A Cure for the Code Blues? Vasopressin, Steroid and Epinephrine Cocktail for Use in Advanced Cardiac Life Support

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1 A Cure for the Code Blues? Vasopressin, Steroid and Epinephrine Cocktail for Use in Advanced Cardiac Life Support Hannah Davis, Pharm.D. PGY2 Emergency Medicine Pharmacy Resident University Health System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio August 28, 2015 Learning Objectives 1. Define therapeutic endpoints for basic life support and advanced cardiac life support (ACLS) 2. Describe the current level of evidence for vasopressor agents recommended by national ACLS guidelines 3. Identify complications following return of spontaneous circulation which may decrease survival 4. Analyze evidence for role of combination vasopressin, steroids and epinephrine in ACLS

2 I. Cardiac arrest (CA) Figure 1. Introduction to CA Medical emergency Sudden cessation of effective blood circulation Prevents delivery of oxygen and nutrients Results in loss of consciousness and death A. Incidence 1,2 i. Out-of-hospital cardiac arrests (OHCA): 94 per year per 100,000 people ii. In-hospital cardiac arrests (IHCA): 1-5 per 1,000 patient admissions a. Bias due to lack of official reporting and documenting B. Survival rates 1-7 i. Favorable determinants a. Younger age b. Fewer comorbidities c. Ventricular fibrillation (VFib) or pulseless ventricular tachycardia (VTach) d. Witnessed arrest e. Shorter time to chest compressions and defibrillation f. Shorter duration of code g. IHCA h. Occurrence during the day on a weekday ii. National OHCA survival to hospital discharge: 3-16% iii. National IHCA survival to hospital discharge: 23% a. VFib or VTach: 18-64% b. Pulseless electrical activity (PEA) or asystole arrests: 1-14% iv. 60% of patients do not survive to discharge after return of spontaneous circulation (ROSC) a. Most deaths following ROSC occur within 24 hours v. Neurologic function a. Severe cerebral disability or vegetative state in 25-50% b. Post-cardiac arrest brain injury manifests as coma, seizures, myoclonus, neurocognitive dysfunction and brain death c. Contributory factors: microcirculatory failure, impaired cerebral autoregulation, hypercarbia, hyper/hypoxia, pyrexia, hyperglycemia and seizures H. Davis Page 2

3 Figure 2. HPA axis C. Pathophysiology of CA 8-11 i. Lack of effective cardiac contraction with minimal cardiac output (CO) ii. Presenting rhythms a. Shockable 1. VTach organized electrical activity of ventricles 2. VFib disorganized electrical activity of ventricles b. Non-shockable 1. PEA additional rhythms with lack of sufficient ventricular activity to generate pulse 2. Asystole absence of detectable ventricular electrical activity aa. End-stage rhythm following prolonged VFib or PEA ab. Worst prognosis iii. Etiology a. Underlying cause 1. Non-reversible causes 2. Reversible causes, H s and T s (see Appendix A) iv. Physiologic response a. Activation of sympathetic nervous system 1. Increases plasma catecholamines 2. Releases vasopressin (VASO) and activates renin-angiotensinaldosterone system b. Hypothalamic-pituitary-adrenal (HPA) axis response Posterior pituitary VASO H. Davis Page 3

4 II. Basic Life Support (BLS) and Advanced Cardiac Life Support (ACLS) A. Guidelines 8,12 Figure 3. Chest compressions 8 i. American Heart Association (AHA) ACLS 2010 ii. European Resuscitation Council (ERC) 2010 Push hard and fast Compression = systole Recoil = diastole Generates CO 2 inches deep Good recoil 100 per min 1 cycle = 2 min Increases odds of defibrillation success Improves survival A. Defibrillation 8 i. VFib or VTach rhythms following every cycle of chest compressions a. Biphasic preferred, initial J ii. Increases survival B. Ventilation 8 i. Bag-mask-valve with 100% FiO2 a. 2 breaths every 30 seconds without advanced airway b. 1 breath every 6-8 seconds with advanced airway ii. Minimize excessive ventilation a. Increases intrathoracic pressure, decreases blood flow to vital organs b. Other complications: gastric inflation, regurgitation, aspiration C. Medications in ACLS 8,12,14,15 i. Administered by intravenous (IV) or intraosseous (IO) route ii. Increase cardiac and cerebral perfusion pressure iii. Facilitate restoration and maintenance of a perfusing spontaneous rhythm iv. Guideline recommended drug therapy (See Appendix B) a. All rhythms 1. Epinephrine (EPI) 2. VASO b. Refractory VFib/VTach 1. Amiodarone aa. α, β, Na +, K +, Ca ++ channel antagonist ab. After 1 st defibrillation attempt, following 2 minutes of chest compressions ac. Increases ROSC and survival to hospital admission H. Davis Page 4

