Disclosure TARGETED TEMPERATURE MANAGEMENT POST CARDIAC ARREST I have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation. Kristen E. Heiner, PharmD Emergency Medicine Clinical Pharmacist Objectives Explain the rationale of therapeutic hypothermia and targeted temperature management post cardiac arrest Compare and contrast available methods for cooling Discuss clinical evidence for patient selection and degree of hypothermia Evaluate the impact of hypothermia on commonly used drugs post cardiac arrest Patient Case Patient Case-TM 63 y/o M Out of hospital cardiac arrest with bystander CPR Initial rhythm was ventricular fibrillation (VF) Return of spontaneous circulation (ROSC) achieved within 15 minutes In the ambulance bay, pulses lost again; VF requiring further shocks ROSC in the emergency department after 3 minutes Comatose patient, EKG w/ inferior ST-segment elevations Taken for primary coronary intervention Post cardiac arrest pathophysiology Circulation.2013;127:244. 1
Post Cardiac Arrest Syndrome Myocardial dysfunction Systemic ischemia Reperfusion responses Brain injury Brain Injury Irreversible brain injury is the most common cause of death Cerebral damage occurs during cardiac arrest and during the phase of reperfusion Generation of free radicals and other mediators Randomized controlled trials using pharmacological interventions found no benefit in improvement of neurological outcome Thiopental Corticosteroids Nimodipine Increased production of endogenous catecholamines Increased heat production Decreased heat loss/altered distribution of body heat due to vasoconstriction Hyperthermia Loss of thermoregulatory mechanisms Infection Effects of Hyperthermia Production of oxygen radicals during the reperfusion period 4- to 5-fold increase in oxygen radicals Brain metabolism Depletion of ATP Release of and decreased uptake of glutamate and aspartate Calcium shifts Mitochondrial damage and apoptosis Neuroscience. 1995;69:395. Brain Res. 1997;746:43. Hypothermia Reduces the cerebral metabolic rate for oxygen Reduced normal electrical activity Suppress the chemical reactions associated with reperfusion injury Attenuates pro-apoptotic signals and activates anti-apoptotic mechanisms The levels of neuron-specific enolase, a marker of neuron death, are also reduced in patients treated with hypothermia following CPR Targeted temperature management aims to attenuate and prevent the secondary cascade of events and injury mechanisms 2
Assessment Q1 The team is evaluating TM for therapeutic hypothermia post cardiac arrest. Hypothermia would be expected to reduce all of the following activities in TM except. A. Free radical production B. Anti-apoptotic signals C. Excitatory amino acid release D. Calcium shifts Circulation. 2013;127:244. Cooling Techniques METHODS FOR COOLING Conventional cooling techniques Surface cooling systems Intravascular cooling systems Conventional Cooling Techniques Prehospital Hypothermia Cold saline infusion Ice packs Advantages Availability Low cost Adjunct therapy Disadvantages Labor intensive Accuracy Effectiveness cooling with IV cold saline can be initiated safely in the prehospital setting. -2010 Guidelines Circulation. 2010;122:S768. 3
Survival to Hospital Discharge Favorable Neurological Outcome at Hospital Discharge Resuscitation. 2013; 84:1021. Resuscitation. 2013; 84:1021. Prehospital Hypothermia Risk Surface Cooling Systems Intervention group experienced re-arrest in the field more than the control group 26% [95% CI, 22%-29%] vs 21% [95% CI, 18%-24%] (p =0.008) Increase in diuretic use and pulmonary edema on first chest x-ray Resolved within 24 hours after admission Recommend against routine prehospital cooling of patients after ROSC with rapid infusion of cold intravenous fluids (Class III: No Benefit, LOE A) Circulate cold fluid or cold air through blankets or pads that are wrapped around the patient Advantages Ease of application Rapid initiation Auto-feedback mechanisms Disadvantages Skin burn Skin irritation Shivering JAMA. 2014;311:45 Circulation. 2015;132:S465. Intravascular Cooling Systems Intravascular Cooling Systems Percutaneously placed central venous catheter Subclavian, internal jugular or femoral veins Cool or warm saline is circulated in a closed loop through the catheter s balloon Various catheter options Advantages Computerized temperature control with auto-feedback Precision Less shivering Fewer incidences of failing to reach target/overcooling Disadvantages Catheter related blood stream infections Venous thrombosis 4
