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This presentation provides rationale , feasibility and methods of providing cooling during retrieval , in hypoxic ischemic encephalopathy
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Therapeutic cooling during neonatal transport –
Feasibility and Challenges
Dr.Gopakumar Hariharan
Neonatal Cooling in birth asphyxia
Introduction Mechanism of benefit –
Pathophysiology Relevant researches Why , who , when and how
to cool Discussion
Pregnancy at term Mum presented to ED with severe
abdominal pain and bleeding pervaginum . Emergency LSCS –Heart rate – 10 / min , no
respiratory effort , hypotonic and pale Required prolonged respiration – lasted for
more than 10 minutes for adequate heart rate to ensue
Cord PH – 6.9 , BE – 18 ???? Cooling ???
Typical Scenario
Perinatal asphyxia is an insult to the fetus or the newborn due to lack of oxygen (hypoxia) and/or a lack of perfusion (ischemia) to various organs.
Hypoxia ischaemia remains a significant cause of neonatal mortality and morbidity and adverse neurodevelopmental outcome
Therapeutic cooling – found to improve neurodevelopmental outcome in asphyxiated babies
Introduction
1960’s versus 1980’s Hypothermia in cardiac arrest and traumatic
brain injury in adults – probable benefit in neurological outcome
Mariane Thorensen (Researcher on Cerebral perfusion ) - Intrigued by stories of children who fell through norwegian ice and suffered prolonged drowning in iced water - emerged with preserved cerebral function
Data from animal studies – beneficial effect
The concept of cooling
Pathophysiology
Result of decreased cerebral blood flow and oxygen delivery - failure of aerobic metabolism
Anaerobic glycolysis - excessive production of lactic acid, as well as tissue acidosis, depletion of the high energy phosphate compounds ATP and phosphocreatine, and inability to maintain cell membrane function.
Primary energy failure
Results in loss of electrolyte gradients, with cell swelling and necrosis.
Damage during this period occurs prior to hypothermia therapy and will not be affected by treatment
Consequence of Primary energy failure
Follows reperfusion of the brain - Accounts for the major neuronal cellular loss
The decline in phosphocreatine and ATP is not accompanied by brain acidosis, but it results in apoptosis, or programmed cell death.
Secondary energy failure( 6 to 100 hours )
Hyperaemia, cytotoxic oedema, mitochondrial failure, accumulation of excitotoxins, apoptosis NO synthesis and activation of microglia
Degree of energy failure and apoptosis - proportional to the severity of adverse neurodevelopmental outcomes
Consequence
Increased seizure activity - may further deplete energy reserves.
Magnetic resonance spectroscopy studies in infants with moderate to severe HIE have confirmed normal cerebral oxidative metabolism shortly after birth followed by evidence of secondary energy failure.
Delayed phase
Therapeutic ‘window of opportunity’ Interval following resuscitation of the asphyxiated newborn, before the secondary phase of impaired energy metabolism and injury is fully established.
Why cooling ??
Reduced loss of high energy phosphates during ischaemia
Attenuates bloodbrain barrier damage and neuronal apoptosis
Reduced release of excitatory tranmitters and free radical production
Decreased cerebral metabolic rate for glucose and oxygen
Prevents or ameliorates secondary cerebral energy failure.
Benefits of hypothermia
Williams C, et al. Outcome after ischemia in the developing sheep brain: an electroencephalographic and histological study. Ann Neurol 1992; 31: 14-21.
Hypothermia to between 33oC and 34oC initiated as soon as possible after delivery reducesmortality and disability in babies with HIE(Level 1a evidence)
The time factorTime critical
Sheep brain EEG and
Histological
Shows the statistically significant (p =0.0006) therapeutic benefit of hypothermia after HIE on death and neurodevelopmental disability with a relative risk of 0.76 (95%CI, 0.65 - 0.89).
