Brain injury and Resuscitation! Turning Back the Clock!

Transcription

1 Brain injury and Resuscitation! Turning Back the Clock! Dec 2008 Patrick J McNamara

2 Learning Objectives Understand the benefits of Hypothermia and how it works? Identify patients who may benefit from treatment.

3 Case I

4 EEG: Severely abnormal trace with global low voltages 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 Transferred from Level II community hospital Severe Encephalopathy with Intractable seizures Phenobarbitone & mizadozalam

5 MRI: Diffuse hypoxic-ischemic changes ICU support withdrawn on day 3 of life

6 Cardiorespiratory Arrest Prevention Resuscitation Post-Resuscitation Care Improved Bad Outcome Outcome

7 Evidence from Human Studies Neonate Child Adult Oxygen Yes No No Ventilation No No Yes Chest compressions No No Yes Epinephrine No Yes Yes Sodium Bicarbonate No No Yes

8 Lessons learned by re-examining practice

9 Experimenting with Gas mixtures Fumigation method Introduced by North American Indians and American colonists Practice spread to England in 1767

10 Is oxygen the most appropriate resuscitation gas? Dilemma

11 O 2 Saturations & Resuscitation Saugstad 2005 Early Human Dev

12 Oxygen Paradox Hypoxia-ischaemia O 2 Hypoxanthine Oxygen free Radicals Hyperoxaemia-Reperfusion Cell Injury Reperfusion

13 One death prevented for every 20 babies resuscitated with room air

14 Neonatal Resuscitation: Canadian Context 2006

15 Established Insult But if the horse has bolted.

16 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 palsy Hagberg 2001 Acta Paed Burden: Lifetime cost: $5,000,000 for care worldwide

17 Is there an opportunity to intervene?

18 PRETERM TERM Intraventricular Hemorrhage White matter damage Periventricular Leucomalacia Basal ganglia damage

19 Nitric oxide accumulation (Ca med) Accumulation of Excitotoxic mediators i.e. Glutamate/Aspartate Hypoxic-ischemic Insult Anaerobic Glycolysis Accumulation of NADF, FADH, Lactic acid FFA accumulation (Ca med) Lipid peroxidation Cellular ATP demands excessive Depletion of High Energy Phosphates Failure of Transcellular ion pumps Cytotoxic edema

20 Pathophysiology Fetal/perinatal hypoxia &/or ischaemic cerebral insult Primary neuronal injury Primary energy failure NECROSIS Derangement of cellular function [Na/K ion pump failure. Release of excitatory amino acids (glutamate), interleukin, free radical activity] Secondary energy failure APOPTOSIS Secondary neuronal injury, further necrosis & apoptosis

21 Hypothermia & Delayed Energy Failure Pediatr Res 1994;36:

22 Dev Med and Child Neurol 1992;34:

23 Abnormal outcome is related to abnormal brain cellular metabolism.. Is brain injury reversible?

24 Hypoxic-ischemic Insult Resuscitation practice Cellular edema Inflammation Necrosis Post-resuscitation practice Delayed Cell Death

25 Neuroprotective therapies Pharmacological 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

26 Is cerebral hypothermia practical, safe and effective in preventing brain injury in neonates? Dilemma

27 The Cooling Dilemma RUSSIAN METHOD "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." 1803 Sir John Floyer, 1697

28 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: Westin B, Nyberg R, Miller JA, Wedenberg E. Hypothermia and transfusion with oxygenated blood in the treatment of asphyxia neonatorum. Acta Paediatr Scand. 1962;(suppl)139:1-80 Westin B Infant resuscitation and prevention of mental retardation. Am J Obstet Gynecol. 1971; 110: [

29 The influence of the thermal environment upon the survival of newly born premature infants WA Silverman, JW Fertig and AP Berger 3975 Broadway, New York 32, New York. Pediatrics, Nov 1958, , 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

30 Does Induced Hypothermia work? When? How much? How long?

31 Nitric oxide accumulation (Ca med) Accumulation of Excitotoxic mediators i.e. Glutamate/Aspartate Hypoxic-ischemic Insult Anaerobic Glycolysis Accumulation of NADF, FADH, Lactic acid FFA accumulation (Ca med) Lipid peroxidation Cellular ATP demands excessive Hypothermia Depletion of High Energy Phosphates Failure of Transcellular ion pumps Cytotoxic edema

32 Hypothermia & Brain Cell death Thoreson 1996 Arch Dis Child

33 Mechanics I Magnitude of Hypothermia Critical depth of cooling (Deep brain structures) 1 C fall = Cerebral metabolic rate 6-7% Parasagittal neuronal loss (%) Sham Hypothermia Hypothermia, 90 min Extradural temperature, 4-8 h ( o C) Critical brain temperature < 35 O

34 Mechanics II Temporal Window of Opportunity Parasagittal Neuronal Loss ** ** 0 Control 1.5 h 5.5 h 8.5 h Time Delay in Initiation of Cooling Neural protection is long lasting, but benefit is reduced if cooling is delayed.

