Update in Therapeutic Hypothermia Post Cardiac Arrest

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1 Learning Objectives Update in Therapeutic Hypothermia Post Cardiac Arrest Allison Forni, PharmD, BCPS Clinical Pharmacy Specialist UMass Memorial Medical Center, Worcester MA Learning Objective 1: Describe controversies on who, how, and when to initiate therapeutic hypothermia post cardiac arrest. Learning Objectives 2: Breakdown and evaluate the pharmacotherapy considerations for patients requiring therapeutic hypothermia. Patient Case AS is a 92 yo male suffering a cardiac arrest at SNF due to respiratory failure. The patient was down for unknown period of time. Bystander CPR was initiated, EMS arrived 4 minutes after call, presenting rhythm was asystole. Patient received 1 round of epinephrine and atropine and had ROSC 5 minutes after EMS arrival. Patient transferred to BWH ED, initial GCS 3 (no sedatives given), in sinus tachycardia. What elements of this patient case make the application of TH controversial? Ischemic Insult Loss of cerebral perfusion Anaerobic glycolysis Depolarization ATP depletion, intracellular acidosis Cardiac Arrest Reperfusion Normalization of blood flow Free oxygen radical generation Inflammatory response History Targeted Temperature Management (TTM) as a treatment modality for cardiac arrest Clinical practice of TTM should specify: A description of the intended temperature profile The thermoregulatory interventions used to achieve the target The actual performance of the TTM strategy The primary and secondary outcomes that the TTM intended to achieve Nunnally ME. CCM 2011; 29(5): Temperature Effect 36 C Increased activity attempting to warm up, skin pale, numb, and waxy, muscles tense, fatigue, and signs of weakness. 34 C 35 C Uncontrolled intense shivering, still alert but movements uncoordinated, and pain and discomfort due to coldness. 31 C 33 C Shivering slows or stops, muscles stiffen, mental confusion, apathy, speech slowed and slurred, breathing slower and shallow, and drowsiness. 31 C Skin cold, pupils dilated, extreme weakness, slurred speech, exhausted, denies problems, resists help, gradual loss of consciousness, and progressive respiratory arrest and arrhythmias American Society of Health-System Pharmacists 1

2 Rationale for TTM Post ischemic effects are temperature dependent Increased temperature enhances harmful effects of free radicals and activates NMDA receptors AHA recommendation: We recommend that comatose (ie, lack of meaningful response to verbal commands) adult patients with ROSC after out 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). 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). Critical Care Consensus Recommendations: The jury STRONGLY RECOMMENDS targeted temperature management to a target of 32 C 34 C as the preferred treatment (vs. unstructured temperature management) of out of hospital adult cardiac arrest victims with a first registered electrocardiography rhythm of ventricular fibrillation or pulseless ventricular tachycardia and still unconscious after restoration of spontaneous circulation (strong recommendation, moderate quality of evidence). Protective Physiologic effects of TTM Reduce cerebral metabolism Reduce cerebral blood flow Reduce ion pump dysfunction and neuroexcitation Reduce mitochondrial injury Decrease intracellular acidosis and intracranial hypertension Decrease free radical production Deleterious Cardiovascular effects Glucose and electrolyte abnormalities Reduction in GI motility Coagulopathy Immunosuppression Peberdy MA et al. Circulation 2010, 122:S768 S786 Nunnally ME et al. CCM 2011; 29(5): Castren M, et al. Acta Anaesthesiol Scand 2009; 53: Decrease apoptosis Side Effects of TTM Randomized Controlled Trials Biochemical and Hematologic Values Urine output Electrolyte loss Insulin secretion Insulin sensitivity Creatinine Clearance Cardiac Effects VT/VF Cardiac Output Patients Intervention Endpoints 275 enrolled Differences= DM, CV disease, bystander CPR Exclusion Criteria 32-34ºC by bladder temp with surface cooling over 24hrs (cooled over 4hrs, warmed over 8hrs) Primary= favorable neurologic outcome at 6 months 77 randomized No differences in baseline characteristics Exclusion Criteria 33ºC within 2 hrs of ROSC and maintained for 12hrs with active rewarming over 6 hrs Primary= neurologic outcome at discharge Platelet count Platelet aggregation Bradycardia Infection Bernard SA, et al. NEJM 346: ; HACA Investigators. NEJM 2002; 346(8): Bernard SA, et al. NEJM 346: Patient Case AS is a 92 yo male suffering a cardiac arrest at SNF due to respiratory failure. The patient was down for unknown period of time. Bystander CPR was initiated, EMS arrived 4 minutes after call, presenting rhythm was asystole. Patient received 1 round of epinephrine and atropine and had ROSC 5 minutes after EMS arrival. Patient transferred to BWH ED, initial GCS 3 (no sedatives given), in sinus tachycardia. What else do you want to know about this patient? Is this patient a candidate for TH? 2014 American Society of Health-System Pharmacists 2

