Tina Yoo, PharmD Clinical Pharmacist Alameda Health System Highland Hospital 1
Review changes in the 2015 AHA ACLS guidelines with emphasis on changes in therapeutic hypothermia Provide overview of ACLS in pregnancy 2
Review the original studies of therapeutic hypothermia (TH) Review the new trials of TH Review updates in the 2015 ACLS guidelines on TH Review other major updates from the 2015 ACLS guidelines Review major recommendations for ACLS in pregnancy 3
Therapeutic Hypothermia 4
Done in 2002 Patients in emergency room Let s look at details 5
Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 6
Randomized, controlled, blinded trial to compare normothermia vs. mild hypothermia after out-of-hospital cardiac arrest Healthcare givers unblinded during first 48h Physicians assessing neurologic outcomes within first 6 months blinded The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 7
Patient population Inclusion criteria Age 18-75 yo Witnessed cardiac arrest Presumed cardiac origin of arrest Ventricular fibrillation or non-perfusing ventricular tachycardia Estimated 5-15min from patient collapse to start of resuscitation by emergency personnel 60 min from collapse to ROSC Have return of spontaneous circulation (ROSC) after cardiac arrest seen in the ER The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 8
Patient population Exclusion criteria Tympanic membrane temperature <30 C on admission Comatose before cardiac arrest due to drugs Pregnancy Terminal illness before arrest Known preexisting coagulopathy After ROSC and before randomization if: Responsive to verbal commands Hypotension (MAP<60mmHg) for >30min Hypoxia (O2Sat<85%) >15min Unable to complete follow-up or enrollment in another study Occurrence of cardiac arrest after arrival of emergency personnel The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 9
Treatment Medications allowed: Midazolam and fentnayl drips for sedation Pancuronium (0.1mg/kg q2h) x32h to prevent shivering Treatment arms Normothermia on conventional hospital bed Hypothermia (32-34 C) with cooling mattress ± ice packs Goal target within 4h from ROSC Cooled temperature maintained x24h then patients were rewarmed over 8 hours The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 10
Primary outcomes Favorable neurologic outcome within six months Pittsburgh cerebral-performance category of 1 (good recovery) or 2 (moderate disability) out of 5 Intention to treat The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 11
Results Study duration: March 1996 January 2001 N=275 137 to hypothermia group 14 did not complete hypothermia Median interval between ROSC and Cooling = 105 minutes target temperature = 8 hours (19 cannot reach target) Median duration of cooling = 24 hours Passive re-warming to 36 C lasted for a median of 8 hours 138 to normothermia group The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 12
Baseline characteristics Median age: 59 yo Witnessed cardiac arrest: 98-99% Basic life support by bystander: 43-49% Median time from collapse to restoration of spontaneous circulation: 21-22 min The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 13
Baseline characteristics con t Similar in general except patients in normothermia group are more likely To have diabetes To have coronary heart disease To receive bystander basic life support The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 14
Outcomes Lost to follow-up: one from each group The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 15
Outcomes con t P=0.02 Most patients from either group with unfavorable neurologic outcomes died within 6 months after discharge from the hospital The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 16
Complications No statistical difference between the two groups for complications (p=0.09) The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 17
Limitations Study groups unblinded to attending physicians Outcomes objective Small n Included very specific patients- decrease generalizability of study 15% did not reach target temperature in hypothermia group slight cross-over? The hypothermia after cardiac arrest study group. NEJM. 2002;346(8):549-556 18
Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 19
Prospective, randomized, controlled trial to compare moderate induced hypothermia with normothermia in comatose survivors of out-of-hospital cardiac arrest Randomization Patients were assigned to hypothermia group on odd number days of the month Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 20
Inclusion criteria Initial cardiac rhythm of ventricular fibrillation at time of ambulance arrival Return of spontaneous circulation (ROSC) Persistent coma after ROSC Transfer to one of the four participating emergency departments for the study Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 21
Exclusion criteria <18 yo for men and <50 yo for women (exclude pregnancy) Cardiogenic shock (SBP<90 mmhg despite epinephrine infusion) Possible causes of coma other than cardiac arrest Intensive care bed unavailable at time of inclusion Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 22