35 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

36 Longterm Neuroprotection Agnew 2003 Ped Res

37 Summary Cell death is preventable..but only if applied early and a critical temperature range is achieved Is Hypothermia Effective in Humans?

38 Is Hypothermia Effective in Humans?

39 Hypothermia & Adult Cardiac Arrest HACAS group 2002 NEJM

40 HACAS group 2002 NEJM

41 Is hypothermia effective in newborns.. Whole body vs selective heading cooling?

42 Hypothermia Whole Body Selective Head Cooling blanket Coolcap method ICE trial method

43 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)]

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45 Normal trace Moderately abnormal trace Severely abnormal trace

46 aeeg vs EEG & Outcome (n=47) Hellstrom-Westas 1995 Arch Dis Child Correlation with EEG Normal = 0.82 Abnormal = 0.96 Al Naqeeb 1999 Pediatrics

47 Toet 1999 Arch Dis Child Early aeeg & Outcome N = 33 De Vries 2005 Arch Dis Child

48 Hypothermia & aeeg Gluckmann 2005 NEJM

49 Early abnormal aeeg background activity is a sensitive and specific predictor of abnormal neurodevelopmental outcome How long should patients be monitored?

50 aeeg recovery < 72 hrs & Outcome Ter Horst 2004 Ped Res

51 Recovery of SWS & Outcome n=171 Odds of good outcome (2-yrs) 0.96 fold (p< 0.001) hour SWS was delayed 96.1% neonates with normal SWS by 36 hours had a normal outcome 80% neonates with abnormal SWS > 36 hours had an abnormal outcome Osredkar 2005 Pediatrics

52 Selective Head Cooling

53 Rutherford 2005 Pediatrics

54 Overview of the Evidence Shah 2007 Arch Pediatr

55 Death / Disability

56 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.

57 Ancillary effects of Hypothermia Drug pharmacokinetics / metabolism altered Effect on other end-organ injury Resetting of metabolic and nutiritional needs

58 Hypothermia and End-organs Roka 2007 Acta Paed

59 Which babies may benefit from Whole Body Hypothermia?

60 Implementing Change Cooling in routine clinical care? Who? When? How?

61 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

62 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

63 Category 1. Level of consciousness 2. Spontaneous activity Moderate Encephalopathy Lethargic Decreased activity 3. Posture Distal flexion, full extension 4. Tone Hypotonia (focal, general) 5. Primitive reflexes e.g. Suck, Moro 6. Autonomic system Weak Incomplete Constricted Bradycardia Periodic breathing Severe Encephalopathy Stupor/coma No activity Decerebrate Flaccid Absent Absent Dilated/non-reactive to light Variable HR Apnea

64 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

65 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

66 Khurshid et al 2009 HIE n=41 Eligible for cooling n=29 (71%) Cooled n=16 (67%) Excluded n=5 (12.1%) Not cooled n=8 (33%) Cooled 72 hr n=13 Cooled <72 hr n=3 Delay-referral n=5 PPHN (n=1) Bleeding (n=1) Poor neurological outcome (n=1) Delay- recognition of severity/diagnosis n=3

67 Count Hypothermia [Age at Initiation] Median 6 hours (range 1, 11; IQR age start cooling hours Khurshid et al 2009

68 mins 12 m 69 mins 122 mins 151 mins Birth to Call To Dispatch To Arrival To Cooling start To tertiary NICU

69 Is there harm from elevated temperature?

70 Are there side effects of Induce Hypothermia?

71 Adverse Effects Cardiac Contractility, BP* Bradycardia* Arrhythmias* (< 28 C) Resp Pulmonary hypertension CVS Hyperviscosity* Diuresis Gastrointestinal NEC Coagulopathy & platelet dysfunction Metabolic Acidosis* O 2 dissociation curve to left Hypokalaemia* Hypoglycaemia* Dermatological Traumatic Fat necrosis Immunological Sepsis

72 How can you Help Early Referral Avoid Hyperthermia aeeg may useful tool for determination of the extent of the encephalopathy

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74 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

75 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)

76 Ongoing Initiatives Gender and genetic influences Hypothermia in other clinical settings e.g. postcardiac arrest, preterm brain injury, encephalopathy Beyond 6 hours, duration of cooling, rewarming rate Combination therapies (anticonvulsants, antiinflammatory agents)

77 Thankyou...