Brain injury and Resuscitation! Turning Back the Clock!

Dec 2008

Patrick J McNamara

Learning Objectives

• Understand the benefits of Hypothermia and how it works?

• Identify patients who may benefit from treatment.

Case I

Full term male Birth weight 3.43 Kg

Meconium stained liquor Fetal bradycardia to 60

High forceps delivery → CPR for 20 mins

Cord pH 7.01 Apgars 11 25 210 715

Transferred from Level II community hospital

Severe Encephalopathy with Intractable seizures →Phenobarbitone & mizadozalam

EEG: Severely abnormal trace with global low voltages

• MRI: Diffuse hypoxic-ischemic changes • ICU support withdrawn on day 3 of life

Cardiorespiratory Arrest

Bad Outcome

Resuscitation

Post-ResuscitationCare

Improved Outcome

Prevention

Neonate Child Adult

Oxygen Yes ∗ No NoVentilation No No YesChest compressions No No Yes

Epinephrine No Yes ∗ Yes ∗

Sodium Bicarbonate No No Yes ∗

Evidence from Human Studies

Lessons learned by re-examining practice

Experimenting with Gas mixtures

• Fumigation method

• Introduced by North American Indians and American colonists

•Practice spread to England in 1767

Dilemma

Is oxygen the most appropriate

resuscitation gas?

O2 Saturations & Resuscitation

Saugstad 2005 Early Human Dev

Oxygen Paradox

Hyperoxaemia-Reperfusion Cell Injury

Hypoxia-ischaemia

Reperfusion

O2Hypoxanthine

Oxygen free Radicals

“One death prevented for every 20 babies resuscitated with room air”

Neonatal Resuscitation: Canadian Context 2006

Established Insult

But if the horse has bolted…………….

Hypoxic-ischemic Encephalopathy• Intrapartum hypoxia 3-5/100 live births

Levene 1986 Lancet

• Hypoxic Ischaemic Encephalopathy (HIE) complicates ~1/1000 live births – Neurological sequelae: > 25% – Mortality: 10-60% – 23% of annual global neonatal deaths

Vannuci 1990 Pediatrics

• HIE accounts for 20-30% cerebral palsyHagberg 2001 Acta Paed

• Burden:– Lifetime cost: $5,000,000 for care worldwide

Is there an opportunity to intervene?

PRETERM TERM

Intraventricular Hemorrhage

Periventricular Leucomalacia

White matter damage

Basal ganglia damage

Hypoxic-ischemic Insult

Anaerobic Glycolysis

Accumulation of NADF, FADH, Lactic acid

Cellular ATP demands excessive

Depletion of High Energy Phosphates

Failure of Transcellular

ion pumps

Cytotoxic edema

Accumulation of Excitotoxic mediators i.e.

Glutamate/Aspartate

Nitric oxide accumulation (Ca med)

FFA accumulation (Ca med)

Lipid peroxidation

Pathophysiology

Fetal/perinatal hypoxia &/or ischaemic cerebral insult

Primary neuronal injury

Primary energy failure

Derangement of cellular function [Na/K ion pump failure. Release of excitatory amino acids (glutamate), interleukin, free radical activity]

Secondary energy failure

Secondary neuronal injury, further necrosis & apoptosis

NECROSIS

APOPTOSIS

PediatrPediatr ResRes 1994;36:6991994;36:699--706706

Hypothermia & Delayed Energy Failure

Dev Med and Child Dev Med and Child NeurolNeurol 1992;34:2851992;34:285--295295

Abnormal outcome is related to abnormal brain cellular metabolism…..

Is brain injury reversible?

Hypoxic-ischemic Insult

Necrosis

Delayed Cell Death

Cellular edemaInflammation

Resuscitation practice

Post-resuscitation practice

Neuroprotective therapiesPharmacological• Oxygen free radical scavengers (i.e Vit E, Vit C,

allopurinol, indomethacin)• Excitatory AA antagonists (i.e NMDA, MK801)• Calcium channel blockers (i.e. nicardipine, flunarizine)• Inhibition of NO production (NOS inhibitors)• Corticosteroids• Barbiturate coma (phenobarbitone, Thiopental)

Non-Pharmacological• Hyperglycemia (conflicting rodent vs porcine data)• Therapeutic hypercapnia

Dilemma

Is cerebral hypothermia practical, safe and

effective in preventing brain injury in

neonates?

The Cooling Dilemma

"Sarah Parks ... gave still-birth to a baby boy ... A young doctor assisting the Parks' regular physician begged for an opportunity to experiment with an idea he had to rouse the lifeless infant. A tub of ice was ordered and the young doctor plunged the baby into it. Out came the screaming little Parks and he was named Gordon after the doctor who prodded him to life."