5 (ng/ml) II. EPI v. Clinically evaluated endpoints a. ROSC b. Short term survival/survival to hospital admission c. Survival to hospital discharge d. Survival to hospital discharge with favorable neurologic recovery 1. Cerebral Performance Category (CPC) (See Appendix C) e. Long term survival vi. Evidence for medications a. Increase ROSC and survival to hospital admission when compared to no medications b. Every 1 minute delay in vasopressor administration is a 4% decrease in ROSC c. None for long-term survival or favorable neurologic outcomes vii. Consider reversible causes and treat underlying pathophysiology (See Appendix A) A. Background 13,16 Figure 4. EPI plasma concentrations 10 i. Catecholamine hormone and neurotransmitter ii. Chemical mediator conveying nerve impulses to organs (heart, lung, etc.) iii. First used in 1906 to treat CA iv. Integral part of CPR recommendations since Before EPI After EPI After ROSC 1 Hr After ROSC ROSC Achieved No ROSC B. Dosing 8, i. 1 mg every 3-5 minutes IV/IO C. Mechanism of action 8,12,17,19-24 i. α- and β-adrenergic receptor stimulation ii. α1/α2 vasoconstriction a. Most potent catecholamine for α stimulation b. Increases coronary and cerebral perfusion pressures 1. Increases ROSC c. Decreases microcirculatory cerebral blood flow 1. Increases severity of cerebral ischemia during CPR 2. Impairs neurologic function H. Davis Page 5

6 iii. β1 inotropic, chronotropic a. No evidence of benefit from β-stimulation 1. β-agonism has demonstrated harm over BLS alone 2. Decreases survival vs. phenylephrine or EPI + esmolol 3. Increases defibrillation attempts required to attain ROSC b. Detrimental effects 1. Increases myocardial work, oxygen consumption and utilization of scarce energy reserves aa. Lactic acid production ab. Ectopic ventricular arrhythmias ac. Secondary VFib 2. Transient hypoxemia due to pulmonary arteriovenous shunting 3. Post-ROSC tachycardia and hypertension aa. Precipitates recurrence of VFib 4. Post-cardiac arrest myocardial dysfunction aa. Greater incidence of post-resuscitation shock iv. β2 vasodilation a. Increases blood flow to skeletal muscles b. Predominantly masked by α1 effects D. Efficacy data 14,25-28 Table 1. EPI vs. Placebo Author (n) Patients Intervention Results Prospective RCT HDE= 10 mg x 2 vs. Woodhouse et al OHCA/IHCA 339 SDE= 1 mg x 2 or Immediate survival Asystole or resistant VFib placebo (not randomized) x 2 Followed by open label 1 mg EPI Herlitz et al OHCA VFib Ong et al OHCA Olsveengen et al OHCA Jacobs et al OHCA Retrospective EPI after 3 rounds defibrillation vs. no EPI regardless of defibrillation attempts Prospective observational Before vs. after protocol: EPI 1 mg x 1 prior to transport with 1 mg dose x 1 in ED Prospective RCT ACLS with vs. without IV access and standard drugs Prospective, DB, RCT EPI 1 mg vs. placebo every 3 min ROSC hospital admission ROSC Hospital admission ROSC hospital admission CPR time Favorable neurologic outcome ROSC hospital admission *All differences demonstrated statistical significance OHCA: out-of-hospital cardiac arrest; IHCA: in-hospital cardiac arrest; RCT: randomized controlled trial; HDE: high dose epinephrine; SDE: standard dose epinephrine; EPI: epinephrine; VFib: ventricular fibrillation; ROSC: return of spontaneous circulation; ED: emergency department; ACLS: advanced cardiac life support; IV: intravenous; CPR: cardiopulmonary resuscitation; DB: double blind H. Davis Page 6

7 (pg/ml) E. Bottom line 19,29 i. EPI increases likelihood of achieving ROSC and survival to hospital admission ii. Effects on long-term survival remain uncertain iii. No role for higher doses a. No improvement in survival with EPI doses > 1 mg iv. Dose-dependent adverse effects a. Unfavorable neurologic outcomes III. VASO A. Background 8,12 i. Endogenous peptide and antidiuretic hormone ii. Regulates water retention and electrolyte homeostasis iii. Increases peripheral vascular resistance iv. Guideline recommendations a. AHA: alternative to EPI since 2000 b. ERC: not enough evidence to recommend or refute use Figure 5. VASO plasma concentrations Before EPI After EPI After ROSC 1 Hr After ROSC 24 ROSC Achieved No ROSC B. Dosing 8 i. 40 units once IV/IO a. May replace first or second dose of EPI C. Mechanism of action 12 i. Non-adrenergic peripheral vasoconstrictor a. Stimulates smooth muscle V1 receptors D. Physiologic effects i. Increases coronary perfusion pressure ii. Causes cerebral vasodilation iii. Minimal effect on pulmonary vasculature iv. Longer t1/2 and duration of effect than EPI a. Increases mean arterial pressure (MAP) post-resuscitation v. Potentiates release of ACTH and cortisol vi. Greater stability in acidic environment compared to catecholamines H. Davis Page 7

