Cooling For Newborns With Hie

COOLING FOR NEWBORNS WITH HIE

COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2007, ISSUE 4. ART. NO: CD003311. DOI: 10.1002/14651858.CD003311.pub2. • There is evidence that therapeutic hypothermia is beneficial to term newborns with HIE, and that cooling decreases death, without increasing major disability in survivors. • Benefits of cooling on survival and neurodevelopment outweigh the shortterm adverse effectsJacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic

BACKGROUND • PRIMARY NEURONAL DEATH related to cellular hypoxia with primary energy failure • SECONDARY NEURONAL DEATH after a latent period six hours, • Hyperaemia, cytotoxic edema, mitochondrial failure, excitotoxins, nitric oxide synthesis, free radical damage and cytotoxic actions of activated microglia • Associated with encephalopathy and seizure

HOW IS HYPOTHERMIA NEUROPROTECTIVE ? • Modify cells programmed for apoptosis, leading to their survival. • Reducing cerebral metabolic rate, ↓ glutamate release , ↓ toxic nitric oxide and free radicals • Reduces energy expenditure, reduces histological neuronal loss

BASIS FOR HYPOTHERMIA

• Aim: to lower the temperature of basal ganglia 32 -34 celsius. • Whole body cooling may be physiologically harmful • Selective head cooling • Brain produces 70% of total body heat • Mild systemic hypothermia. • Significant reduction in deep brain temperature was achieved only when the core body temperature was lowered to 34

• PRIMARY OBJECTIVES To determine the effect of therapeutic hypothermia on mortality, long-term neurodevelopmental disability • SECONDARY OBJECTIVES : Adverse effects

• SUBGROUP ANALYSES planned on the basis of: 1.Severity of HIE 2.Inclusion criteria: a) preterm vs term/near-term(>35 weeks) b) electrophysiological+clinical criteria vs. Clin criteria

3.Commencement time(<3hours vs. >6hours) 4.Cooling Method 5.Degree [core temperature<34.5 vs. >] 6.Duration (<48hours vs. >) 7.Quality of outcome assessment [high quality (> 18 months with formal psychological

PARTICIPANTS 1.Newborn infants 2.Evidence of peripartum asphyxia one of criteria: a)Apgar <=5 at 10 min b)Mechanical ventilation or resuscitation at 10 min c)Cord pH <7.1 or base deficit of >12 within 1 hr 3.Evidence of encephalopathy : Sarnat staging 4.No major congenital anomalies

PRIMARY OUTCOME: death or major neuro developmental disability [cerebralpalsy, developmental delay, intellectual impairment, blindness, sensorineural deafness] SECONDARY OUTCOMES: 1.Each component of primary outcome: 2.Incidence of adverse effects A)Heart rate sinus bradycardia/prolonged QT/arrhythmia B)Blood pressure MAP<40 mmhg/need for inotrope

C)Blood examination anaemia /leukopaenia/thrombocytopaenia D)Coagulopathy thrombosis/haemorrhage E)Hypoglycaemia F)Hypokalaemia G)↑ lactate H)Renal impairment ↑urea/creatinine/oliguria

3. Secondary outcome Early indicators of neurodevelopmental outcome: A)Severity of encephalopathy B)Severity of EEG: C)Seizures D)Diffusion weighted imaging on early MRI E) late MRI (>day4): Basalganglia, PLIC, WM injury, parasagittal neuronal necrosis F) Standardised neurological assessment day seven

SEARCH STRATEGY • Oxford database of perinatal trials • Cochrane central register of controlled trials • Previous reviews including crossreferences, abstracts, conferences, symposia proceedings, expert informants and journal hand searching.

DESCRIPTION OF STUDIES • Head cooling with whole body cooling ( Gunn; Akisu ;Gluckman; Lin ) • Whole body cooling (Shankaran02; ICE;Eicher;Shankaran05). • The duration was 72hr in all but 48 hr (Eicher). • Six studies rewarmed infants by 0.5 degrees/hour with the rewarming period of 4h • ICE Rewarmed infants by 0.5 degrees Celsius every second hour with a duration of

DATA COLLECTION AND ANALYSIS • Three review authors independently selected, assessed the quality and extracted data. • Meta-analyses using relative risk and risk difference for dichotomous data • Weighted mean difference for continuous data with 95% confidence intervals.

