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