8 E. Efficacy data Table 2. VASO vs. EPI Author (n) Patients Intervention Results Linder et al OHCA Resistant VFib Stiell et al IHCA Wenzel et al OHCA Grmec et al OHCA VFib/VTach Prospective, DB, RCT, VASO 40 units x 1 vs. EPI 1 mg x 1 Followed by standard ACLS medication Prospective, RCT, triple blind VASO 40 units x 1 vs. EPI 1 mg x 1 Followed by open label EPI Prospective MC, DB, RCT VASO 40 units every 3 min x 2 vs. EPI 1 mg every 3 min x 2 Followed by open label EPI Prospective observational cohort (retrospective control) VASO 40 units x 1 then EPI every 3-5 min vs. EPI every 3-5 min x 3 then VASO 40 units x 1 vs. EPI every 3-5 min ROSC hospital admission 24 hr survival Good neurological outcome ROSC Neurologic outcome Survival ( hospital admission, hospital discharge in asystolic patients) Hospital admission Cerebral performance Results include both combo arms vs. only EPI: ROSC hospital admission 24 hr survival Neurologic outcomes *All differences demonstrated statistical significance OHCA: out-of-hospital cardiac arrest; VFib: ventricular fibrillation; DB: double blind; RCT: randomized controlled trial; EPI: epinephrine; VASO: vasopressin; ROSC: return of spontaneous circulation; hr: hour(s); IHCA: in-hospital cardiac arrest; MC: multi-centered; min: minute(s); CPR: cardiopulmonary arrest; ER: emergency room F. Bottom line 35,37,38 i. Many studies included EPI administration in VASO arm ii. Conflicting results on benefit of VASO over EPI a. Some reports of increasing ROSC and hospital admission 1. Small studies 2. Predominantly with repeat dosing of VASO 3. Predominantly in asystolic patients G. EPI + VASO vs. EPI 1,20,37,39,40 i. Stimulates both catecholamine and VASO receptors a. Improves perfusion of vital organs b. Decreases vasopressor-mediated adverse effects ii. EPI + VASO diminishes cerebral microvascular blood flow iii. Subgroup analysis suggests benefit in those requiring > 2 doses of initial vasopressor when VASO is combined with EPI iv. Subgroup analysis suggests benefit of EPI + VASO in patients with ph < 7.2 H. Davis Page 8

9 H. Efficacy data 1,32,39,41-44 Table 3. EPI +VASO vs. EPI Author (n) Patients Intervention Results Retrospective Guyette et al OHCA VASO administration determined by ROSC physician on scene ER arrival EPI 1 mg every 3-5 min + VASO 40 units x 1 vs. EPI 1 mg every 3-5 min Callaway et al OHCA Mally et al Gueugniaud et al OHCA Resistant to defibrillation OHCA resistant VFib/VTach Cody et al OHCA Ducros et al OHCA Ong et al OHCA/IHCA (ED patients) Prospective, DB, RCT VASO 40 units x 1 vs. placebo x 1 after 1 EPI Followed by open label EPI Prospective observational VASO 40 units then EPI 1 mg every 3 min vs. EPI 1 mg every 3 min Prospective DB, MC, RCT VASO 40 units + EPI 1 mg every 3 minutes x 2 Followed by open label EPI vs. EPI 1 mg + placebo every 3 minutes x 2 Followed by open label EPI Retrospective cohort evaluating protocols VASO 40 units + EPI 1 mg Followed by EPI 1 mg every 3-5min vs. EPI 1 mg every 3 min Prospective, DB, RCT EPI 1 mg every + VASO 40 units every 5 min vs. EPI 1 mg every 5 min vs. EPI 1 mg + VASO 40 units + nitroglycerin 300 mcg every 5 min Prospective MC, DB, parallel, RCT VASO 40 units x 1 vs. EPI 1 mg x 1 Followed by open label EPI ROSC Hospital arrival petco2; MAP ROSC 24 hr survival neurologic outcome upon discharge ( hospital discharge in asystole subgroup) No difference: ( hospital discharge in PEA subgroup analysis) ROSC Hospital admission Neurologic recovery 1 year survival Hospital admission Diastolic BP ROSC hospital admission (when variables accounted for) *All differences demonstrated statistical significance OHCA: out-of-hospital cardiac arrest; EPI: epinephrine; mg: milligram; min: minute(s); VASO: vasopressin; ROSC: return of spontaneous circulation; ER: emergency room; DB: double blind; RCT: randomized controlled trial; petco2: end-tidal carbon dioxide; hr: hour; MC: multicentered; mcg: micrograms; BP: blood pressure; IHCA: in-hospital cardiac arrest I. Bottom line 40,45-48 i. Systematic reviews and meta-analyses failed to demonstrate benefit of VASO over EPI or in combination with EPI a. Secondary analysis suggests dose dependent increases in survival rates when treated with VASO vs. EPI in asystolic patients b. Largest OHCA study associated with mean time to medications > 20 minutes ii. Meta-analysis 2014, reviewing 10 RCTs a. No improvement in ROSC, survival to hospital admission or discharge H. Davis Page 9

