3/9/2011 Therapeutic Hypothermia after Cardiac Arrest Asst. Prof. Sombat Muengtaweepongsa, M.D. Division of Neurology Faculty of Medicine Thammasat University Historical Observations • Not Dead till Warm and Dead – Cold patients would wake up in the Morgue • Kids / Hockey Players- fall through ice, long rescue times, times but good recovery • Hibernation: state of low oxygen, acidosis, low energy supply What is the purpose of TH? • Aimed at minimizing the effects of anoxic neurologic injury following cardiac arrest • Other than supportive care TH it is the only identified measure to improve quality of life post resuscitation Mechanisms of neuroprotection by hypothermia • counteract ischemic brain damage by several mechanisms – prevention of the blood–brain-barrier disruption – oxygen-based free-radical production –  excitotoxicneurotransmitter release – anti-inflammatory action – delayed apoptosis 1 3/9/2011 Scope • Therapeutic hypothermia after cardiac arrest • Therapeutic hypothermia in ischemic stroke • Fever control in critical care neurology 2005 ILCOR • There seems to be good evidence (level 1) to recommend the use of induced mild hypothermia in comatose survivors of-out-hospital of out hospital cardiac arrest caused by VF. Level 1 evidence indicates one or more randomized clinical trials in which benefit was shown PostCardiac Arrest Care: 2010 • In summary, we recommend that comatose (ie, lack of meaningful response to verbal commands) adult patients with ROSC after out out-of-hospital of hospital VF cardiac arrest should be cooled to 32°C to 34°C (89.6°F to 93.2°F) for 12 to 24 hours (Class I, LOE B). Therapeutic Hypothermia after Cardiac Arrest (N Engl J Med 2002;346:557-63.) 2 3/9/2011 The RCT of TH after cardiac arrest HACA (European) Bernard trial (Australia) Sample N=275 N=77 Cooled verses normothermia 137 cooled 138 normothermia 43 cooled 34 normothermia Intervention Cooling blankets and ice packs Ice packs Target temperature 32-34 degrees 33 degrees Initiation Prehospital ER Duration 24 hours 12 hours Follow up 6 months 30 days 2. 3. 4. • NNT of 7 to prevent 1 death with TH • NNT of 6 to reduce neurologic impairment with TH The NNT is the number of patients who need to be treated in order to prevent one additional bad outcome HACA study group, 2002. New England Journal of Medicine 346(8). Standard treatment for AIS 1. Benefit Adverse Events Intravenous rt-PA within 3 hrs window (NNT = 10) Stroke unit (NNT 30 – 40) ASA within 48 hrs (NNT = 140) E l decompressive Early d i surgery for f malignant li t MCA infarction (NNT = 2 for death prevention) • Bleeding, pneumonia, sepsis, pancreatitis, renal failure, pulmonary edema, seizures, arrhythmias and pressure sores were g recorded in both trials with no significant adverse events. “ Sepsis was more likely to develop in the patients with hypothermia than those in normothermia, although this difference was not statistically significant” (HACA study group, 2002) Side effects of moderate hypothermia on various organ systems Variable Plt count aPTT lipase K+ Na+ Normothermia Hypothermia After-rewarming 183 (145-310) 110 (20-180) 160 (50-210) 27 (20-45) 34 (25-50) 30 (20-55) 140 (60-190) 250 (140-1200) 200 (135-1000) 4.1 (3.5-4.7) 3.4 (3.1-3.9) 4.4 (4.0-5.2) 139 (134-145) 140 (138-150) 145 (139-155) Cr Clearance 81 (60-100) 65 (45-90) 70 (45-95) Norepinephrine 0 0.32 (0.0-0.45) 0.08 (0.0-0.24) So why is TH not done more often? Both of these studies involved a highly selected group of patients, excluding up to 92% of patients with out-of-hospital cardiac arrest initially assessed for eligibility 3 3/9/2011 Suggested Inclusion Criteria • TH is indicated if the patient meets all of the following criteria: 1. Witnessed arrest 2. Initial rhythm VF or pulseless VT…. But 3. Time to ACLS was less than 15 minutes and total of ACLS time less than 60 minutes 4. GCS of 8 or below 5. SBP of > 90 with or without vasopressors 6. Less than 8 hours have elapsed since return of spontaneous circulation (ROSC) Suggested Exclusion Criteria 1. 2. 3. 4. 5 5. 6. 7. Pregnancy GCS 10 and improving Down time of > 30 minutes ACLS preformed for > 60 minutes Known terminal illness Comatose state prior to cardiac arrest Prolonged hypotension (ie MAP < 60 for >30 minutes) 8. Evidence of hypoxemia for > 15 min following ROSC 9. Known coagulopathy that cannot be reversed Ideal temperature curve Temperature Induction Sustainment Rewarming Time Methods of Cooling Methods to Control Brain Temperature in Post-cardiac arrest Patients • Selective head cooling – Cooling helmet: ineffective in adult • Internal cooling by intravenous and intraarterial ice ice-cold cold saline – Need large volume • Surface cooling • Endovascular cooling 4 3/9/2011 Surface blanket Surface cooling Surface cooling Figure 1. The Reprieve Endovascular Temperature Management System Endovascular catheter De Georgia, M. A. et al. Neurology 2004;63:312-317 5 3/9/2011 Intravascular Hypothermic Machine Intravascular