3 Who What When How Why Patient Selection Comatose lack of meaningful response to verbal commands Return of spontaneous circulation Variability in: Initial rhythm Witnessed vs unwitnessed In hospital vs out of hospital Time to BLS Total ischemic time Time since ROSC Baseline body temperature Etiology of arrest Hemodynamic parameters Exclusion criteria McNicol DR et al. Circulation 2012; 26(21) Supplement Complications during TH Who What When How Why HACA Investigators. NEJM 2002; 346(8): Time Course of TH Time to initiation Time to achievement of target temperature Duration of TH Goal: To tightly control the patients core body temperature with a maximum fluctuation of º Celcius Increased stability of the patient but longer term side effects Induction Maintenance Reversion Maintain controlled normothermia 0 hrs? hrs? hrs Nielsen N et al. Acta Anaesthesiol Scand 2009; 53: Wolff B et al. International Journal of Cardiology 2009; 133: Goal: To reduce the patient s body temperature to goal as quickly as possible Rapid induction reduces risk for side effects Patient management problems Polderman KH, et.al Critical Care Med (3); Goal: To rewarm the patient in a slow and controlled fashion at 0.2 to 0.5 º Celsius per hour Risks associated with speed of rewarming 2014 American Society of Health-System Pharmacists 3

4 Who What When How Why In hospital vs out of hospital Timing of TH Out of hospital patients are generally well or at least physiologically well compensated before cardiac arrest whereas hospitalized patients are heterogeneously ill Time since ROSC The relationship between the onset of hypothermia and the resulting neuroprotection is unclear Nielsen N et al. Acta Anaesthesiol Scand 2009; 53: Nunnally ME et al. CCM 2011; 29(5): Wolff B et al. International Journal of Cardiology 2009; 133: Effect of Presenting Rhythm TH and favorable outcome: Nonshockable rhythm Retrospective cohort study of patients with a witnessed out of hospital cardiac arrest with an initial rhythm of PEA or asystole TH and unfavorable outcome: Shockable vs Nonshockable rhythm Retrospective cohort study of patients with a witnessed out of hospital cardiac arrest treated with TH Who What When How Why Testori C et al. Resuscitation 2011; 82: Terman SW et al. CCM 2014; 42: Which of the following should be considered when selecting a technique for cooling: Speed of induction Maintenance of a narrow temperature range Ability to provide controlled rewarming All of the above Ideal Technique for Cooling Ideal technique: Rapid temperature reduction Cooling of target organs Maintain temperature in a narrow range Controlled rewarming Easy transport and use during CPR Easy to use during routine care 2014 American Society of Health-System Pharmacists 4

5 Temperature Management Temperature Induction & Maintenance Cold fluids (4ºC) ml/kg Limitations: poor for maintenance, overcooling, volume Ice packs and cooling blankets Advantages: low cost Limitations: low cooling rate, skin damage, temperature maintenance, nursing care Hydrogel coated cooling pads Advantages: temperature maintenance, use with routine care Limitations: high cost, skin complications (rare) Intravascular devices Seder DB, et al. CCM 2009; 37(7): S211 S222. Hoedemaekers CW et al. Critical Care 2007; 11(4): 1 9. Temperature < 32 C 20 < 31 C 9 < 30 C 4 # pts Total n=32 Overcooling Survival to hospital discharge: 30 % temp < 32 C 58% temp > 32 C NS The target temperature for TH is well defined: Yes No Retrospective chart review at 3 large teaching hospitals Target temperature C Utilized surface cooling techniques Merchant RM et al. CCM 2006; 34 (12): S490 Normothermia vs Hypothermia Outcome 33C group 36 C group P value 1 serious ADE 93% 90% 0.09 Hypokalemia 19% 13% 0.02 Retrospective chart review of 828 adult patients following a witnessed out of hospital cardiac arrest with a GCS < 8 at admission. Evaluated the effects of spontaneuous normothermia (< 37.5 C) comparded with mild TH. Horburger D et al CCM 2012; 40: International trial in 36 ICUs that randomly assigned 950 unconscious adult patients to a target temperature of 33 C or 36 C following cardiac arrest Nielson N et al. NEJM American Society of Health-System Pharmacists 5

