Therapeutic hypothermia during neonatal transport – feasibility and
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 ???
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
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
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.
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
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.
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
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.
Therapeutic ‘window ofopportunity’Interval followingresuscitation of theasphyxiated newborn,before the secondaryphase of impaired energymetabolism and injury isfully established.
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.
The time factorTime critical Hypothermia to between 33oC and 34oC initiated as soon as possible after delivery reduces Sheep brain mortality and disability EEG and in babies with HIE(Level Histological 1a evidence)
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 )
Cool cap trial NICHD trial TOBY trial ICE trial
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 thatcooling increases an infants chance ofsurviving without neurological deficits at 18months and reduces neurodevelopmentalimpairment in survival
Reduction of systemic temperature necessary to achieve deep brain cooling Head cooling equipment expensive Delays the cooling process in case of retrieval
All the 4 criteria should be met1) More than or equal to 35 weeks of gestation2) Less than 6 hours post birth3) Evidence of asphyxia4) The presence of moderate / severe HIE
Apgar less than 6 at 10 minutes or continued need forresuscitation with PPV with or without chest compressions at 10 minutesAny acute perinatal event that may result in HIE ( ie abruptioplacentae , cord prolapse , severe FHR abnormality etc ) Cord PH less than 7 or BE of -12 mmol / L or lessIf cord PH not available , arterial PH less than 7 or BE lessthan -12 mmol / L within 60 minutes of birth
Category Moderate Severe Encephalopathy encephalopathyLevel of consiousness Lethargy Stupor / comaSpontaneous activity Decreased activity No activityPosture Decorticate DecerebrateTone Hypotonia FlaccidPrimitive reflexes Weak suck,Incomplete Absent suck,absent moro moro Autonomic system ( any one of these )Pupils Constricted Dilated / Non reactiveHeart rate Bradycardia Variable heart rateRespirations Periodic breathing Apnea
Moderate or severe asphyxia - defined asseizures OR presence of signs in atleast 3 ofthe 6 categoriesIf the neonate meets elibility criteria 1 , 3 and 4 , but is 6 – 12hours of age , delayed initiation of cooling may be considered atthe discretion of the attending neonatologist
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 )
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 Neonatology clinical guidelines KEM & Princes Margeret Hospitals Perth
Temp ranges No of cool packs Areas to be applied applied> 37 degrees 4 Head , Shoulders , neck , trunk36.1 - 37.0 3 Shoulders , neck , trunk35.1 – 36.0 2 Shoulders , trunk34.1 – 35.0 1 Trunk33 . 0 – 34.0 0 NilWatch temp range more closily in infants treated with anticonvulsants ormuscle relaxants ( tend to cool rapidly )Keep cold packs in cotton bags
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 )
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
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
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
Servo –controlled N =9Johnston 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 instabilityJohnston ED, Becher J-C, Mitchell AP, et al. Arch Dis Child Fetal Neonatal Ed(2011).
Chance of overcooling with active cooling withadjuncts 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
1) Feasible method - Active vs passive cooling2) Best method of temperature monitoring – Rectal versus esophageal3) Equipments and packs4) 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.Adverse effects of hypothermia are physiological, transient and reverse withrewarming ( 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 )
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