Intravascular vs Surface Cooling Intravascular vs Surface Cooling Methods Retrospective analysis of data from the TTM trial Intravascular devices (n=240) vs surface devices (n=694) Outcomes: speed, precision, mortality, neurological outcome Results Time to target temperature (p=0.58); maximum rate of cooling (p=0.44); overcooling episodes (p=0.15) Patients ever out of range 57.0% vs 91.5%, p = 0.006 Time out of range 1 [IQR 4.0] hours vs 8.0 [IQR 9.0] hours,p= <0.001 Crit Care 2016; 20:381. No difference in mortality or poor neurological outcome No difference in adverse events Intravascular and surface cooling was equally effective during induction of hypothermia Surface cooling was associated with less precision during the maintenance phase Conclusion: Either device is reasonable, ensure user is comfortable operating the device Crit Care 2016; 20:381. Assessment Q2 The team is evaluating available cooling technique to use and asks for your opinion. Which of the following information could you provide regarding cooling techniques? A. There is increased mortality with surface cooling B. There is shorter time to target temperature with intravascular cooling C. There is less time out of target temperature range with intravascular cooling D. There is increased adverse events with surface cooling PATIENT SELECTION AND DEGREE OF HYPOTHERMIA Cerebral Performance Category Good cerebral performance: conscious, alert, able to work, might have mild neurologic or psychologic deficit CPC 1 European Trial Australian Trial 2010 Guidelines TTM Trial 2015 Guidelines Moderate cerebral disability: conscious, sufficient cerebral function for independent activities of daily life Able to work in sheltered environment CPC 2 Severe cerebral disability: conscious, dependent on others for daily support because of impaired brain function Ranges from ambulatory state to severe dementia or paralysis CPC 3 CPC 4 Coma or vegetative state: any degree of coma without the presence of all brain death criteria Unawareness, even if appears awake (vegetative state) without interaction with environment Brain death: apnea, areflexia, EEG silence, etc CPC 5 Lancet 1975;1:480. 5
Results Out of hospital cardiac arrest Initial rhythm: ventricular fibrillation Randomized Normothermia (n=34) Hypothermia (n=43) 33 C 12 hours of cooling Ice packs Primary Endpoint Survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility Favorable neurologic function at discharge Hypothermia 49% (21) Normothermia 25% (9) p=0.05 OR 5.25 (95% CI 1.47, 18.76; p=0.01) No difference in the frequency of adverse events N Engl J Med. 2002;346:557. N Engl J Med. 2002;346:557. Core Temperature Multicenter, blind outcome Out of hospital cardiac arrest Initial rhythm: ventricular fibrillation or pulseless ventricular tachycardia Randomized Normothermia (n=138) Hypothermia (n=137) 32-34 C 24 hours of cooling Cool air Primary Endpoint Favorable neurologic outcome within six months after cardiac arrest Secondary Endpoints Mortality within six months Rate of complications within 7 days N Engl J Med. 2002;346:549. N Engl J Med. 2002;346:549. Results 2010 Guidelines Comatose adult patients with ROSC after out-of-hospital VF cardiac arrest should be cooled to 32 C to 34 C for 12 to 24 hours Class I, LOE B Induced hypothermia also may be considered for comatose adult patients with ROSC after in-hospital cardiac arrest of any initial rhythm or after out-of-hospital cardiac arrest with an initial rhythm of pulseless electric activity or asystole Class IIb, LOE B No difference in rate of complications (p=0.70) N Engl J Med. 2002;346:549. Circulation. 2010;122:S768. 6
The effect of therapeutic hypothermia on neurological outcome in non-randomized studies Effect of therapeutic hypothermia on in-hospital mortality in non-randomized studies Resuscitation. 2012;83:188. Resuscitation. 2012;83:188. N Engl J Med. 2013;369:2197. Trial Design Patients Treatment Arms Primary Outcome Secondary Outcome International, randomized Out of hospital cardiac arrest of presumed cardiac cause TTM at 33 C vs TTM at 36 C All-cause mortality Poor neurologic function or death at 180 days N Engl J Med. 2013;369:2197. TTM Results-Body Temperature TTM Results-Survival N Engl J Med. 2013;369:2197. N Engl J Med. 2013;369:2197. 7
TTM Results 2015 Guidelines 33 C Group 36 C Group Hazard Ratio Outcome or Risk Ratio pvalue no. / total no. (%) (95% CI) Primary Outcome Deaths at end of trial 235/473 (50) 225/466 (48) 1.06 (0.89-1.28) 0.51 Secondary Outcomes Neurologic function at follow- up CPC of 3-5 251/469 (54) 424/464 (52) 1.02 (0.88-1.16) 0.78 MRS score 4-6 245/469 (52) 239/464 (52) 1.01 (0.89-1.14) 0.87 Deaths at 180 days 226/473 (48) 220/466 (47) 1.01 (0.87-1.15) 0.92 Comatose adult patients with ROSC after cardiac arrest should receive TTM Class I, LOE B-R for VF/pVT OHCA Class I, LOE C-EO for non-vf/pvt and in-hospital cardiac arrest. Select and maintain a constant temperature between 32 C and 36 C during TTM Class I, LOE B-R N Engl J Med. 2013;369:2197. Circulation. 2015;132:S465. Who? What temperature? How long? Essentially no patients for whom temperature control somewhere in the range between 32 C and 36 C is contraindicated Lower temperatures Seizures Cerebral edema Hypothermic Higher temperatures Bleeding Hyperthermia Temperature sensitivity of the brain after cardiac arrest may continue for as long as brain dysfunction (ie, coma) is present Duration of at least 24 hours was used in 2 of the largest trials It is reasonable that TTM be maintained for at least 24 hours after achieving target temperature Class IIa, LOE C-EO Circulation. 2015;132:S465. Circulation. 2015;132:S465. Assessment Q3 The team has decided to initiate TTM in TM. His current core temperature is 34 C. What temperature and duration would your recommend in TM? A. 36 C for 12 hours B. 36 C for 24 hours C. 34 C for 12 hours D. 34 C for 24 hours MEDICATIONS POST CARDIAC ARREST 8