• Meta-analyses were performed using the fixed effects model. Relative risk (RR) and risk difference (RD) were calculated for dichotomous dataand weighted meandifference(WMD)for continuousdata, with95% confidenceintervals(CI)forall analyses.Thenumber needed to treat (NNT) and associated 95% CI were determined for a statistically significant reduction in the RD. Heterogeneity was examined using the I squared test. Outcome data are reported and analysed in this review for all randomisedparticipants withknown outcomes.Those with missing outcome data are excluded from analysis. For the primary outcome,death ormajordisability, asensitivity analysis wasperformed toallowfortheadditional

MAIN RESULTS • 8 RCT : 638 term infants • MORTALITY All demonstrated significant reduction • MAJOR NEURO DEVELOPMENTAL DISABILITY : • Selective head cooling with mild systemic hypothermia(Gunn;Gluckman) failed to show a statistically significant effect • Whole body cooling (Eicher; Shankaran) demonstrated significant reduction

NO SIGNIFICANT STATISTICAL REDUCTION • Cerebral palsy • Neuro motor disability • Developmental delay • Blindness • Sensorineural hearing loss

ADVERSE EFFECTS • Borderline significant effect on the need for inotrope support and thrombocytopaenia. • No significant anemia, leukopenia or coagulopathy • No significant hypoglycemia, hypokalemia or oliguria • No effect on sepsis • No seizures or poor Short-term neurological outcomes

STAGES OF ENCEPHALOPATHY • Severe : significant reduction in mortality • no effect on disability in survivors • Moderate: Failed to show a significant effect

DISCUSSION • relative risk reduction of 24%, absolute risk reduction of 15% and NNT of 7. • To prevent one death or major disability, need to treat as many as 14 or as few as four infants. • Significant for severe encephalopathy and is of borderline significance for moderate encephalopathy. • Therefore, cooling reduces mortality and if an infant survives, also decreases chance of major disability.

LIMITATIONS • Caretakers could not be blinded • Assessors of neurodevelopment were blinded • Number studied is substantial; • Estimates of treatment on primary outcome precise. • Subgroup analyses based on degree of encephalopathy, method of cooling, and quality of follow-up not precise. • Better method of cooling may remain uncertain until selective head cooling and

CONCLUSIONS • Therapeutic hypothermia is beneficial to term newborns with HIE. Reduces mortality without increasing major disability in survivors. Benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. • Based on analysis of less than half of all studies. • Data from ongoing and completed trials (829) to clarify the effectiveness of cooling and to provide more information on the safety

IMPLICATIONS FOR RESEARCH • Determine most appropriate method • Compare whole body with selective head cooling with mild systemic hypothermia • Evaluate simpler methods • Earlier initiation, most appropriate method and duration of rewarming and hypothermia

COOL-CAP SYSTEM

COOL CAP • Water recirculating cap next to skin covered by insulated outer cap. • Inner cap has a network of channels that recirculate water from the cooling unit , cooling brain to 92 degrees for 72 hours. • Pattern of the water channels provides maximum and uniform cooling contact with the head and prevents pressure points. • Outer cap insulated and covered with reflective metal foil to minimize heating by the radiant warmer. • Scalp edema (massage, changing position, or cap adjustment) • CONTRAINDICATION: imperforate anus, head trauma or skull fracture causing major intracranial hemorrhage, < 1800g

TECOTHERM TSMED 200 N TOTAL BODY COOLING FOR THE NEONATE 

• cooling unit, connecting tubes and a special mattress. The infant is placed on the AquaPad mattress, in which circulates the cooling fluid. • rectal temperature probe neonate’s core temperature. • post-procedure warming solution for neonates. • Provides both cooling & warming