h Miracle on Ice Conference Minneapolis Heart Institute at Abbott Northwestern Hospital

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1 Intensive Care Management from the Experts Dr. David Seder Maine Medical Center Dr William Parham ANW Intensivist Program Dr Lisa Kirkland ANW Intensivist Program Dr. Michael Mooney Program Director and Moderator Objectives Review the anticipated impact of therapeutic hypothermia on cardiac output measurements Describe the intravenous fluid infusion process for lowering body temperature Discuss use of short-acting sedation and paralytics for therapeutic hypothermia Summarize the induction, maintenance and rewarming phases of therapeutic hypothermia h

2 Neurological Resuscitation after Cardiac Arrest Managing the patient during Induction, Maintenance, and Rewarming David Seder MD Maine Medical Center Director of Neurocritical Care Disclosures No financial conflicts ALL applications described are offlabel! Grant support from MMC NSI and MRC

3 Crit Care Med 2009;37 (Suppl):S211-S222. Epidemiology of OHCA Cardiac arrest is common 295,000 OHCA per year in US 23% VF 31% Bystander CPR Median survival all rhythms 7.9%, VF 21% Best EMS systems: ie: Seattle (resuscitated) 17.5% survival to hospital discharge 34% VT/VF subgroup IHCA adults: 19% (despite 95% witnessed or monitored) Mortality among patients surviving to be hospitalized Ontario 72% ( ) Taipei 75% (2003-4) Goteborg 68% (2003-5) Rochester 65% ( ) Circulation 2010;Jan 26:e12-13

4 Is the cup half empty? Nationally, the survival rate of OHCA is < 8% Half of patients who survive to be hospitalized die in the hospital Half of those who are discharged from the hospital have neurological disability Why bother? or half full? 40% of MMC OHCA survivors have GNO 55-60% with VT/VF & without shock have GNO A statewide program in Az of bystander CPR, CCR, and hypothermia led to a tripling of OHCA survival! These patients have a chance

5 Northern Hypothermia Network Acta Anaesthesiol Scand Aug;53(7): Acta Anaesthesiol Scand Aug;53(7):926-34

6 NHN CA outcomes 37 centers, 7 countries 986 patients received TH after CA % CPC 1-2 among asystole/pea Acta Anaesthesiol Scand Aug;53(7): Factors associated with survival Acta Anaesthesiol Scand Aug;53(7):926-34

7 From what do survivors die? Cause of Death in OHCA Cause of death in IHCA 23% 9% 68% HIE Cardiac MOSF 51% 23% 26% HIE Cardiac 3d 3rd MOSF Laver. Intensive Care Med 2004;30:2126 Mechanisms of brain injury in circulatory arrest Primary Injury: Energy failure due to ATP depletion Secondary injury: Loss of transcellular electrolyte gradients Ca h, Na +, Cl - enter, K + exits cell Water follows Na + into cells causing cytotoxic edema Lipid peroxidases damage membranes Neurotransmitter release causes excitotoxicity Activation of apoptotic pathways Microvascular thrombosis Reperfusion injury

8 Other secondary injury Uncontrolled seizure activity Hypotension, hypoperfusion Postresuscitation syndrome ICP crisis Autoregulatory failure Fever Re-arrest Hypoxia Derangements of glucose metabolism Neurology 2008;72:744 The hours after ROSC Mediators of cerebral blood flow after CA: Changes in blood viscosity Sludging of erythrocytes Development of platelet aggregates Heavy concentrations in post-ischemic tissue beds Imbalance of the coagulation system Endothelial flaps Compression by swollen glial cells Increased cerebral vascular tone and resistance Resuscitation 2003;58:337

9 Cardiac arrest associated brain injury CAABI No flow affects the most metabolically active areas of brain Cortex Basal ganglia Cerebellum Low flow affects the watershed areas between vascular territories 75 yo man OHCA Unwitnessed arrest VF on EMS arrival 35 minutes CPR and resuscitation Therapeutic hypothermia 108h after ROSC, GCS 4 CMO at family request