10 b. IHCA subgroup analysis 1. Higher ROSC 2. Higher survival to hospital admission and discharge 3. Favorable neurologic outcomes 4. Non-traditional, repeated dosing of vasopressin 5. All vasopressin, steroid, epinephrine (VSE) data IV. Complications after ROSC A. Adrenal insufficiency (AI) of CA 11,49-52 i. Inability to adequately increase cortisol secretion in response to ACTH during and after ACLS ii. Etiology a. Adrenal gland ischemia b. Inflammatory response to ischemia results in further damage iii. Increases mortality iv. Diminishes response to catecholamines v. Leads to hemodynamic instability and circulatory collapse B. Inflammatory mediated ischemic/reperfusion injury 50,52-54 i. Activation of cytokines, endotoxins, and reactive species after CA ii. Inflammatory response further damages ischemic organs a. Compounds neurologic damage b. Cytokines associated with mortality and unfavorable neurologic outcomes iii. Normal physiologic response to cytokines is stimulation of cortisol release a. Unable to adequately respond due to AI C. Post-resuscitation shock 6,51,55-60 i. Precise definitions of hemodynamic instability/shock are lacking ii. Impaired contractile function and diastolic function that reverses several hours to days after resuscitation iii. Hyperdynamic phase, lasting minutes a. Tachycardia and hypertension iv. Post-resuscitation cardiovascular collapse phase a. Cardiac index (CI) and filling pressures are low 1. Lactic acid produced 2. Myocardial stunning results in left ventricular dysfunction 3. Pro-inflammatory response resulting in loss of vascular tone b. Occurs several hours after CA c. Results in multi-system organ dysfunction which may progress to mortality 1. Decreases cerebral blood flow H. Davis Page 10

11 V. Steroids d. CI increases approximately 24 hours after arrest 1. Independent of filling pressures or inotropic agents e. Vasodilation continues and requires vasoactive drugs 1. Recovery often seen within 3 days v. Risk factors for development of post-resuscitation shock a. Fifteen minute time interval between onset of arrest and ROSC b. More frequent doses of EPI c. Greater number of defibrillation attempts vi. Treatment a. Avoid hypotension b. AHA recommends maintaining systolic blood pressure 90 mmhg and MAP 65 mmhg c. Other authors advocate for more aggressive goals 1. American Academy of Neurology and the Rocky Mountain Critical Care Conference recommend MAP goal of mmhg aa. Based on expert opinion ab. Theoretical improvement in neurologic outcomes d. Hemodynamic instability was not associated with worse neurologic outcomes when aggressively treated 1. MAP goal 75 mmhg 2. Volume expansion based on left ventricle end diastolic pressure 3. Vasoactive drugs: epinephrine or dobutamine with advanced hemodynamic monitoring A. Background 8,12 i. Decrease inflammatory response and regulate homeostasis ii. No role for steroids in AHA or ERC guidelines B. Cortisol plasma concentrations 10,49,50,53 i. Normal range a. Without stress: 5-20 mcg/dl b. Under stress: mcg/dl ii. Low levels during or after CA indicate lack of appropriate response a. Associated with early post-resuscitation mortality iii. Higher cortisol levels have been associated with neurologically intact survival and survival > 1 month C. Mechanism of action 11 i. Regulates gene expression a. Decreases production of kinins, histamines, liposomal enzymes, prostaglandins, leukotrienes b. Inhibits cell migration to area of injury c. Decreases vessel permeability H. Davis Page 11

12 D. Physiologic effects 11,49,50,61,62 i. Homeostasis a. Fluid and electrolyte balance 1. Decreases cell apoptosis and provides positive inotropy through calcium homeostasis b. Maintains integrity of membrane structures ii. Anti-inflammatory a. Decreases ischemia/reperfusion injury iii. Vascular a. Decreases permeability, increases SVR b. Decreases production of vasodilators c. Increases vascular reactivity to catecholamines and angiotensin II iv. Cardiac a. Increases coronary perfusion pressure i. Increases production of coronary vasodilators b. Increases contractility v. Endocrine a. Supplements cortisol not produced during AI E. Detrimental effects 62 i. Electrolyte disturbances, sodium or glucose ii. Infections iii. Negative regulation on HPA axis, may result in AI F. Dosing 5,52,61 i. ACLS a. Hydrocortisone (HCT) 100 mg IV push once b. Methylprednisolone 40 mg IV push once ii. Stress dose steroids a. HCT 300 mg IV per day H. Davis Page 12