6 Who What When How Why Outcomes following cardiac arrest have improved over time: True False Cardiac Arrest Outcomes Survival to hospital discharge has improved over time For all rhythms % % Rates of clinically significant neurologic disability (CPC score at discharge, >1) among survivors has decreased over time For all rhythms % % Early recognition, resuscitation, postresuscitation care Patient Case AS is a 92 yo male suffering a cardiac arrest at SNF due to respiratory failure. The patient was down for unknown period of time. Bystander CPR was initiated, EMS arrived 4 minutes after call, presenting rhythm was asystole. Patient received 1 round of epinephrine and atropine and had ROSC 5 minutes after EMS arrival. Patient transferred to BWH ED, initial GCS 3 (no sedatives given), in sinus tachycardia. Girota S et al. N Engl J Med 2012;367: Key Takeaways What elements of this patient case make the application of TH controversial? Key Takeaway #1 Clinical Controversy regarding the application of TTM exists in multiple areas including who, what, when, how, and why Key Takeaway #2 The strongest grade of recommendation is given for out of hospital adult cardiac arrest patients with a first registered rhythm of ventricular fibrillation or pulseless ventricular tachycardia who are unconscious after ROSC 2014 American Society of Health-System Pharmacists 6

7 Pharmacotherapy Considerations in Management of Therapeutic Hypothermia: focus on shivering and glucose Paul M. Szumita, PharmD, BCPS Clinical Pharmacy Practice Manager Director Critical Care Pharmacy Residency Program Brigham & Women s Hospital, Boston, MA Objective Breakdown and evaluate the pharmacotherapy considerations for patients requiring therapeutic hypothermia wit a focus on shivering management and glucose management Complications of TH Infection/pneumonia bleeding Acid/base Shivering/not meeting target temperature Electrolytes (Potassium, magnesium, phosphate) Glucose management Hemodynamics (Bradycardia and hypotension) Mechanical ventilation Pharmacokinetic alterations Seizure and myoclonus Empey PE, et al. Crit Care Med Oct;41(10): Perbet, S, et al. Am J Respir Crit Care Med. Vol : , 2011 Geurts M, et al. Crit Care Med Feb;42(2): Mikkelsen M, et al. Crit Care Med Jun;41(6): Noyes AM, Lundbye JB. J Intensive Care Med Dec 25. [Epub ahead of print] Does your institution have a protocol for prevention, assessment and management of shivering? Yes No Not formalized Not sure Involuntary oscillatory skeletal muscle activity Shivering threshold is ~1 C below the vasoconstriction threshold Activates autonomic and hemodynamic responses Increases the resting energy expenditure and caloric consumption Typically happens in the induction phase Once in maintenance of TH shivering less frequently a complication Shivering Frequent assessment is key Pharmacologic and nonpharmacologic strategies can be used to prevent and treat shivering Non pharm Head and hand warming Warming blankets Pharm: Neuromuscular blockers, opioids and sedative use and higher magnesium levels have been associated with significant reductions in shivering Seder DB, Van der Kloot TE. Crit Care Med. 2009; 37: S Badjatia N, Strongilis E, et al. Stroke 2008; 39: Logan A, et al. Crit Care Nurse Dec;31(6):e Park SM, et al. Crit Care Med Nov;40(11): Thermoregulatory Defenses Threshold (Celsius) Women 36 Men 35 Sweating Constriction Shivering Sessler DI. CCM 2009; 37(7): S203 S American Society of Health-System Pharmacists 7

8 Induction Phase Shivering Timeline Maintenance Phase 24 hrs Rewarming Phase Maintenance of Normothermia 0 hrs Goal: To rewarm the patient 72 hrs in a slow and controlled fashion at 0.2 to 0.5 º Celsius per hour Risks associated with speed of rewarming Maintain normothermia with cooling pads for 48 hours after rewarming Shivering assessment Bedside Shivering Assessment Scale 0 = none No shivering noted on palpitation of masseter, neck or chest wall 1 = Mild Shivering localized to the neck and/or thorax only 2 = Moderate Shivering involves gross movement of the upper extremities 3 = Severe Shivering involves gross movement of the trunk and upper and lower extremities Badjatia N, Strongilis E, et al. Stroke 2008; 39: Which primary agent is the primary sedative agent used to management of shivering at your institution? Propofol Midazolam Dexmedetomidine Neuromuscular blocker with a sedative Medication used to Manage Shivering Magnesium Opioids Remifentanil Meperidine Fentanyl Morphine Dexmedetomidine Clonidine Propofol Neuromuscular blockers Ketamine Midazolam buspirone Bjelland T, et al. Intensive Care Med (2012) 38: Controversies and Questions What agent or combination of agents to has the best outcomes? Should all patients get NMB? How deep should we sedate the patients? Light vs. Deep Sedation on clinical outcomes and mental health after critical illness p = 0.02 p = 0.03 p =0.47 Significant patient characteristics/metrics/outcomes PTSD score ICU discharge* PTSD score 4wks post ICU* Light Deep P value *Data presented in mean Event Scale-Revised PTSD Data presented as n (%) of Single center, prospective, open label trial of 137 ICU patients requiring mechanical ventilation randomized to light (Ramsey 1 2) or deep (Ramsey 3 4) sedation at Geneva Hospital Switzerland. Extensive exclusion criteria, removing high risk patients and those with baseline cognitive dysfunction. Treggiari MM, et al. Crit Care Med Sep;37(9): American Society of Health-System Pharmacists 8