10 Shrunken eosinophilic neuron (anoxic neuron) is the hallmark of HIE Pseudolaminar necrosis Rationale for temperature modulation after brain injury Death Spiral Hypothermia drives fatally injured cells away from lysis and toward apoptosis Hypothermia drives marginally injured cells away from apoptosis and toward recovery Intracellular calcium mediates injury and most apoptotic pathways Crit Conn 2008;7(4):16

11 Anesthesia and Analgesia 1959;38 (6): 423 Anesthesia and Analgesia 1959;38 (6): 423

12 Clinical evidence for TH after CA Largest RCT of TH in OHCA survivors 275 patients randomized to TH or routine care Europe Absolute 16% increase in chance of a good neurological outcome Absolute 14% decrease in 6 month mortality N Engl J Med 2002;346: Clinical evidence for TH after CA N Engl J Med 2002;346:549-56

13 Clinical evidence for TH after CA New Engl J Med 2002; 346: Australian Randomized clinical trial conducted Randomized on alternating days to TH or routine care TH: good outcome 49%, routine care good outcome: 26% (p=0.046) Nonrandomized data Polderman. Lancet 2008, 371:

14 Lausanne 55 VT/VF OHCA treated with TH Compared to historical controls Similar DT, severity of illness CPC 1-2: 56% vs. 26% pre-th Effect of the implementation of a therapeutic hypothermia protocol on neurological outcome after out-of-hospital VF/VT arrest -Crit Care Med 2006;34:1865 Japan 400 patients with variable implementation ti of TH Developed model to isolate the interaction between use of TH and outcomes at different time points. No benefit of TH in DT < 15 minutes. Crit Care Aug 16;14(4):R155

15 What are the risks of TH? More infections Lung Trends toward more bleeding* Electrolyte shifts Clinically insignificant bradycardia Changes in drug metabolism HCASG. NEJM 2002;346: Skeptic s arguments 3300 patients screened in HACA to enroll 275 over 6 years Does not reflect real world experience Most commonly managed patients not included Many non TH patients t were allowed to develop fever Unfair comparitor? Single multicenter RCT should not set standard of care

16 TTM Trial European trial of TH (33C) vs TN (36.5C) in CA survivors Niklas Neilsen PI (INTCAR founder) Multinational trial Do we need to prove the efficacy of TH, again? What are the consequences of a poorly designed or inconclusive trial result? 2005 AHA ACLS Guidelines Unconscious adult patients with ROSC after out-of- hospital cardiac arrest should be cooled to 32 C to 34 C (89.6 F to 93.2 F) for 12 to 24 hours when the initial rhythm was VF (Class IIa). Similar therapy may be beneficial for patients with non- VF arrest out of hospital or for in-hospital arrest (Class IIb).

17 Only 10% patients with OHCA will meet RCT criteria for TH The decision to initiate TH is usually based on clinical judgement of risk and benefit, not on proof! Risks Infections Bleeding Need for sedation N Engl J Med 2002;346: Benefits Strongly neuroprotective Decreased mortality Better neurological outcome TH after Cardiac Arrest Clinical criteria for therapeutic hypothermia No more than 8 hours have elapsed since the return of spontaneous circulation. Encephalopathy is present, typically defined as the patient being unable to follow verbal commands. There is no life-threatening infection or bleeding. Aggressive care is warranted and desired by the patient or the patient s surrogate decision-maker Terminal underlying disease Impending cardiopulmonary collapse

18 The Devil s in the details How to cool Baltimore, 1955 Portland, Maine, 2006

19 Basics of Therapeutic Hypothermia There are 3 phases of treatment: Induction Rapidly bring the temperature to 32-34C Sedate with propofol or midazolam during TH Paralyze to suppress heat production Maintenance maintain the goal temperature at 33C Standard hours (optimal duration is unknown) Suppress shivering De-cooling (rewarming) Most dangerous period: hypotension, cerebral edema, seizures Goal is to reach normal body temperature over 12-24h Stop all sedation when normal body temperature is achieved Induction: how to cool Monitor core temperature Bladder, esophagus, or central venous/pulmonary arterial Cold fluid 30cc/kg LR or 0.9%NS over 30 minutes 2-2.5C temperature reduction No adverse cardiovascular results Rare to cause pulmonary edema Ice packs and cooling mats Effective, but difficult to control rate of temperature change Overcooling is dangerous