Hypothermic Catheter Site of temperature probe Thermoregulatory Defenses Against Hypothermia • PA cath – Most accurate but high complication rate • Esophagus – High Hi h accuracy b butt may nott comfortable f t bl tto patient • Rectum • Vasoconstriction – Primary autonomic defenses – Threshold: 36.5o C • Shivering – “last resort” response – Threshold: 35.5o C – Medium accuracy with lag behind core temp 10 – 15 min. but easy to use Introduction of thermoregulatory tolerance • Nonpharmacological treatments – Whole body surface warming • Pharmacological treatments – Anesthetics A th ti and dM Muscle l relaxants l t – Meperidine – Drug combination • Meperidine and Buspirone • Meperidine and Dexmedetomidine 6 3/9/2011 Reductions in the shivering threshold (compared with the control day) for the dexmedetomidine (Dex), meperidine (Mep), and 2-drug combination (Combo) days Doufas, A. G. et al. Stroke 2003;34:1218-1223 Copyright ©2003 American Heart Association Induction • Get below 34oC and to target temperature as quick as possible ! – 2-4 hrs Sustainment • Should be reliable • No or minor fluctuations – Maximum 0.2 – 0.5 oC • Small overshoot acceptable – Temp > 30oC Rewarming • The most critical period of risk related to therapeutic hypothermia • Vasodilation • Hypermetabolic response – Systemic inflammatory response syndrome (SIRS) • Passive controlled rewarming – Stepwise rewarming rate: 0.1-0.5 oC per hr Rewarming • Cerebral side effects – Rebound edema and ICP elevation • Extracerebral side effects – Infection • Pneumonia P i • Sepsis – Cardiopulmonary • Elevation of catecholamines: arrhythmia – Hematologic • Induced thrombosis 7 3/9/2011 Therapeutic Hypothermia for Ischemic Stroke 8 3/9/2011 A case scenario 69 y/o woman presented to an outside hospital with sudden onset of right sided weakness and speech impairment. She arrived at the OSH at 20 minutes after onset. CT-brain was negative. TPA was started at 90 minutes after the onset before she was transferred to SLUH. A case scenario (cont.) She was alert and awake, but aphasic. NIHSS was 8 with: LOCb 2, partial hemianopia hemianopia, right arm drifting, some effort against gravity on right leg, partial sensory loss on the left side moderate aphasia. A case scenario (cont.) Without either intubation or sedation, therapeutic hypothermia with endovascular cooling technique was started at 5 hours after onset. Target core temperature of 33oC was reached within 3 hrs. Shivering was under control with combination of surface warming and meperidine plus buspirone. Gradual rewarming was applied after target temperature was maintained for 24 hrs. Temperature and stroke For each 1 degrees C increase in body temperature the relative risk of poor outcome rose by 2.2 (95 percent CI 1.4-3.5) (p less than 0.002). 9 3/9/2011 She was discharged to a rehab after 5 days of admission with NIHSS of 5 and mRS of 3. At day 30, 30 She walked by herself to follow up at DOB. NIHSS was only 3 including hemianopia and partial sensory loss. mRS was 2. Fever-related Brain Injury in the Neuro-ICU Hypothermia for Malignant MCA Infarction Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system Diringer MN, CCM 2204;32:559 • Cerebral Infarction • Elevated temperature is associated with poor outcome after stroke Hajat et al, Stroke 2000;31:410 • Subarachnoid Hemorrhage • Fever burden independently associated with mortality & poor functional outcome. Mayer et al, Crit Care Med 2003 (Suppl);30:A5 • Intracerebral Hemorrhage • Duration of fever (>37.5° C) within the first 72 hours is independently associated with poor outcome • 296 patients with T ≥38° C for at least 2 occasions – SAH, TBI, ICH and cerebral infarction • Alsius Cool Line endovascular heat exchange catheter plus standard surface cooling • Fever Burden >38 °C 64% relative reduction (P<0.01) – 7.92 °C-hours – 2.87 °C-hours • Shivering “of concern” in four patients (3.7%) Schwarz et al, Neurology 2000;54:354 10 3/9/2011 Clinical Trial of a Novel Surface Cooling System for Fever Control in Neurocritical Care Patients Mayer, et al, Crit Care Med 2004 • 47 patients with T ≥38.3° C for >2 consecutive hours after receiving acetaminophen – Median GCS 8.0 – SAH, ICH, infarction, TBI – Mean 42 hours >38 >38.3 3° C prior to randomization • Interventions – Standard SubZero cooling blanket – Medivance Artcic Sun surface cooling system • Main outcome measure – 24 hour fever burden Change in Glasgow Coma Scale P=.038, GEE model Clinical Trial of a Novel Surface Cooling System for Fever Control in Neurocritical Care Patients P=0.001 Conclusion • TH is a standard treatment in selected patients after cardiac arrest. • TH should be benefit for penumbra salvaging in acute ischemic stroke stroke. • TH is one of treatments for increase ICP. • Fever control is essential, particularly in such a bad neurological conditions. Take home message “ No evidence” doesn’t mean “Evidence does not exist”. Thank you for your attention sombatm@hotmail.com 11