13 G. Efficacy data 49,52,63-66 i. Animal data demonstrates increase ROSC with corticosteroids Table 4. Steroids Author (n) Patients Intervention Results Retrospective case series White et al DEX 100 mg once after conventional IHCA therapy failed Refractory VFib or asystole Plus: EPI, atropine, bicarbonate, isuprel Compared to historical control White et al Paris et al Grafton et al IHCA VFib or asystole OHCA PEA After OHCA VFib or asystole Tsai et al OHCA Retrospective case series DEX 100 mg once Plus: atropine, isoproterenol, EPI, calcium Compared to historical control Prospective, RCT, DB Pre-hospital DEX 100 mg vs. placebo Plus: bicarbonate, EPI, and atropine Retrospective Steroid use following ROSC for brain ischemia or lung injury Predominantly low dose DEX Prospective, non-randomized (required family member pre-approval) HCT 100 mg vs. placebo Plus: EPI, VASO in ~1/3 Corrected rhythm** ROSC** long term survival** ROSC Long term survival Regaining consciousness ROSC Adverse effects Survival Neurologic function *Unless specified, results demonstrated statistical significance **Statistical significance not evaluated IHCA: in-hospital cardiac arrest; VFib: ventricular fibrillation; DEX: dexamethasone, EPI: epinephrine; CO: cardiac output; PEA: pulseless electrical activity; ROSC: return of spontaneous circulation; OHCA: out-of-hospital cardiac arrest; RCT: randomized controlled trial; HCT: hydrocortisone; VASO: vasopressin; min: minutes VI. VSE data H. Bottom line 52,66,67 i. Weakly associated with increases in ROSC a. Time dependent b. Driven by subgroup receiving hydrocortisone within 6 min of ED arrival or 22 min from collapse ii. No role for steroid administration following ROSC to treat brain ischemia iii. No increases in adverse effects A. Is a cocktail of stress hormones the solution? i. EPI has been the mainstay of ACLS drug therapy but is associated with consequences linked to worse outcomes after ROSC ii. VASO alone or in combination has not shown to be superior to EPI iii. VASO administration increases serum ACTH but does not result in an adequate physiologic response of cortisol iv. Evidence of relative AI and inflammatory mediated ischemia/reperfusion injury of CA linked to post-resuscitation shock which is known to increase mortality H. Davis Page 13

14 B. Efficacy data 61 Table 5. Mentzelopoulos S, Zakynthinos S, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med. 2009;169: Objective Determine if VSE supplementation during and after resuscitation improves survival in refractory IHCA Prospective, single-center, double blind, placebo-controlled, parallel group, randomized controlled trial Study Design Intervention: Methylprednisolone 40 mg x 1 EPI 1 mg + VASO 20 units (per resuscitation cycle) Following ROSC, HCT 300 mg/day continuous infusion x 3-7 days, followed by taper, if postresuscitation shock present Control: Placebo x 1 EPI 1 mg + placebo (per resuscitation cycle) Following ROSC, placebo x 3-7 days, followed by taper, if post-resuscitation shock present Patients Statistics Results Authors Conclusions Critique Post-resuscitation shock sustained > 4 hours, MAP 70 mmhg despite appropriate fluid resuscitation, or doubling of peri-arrest vasopressor requirements Inclusion: IHCA with PEA/asystole or VFib/VTach after 2 defibrillation attempts Exclusion: pediatric, terminal illness, do not resuscitate order, arrest due to exsanguination, recent treatment with IV corticosteroids ITT analysis Dichotomous variables: χ 2 or Fisher exact test Continuous variables: independent t test or Mann-Whitney exact test Linear mixed-model analysis for post-resuscitation shock Kaplan-Meier for survival Multivariate analysis for independent predictors of death VSE: n=100 ROSC: 39/48 (81%) vs. 27/52 (52%) p=0.003 survival to discharge: 9/48 (19%) vs. 2/52 (4%) p=0.02 Following ROSC: MAP, vasopressor requirements, cytokine levels, central venous oxygen saturation, in lactate, renal-failure free days Stress dose steroids: hospital discharge 8/27 (30%) vs. 0/15 (0%) p=0.02 organ failure free days VSE during resuscitation and stress-dose HCT in post-resuscitation shock improves survival by a factor of 4.5 in refractory IHCA Examined IHCA, did not exclude trauma patients Examined physiologic endpoints potentially associated with improvements in survival Predominantly asystole patients (75-80%) More reversible causes of CA in study group Use of multiple interventions; unclear if individual interventions are beneficial Used a previously unstudied dose of VASO Administered EPI and VASO every 2-3 minutes vs. 3-5 minutes Feasibility of administering VASO and EPI at the same time when not prepared ahead of time by study personnel C. Bottom line i. Combination VSE demonstrates improvement in ROSC and survival to hospital discharge compared to EPI alone ii. Benefits in ROSC likely from EPI + VASO iii. Benefits in survival likely from methylprednisolone iv. Neurologically favorable survival not demonstrated in this study H. Davis Page 14