20 Induction: how to cool Commercial cooling devices Servo mechanism varies temperature re of circulating water or air (prevents overcooling) External (surface cooling) systems Hydrogel heat exchange pads Cold water circulating through plastic suit Cold water immersion awaiting safety data Invasive (catheter based) systems Heat exchange catheter in SVC or IVC Plastic or metalic heat-exchange catheter Cold IVF Polderman patients, 2-3L over C to 34.6 C, MAP increased by 15mmHg, no pulmonary edema Bernard patients 30cc/kg LR at 4 C over 30 min: 35.5 C to 33.8 C Improvements in MAP, renal function, no pulmonary edema Polderman. Crit Care Med 2005;33:2744 Bernard. Resuscitation 2003;56:9

21 Cold IVF 2-3L of Ringers or Saline at 4C decreases body temperature No effect on LVEF by echo Improved hemodynamic indices Kim. Circulation 2005;112:715

22 Induction How I do it Examine and place BIS monitor Give 30-40cc/kg IVF at 4ºC over 30 minutes LR or NS Pressure bag, not IV pump Sedate and paralyze the patient Apply a commercial cooling device Monitor and replace potassium and magnesium Antibiotics, usually Ventilate to a normal ph, and PaO2>110 Maintain i a MAP > 80 CVC, Arterial catheter, CO/CI/SVV device Comparison of cooling methods Traditional cooling inexpensive & available Effective Very high incidence overcooling Noninvasive cooling devices Safe no insertion, lots of clinical experience Effective, unless patients very heavy Expensive Invasive cooling devices Most effective at tight temperature control Better for heavy patients Insertional dangers: thrombosis, infection, placement-related injury Expensive Crit Care 2007;11:R91 INDUCTION MAINTENANCE

23 Outcomes with Surface vs Endovascular Cooling

24 Utility of the Medivance Arctic Sun for TH after Cardiac Arrest Effective at Induction 80% within 4h 90% within 6h 100% within 9h 2 pts got adjuvant cooling: ice or fluids Effective at maintenance 96.7% of the maintenance phase was spent in the target temperature range Jarrah. Neurocrit Care 2009;11:S23 90 patients with OHCA VF arrest and TH randomized mg/dl mg/dl Hypoglycemia defined as <54mg/dl Moderate hypoglycemia 18% vs 2% No mortality diff (33% 35%) mg/dl difference (33% vs

25 Measurement of Blood Glucose MMC prospectively enrolled 12 CA survivors and measured concurrent AG, VG, FBG Mean glucose values higher during TH >20% discrepancy FBG vs AG in 5% when T>36C, and 17% when T<34% FBG values uniformly higher than AG values Maintenance: How I do it Surface cooling for most patients with bladder or esophageal temperature Intravascular cooling if they need a CVC, have skin problems, or if I have extra time ceeg CO/CI and preload monitoring MAP > 80 Bispectral index when paralyzed to make sure they re out

26 Five patients who were not out 5/204 awoke during TH after CA All witnessed arrests 0-1 minute low flow minutes No flow BIS1 = BIS after first dose of NMB BIS1: 43,52,54,52,63 All were receiving propofol and/or fentanyl De-cooling Vasodilation causes hypotension May require several liters IVF, increased vasopressors More shivering Inflammation increases at higher temperature post-resuscitation syndrome Increased ICP Watch for hyperkalemia Primarily in renal failure SEIZURES

27 Patients do not like to rewarm, even if you call it decooling. Shivering Drives up systemic metabolic rate Increased CO2 production Increased O2 consumption Major cardiac stressor Drives up cerebral oxygen consumption Favors ischemia Uncomfortable Stroke Dec;39(12):