Sir John Floyer, 1697

RUSSIAN METHOD

1803

An Era of Cooling• Westin B, Miller JA, Nyberg R,

Wedenberg E Neonatal asphyxia pallida treated with hypothermia alone or with hypothermia and transfusion of oxygenated blood. Surgery.1959; 45:868-879

• Westin B, Nyberg R, Miller JA, Wedenberg E. Hypothermia and transfusion with oxygenated blood in the treatment of asphyxia neonatorum. ActaPaediatr Scand.1962;(suppl)139:1-80

• Westin B Infant resuscitation and prevention of mental retardation. Am J ObstetGynecol. 1971; 110:1134-1138 [

The influence of the thermal environment upon the survival of newly born premature infants

WA Silverman, JW Fertig and AP Berger3975 Broadway, New York 32, New York.

Pediatrics, Nov 1958, 876-886, Vol 22, No. 5 Copyright © 1958, American Academy of Pediatrics

•“Survival overall was 68% in the hypothermic group vs 83% in the warmer incubators”.

• However the majority of the effect was in infants with birth weights <1000 g

Does Induced Hypothermia work?

When?How much?How long?

Hypoxic-ischemic Insult

Anaerobic Glycolysis

Accumulation of NADF, FADH, Lactic acid

Cellular ATP demands excessive

Depletion of High Energy Phosphates

Failure of Transcellular

ion pumps

Cytotoxic edema

Accumulation of Excitotoxic mediators i.e.

Glutamate/Aspartate

Nitric oxide accumulation (Ca med)

FFA accumulation (Ca med)

Lipid peroxidation

Hypothermia

Hypothermia & Brain Cell death

Thoreson 1996 Arch Dis Child

Mechanics IMagnitude of Hypothermia

• Critical depth of cooling (Deep brain structures)– 1°C fall = ↓ Cerebral metabolic rate 6-7%

• Critical brain temperature < 35O

Parasagittal neuronal loss (%)

30 32 34 36 38 400

25

50

75

100

Sham HypothermiaHypothermia, 90 min

Extradural temperature, 4-8 h (oC)

Mechanics II‘Temporal Window of Opportunity’

• Neural protection is long lasting, butbenefit is reduced if cooling is delayed.

Control 1.5 h 5.5 h 8.5 h0

25

50

75

100

**

**

Time Delay in Initiation of Cooling

Para

sagi

ttal N

euro

nal L

oss

Duration of cooling

• Long enough to prevent, not delay cell loss

• Continued throughout period of secondary energy failure [Presumption 72 hours] – Seizures on rapid rewarming - fetal ovine data– Extrapolation to the human [heterogenous

insult] is difficult

Longterm Neuroprotection

Agnew 2003 Ped Res

Summary

Cell death is preventable

…..but only if applied early and a critical temperature range is achieved

Is Hypothermia Effective in Humans?

Is Hypothermia Effective in Humans?

Hypothermia & Adult Cardiac Arrest

HACAS group 2002 NEJM

HACAS group 2002 NEJM

Is hypothermia effective in newborns…..

Whole body vs selective heading cooling?

Whole Body Selective Head

Cooling blanket Coolcap method

ICE trial method

Hypothermia

Reduction in death or moderate/severe disability from 62% (n=64) to 42% (n=45) with whole body cooling

No difference in death or moderate/severe disability between control [66%, (n=73)] and selective head cooling group [55%, (n=59)]

Normal trace

Moderately abnormal trace

Severely abnormal trace

Hellstrom-Westas 1995 Arch Dis Child

aEEG vs EEG & Outcome (n=47)

Correlation with EEG

Normal = 0.82 Abnormal = 0.96

Al Naqeeb 1999 Pediatrics

Toet 1999 Arch Dis Child

Early aEEG & Outcome N = 33

De Vries 2005 Arch Dis Child

Gluckmann 2005 NEJM

Hypothermia & aEEG

Early abnormal aEEG background activity is a sensitive and specific predictor of abnormal neurodevelopmental outcome

How long should patients be monitored?

Ter Horst 2004 Ped Res

aEEG recovery < 72 hrs & Outcome

Recovery of SWS & Outcome

Osredkar 2005 Pediatrics

• Odds of good outcome (2-yrs) ↓ 0.96 fold (p< 0.001) hour SWS was delayed

•• 96.1% neonates with 96.1% neonates with normal SWS by 36 hoursnormal SWS by 36 hours had a normal outcomehad a normal outcome

•• 80% neonates with 80% neonates with abnormal SWS > 36 hoursabnormal SWS > 36 hours had an abnormal outcomehad an abnormal outcome

n=171n=171

Selective Head Cooling

Rutherford 2005 Pediatrics

Overview of the Evidence

Shah 2007 Arch Pediatr

Death / Disability

Summary: The Evidence

• Adult (cardiac arrest) and newborn animal and human studies suggest that hypothermia after hypoxia-ischemia:

– Is safe– May reduce or prevent brain injury

• Hyperthermia is harmful.