Absorption Distribution Hypothermia decreases the rate of drug absorption time to maximum concentration Greater variability in absorption exists with oral drugs than intravenous ones Neurologic dysfunction association with decreased gut motility Altered perfusion Blood shunted away from the gut and towards vital organs, decreasing intravascular distribution volume, and cardiac output ph increases Greater partial pressure of carbon dioxide in arterial blood Ionization of drugs Plasma protein binding may be unchanged, increased, or decreased Less drug transfer into lipid tissues Altered tissue-binding capacity Acta Clin Belg. 2017;72:116. Acta Clin Belg. 2017;72:116. Metabolism and Excretion Sedation and Analgesia Reduced metabolism Function of cytochrome P450 and other enzymes decline during hypothermia Reduced excretion Altered perfusion and protein binding High-clearance drugs more effected than low-clearance drugs Acta Clin Belg. 2017;72:116. Crit Care Med. 2012;40:1221. Sedation and Analgesia Neuromuscular Blockers Drug Populations Effects Recommendations Morphine Adult, infant, animal Fentanyl Adult, animal Drug sequestration in periphery Volume of distribution Serum concentrations Clearance Consider lower starting dose Serum concentrations Conservative dose titration Potential for decreased efficacy Consider lower starting dose Conservative dose titration Monitor for increased response during rewarming Last resort for attenuation of shivering Increased probability of survival when NMB are used for 24-48 h in patients after cardiac arrest Associated with the occurrence of critical illness polyneuropathy and myopathy during and after intensive care Hypothermia prolongs duration of action of NMB Midazolam Adult, animal Clearance Volume of distribution Serum concentrations Consider lower starting dose Conservative dose titration Monitor for withdrawal or seizures during rewarming J Perinatol. 2011; 31: 377. Resuscitation 2013;84:1728. Chest. 2017;151:697. Acta Clin Belg. 2017;72:116. 9
Results Randomized, double blinded, double dummy study Continuous rocuronium (n=32) vs bolus rocuronium (n=31) Primary Outcome Number of shivering episodes Secondary Outcomes Survival and neurological status one year after cardiac arrest Cumulative dose of rocuronium, midazolam and fentanyl Shivering episodes were detected in 94% of the bolus group compared to 25% of the continuous infusion group (p < 0.01) The continuous infusion group received significantly lower doses analgesics and sedation Midazolam 4.3 ± 0.8 mg/kg vs 5.1 ± 0.9 mg/kg, p < 0.01 Fentanyl 62 ± 14 g/kg vs 71 ± 7 g/kg, p < 0.01 Higher cumulative doses of rocuronium 7.8 ± 1.8 mg/kg vs 2.3 ± 1.6 mg/kg, p < 0.01 No significant differences in survival and quality of life at 12 months Resuscitation. 2017 30;120:14. Resuscitation. 2017 30;120:14. Results Single-center, retrospective study Shivering was managed with bolus doses of atracurium, escalated to a continuous infusion as needed Three groups: bolus (n=119), continuous infusion (n=97), none (n=93) Primary Outcome CPC 1-2 at discharge Secondary Outcomes Mortality Lactate levels and clearance J Crit Care, 2017;40:218. Continuous NMB independently associated with better neurologic outcome Adjusted odds ratio, 0.313; 95% CI, 0.120 0.815; p= 0.017 Continuous NMB independently associated with lower in-hospital mortality Adjusted OR, 0.414; 95% CI, 0.183 0.941; p= 0.035 Serum lactate level significantly decreased over time (p=0.001) No differences in serum lactate level among the three NMB groups (p=0.658) J Crit Care, 2017;40:218. NMB Conclusions Assessment Q4 Continuous NMB may improving outcomes is likely confounded by the fact that patients with the most severe brain injury likely have less shivering Goals: Limit shivering Lowest dose possible Monitor for convulsive activity with EEG Recognize the potential for overdosing with rewarming The team is starting fentanyl on TM for sedation and to reduce shivering. What recommendation(s) would you make? A. Conservative dose titration B. Consider a higher starting dose C. Monitor for increased response during rewarming D. A & C Best Pract Res Clin Anaesthesiol. 201529:435. 10
Thank you! TARGETED TEMPERATURE MANAGEMENT POST CARDIAC ARREST Kristen E. Heiner, PharmD Emergency Medicine Clinical Pharmacist 11