28 BIS monitor can be used to quantify shivering p=0.001 CC EMG db from BIS monitor correlated with the validated BSAS EMG power correlates with rate of cooling May. Crit Care Med 2009;37 (12 Supp); A467 Shiverplots EMG BSAS EMG Power (db) * * * 22:55 0:13 1:31 2:49 4:07 5:25 6:43 8:01 9:19 10:37 11:55 13:13 14:31 16:30 17:48 19:06 20:24 21:42 23:00 Time * BSAS

29 Shiverplots Each additional shivering episode associated with 35% increase in odds of GNO Management of shivering Neuromuscular blockade Vecuronium bolus 0.1mg/kg prn BSAS>2 Cisatricurium in renal failure Propofol Alpha blockade Dexmedetomidine infusion or clonidine Scheduled acetaminophen, buproprion p Meperidine or fentanyl Focal counterwarming Magnesium infusion (serum level 3-4mg/dl)

30 Sedation and analgesia during therapeutic hypothermia Comfort Antiepileptic effects HCASG Midaz 0.125mg/kg/hr Fentanyl 2mcg/kg/hr Pancuronium 0.1 mg/kg q2h 70kg man/32h 280mg midazolam 4480mcg fentanyl 224 mg pancuronium That s a lot of drugs! New Engl J Med 2002;346:549 Crit Care Med 2006;34:1865 Drug metabolism during hypothermia: what do we know? Propofol concentrations 30% higher at 34ºC than 37ºC (healthy volunteers) Fentanyl concentrations 5%/ ºC (healthy swine) Pharmacotherapy 2009;28:102 Anesth Analg 1995;80:1007 Anesthesiology 1999;91:A444

31 Sedation Deep, antiepileptic sedation, or Light sedation with ceeg, or BIS-guided sedation Seizures prior to therapeutic hypothermia 19-34% incidence overall Myoclonic status epilepticus traditionally associated with 100% mortality NCSE present, less common due to absence of NMB Patients rarely received propofol or BDZ -Ann Neurol 1994; 35: Neurology 1988; 38: Intensive Care Med 2006; 32:

32 19 children ceeg x72h during TH after CA 9 (47%) seized 6/9 NCSE 7/9 generalized 8/9 during late TH or rewarming periods 6 (32%) had SE What do the seizures mean? Are they markers for terrible and irreversible brain injury? Are they causing active, ongoing injury? Should we treat? If so, how? MSE NCSE Neurology 2008;72:744

33 ICU care following CA Many techniques for performing TH Electrolytes Glucose management Management of shivering Perfusing BP Seizure detection Antibiotics for aspiration or ALI Analgosedation Medication dosing Hospital size and CA outcome >109, patients in the NIS Mortality was lower at urban, teaching, and large hospitals Intensive Care Med 2009;35(3):505-11

34 CA volume vs outcomes 4674 patients from 39 hospitals Overall mortality was 56.8% Not all patients comatose After adjusting for age and severity of illness, institutional mortality ranged from 46% to 68% Annual case volume strongly associated with outcome Resuscitation Jan;80(1):30-4 Thank You! Horstmann et al. Brain atrophy in the aftermath of cardiac arrest. NEUROLOGY 2010;74:

35 1. Central Venous Pressures Managing MAP > 60 and CVP >8 CO /Index frequency Value during hypothermia? Cardiac outputs on done upon arrival to ICU; what should a protocol suggest to follow Cooling Cardiac output vs normal temp Cardiac Output? 2. Sedation vs Paralytics Shorter acting Sedation and use of Paralytics What about Versed, Precedex, Propofol? Train of 4 monitoring, D/C paralytic when temp back at 36. C vs 37.0 C Consider bolus dosing vs continuous drip

36 3. EEG Monitoring Continuous EEG monitoring (Neuro Prognostication) Practicality/Benefits Seizures 4. LINES IV Fluids and Line Placement Order of events to utilize IV fluids to cool faster Where is the best place to place lines ICU, Cath Lab or ED?

37 5. Non Phamaceutical Interventions for shivering Shivering, how do we control it? What are some Non pharmaceutical interventions we can apply? Do heated vent circuits it have impact? 6. Management of fever post cooling How should we treat the rebound fever after cooling is stopped?

38 7. Magnesium Levels Magnesium levels, importance Goal of magnesium level during TH