Ancillary effects of Hypothermia

• Drug pharmacokinetics / metabolism altered

• Effect on other end-organ injury

• Resetting of metabolic and nutiritionalneeds

Roka 2007 Acta Paed

Hypothermia and End-organs

Which babies may benefit from

Whole Body Hypothermia?

Implementing Change

………Cooling in routine clinical care?

Who?

When?

How?

Hypothermia: the mechanics

• Need to be easily recognisable:Simple clinical eligibility criteria

• Need to commence ASAP:Cool at the birth hospital

• Needs to be ‘pragmatic’: Moderate systemic hypothermia

Inclusion criteria• < 6 hours (maximum of 12 hours)

• > 35 weeks gestational age

• Evidence of intrapartum hypoxia– Apgar score < 5 at 10 minutes– need for mechanical ventilation or resuscitation

beyond 10 minutes, – cord pH < 7 or arterial pH < 7, base deficit > 16 within

60 minutes of birth.

• Moderate or severe encephalopathy

Category Moderate Encephalopathy

Severe Encephalopathy

1. Level of consciousness

Lethargic Stupor/coma

2. Spontaneous activity

Decreased activity No activity

3. Posture Distal flexion, full extension

Decerebrate

4. Tone Hypotonia (focal, general)

Flaccid

5. Primitive reflexes e.g. Suck, Moro

WeakIncomplete

AbsentAbsent

6. Autonomic system

ConstrictedBradycardiaPeriodic breathing

Dilated/non-reactive to lightVariable HR Apnea

Exclusion Criteria

– Patients < 2 kg

– Chromosomal abnormalities, or a syndrome not compatible with long term survival

– External evidence of significant head trauma or radiological evidence of a skull fracture

– Coagulopathy requiring aggressive treatment

Cooling in Toronto

• ICE TRIAL: No adverse short-term effects or difference in mortality

• Await 2 year neurodevelopmental outcome

• Cooling offered at all three tertiary sites

Eligible for cooling n=29 (71%)

Cooledn=16 (67%)

Excludedn=5 (12.1%)

Not cooledn=8 (33%)

Cooled 72 hrn=13

Cooled <72 hrn=3

PPHN (n=1)Bleeding (n=1)

Poor neurological outcome (n=1)

Delay- recognition ofseverity/diagnosis

n=3

HIE n=41

Delay-referraln=5

Khurshid et al 2009

Hypothermia[Age at Initiation]

2 4 6 8 10

age start cooling hours

0

2

4

6

Cou

nt

Median 6 hours (range 1, 11; IQR

Khurshid et al 2009

116 mins

12m

122mins

69mins

151mins

0 1 2 3 4 5 6 7 8

Birth to Call

To Dispatch

To Arrival

To Cooling start

To tertiary NICU

Is there harm from elevated temperature?

Are there side effects of Induce Hypothermia?

Adverse EffectsCardiac

– Contractility, BP*– Bradycardia*– Arrhythmias* (< 28°C)

Resp– Pulmonary hypertension

CVS– Hyperviscosity*– Diuresis

Gastrointestinal– NEC

Coagulopathy– & platelet dysfunction

Metabolic– Acidosis*– O2 dissociation curve to left– Hypokalaemia*– Hypoglycaemia*

Dermatological– Traumatic Fat necrosis

Immunological– Sepsis

How can you Help

• Early Referral

• Avoid Hyperthermia

• aEEG may useful tool for determination of the extent of the encephalopathy

Conclusion• Hypothermia is now a standard therapeutic

option for neonates with moderate/severe encephalopathy– Recommended by AAP, Canadian NRP, NICHD &

ILCOR– Hyperthermia should be avoided

• Refinement of intensive care support (e.g. drugs, fluids, nutrition)

• Challenges of patient selection and strategic approach to other populations remain

Conclusion• Cautious use of oxygen for resuscitation

• Avoid hyperthermia

• Hypothermia is now a standard therapeutic option for neonates with moderate/severe encephalopathy and adults with VF-cardiac arrest

• Challenges of patient selection remain

• Refinement of intensive care support (e.g. drugs, fluids, nutrition)

Ongoing Initiatives• Gender and genetic influences

• Hypothermia in other clinical settings e.g. post-cardiac arrest, preterm brain injury, encephalopathy

• Beyond 6 hours, duration of cooling, rewarmingrate

• Combination therapies (anticonvulsants, anti-inflammatory agents)

Thankyou …...