9 Moderate Level of Sedation/Analgesia May be Appropriate however Moderate level of sedation/analgesia is possible with minimal need for NMB In healthy volunteers; cooling has been achieved in conscious patients However: Lower requirements for sedatives have been associated with worse outcomes in some studies May be a marker of poor neurologic outcomes (patients are worse off to begin with) NMB MAY be associated with better outcomes. May TL, et al. Neurocrit Care Jun 25. [Epub ahead of print] Testori C, et al. Crit Care. 2011;15(5):R248. Burjek, NE, et al. Crit Care Med May;42(5): Salciccioli JD, et al. Resuscitation Dec;84(12): Neuromuscular blockers: to add or not? Shivering is associated with better outcomes observationally Shivering patients are more likely to receive NMB; therefore selection bias may explain Continuous or bolus? Bolus was associated with: Quicker to target temp Less total exposure to NMB Equal time in TOF Many believe NMB should be used for breakthrough shivering only due to side effects of NMB Perhaps a X1 dose at induction (future study) Noyes AM, Lundbye JB. J Intensive Care Med Dec 25. [Epub ahead of print} Jurado LV, et al. Pharmacotherapy Dec;31(12): Noyes AM, Lundbye JB. J Intensive Care Med Dec 25. [Epub ahead of print Magnesium Therapy Reduces shivering thresholds Produces peripheral vasodilation and increases cooling rates Has antiarrhythmic properties Some animal data indicate added neuroprotection Patient Case AS 92 yo male suffering cardiac arrest at SNF due to respiratory failure. Patient was down for unknown period of time. Bystander CPR initiated, EMS arrived 4 minutes after call, presenting rhythm was asystole. Patient received 1 round of epinephrine and atropine and had ROSC 5 minutes after EMS arrival. Patient transferred to BWH ED, initial GCS 3 (no sedatives given), in sinus tachycardia. Pt on propofol and fentanyl infusion 2 hours into cooing pt temp is 35 degrees with shivering score of 2 Zweifler RM, Voorhees ME, et al. Stroke 2004; 35: For AS what would you do to treat the current shivering? Increase Propofol and fentanyl infusions bolus NMB Start dexmedetomidine Continuous NMB Example Prevention and Management of Shivering Strategy Prevention Non pharmacologic Warm hand, head and heating blanket Magnesium bolus 4 6 grams X1 (run over 4 hours) Low dose opioid and propofol infusions Frequent assessment with bedside shivering scale Treatment of breakthrough 1. Simultaneous Bolus opioid and propofol drip titration Q 10 min X3 2. NMB bolus Q10 min X3 3. NMB infusion (refractory only) Turn off infusions during rewarming 2014 American Society of Health-System Pharmacists 9

