

Suppression of epileptic activity &

seizures

Apoptosis, calpain-mediated proteolysis,

DNA injury

Local generation of endothelin & TxA2; generation of prostaglandins

Improved tolerance for ischemia

Spreading depression-like depolarizations

Activation of protective

“Early genes”

...and inhibitedby hypothermia!

This is a LINEAR relationship. In general, fever control is protective, but hypothermia is more protective.For example, the metabolic rate

decreases by 7-10% per oC

Guinea pigs Hamsters Rats Mice

Cats

Dogs

Orang utangs

Pigs

Sheep

Chimpanzees

Pigtail monkeys

Rhesus monkeys

Baboons

Arguments 2 & 3.Dose-dependent effects of temperature

on brain injury (and injury to other organs) have been demonstrated in hundreds of experiments, in every

species used for experiments.

Group A (controls);Group D (cold fluids & surface cooling)

Group E (rapid cooling with cardiac device)

Dae MW et al. Am J Physiol Heart Circ Physiol 2002; 282: H1584–H1591

Normothermia

Hypothermia

Dose dependent

Argument 4.

The baby studies….

Cooling for neonatal asphyxia.

0%

10%

20%

30%

40%

50%

60%

70%

80%

Eicher DJ et al. Ped Neurol 2005

Shankaran S et al.New Engl J Med 2005

Gluckman PD et al. Lancet 2005

N=65 N=208 N=218

Goo

d ne

urol

ogic

al o

utco

me

(%)

Perinatal asphyxia - Multicenter RCT’s% Favourable outcome; n=1329 patients

N=325

Azzopardi D et al. New Engl J Med 2009

Zhou W et al. J Pediatr 2010

+32%+210%P=0.02

+20% +46%

P=0.01

Hypothermia Controls

+11% +32%

P=0.05

+16% +53%

P=0.003

N=194

+18% +48%

P=0.01

Simbruner G et al. Pediatr 2010

N=111

+32% +160%

P=0.001

Jacobs S et al. Arch Ped Ad Med 2011

+15% +53%

P=0.03

N=208

Grafiek2

0.480.16

0.560.36

0.450.34

0.440.28

0.690.51

0.4910.172

0.4860.337

Blad1 (4)