15 D. Efficacy data 5 Table 6. Mentzelopoulos S, Malachias S, Charnos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310: Objective Determine if combination VSE improves outcomes compared to standard of care for IHCA Study Design Prospective, multi-centered, double blind, placebo-controlled, parallel-group, randomized controlled trial Intervention Methylprednisolone 40 mg x 1 EPI 1 mg + VASO 20 units (per resuscitation cycle) Following ROSC, HCT 300 mg/day continuous infusion x 3-7 days followed by taper, if postresuscitation shock present Control Placebo x 1 EPI 1 mg + placebo (per resuscitation cycle) Following ROSC, placebo x 3-7 days followed by taper, if post-resuscitation shock present Patients Statistics Results Authors Conclusions Critique Post-resuscitation shock sustained > 4 hours, MAP 70 mmhg despite appropriate fluid resuscitation, or doubling of peri-arrest vasopressor requirements Inclusion: IHCA, requiring EPI Exclusion: pediatric, terminally ill, do not resuscitate orders, arrests due to exsanguination, current treatment with steroids ITT analysis Kolmogorov-Smirnov for normality Dichotomous variables: 2-sided χ 2, Fishers exact test Continuous variables: 2-sided t test, Mann-Whitney exact U test Bonferroni correction Linear mixed model analysis to determine effect of groups Logistical regression for ORs with 95% Cis Multivariable Cox regression for HRs with 95% CIs VSE: n=268 ROSC: 109/130 (84%) vs. 91/138 (66%) p=0.005 discharge with CPC score 1 or 2: 18/130 (14%) vs. 7/138 (5%) p=0.02 duration ACLS, total EPI dose, hemodynamics, central venous oxygen saturation, cerebral perfusion pressure, renal-, neurologic-, ventilator-failure free days, organ dysfunction, similar adverse effects Stress dose steroids: discharge with CPC score of 1 or 2: 16/76 (21%) vs. 6/73 (8%) p= EPI patients received HCT, circulatory-, renal-, hepatic-, coagulation-, respiratory-failure free days No difference in incidence of adverse effects due to steroids VSE and stress-dose HCT vs. EPI results in survival to hospital discharge with favorable neurologic outcomes Post-arrest HCT may decrease poor outcomes, but requires further investigation Examined IHCA, large sample, did not exclude all trauma patients CPR quality assessed with diastolic blood pressures Utilized CPC score to evaluate neurologically favorable survival Detailed protocol for treatment of underlying conditions, therapeutic hypothermia, sedation/analgesia, etc Predominantly asystolic medicine patients Chest compression cycles lasted approximately 3-4 minutes Frequent use of atropine and bicarbonate E. Bottom line i. VSE increases ROSC and neurologically favorable survival a. ROSC, number needed to treat (NNT)= 6 b. Neurologically favorable survival, NNT = 12 ii. Overall reduction in EPI doses, length of ACLS, improved peri-arrest hemodynamics and perfusion which results in improved long-term outcomes iii. No increase in complications from steroids iv. Medications administered approximately every 3-4 minutes H. Davis Page 15

16 VII. Summary of evidence A. Majority of studies are in OHCA vs. IHCA of non-traumatic origin and are powered for detecting differences in hospital admission B. Many variables throughout studies over the years i. Time to initiation of BLS/ACLS ii. Variation in protocols of emergency responders iii. Unknown quality of chest compressions and approach to ventilatory support iv. Change in availability of AEDs and defibrillators v. Change in standard medications and doses C. Many of the principles of therapy are based on data from previously healthy animals D. Prior to VSE, no ACLS medication or combination of medications has improved survival to discharge or neurologically favorable survival E. VSE demonstrated neurologically favorable survival VIII. Conclusions A. Addition of methylprednisolone complements EPI + VASO in improving ROSC rates i. Improves hemodynamic stability ii. Decreases ischemia/reperfusion injury iii. Reduces end-organ damage B. Improves neurologic outcomes and overall survival in IHCA requiring vasopressors IX. Recommendations A. IHCA i. Administer methylprednisolone 40 mg IV x 1 during first compression cycle requiring medications ii. Alternate every compression cycle (2 minutes) between a. EPI 1 mg IV every 4 minutes b. VASO 20 units IV every 4 minutes 1. Maximum of 5 doses iii. Continue standard use of other adjunctive treatments during ACLS when indicated based on clinical scenario B. If ROSC is obtained, observe for post-resuscitation shock i. At minimum maintain a MAP of 65 mmhg consider goals of 75 mmhg a. After appropriate volume resuscitation b. After appropriate vasopressors are initiated i. If norepinephrine requirements mcg/kg/min, consider additional stress dose steroids ii. Avoid inotropes H. Davis Page 16