ICE trial based in Australia and the TOBY trial based in the UK ceased recruitment during 2007 ( categorical benefit noted )
Cochrane review
CoolingTrials
Cool cap trial NICHD trial TOBY trial ICE trial
Cool cap study
Cooling for 72 hours started within 6 hours of delivery – based on auckland pilot studies arbitrary based on animal studies
Whole body temperature - 34. 5 degrees
Result – Nonsignificant trend towards improvement in the primary outcome of death or disability at 18 months overall
TOBY trial unequavocally demonstrated that cooling increases an infants chance of surviving without neurological deficits at 18 months and reduces neurodevelopmental impairment in survival
TOBY trial
Reduction of systemic temperature necessary to achieve deep brain cooling
Head cooling equipment expensive Delays the cooling process in case of
retrieval
Whole body cooling favoured to selective head cooling
When to cool??
All the 4 criteria should be met
1) More than or equal to 35 weeks of gestation
2) Less than 6 hours post birth
3) Evidence of asphyxia
4) The presence of moderate / severe HIE
Selection criteria
Evidence of asphyxia ( atleast 2 of the following )
Apgar less than 6 at 10 minutes or continued need for resuscitation with PPV with or without chest compressions at
10 minutes
Any acute perinatal event that may result in HIE ( ie abruptio placentae , cord prolapse , severe FHR abnormality etc )
Cord PH less than 7 or BE of -12 mmol / L or less
If cord PH not available , arterial PH less than 7 or BE less than -12 mmol / L within 60 minutes of birth
Category Moderate encephalopathy
Severe Encephalopathy
Level of consiousness Lethargy Stupor / coma
Spontaneous activity Decreased activity No activity
Posture Decorticate Decerebrate
Tone Hypotonia Flaccid
Primitive reflexes Weak suck,Incomplete moro
Absent suck,absent moro
Autonomic system ( any one of these )
Pupils Constricted Dilated / Non reactive
Heart rate Bradycardia Variable heart rate
Respirations Periodic breathing Apnea
Assessing severity ( NICHD trial ) ( Shankaran S, et al. Whole body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353: 1574-84)
Moderate or severe asphyxia - defined as seizures OR presence of signs in atleast 3 of the 6 categories
Assessing severity
If the neonate meets elibility criteria 1 , 3 and 4 , but is 6 – 12 hours of age , delayed initiation of cooling may be considered at the discretion of the attending neonatologist
How to cool ??
Switch off warmer in case of radiant warmer Switch of incubator , open port holes Nurse baby naked Keep nappy undone Temperature monitoring Consider reducing environmental temp by
adding fan ( ? A/C )
Passive cooling
Arch Dis Child Fetal Neonatal Ed 2010;95:F408–F412.
4 cold packs in fridge temperature ( 10 degrees )
2 frozen cold packs Disposible rectal probes Cable for connecting rectal probes Cotton covers for cold packs Cardiopulmonary monitoring
Equipment required for cooling
Neonatology clinical guidelinesKEM & Princes Margeret HospitalsPerth
Temp ranges No of cool packs applied
Areas to be applied
> 37 degrees 4 Head , Shoulders , neck , trunk
36.1 - 37.0 3 Shoulders , neck , trunk
35.1 – 36.0 2 Shoulders , trunk
34.1 – 35.0 1 Trunk
33 . 0 – 34.0 0 Nil
Watch temp range more closily in infants treated with anticonvulsants or muscle relaxants ( tend to cool rapidly ) Keep cold packs in cotton bags
Active cooling with adjuncts
Commercially available water bottles filled with water ( 25 degrees )
Phase changing mattress with a melting point of 32 degrees ( acts as heat buffers and stabilizes temp of objects with which it comes in contact )
Alternatives
Passive heating and cooling substances , usually made of a salt hydride , fatty acid and ester or paraffin such as octadene .
