Induced hypothermia following cardiac arrest

Induced hypothermia following cardiac arrest Kevin Morris Birmingham Children’s Hospital Outcome following cardiac arrest • related to duration of arrest • in US only 3-10% of adults who can be resuscitated from cardiac arrest return to baseline level of functioning • in children the prognosis for neurological recovery is equally grim •101 children presenting to ED with apneoa or no palpable pulse (or both) •15 survived to hospital discharge •13 alive 12 months later •80 of cases had cardiac arrest •6 survived to hospital discharge, all neurologically impaired Hypoxic – ischaemic brain injury Can an intervention applied after return of spontaneous circulation improve neurological outcome and/or survival? Phases of brain injury Primary injury Secondary injury time Phases of brain injury Primary injury Secondary injury time Neuroprotection Mechanisms of ‘secondary’ brain injury • release of excitotoxins (glutamate) • increased NO production • neutrophil invasion, cytokine production • membrane destabilisation • exhaustion of high energy phosphates • induction of apoptosis • free radical production Does body temperature impact on secondary injury? Hyperthermia after ischaemic brain injury • is common • is associated with a worse neurological outcome Body temperature after cardiac arrest Hickey, R. W. et al. Pediatrics 2000;106:118-122 Outcome after acute stroke Reith et al, Lancet 1996: 347: 422-425. • prospective study of 390 stroke patients • admitted within 6 hours • assessed factors associated with outcome Body temperature in acute stroke Reith et al, Lancet 1996: 347: 422-425. 100 90 Poor outcome 80 (%) 70 60 50 40 30 20 10 0 V. Severe Severe Moderate Mild Hyperthermia Normothermia Hypothermia Initial stroke severity Hyperthermia after deep hypothermic circulatory arrest Shum-Tim et al, J Cardiovasc Surg 1998: 116: 780-792. • animal model of circulatory arrest • 100 minutes of DHCA at 15OC • randomised to 24 hrs at 34OC, 37OC, 40OC following cardiopulmonary bypass • endpoints • neurologic deficit score • brain histology Hyperthermia after deep hypothermic circulatory arrest Shum-Tim et al, J Cardiovasc Surg 1998: 116: 780-792. 300 250 Neurologic Deficit Score Normothermia Hyperthermia 200 150 100 50 0 Day 2 Day 3 Time after DHCA Day 4 Hyperthermia after deep hypothermic circulatory arrest Shum-Tim et al, J Cardiovasc Surg 1998: 116: 780-792. 3 2.5 Neocortex Hippocampus Dentate Gyrus Caudate Pathology Score 2 1.5 1 0.5 0 Normothermia Hyperthermia Hyperthermia and outcome post cardiac arrest Zeiner A et al. Arch Intern Med 2001: 161: 2007-2012 • 151 adults • 77 with poor outcome at 6 months • lower temperature in first 4 hours • higher temperature in subsequent 48 hours • OR 2.26 (1.24-4.12) for each degree above 37OC Delayed hyperthermia harmful after cerebral ischaemia Baena et al, Neurology 1997: 48: 768-773. • animal model of brain ischaemia (rat) • 7 minute carotid artery occlusion • 24 hours later body temperature increased in one group to 39-40oC for 3 hours • 1 week later brain was perfusion-fixed • sham hyperthermia group included as a control Delayed hyperthermia aggravates neuronal damage Baena et al, Neurology 1997: 48: 768-773. 60 50 Ischaemic cell 40 count 30 20 10 0 Lateral Middle Medial Hippocampal subsectors Sham hyperthermia Ischaemia normothermia Ischaemia hyperthermia Cooling post neonatal hypoxia-ischaemia (animal) Thoresen et al, Arch Dis Child 1996: 74: F3-F9. • 7 day old rats • unilateral hypoxic-ischaemic brain damage • carotid ligation / hypoxic gas mixture (8% O2) for 2 hrs • compared 3 hrs hypothermia (32.5oC) with normothermia • sacrificed after 7 days • neuropathology outcome Cooling post neontal hypoxia-ischaemia (animal) Thoresen et al, Arch Dis Child 1996: 74: F3-F9. 2 1.8 Pathology 1.6 score 1.4 1.2 1 0.8 0.6 0.4 0.2 0 Normothermia Hypothermia Cortex Hippocampus Basal ganglia Thalamus Lancet 2005: 365: 663-670 N Engl J Med 2005: 353: 1574-1584 N Engl J Med 2005: 353: 1574-1584 RR for death in hypothermia group 0.68 (0.44-1.05); p=0.08 RR for death or poor neurological outcome 0.72(0.54-0.95);p=0.01 Lack of benefit of hypothermia in severe brain injury Both neonatal trials suggested a lack of benefit in the most severely affected infants Du et al, J Cerebr Blood Flow Metab 1996: 16:195-201 180 160 Infarct 140 volume 120 (mm3) 100 80 60 40 20 0 30 min ischaemia 90 min ischaemia 1 day 3 days 14 days Maturation time Hypothermia after deep hypothermic circulatory arrest Shum-Tim et al, J Cardiovasc Surg 1998: 116: 780-792. 