Treatment Hypothermia (target 33 vs. 37 C until 18h after arrival at hospital then re-warmed over 6h) After initial neurologic exam, all patients given as: Midazolam 2-5mg for sedation Vecuronium 8-12mg prn shirvering Partial pressure oxygen of 100 mmhg Partial pressure carbon dioxide of 40 mmhg Mean arterial pressure (MAP) of 90-100 mmhg Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 23
Treatment If no contraindications Thrombolytics for myocardial infarction (MI) Heparin drip for ischemic coronary syndrome without MI Aspirin to all patients Lidocaine (1mg/kg bolus then 2mg/min) x24h to prevent ventricular arrhythmia K maintained at 4mmol/L Glucose maintained at 180mg/dL Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 24
Outcomes Discharge status Assessed by a blinded specialist Discharged home = good outcome Death in the hospital or discharge to a long-term care facility (conscious or unconscious) = poor outcome N = 62 required for power of 80% and significance level of 0.05 Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 25
Results N=77 hypothermia:= 43 Normothermia= 34 Baseline characteristics Median age: 65-67 yo Witnessed cardiac arrest: 94-95% Basic life support by bystander: 49-71% Median time from first shock to restoration of spontaneous circulation (ROSC): 12-14 min No significant difference between the two groups Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 26
Results Outcomes Good outcome rates Hypothermia= 49% Normothermia= 26% P=0.046 Odds ratio after adjustment for age and time from collapse to ROSC= 5.25 (95%CI, 1.47-18.76, p=0.011) No difference in mortality No hematologic complications Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 27
Study limitations Small n No clinician blinding Protocol in place Even and odd days randomization Difficulties of out-of-hospital randomization Comparable baseline characteristics Bernard SA, Gray TW, Buist MD, et al. NEJM 2002;346:557-63 28
Comatose adult patients should be cooled to 32-34 C for 12-24h in patients that have: Out-of hospital Vfib, pulseless electric activity or asystole cardiac arrest In-hospital cardiac arrest (any rhythm) Active re-warming should be avoided in comatose patients who spontaneously develop a mild hypothermia during the first 48 hours after ROSC Peberdy MA, Callaway CW, Neumar RW, et al. Circulation. 2010;122[suppl ]:S768 86 29
Different targeted temperature? First new study Targeted temperature management at 33 C vs. 36 C after cardiac arrest (TTM trial) Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 30
Multicenter randomized controlled trial Main inclusion criteria 18 yo Out-of hospital cardiac arrest Unconscious (Glasgow Coma Scale score <8) on admission to hospital Cardiac arrest presumed cardiac origin Any cardiac rhythm 20 consecutive minutes of spontaneous circulation after resuscitation Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 31
Main exclusion criteria Interval from ROSC to screening >240 minutes Unwitnessed arrest with initial asystole rhythm Suspected or known intracranial hemorrhage stroke Body temperature <30 C Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 32
Methods Trial arms for targeted body temperature 33 C vs. 36 C Randomized by computer generated sequence All patients sedated until end of intervention period Goal is to cool patients as soon as possible Re-warming after 28 hours to 37 C at 0.5 C increments for 8 hours After intervention period (36 hours total), maintain body temperature below 37.5 C until 72 hours after cardiac arrest Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 33
Methods con t Blinding None for clinicians of the patients Yes for physicians performing neurologic prognostication, assessment and follow-up of final outcome as well as authors and statisticians of the trial Neurologic assessment was done at 72 hours after completion of intervention period for patients who remained unconscious All clinical decision remain at the discretion of the treating team Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 34
Methods con t Follow-up: until 180 days Primary outcome All cause mortality Major composite secondary outcome Poor neurologic function (Cerebral Performance Category of 3-5 + modified Rankin scale of 4-6) or death at 180 days Mortality at 180 days and individual neurologic scores Required n=950 Modified intention-to-treat population Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 35
Results N=950 (476 in 33 C and 474 t0 36 C) Similar baseline characteristics Age: ~64 yo Male: 79-83% Patient residence as location of cardiac arrest: 52-55% Bystander witnessed: 89-90% Bystander CPR done: 73% Vfib: 74-75% Time from cardiac arrest to (min): Start of BLS: 1 Start of ACLS: 9-10 ROSC: 25 Initial body temperature ( C): 35 Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 36
Results con t Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 37
Results con t Mean follow-up period: 256 days Results did not change for in the intention-to-treat or per protocol populations Effect was consistent across all predefined subgroups Adverse events 439/472 (93%) in 33 C 417/464 (90%) in 36 C RR=1.03; 95%CI 1.00-1.08; P=0.09 Hypokalemia 19% in 33 C 13% in 36 C P=0.02 Presumed cause of death similar in both groups Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 38