17 Appendices Appendix A. H s & T s of Cardiac Arrest 8 Cause Indications Treatment Distributive shock Crystalloids Hypovolemia Anaphylactic shock Crystalloids, EPI, H1RA, H2RA, steroids Hemorrhagic shock Blood products Hypoxia oxygen saturation, cyanosis, PEA Oxygen ph, CO2 Sodium bicarbonate Treat underlying condition Hypokalemia K + Mg ++ K +, Mg ++ replacement Hydrogen ion (acidosis) Hyperkalemia EKG progressing from peaked T waves to absent P waves to prolonged PR and QRS to sine-wave prior to loss of pulse Hypothermia Core temp 30 C Tension pneumothorax Cardiac tamponade Toxins Thrombosis (pulmonary) Thrombosis (cardiac) Tracheal deviation away from tension, tachycardia, tachypnea, hypoxia resulting in CA associated with PEA ventricular filling and cardiac output causing hypotension and ultimately CA Toxidrome presentations, patient history, UDS or other laboratory indicators Tachycardia, tachypnea prior to arrest, right heart strain, PEA with rapid/narrow QRS, evidence of DVT Chest pain, diaphoretic, EKG findings prior to arrest, troponin elevation, cardiac history Shift K + : Calcium, insulin, dextrose Sodium bicarbonate Prevent additional heat loss Rewarm Needle decompression initially Chest tube for definitive management Pericardiocentesis needle aspiration Pericardial window hole in pericardium CCB/β blockers: calcium, glucagon, high dose insulin/d50, fat emulsions Digoxin: antidigoxin Fab antibodies Cyanide: hydroxocobalamine or sodium nitrite/sodium thiosulfate Local anesthetics: fat emulsion Fibrinolytics and prolonged chest compressions Early coronary revascularization Fibrinolytics as a less favorable alternative Appendix B. Guideline Concordant ACLS Medication Dosing 8 Medication Dose Indication Epinephrine 1 mg every 3-5 minutes All rhythms Vasopressin 40 units x 1 To replace the 1 st or 2 nd dose of epinephrine per AHA guidelines All rhythms 1 st dose: 300 mg x 1 Amiodarone After 3-5 minutes 2 nd dose: 150 mg x 1 After 3-5 minutes Per ERC guidelines: 900 mg IV drip over 24 hours All medications may be administered by IV or IO routes Refractory VFib or VTach H. Davis Page 17

18 Appendix C. Cerebral-preformance Category 5,61 References CPC Indicates 1 Conscious with normal function or only slight disability 2 Conscious with moderate disability 3 Conscious with severe disability 4 Comatose or in a vegetative state 5 Brain-dead or dead 1. Guyette F, Guimond G, Hostler D, et al. Vasopressin administered with epinephrine is associated with a return of a pulse in out-of-hospital cardiac arrest. Resuscitation. 2004;63: Sandroni C, Nolan J, Cavallaro F, et al. In-hospital cardiac arrest: incidence, prognosis, and possible measures to improve survival. Intensive Care Med, 2007;33: Moulaert V, Verbunt J, vanheugten C, et al. Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review. Resuscitation. 2009;80: Stiell I, Wells G, Field B, et al. Advanced cardiac life support in out-of-hospital cardiac arrest. N Engl J Med. 2004;351(7): Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310(3): Laurent I, Monchi M, Chiche J, et al. Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest. J Am Coll Cardiol. 2002;40(12): Ruiz-Bailen M, Aguayo de Hoyos E, Ruiz-Navarro S, et al. Reversible myocardial dysfunction after cardiopulmonary resuscitation. Resuscitation. 2005;66: Neumar R, Otto C, Link M, et al. Adult advanced cardiovascular life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122: Vanden Hoek T, Morrison L, Shuster M, et al. Cardiac arrest in special situations: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122: Linder K, Haak T, Keller A, et al. Release of endogenous vasopressors during and after cardiopulmonary resuscitation. Heart. 1996;75: Varvarousi G, Stefaniotou A, Varavaroussis D, et al. Glucocorticoids as an emergency pharmacologic agent for cardiopulmonary resuscitation. Cardiovasc Drugs Ther. 2014;28: Nolan J, Soar J, Zideman D, et al. European Resuscitation Council guidelines for resuscitation Resuscitation. 2010;81: Sunde K, Steen P. The use of vasopressor agents during cardiopulmonary resuscitation. Crit Care Clin. 2012;28: Olasveengen T, Sunde K, Brunborg C, et al. Intravenous drug administration during out-of-hospital cardiac arrest. JAMA. 2009;302(20): Hubble M, Johnson C, Blackwelder J, et al. Probability of return of spontaneous circulation as a function of timing of vasopressor administration in out-of-hospital cardiac arrest. Prehosp Emerg Car. 2015; Crile G, Dolley D. An experimental research into the resuscitation of dogs killed by anesthetics and asphyxia. J Exp Med. 1906;8: Epinephrine. Clinical Pharmacology. July 14, Accessed: August 25, Ditchey R, Lindenfeld J. Failure of epinephrine to improve the balance between myocardial oxygen supply and demand during closed-chest resuscitation in dogs. Circulation. 1988;78: Dumas F, Bougouin W, Geri G, et al. Is epinephrine during cardiac arrest associated with worse outcomes in resuscitated patients? J Am Coll Cardiol. 2014;64(22): H. Davis Page 18