PCMs are solid at room temperature , but when in contact with warmer objects they liquify and absorb and store heat
Liquid PCMs can solidify and give off heat Temp monitoring required – additional
blankets if low temp , or additional PCMs if temp high outside therapeutic range
Phase contrast materials
S Iwata,O Iwata,L Olson,A Kapetanakis,T Kato,S Evans,Y ArakiT Kakuma,T Matsuishi, F Setterwall,H Lagercrantz,N J Robertson. Therapeutic hypothermia can be induced andmaintained using either commercial water bottles ora ‘‘phase changing material’’ mattress in a newborn piglet model . Arch Dis Child 2009;94:387–391.
Criticool Hypothermia achieved by adjusting
temperature of water pumped through the cooling mattress using feedback from patients core ( rectal ) and surface temperature
Disadv – weighs 35 kg ( not including 1 to 4 L of water ) & must be secured well
Servocontrolled cooling machine
Scottish Neonatal Transport Ambulance with the servo controlled cooling machine
Tecotherm Neo Alternative – weighs
only 7 kg Both Requires AC
power . No battery back up
Not certified for air transfer
Used in TOBY trial
Advise the peripheral hospital , prior to arrival of Medstar team
Full blood examination , Platelet count Urea and electrolytes S.Electrolytes , S . Calcium PT , APTT Blood glucose ABG / CBG LFT Neurological assessment + Sarnat staging
Suggested investigations
Evidence on various modalities
Kendall GS, Kapetanakis A, Ratnavel N, et al. Passive cooling for initiationof therapeutic hypothermia in neonatal encephalopathy. Arch Dis Child FetalNeonatal Ed 2010;95:F408–12.
Passive cooling
O’Reilly KM , Tooley J , Winterbottom S . Therapeutic hypothermia during neonatal transport .Acta Pædiatrica 2011 100, pp. 1084–1086
Median
Median Median
N=10N=17
N=19
35.2( 31.5-36.60
33.329.8-36.3
StMichaels HospitalBristol
Comparison
O’Reilly KM , Tooley J , Winterbottom S . Therapeutic hypothermia during neonatal transport .Acta Pædiatrica 2011 100, pp. 1084–1086
Comparison of Temp maintanance
Servo controlled cooling ( Scottish Neonatal transport service )
Johnston ED, Becher J-C, Mitchell AP, et al. Arch Dis Child Fetal Neonatal Ed (2011).
N =9
Servo –controlled
Servo controlled cooling
Johnston ED, Becher J-C, Mitchell AP, et al. Arch Dis Child Fetal Neonatal Ed (2011).
Median time for achieving target- 45 min
Temp increased due to CVS instability
Message
Chance of overcooling with active cooling with adjuncts would be decreased as experience
improves ( Fairchild et al,2010 )
Long term neurological outcome – 18 months early to diagnose CP and cognitive deficits
Best way of assessing core temperature Does temperature fluctuations cause any
adverse outcome How best is brain cooled with reduction in
rectal temperature
Questions unanswered
Challenges
1) Feasible method - Active vs passive cooling
2) Best method of temperature monitoring – Rectal versus esophageal
3) Equipments and packs 4) Education of Peripheral
centres
Sinus bradycardia, increased blood pressure and increased oxygen requirement - transient and reversible with rewarming
Thrombocytopenia
Arrhythmias – Long QT
Less likely to occur when the rectal temperature remained within 33.0oC- 34.0oC.
Risks of hypothermia
Adverse effects of hypothermia are physiological, transient and reverse with rewarming ( Level 1a evidence )
End point was composite – death or severe disability . Statistically robust but doubtful clinical utility
No blinding – not possible given the patient population . But introduces unquantifiable bias
Disability assessed at 18 months of gestation . Not possible to rule out possibility of cerebral palsy in evolution
Remains to see whether the benefit retained through out childhood and beyond ( cognitive defects )
Deficiencies in evidences
Neonatal cooling initiated during retrieval definitely provides benefit for asphyxiated babies
Active cooling ( with adjuncts or custom made ) gives better temperature control than passive cooling . Regardless attempts at any form of cooling is good enough
Close core temperature monitoring with rectal probe allows to maintain temp in therapeutic range
No major adverse events noted in neonates
Summary
So ….. Shall we have some cooool discussion ……
Thank you