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• MRI: Diffuse hypoxic-ischemic changes • ICU support withdrawn on day 3 of life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