Author s conclusions Both temperature produced similar outcome results No harm for 33 C but no benefit either Included shockable and nonshockable rhythms Limitations ICU staff members unblinded Blinded assessors Objective scale scores No details on dose and type of sedation and /or neuromuscular bloackade agents used Protocol is to treat similarly Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 39
Comparison with the old studies N=939 vs. n=213 of the 2 combined older studies Has a withdrawal of life protocol Population less selective Emphasized importance of controlling temperature Older trials had more normothermic patients becoming hyperthermic 40
Final thoughts Why the difference Less selected patients in this trial including both shockable and nonshockable rhythms Evolving intensive care throughout the years reducing benefit of a single intervention Active prevention of hyperthermia One regimen of hypothermia may not fit all due to differing severity of disease Results a reflection of preventing hyperthermia? Nielsen N, Wetterslev J, Cronberg T, et al. TTM Trial. NEJM 2013;369:2197-206 41
Different targeted temperature? Second new study Neurologic function and health related quality of life in patients following targeted temperature management at 33 C vs. 36 C after out-of-hospital cardiac arrest. A randomized clinical trial (the California TTM trial exploratory analysis) Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 42
Exploratory analysis of cognitive function and quality of life in the cardiac arrest (CA) population included in the TTM trial Performance measures Observer-reported measures Patient-reported measures Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 43
Trial design, inclusion and exclusion criteria were as described the in above slides on the TTM trial Clinical outcomes assessment Patients alive after the discharge for the index cardiac arrest (CA) event from the TTM trial were invited to a structured assessment 6 months after the event Personal or telephone assessment Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 44
Clinical outcomes assessment con t Clinician-reported measures Cerebral Performance Category (CPC) Modified Rankin s Scale(mRS) Performance measures Mini-Mental State Examination (MMSE) MMSE Adult lifestyles and Function Interview (ALFI) if patients were assessed over the phone Observer-reported measures Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE) Patient-reported measures Two Simple Questions Medical Outcomes Study 36-Tiem Short Form Health Survey version 2 (SF-36V2) Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 45
Statistics Modified Intent-to-treat population Non-survivors are assigned the worst scores Hypothesis-generating and exploratory outcomes Outcomes presented in this article is not included in the power of the original TTM trial Post-hoc analyses Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 46
N=939 Intent-to-treat population N= 473 in 33 C N=466 in 36 C Alive at follow-up who participated N= 229 in 33 C N= 226 in 36 C Similar baseline characteristics at follow-up Prognostic baseline, occupational status, place of stay More patients in 33 C group has <12 years education 31.6% post CA were able to work in both groups Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 47
Median time to follow-up = 186 days Face to face = 92.1% Telephone 7.9% Tests completed MMSE: 86.2% by survivors MMSE-ALFI: 6.1% by phone IQCODE: 88.6% by observer SF-36 v2: 91.0% by survivors The Two Simple Questions: 92.3% by survivors Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 48
Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 49
Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 50
Final thoughts Limitations More patients in the 33 C group had <12 years of education could affect the IQCODE results Informants can be aware of the temperature patients received and could have let patients know may cause bias Quality of life was similar between cardiac arrest receiving TTM at 33 C vs. 36 C Largest prospective cognitive outcome and quality of life study in patients with out-of-hospital cardiac arrest to date Cronberg T, Lilja G, Horn J, et al. JAMA Neurol. 2015 Jun 1;72(6):634-41 51
Comatose adult patients with ROSC after cardiac arrest should have TTM Target temperature 32 C or 36 C Do not provide routine pre-hospital cooling after ROSC with rapid infusion of cold IV fluids Consider actively preventing fever Consider waiting until 72h after return to normothermia before prognosticating neurological outcome Neumer RW, et al. Circulation. 2015;132[supp 2]: S315-67 (executive summary) 52
Other Major 2015 ACLS Recommendations 53
General Can use cell phone AHA- Highlights of the 2015 American Heart Association guidelines update for CPR and ECC 54
Lay rescuer BLS recommendations Dispatchers should be educated to help bystanders recognize agonal breaths Perform compression only CPR Perform high quality CPR AHA- Highlights of the 2015 American Heart Association guidelines update for CPR and ECC 55