300 Neurologic Deficit Score 200 150 100 50 0 Day 2 Day 3 Time after DHCA Day 4 250 Hypothermia Normothermia Hyperthermia Hypothermia after deep hypothermic circulatory arrest Shum-Tim et al, J Cardiovasc Surg 1998: 116: 780-792. Neocortex Hippocampus Dentate Gyrus Caudate 3 Pathology Score 2.5 2 1.5 1 0.5 0 Hypothermia Normothermia Hyperthermia Hypothermia in out-of-hospital cardiac arrest Bernard et al, Ann Emerg Med 1997: 30: 146-153. • 22 adults remaining unconscious in A/E after return of spontaneous circulation following out-of-hospital cardiac arrest • 22 historical controls, maintained at normothermia • moderate hypothermia (32oC) by surface cooling for 12 h • no adverse effects seen • balanced for key variables Hypothermia in out-of-hospital cardiac arrest Bernard et al, Ann Emerg Med 1997: 30: 146-153. GOS category Hypothermia (n=22) 8 3 1 0 10 Normothermia (n=22) 2 1 1 1 17 Normal /mild disability Moderate disability Severe disability Vegetative state Death RCT 1 • witnessed out-of-hospital arrest • 18-65 years of age • VF or ventricular rhythm • 5-15 minutes between arrest and resuscitation • <60 minutes resuscitation duration • n=255 patients HACA Study HACA Study NNT= 7 to prevent one death NNT=6 to prevent one unfavourable neurologic outcome HACA Study HOME | SUBSCRIBE | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | HELP | Search NEJM GO Advanced Search You are signed in as morriskp at Registered Visitor level | Sign Out | Edit Your Information Previous Volume 346:557-563 February 21, 2002 Number 8 Next Treatment of Comatose Survivors of Out-ofHospital Cardiac Arrest with Induced Hypothermia Stephen A. Bernard, M.B., B.S., Timothy W. Gray, M.B., B.S., Michael D. Buist, M.B., B.S., Bruce M. Jones, M.B., B.S., William Silvester, M.B., B.S., Geoff Gutteridge, M.B., B.S., and Karen Smith, B.Sc. • witnessed out-of-hospital arrest, adult • VF rhythm • ROSC at the scene • hypothermia commenced at the scene • 330C for 12 hours • n=77 patients NEJM 2002; 346: 557-563. OR for favourable outcome 5.25 (1.47-18.76) (p=0.11) Meta-analysis CJEM 2006; 8: 329-337 Limitations of current evidence • • • • • adult data out-of-hospital arrest VF rhythm strict inclusion criteria only 275 patients enrolled of the 3551 assessed for eligibility in the HACA study ILCOR guidance Circulation 2003; 108: 118-121 • unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 3234OC for 12 to 24 hours when the initial rhythm was ventricular fibrillation • such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest • do not actively rewarm a patient with mild spontaneous hypothermia (>33OC) • avoid hyperthermia What is actually happening in adults? ERC registry of patients cooled post arrest 650 patients across 19 sites in Europe Hypothermia being used in non-VF situation Crit Care Med 2007: 35: 1041-1047 Survey of adult ICUs in the UK suggests that only 28% have cooled patients after cardiac arrest. Logistical and resource issues cited as reasons. Anaesthesia 2006: 61: 873-877. What is the evidence for children • There isn’t any! • ILCOR statement: ‘there is currently insufficient evidence in children resuscitated from cardiac arrest’ What do paediatric intensivists do post cardiac arrest? Haque I et al. Pediatr Crit Care Med 2006: 7: 7-14. • • • • • 65% aware of the adult RCTs 9% (always) and 38% (sometimes) use hypothermia most cool to 33-35OC for anything between 12 and 96 hrs 95% would be willing to randomise patients in an RCT also keen to investigate hypothermia in other settings A randomised controlled trial is needed How to cool? • • • • • rapid infusion of iced saline (30 mls /kg) to initiate cooling surface cooling (ice, cooling blankets) selective head cooling endovascular cooling devices body cavities (peritoneal, pleural) How to monitor temperature • continuous core temperature monitoring – rectal – nasopharyngeal – oesophageal – bladder – brain BCH use of induced hypothermia • for tachy-dysrhythmias post cardiac surgery • post traumatic brain injury as a second tier therapy to control raised ICP – incremental hypothermia • as neuro-protection post cardiac arrest if estimated prospect of survival is reasonable – cooled to 33-35OC Potential side effects of hypothermia • • • • • • • • • temperature dependent, less severe above 32oC arrhythmias (more common in adults) coagulation changes, thrombocytopenia hyperglycaemia sepsis pancreatitis lowering of GFR, hypokalaemia ?pulmonary complications alteration in drug metabolism Summary • induction of hypothermia improves neurological outcome in selected adults with coma following OOHA • many questions still remain in adults • no good evidence of what to do in children post-arrest • hyperthermia may be harmful and should be avoided • do not actively rewarm a child with mild hypothermia • neonatal data supports value of hypothermia in ameliorating brain injury following perinatal hypoxicischaemic insult