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20 46. Aung K, Htay T. Vasopressin for cardiac arrest. Arch Intern Med. 2005;165: Mentzelopoulos S, Zakynthinos S, Siempos I, et al. Vasopressin for cardiac arrest: meta-analysis of randomized controlled trials. Resuscitation. 2012;83: Layek A, Maitra S, Pal S, Bhattacharjee S, et al. Efficacy of vasopressin during cardio-pulmonary resuscitation in adult patients: a meta-analysis. Resuscitation. 2014;85: Smithline H, Rivers E, Appleton T, et al. Corticosteroid supplementation during cardiac arrest in rats. Resuscitation. 1993;25: Ito T, Saitoh D, Takasu A, et al. Serum cortisol as a predictive marker of the outcome in patients resuscitated after cardiopulmonary arrest. Resuscitation. 2004;62: Wijdicks E, Hijdra A, Young G, et al. Quality standards subcommittee of the American Academy of Neurology. Practic parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2006;67(2): Tsai M, Huang C, Chang W, et al. The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients: a pilot study. Am J Emerg Med. 2007;25: Tavakoli N, Bidari A, Vahdati S. Serum cortisol levels as a predictor of neuroloigic survival in successfully resuscitated victims of cardiopulmonary arrest. J Cardio Thor Res. 2012;4(4): Adriel C, Adib-Conquy M, Laurent I, et al. Successful cardiopulmonary resuscitation after cardiac arrest as a sepsis-like syndrome. Circulation. 2002;106: Menegazzi J, Ramos R, Wang H, et al. Post-resuscitation hemodynamics and relationship to the duration of ventricular fibrillation. Resuscitation. 2008;78: Mayr V, Luckner G, Jochberger S, et al. Arginine vasopressin in advanced cardiovascular failure during the post-resuscitation phase after cardiac arrest. Resuscitation. 2007;72: Jones A, Shapiro N, Kilgannon J, et al. Goal-directed hemodynamic optimization in the post-cardiac arrest syndrome: a systematic review. Resuscitation. 2008;77: Bell D, Brindley P, Forrest D, et al. Management following resuscitation from cardiac arrest: recommendations from the 2003 Rocky Mountain Critical Care Conference. Can J Anesth. 2005;52(3): Pene F, Hyvernat H, Mallet V, et al. Prognostic value of relative adrenal insufficiency after out-of-hospital cardiac arrest. Intensive Care Med. 2005;31: Rittenberger J, Doshi A, Reynolds J. Postcardiac arrest management. Emerg Med Clin N Am. 2015;33: Mentzelopoulos S, Zakynthinos S, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for inhospital cardiac arrest. Arch Intern Med. 2009;169: Czock D, Keller F, Rasche F, et al. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005;44(1): White B. Pulseless idioventricular rhythm during CPR: an indication for massive intravenous bolus glucocorticoids. JACEP. 1976;5(6): White B, Petinga T, Hoehner P, et al. Incidence, etiology, and outcome of pulseless idioventricular rhythm treated with dexamethasone during advanced CPR. JACEP. 1979;8(5): Paris P, Stweart R, Deggler F. Prehospital use of dexamethasone in pulseless idioventricular rhythm. Ann Emerg Med. 1984;13(11): Grafton S, Longstreth W. Steroids after cardiac arrest: a retrospective study with concurrent nonrandomized controls. Neurology. 1988;38: Jastermski M, Sutton-Tyrrell K, Vaagenes P, et al. Glucocorticoid treatment does not improve neurological recovery following cardiac arrest. JAMA. 1989;262(24): H. Davis Page 20