10 Glucose During TH Hyperglycemia is associated with (observational) increase in poor outcomes Neurologic Mortality Hyperglycemia and hypoglycemia are common Hyperglycemia typically during cooling Hypoglycemia during rewarming Daviaud F, et al. Intensive Care Med Jun;40(6): Kim SH, et al. Am J Emerg Med Aug;32(8): Forni AA et al. Crit Care Med. Dec 20124(12): How does your institution manage hyperglycemia during Therapeutic Hypothermia? Same IV insulin protocol as other ICU patients Same IV insulin protocols as other ICU patients with a few provisions Different IV insulin protocol Not sure Guidelines from Professional Organizations on ICU Blood Glucose (BG) Goal Year Organization 2009 AACE and ADA Surviving Sepsis Campaign Institute for Healthcare Improvement American College of Critical Care Medicine (ACCM) American College of Physicians American Heart Association Patient Population ICU patients ICU patients ICU patients BG Treatment Threshold (mg/dl) ICU 150 BG Target (mg/dl) BG Hypoglycemia Definition (mg/dl) Updated since NICE- SUGAR, <70 Yes 180 <180 Not stated Yes 180 <180 <40 Yes <150 (Trauma) <180 (Stroke+) <70 Yes ICU patient Not stated Not stated Yes ICU patients with ACS Kavanagh BP et al. N Engl J Med. 2010; 363: Qaseem A et al. Ann Intern Med. 2011; 154: Not stated No Jacobi J. Crit Care Med. 2012; 40: Finfer S et al. N Engl J Med. 2009; 360: IV Insulin in the ICU Setting IV Insulin Critically ill patients in the ICU Insulin Recommended Jacobi J. Crit Care Med. 2012; 40: Moghissi ES et al. Diabetes Care. 2009; 32: Antihyperglycemic Therapy SC Insulin Non critically ill patients Oral Antidiabetic Drugs Not generally recommended Managing Hyperglycemia during TH No consensus on how to manage hyperglycemia specifically related to TH Is the typical 180 mg/dl or below appropriate for these patients? Typically require high doses of insulin during cooling Insulin requirements lower during rewarming Ins, n BG, n Forni AA et al. Crit Care Med. 40(12):1 328, December American Society of Health-System Pharmacists 10

11 Example Strategy for Managing Glucose during TH Initiate IV insulin when glucose is greater than 200mg/dl Do not exceed 50 units insulin / hour Stop continuous intravenous insulin when glucose levels drop to less than 200 mg/dl, unless type 1 diabetes mellitus If patient has type 1 diabetes, continue IV insulin at a rate of 0.5 units/hour Check glucose every 30 minutes if glucose < 80 mg/dl until rewarming complete and glucose stabilized > 100 mg/dl Potassium TH increases urine output (wasting of K) and pushes K into the cell during cooling Potassium replacement: Consider replete potassium to maintain levels >4.0 meq/l Typically discontinue K+ repletion 4 hours prior to rewarming, unless K+ is less than 3.5 Potassium levels may continue to be elevated hours past re warming and require continued frequent electrolyte monitoring Alterations in Medication Pharmacokinetics Absorption Slow rate of availability Onset delay Prolongation of time to Cmax Reduction in gastric motility causes variability with oral dosage formulations Distribution V d dependent upon: Blood flow redistribution Blood ph increases and pco2 decreases Drugs with pka of 7 8 are most affected during IH Alterations in protein binding Lipid solubility Tissue binding capacity Metabolism Altered temperature= altered enzyme activity Conformational shape changes at receptor site Less activation or inactivation of drug and metabolite Prolongation of prodrug conversion to active drug Higher serum concentrations of active compounds which result in toxic effects Accumulation of metabolites Elimination Biliary clearance Impaired hepatic blood flow Renal clearance Renal blood flow decreased Impaired CrCL during maintenance and effect reversed upon rewarming Arpino PA and Greer DM. Pharmacotherapy 2008; 28(1): Increased UOP thought to be due Empey PE, et al. Crit Care Med Oct;41(10): to impaired tubular secretion Tortorici MA, et al. CCM 2007; 35: Example Patient Monitoring Guideline Seizure v myoclonus EEG (goal less than 18 hours from admission) BIS in the rare case of NMB Not reliable for sedative drip titration TOF in the rare case of NMB Baseline Continue sedation until a 4/4 TOF is achieved RASS Goal RASS 4 to 5 prior to cooling Temperature 2 methods of measurement Shivering assessment scales Electrolytes, glucose, coag monitoring Hemodynamic Heart rate (bradycardia common) If clinical bradycardia, can warm to to see clinical effect MAP (goal > 90) CVP (goal greater than 8 typically) Badjatia N,et al. Stroke 2008;39: Quality Metrics Example Times Minutes Goal Downtime <15 min ROSC to TH initiation <60 min ROSC to ICU ROSC to target temperature <300 min ED to ICU time TH initiation to target temperature <240 min ICU to target temperature <180 min Arctic Sun to target temperature <180 min ICU to EEG <18 hours Hypoglycemia occur? None Breakthrough shivering meds given? List meds Therapeutic hypothermia after cardiac arrest guideline Core Management Patient selection Cooling and rewarming process Shivering Electrolyte repletion Hemodynamics and ventilation Glucose management Seizure and myoclonus Prognosis 2014 American Society of Health-System Pharmacists 11

12 Key Takeaways Key Takeaway #1 Shivering is common complication leading to delays to target temperature. Prevention, regular assessment and management strategies are imperative. QUESTIONS? Key Takeaway #2 Hyper and hypoglycemia are common during and cooling, maintenance and rewarding and are associated with poor outcomes American Society of Health-System Pharmacists 12