Healthcare provider BLS Minimize delay in call for help (assess while calling for help if possible) When AED is available in a witnessed cardiac arrest, defibrillate as soon as possible Perform high quality CPR Neumer RW, et al. Circulation. 2015;132[supp 2]: S315-67 (executive summary) 56
High quality CPR AHA- Highlights of the 2015 American Heart Association guidelines update for CPR and ECC 57
ACLS Elimination of vasopressin from the PEA/VF/pVT algorithm For nonshockable rhythms, consider giving epinephrine as soon as possible Individualize initiation or continuation of lidocaine after ROSC for cardiac arrest due to ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT) Neumer RW, et al. Circulation. 2015;132[supp 2]: S315-67 (executive summary) 58
ACLS con t Individualize initiation or continuation of betablocker may after hospitalization from cardiac arrest due to VF/pVT For in-hospital cardiac arrest (IHCA)- can consider giving intra-arrest vasopression, epinephrine, methylprednisolone and post-arrest hydrocortisone More studies are needed Neumer RW, et al. Circulation. 2015;132[supp 2]: S315-67 (executive summary) 59
Post-cardiac arrest care Reasonable to avoid SBP<90mmHg and MAP<65mmHg during post-cardiac arrest care Earliest time to prognosticate a poor neurological outcome not treated with TTM is 72h after cardiac arrest For this who dies, consider organ donation Neumer RW, et al. Circulation. 2015;132[supp 2]: S315-67 (executive summary) 60
Special populations If suspect cardiac arrest be due to local anesthetic toxicity, consider administering intralipid emulsion Pregnant patients (below section) For those at high risk for opioid overdose or not breathing due to suspected overdose, it is reasonable to provide training and administer IM or IN naloxone AHA- Highlights of the 2015 American Heart Association guidelines update for CPR and ECC 61
Opioid-related cardiac arrest AHA- Highlights of the 2015 American Heart Association guidelines update for CPR and ECC 62
Cardiac arrest in pregnancy 63
First scientific statement on this topic Challenging clinical scenario Two patients Caregiver should be specialized in both patients Steady increase of maternal mortality in the US from 1989 to 2009 Survival rates after maternal cardiac arrest is higher than most other populations Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 64
Common reasons for maternal arrest Anesthetic complications or accidents/trauma Bleeding Cardiovascular causes Drugs Embolic causes Fever General (non-ob causes: H&Ts) Hypertension Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 65
BLS Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 66
Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 67
ACLS Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 68
Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 69
Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 70
ACLS medications Give usual doses of ACLS drugs In cardiac arrest no meds should be withheld because of concerns about fetal teratogenicity Epinephrine IV/IO every 3-5minutes is preferred over vasopressin since both are considered equivalent and in view of the effects of vasopressin on the uterus Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 71
TTM Individualize need for patients If done in pregnancy Follow the same protocol as non-pregnant patient Monitor fetus throughout TTM There should be neonatal resuscitative team to take care of the neonate if delivered during resuscitation Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 72
Good BLS is key LUD during compressions ACLS Same drug dosages Do not with-hold drugs Two patients, two specialties Pregnant mom Fetus Jeejeebhoy FM, et al. Circulation. 2015;132:1747-73 73
BLS High quality CPR is key Chest compression rate 100-120 bpm Chest compression depth 2-2.4 inches Dispatchers trained to help bystander recognize signs of cardiac arrest Administer naloxone if suspect opioid overdose TTM-can aim for higher target temperature and avoid fever 74
ACLS Vasopressin no longer on PEA/VF/pVT algorithm Individualize giving lidocaine and beta-blockers in patient with VF/pVT Pregnancy Two patients to take care of Assess the causes of arrest Perform high quality CPR with manual LUD Same ACLS as non-pregnant patients Be prepared for emergency C-section 75
T/F-the new targeted temperature that can be considered for TH is 36 C T/F-atropine is removed from the PEA/VF/pVT algorithm in the 2015 guidelines T/F-naloxone is recommended in the 2015 guidelines if there is suspicions for opioid overdose T/F-LUD is important during BLS in pregnant women T/F-you should adjust ACLS medications for Vd changes in pregnant patient during cardiac arrest 76
T/F-the new targeted temperature that can be considered for TH is 35 C T/F-atropine is removed from the PEA/VF/pVT algorithm in the 2015 guidelines T/F-naloxone is recommended in the 2015 guidelines if there is suspicions for opioid overdose T/F-LUD is important during BLS in pregnant women T/F-you should adjust ACLS medications for Vd changes in pregnant patient during cardiac arrest 77
Questions? 78