Tokutomi 200925152818

0.550.39Jiang 200528182721

0.490.26Zhi 200327211812

0.190Gal 200218123715

Polderman 200237153615

Polderman 200136153515

Tateishi 19982412

Marion 199735153818

Metz 19962314

Shiozaki 199338183018

Marion 199330182512

2414

2512Tateishi

ICP values

2818

2721

High ICP TBI1812

StudyN3715

Jiang 200547292153615

Qiu 200565.137.286

Zhi 200338.819.73963116

Gal 2002874730

Polderman 2002298136

Polderman 200115041

Yan 2001452044

Clifton 200157573923515

Aibiki 20008036.426

Jiang 200046.527.3873818

Zhang 200066.759.32463018

Marion 1997623882

Clifton 199352.236.446Tokutomi2512

Shiozaki 1993501833

Marion 1993604040

Tokutomi 2003

Yamamoto 2002

Bernard 1999

Shiozaki 199827.5

Tateishi 1998

Metz 1996

Neurol oucomeDeath

Harris 20020.610.26-1.46na692

Henderson 20020.750.810,56-1,010,59-1,13748

McIntyre 20020.780.810,63-0,980,69-0,961069

Alderson 20040.750.80,56-1,000,61-1,041061

cooledcontrolstotal

Williams 1958144

Benson 19590.50.14312719

Bernard 19970.50.136222244

Yanagawa 19980.230.07131528

Nagao 20000.5223023

Zeiner 20000.5727027

Mori 20000.790.25272754

Felberg 20010.33909

Polderman 20030.330.148284166

Al-Senani 20040.3913013

Busch 20060.320.16273461

Oddo 20060.5580.26434386

Sunde 20070.560.266158119

Kim 20070.660.45292251NS

Belliard 20070.560.36363268

Kim 20070.3330.296362125NS

Oddo 20080.470.27474

Howes 20100.682222

428344772

Neurol oucomeDeath

Harris 20020.610.26-1.46na692

Henderson 20020.750.810,56-1,010,59-1,13748

McIntyre 20020.780.810,63-0,980,69-0,961069

Alderson 20040.750.80,56-1,000,61-1,041061

BernardYanagawaZeinerNagaoMoriFelberg

Hypothermia502352577933

Ctrl (histor.)13.672725

Survival

BarbituratesBarbiturateControlsN

Survival & good outcome

Bohn 19895668OR 1,38 (0,79-2,44)82

Ward 198540.738.5OR 0,96 (0,62-1,64)73n=135

Survival

Eisenberg 198837.947.2OR 1,18 (0,79-1,75)53

Bohm 198973.273.2OR 1,00 (0,49-2,04)82

Ward 198548.150OR 1,09 (0,81-1,47)73n=208

Vs mannitol

OR 1,21 (0,75-1,94)59

OR 1,75 (1,05-2,92)59

Bohn 198956681.38

Ward 198540.738.50.96

1.18

Eisenberg 198837.947.21

Bohm 198973.273.21.09

Ward 198548.150

1.15(0,81-1,64)

1.09(0,81-1,47)Death

ICP control

Schwartz

Neurol oucomeDeath

Harris 20020.610.26-1.46na692

Henderson 20020.750.810,56-1,010,59-1,13748

McIntyre 20020.780.810,63-0,980,69-0,961069

Alderson 20040.750.80,56-1,000,61-1,041061

Brain Trauma Foundation0.680.750,52-0,890,50-1,05

Peterson 20080.520.510,35-0,780,33-0,79781

RCT

Shankaran et al.0.720.680,54-0,950,44-1,05206

Gluckman et al.0.570,32-1,01218

HypotContrHypotContrHypotContr

Neurological outcomeDeathAdverse outcome (death or perm disab)

Gluckman193133385566

Eicher 20050.480.1665

Shankaran 20050.560.36208

Gluckman 20050.450.34218

Azzopardi 20090.440.28325

Zhou W 20100.690.51194

Simbruner G 20100.4910.172111

Jacobs S 20110.4860.337208

1329

0.656250.7407407407

0.80.7714285714

0.87058823530.8333333333

0.60.4888888889

10.8823529412

0.60.5

0.54867256640.4690265487

0.58823529410.4

0.480.16

0.560.36

0.450.34

0.440.28

0.690.51

Blad1 (4)

Blad4

Blad1 (3)

Blad1 (2)

Blad1

Blad2

2818

2721

1812

3715

3615

3116

3515

3818

3018

Blad3

5539

4926

190

High ICP TBI

StudyN

Qiu 20077047.580

Liu 200665.134.866

Qiu 200668.946.790

Jiang 20054729215

Qiu 200565.137.286

Zhi 200338.819.7396

Gal 2002874730

Polderman 2002298136

Polderman 200115141

Yan 2001452044

Clifton 20015757392

Aibiki 20008036.426

Jiang 200046.527.387

Zhang 200066.759.3246

Marion 1997623882

Clifton 199352.236.446

Shiozaki 1993501833

Marion 1993604040

Tokutomi 2003

Yamamoto 2002

Bernard 1999

Shiozaki 199827.5

Tateishi 1998

Metz 1996

Neurol oucomeDeath

Harris 20020.610.26-1.46na692

Henderson 20020.750.810,56-1,010,59-1,13748

McIntyre 20020.780.810,63-0,980,69-0,961069

Alderson 20040.750.80,56-1,000,61-1,041061

5539

4926

190

High ICP TBI

StudyN

Jiang 20054729215

Qiu 200565.137.286

Gal 2002874730

Zhi 200338.819.7396

Polderman 2002298136

Polderman 200115053

Yan 2001452044

Aibiki 20008036.426

Jiang 200046.527.387

Zhang 200066.759.3246

Marion 1997623882

Clifton 199352.236.446

Shiozaki 1993501833

Marion 1993604040

Hypothermia

Controls

5539

4926

190

High ICP TBI

StudyN

Jiang 20054729215

Qiu 200565.137.286

Gal 2002874730

Zhi 200338.819.7396

Polderman 2002298136

Polderman 200115053

Yan 2001452044

Aibiki 20008036.426

Jiang 200046.527.387

Zhang 200066.759.3246

Marion 1997623882

Clifton 199352.236.446

Shiozaki 1993501833

Marion 1993604040

Hypothermia

Controls

Temperature control was applied in controls in all of these studies.

Shankaran S et al. New Engl J Med 2005;353:1574-84.

N=325

N=208Target temp in controls 36.5°C-37.0°C

(active temperature management).

Mean ± SD

Azzopardi D et al. New Engl J Med 2009;361:1349-58.

N=325Target temp in controls 37.0 ± 0.2°C(active temperature management).

Mean ± 2SD

Zhou WH et al, J Pediatr 2010;157:367-72

N=194Target temp in controls 36.5-37.0

(active temperature management).

Mean ± SD

Criticisms of the HACA trial and Bernard trial….

12 hours0.25oC/hr

HACA trial

Cardiac arrest in pediatric patients…..

N=260, 138 treated with TH (temp 33.0oC) and 122 controls (temp 36.6oC)

Difference in survival 9% (relative 31%); p=0.14 Difference in good neurologic outcome: 8% (relative 53%), p=0.13

3. .4. .5. The TTM trial was FLAWED. It almost seems

designed to prove that TH doesn’t work.

The arguments against 36oC (and ≥37.5oC) - 2

Polderman KH, Varon J. Circulation 2015;131:669-675; Polderman KH, Varon J. TherHypothermia 2015;5:73-76. Polderman KH, Varon J. Crit Care 2014;18:130; Varon J, Polderman KH. New Engl J Med 2014;370:1358-59.

Aibiki M et al.; Board of Directors of the Japanese Association of Brain Hypothermia. Ther Hypothermia Temp Manag 2014;4:104. Perchiazzi G et al. N Engl J Med 2014;370:1356; NordBerg P et al., PRINCESS investigators; New Engl J Med 2014;370:1356-57; Oh S P et al., New Engl J Med 2014;370:1357; Taccone F et al., New Engl J Med 2014;370:1357-8; Stub D et al., New Engl J Med 2014;370:1358; Kim et al., Stroke 2015;46:592-597.

It took up to 4 hours to randomize; no temperature management during that time

10 hours to target in the 33oC group. (In animal studies the time window for TH is up to ±6 hours)

Many other problems: potential selection bias, rapid rewarming rate, etc. etc.

Weaknesses….

Øresund bridge

It took up to 4 hours to randomize; no temperature management during that time

10 hours to target in the 33oC group. (In animal studies the time window for TH is up to ±6 hours)

Pre-screening of patients by the ER physician, who decided whether patients would receive the routine treatment (=TH), or whether treatment should be withheld and the study coordinator called to screen them for the study. This almost guarantees selection bias.

This explains the enrollment rate of 65.6%, the highest in any study that I have ever seen

Enrolment number of 1 per center/month (or 1.5, according to a subsequent publication by the authors); ≠ all CA patients admitted in the study period; = selection for sure, possible selection bias

Weaknesses….

Small imbalances between groups, mostly in favor of the 36oC group

Rapid rewarming rate of 0.5oC/hr; why???? Why not 0.25oC which was standard in most centers?

No temperature data beyond 36 hours; in contrast to all other studies looking at temperature in CA and the 7 multicenter RCT’s in neonatal asphyxia. Why was this never provided in any of the 60+ publications resulting from this study, or any of the rebuttals to the published criticisms by myself and others??

Weaknesses….

Slide Number 1Slide Number 2Slide Number 3Topics of my lecture:Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Brain-, blood- and rectal temperature in TBI:Brain and bladder temperature in strokeSlide Number 12In cardiac arrest patients:Slide Number 14Slide Number 15Fever in neurological injury:Fever in neurological injury:Slide Number 18Slide Number 19Fever following out-of-hospital cardiac arrest (OHCA):Fever following in-hospital cardiac arrest (IHCA):Slide Number 22Slide Number 23Slide Number 24Slide Number 25Fever in a mixed neuro-ICU:Fever in hemorrhagic stroke:Does controlling fever improve outcome?Slide Number 29Slide Number 30But don’t we need a febrile response to fight infections?Slide Number 32Slide Number 33Slide Number 34Slide Number 35OK. So, how can we control fever?Slide Number 37Ok. So we start by giving Tylenol, or NSAID’s. Efficacy of oral (or IV) antipyretics:Slide Number 40Slide Number 41Medications to combat shivering:Slide Number 43Slide Number 44Slide Number 45Slide Number 46Slide Number 47Slide Number 48Slide Number 49Slide Number 50Slide Number 51Slide Number 52Slide Number 53So, why do I feel that this study doesn´t settle the case?Slide Number 55Slide Number 56Slide Number 57Slide Number 58Slide Number 59Slide Number 60Slide Number 61Argument 4. �The baby studies….Slide Number 63Slide Number 64Slide Number 65Slide Number 66Slide Number 67Slide Number 68Slide Number 69Slide Number 70Cardiac arrest in pediatric patients…..Slide Number 72The arguments against 36oC (and ≥37.5oC) - 2Slide Number 74Slide Number 75Slide Number 76Slide Number 77Slide Number 78Slide Number 79Slide Number 80Slide Number 81Slide Number 82Are the outcomes really that impressive?Slide Number 84Slide Number 85Slide Number 86Slide Number 87Slide Number 88Slide Number 89Previously reported outcomes and cooling speeds…TTM compared to prior results…Slide Number 92Slide Number 93Slide Number 94The arguments against 36oC (and ≥37.5oC) - 3Slide Number 96Slide Number 97Slide Number 98Slide Number 99Slide Number 100Physiology of temperature control…Physiology of temperature control…32-33oC vs. 36oC…..32-33oC vs. 36oC…..The arguments against 36oC (and ≥37.5oC) - 3Brain-, blood- and rectal temperature in TBI:In cardiac arrest patients:The arguments against 36oC (and ≥37.5oC) - 3Bernard 2014…Slide Number 110Slide Number 111Slide Number 112Slide Number 113Slide Number 114Slide Number 115Slide Number 116And it’s NOT just about temperature…Temperature and hemodynamics….In contrast to what you may have heard....Slide Number 120Slide Number 121Slide Number 122Slide Number 123Slide Number 124Slide Number 125Slide Number 126Slide Number 127Slide Number 128Slide Number 129Effects on the cardiovascular systemSlide Number 131Slide Number 132Slide Number 133Slide Number 134Slide Number 135Slide Number 136Slide Number 137Slide Number 138Slide Number 139Slide Number 140Slide Number 141Slide Number 142Slide Number 143Slide Number 144Slide Number 145Slide Number 146Slide Number 147Slide Number 148Slide Number 149Slide Number 150Hypothermia in neonatal encepalopathyHypothermia has been used to treat cardiogenic shockSlide Number 153Slide Number 154Slide Number 155Slide Number 156Slide Number 157Slide Number 158Slide Number 159Slide Number 160Slide Number 161Slide Number 162ConclusionsSlide Number 164Slide Number 165Slide Number 166ConclusionsSlide Number 168