Does a Resuscitation Pharmacologic Bundle of Epinephrine, Terlipressin, and Corticosteroids Improve Outcome From Asphyxial Cardiac Arrest?* Performing CPR without measuring the effects is like flying an airplane without an altimeter. —Dr. Max Harry ­Weil Robert A. Berg, MD Peter A. Meaney, MD Vinay M. Nadkarni, MD Department of Anesthesia and Critical Care The Children’s Hospital of Philadelphia Philadelphia, PA

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or over a hundred years, resuscitation scientists have known that: 1) cardiopulmonary resuscitation (CPR) can be lifesaving, 2) the success of CPR depends on attaining an adequate coronary perfusion pressure (CoPP), and 3) when necessary, epinephrine/vasopressor administration can increase the CoPP to attain successful return of spontaneous circulation (ROSC) (1–3). Nevertheless, clinical data have never conclusively demonstrated that routine use of epinephrine improves outcomes from cardiac arrest (1). The discrepancy between wellestablished physiologic and pharmacologic effects during CPR in laboratory studies and clinical studies deserves some exploration. During CPR, myocardial perfusion depends primarily on the CoPP or the arterial minus right atrial pressure during the relaxation phase. When the CoPP is not maintained above 20 mm Hg (or aortic “diastolic” pressure above 30 mm Hg), animals rarely attain ROSC (3). Similarly, one small adult series showed a dose-response curve with greater than 75% ROSC when CoPP was greater than 25 mm Hg, nearly 50% when CoPP was 15–25 mm Hg, and 0% when CoPP was less than 15 mm Hg during CPR (4). Importantly, CoPP greater than 20 mm Hg and/or arterial diastolic pressure greater than 30 mm Hg can be attained in adults and children with excellent CPR quality (4, 5). The primary benefit of epinephrine administration during CPR is to increase the CoPP through its α-adrenergic-mediated peripheral vasoconstriction. The clinical studies that have questioned the value of epinephrine during CPR have evaluated the effects of epinephrine on outcomes irrespective of CoPP. Of course, epinephrine has many adverse effects, including increasing myocardial and

*See also p. e280. Key Words: cardiac arrest; cortisol; epinephrine; pediatric; terlipressin Dr. Berg served on the American Heart Association committees that made the present recommendations for vasoactive agents during cardiopulmonary resuscitation. Dr. Meaney is employed by Chop and provided expert testimony for a legal firm. His institution received grant support from the National Institutes of Health and University of Pennsylvania. Dr. Nadkarni has disclosed that he does not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000166

Pediatric Critical Care Medicine

cerebral metabolic demand, arrhythmogenic effects, and myocardial and cerebral vasoconstriction, that can decrease microcirculatory flow (1). Increasing myocardial metabolic demand and arrhythmogenicity are especially concerning for adults with out-of-hospital cardiac arrests who often have concomitant acute coronary syndromes. In addition, epinephrine is only effective when excellent CPR is provided (6). Furthermore, very high doses of epinephrine have been associated with worse neurologic outcomes (1). Because potential harms from epinephrine are mostly due to its β-adrenergic adverse effects on heart rate and oxygen consumption, investigators have focused on the use of vasopressin, a long-acting vasoconstrictor without the harmful β-adrenergic effects of epinephrine. Despite hopeful laboratory studies, several adult randomized controlled trials (RCTs) have failed to show important survival benefits when comparing vasopressin with epinephrine for both out-of-hospital and in-hospital cardiac arrest (7, 8) or when adding vasopressin rescue to epinephrine regimens (9, 10). In a single-center blinded RCT of 100 adults with in-hospital cardiac arrests, Mentzelopoulos et al (11) chose the increasingly used “bundled” approach to quality care with a pharmacologic treatment medley of epinephrine, vasopressin, and methylprednisolone during CPR plus high-dose hydrocortisone postresuscitation. The experimental bundle increased measured CoPP during CPR, increased the rate of ROSC, decreased postresuscitation systemic inflammatory response syndrome (SIRS) (lower interleukin-6 and tumor necrosis factor levels and more organ failure–free days), and improved the rate of 60-day survival. To demonstrate that this bundled approach was generalizable and to have adequate power to determine if this bundle could improve survival, they embarked on a three-center RCT of 268 adults with the same experimental and control groups (12). The bundle resulted in improved diastolic blood pressure during CPR and a higher rate of survival to hospital discharge with a Cerebral Performance Category score of 1 or 2 (adjusted odds ratio, 3.28; 95% CI, 1.17–9.20) (12). In this issue of Pediatric Critical Care Medicine, González et al (13) report that a similar bundle of epinephrine, terlipressin, and corticosteroids during CPR did not improve outcome among 10-kg piglets following experimental asphyxial cardiac arrest. This study is noteworthy for the large number of animals (n = 49) studied in an attempt to overcome the power issues inherent in large animal studies. The group with epinephrine alone had arterial pressures at least as high as the epinephrine/terlipressin/steroid group. Most animal and human studies evaluating V1-agonist therapy with epinephrine have www.pccmjournal.org

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used vasopressin rather than terlipressin and have shown superior arterial diastolic pressures during CPR with the combination of epinephrine and vasopressin compared with epinephrine alone. Consistent with the animal and human literature, González et al (13) showed that the animals attaining ROSC had higher arterial “diastolic” pressures than those without ROSC. Although the main benefit of steroids during and after CPR may be suppression of the postresuscitation SIRS (12), the study by González et al (13) was not designed to test this issue. What evidence should be the basis for evidence-based pediatric advanced life support: extrapolations of pediatric animal models or extrapolations from adult clinical studies? Obviously, the best answer would seem to be pediatric clinical studies, but there is a dearth of data regarding vasopressin use during pediatric CPR (14). Notably, interpretations of both animal and human interventional advanced life support studies are problematic in part because the study designs continue to focus on “rescuer-centric” rather than “patientcentric” goals. Clinical guidelines and clinical practice tend to focus on rescuer-centric goals, such as what pharmacologic agents to consider and what dose to infuse and the intervals between doses, rather than patient-centric goals, such as attaining adequate coronary and cerebral perfusion pressures. Two recent swine CPR studies revealed much worse survival outcomes with a standard “rescuer-centric” strategy of “one-size-fits-all” guideline recommended chest compression depth and vasopressor dosing compared to a “patient-centric” resuscitation strategy with chest compression depth titration to attain systolic pressure of 100 mm Hg and vasopressor titration to attain a CoPP greater than 20 mm Hg (15, 16). So, does a single resuscitation pharmacologic bundle of epinephrine, terlipressin, and corticosteroids improve outcome from asphyxial cardiac arrest? Not in the piglet study by González et al (13). However, this literature suggests that a more fruitful approach may be personalized resuscitation. Most pediatric in-hospital CPR is provided in an ICU, and many of these patients have arterial catheters in place during CPR (17). Perhaps the time has arrived for pediatric intensivists to focus on titration of advanced life support therapies to our patient’s arterial blood pressure rather than administration of a standard dose at the standard time interval without regard to effect.

REFERENCES

1. Kleinman ME, Chameides L, Schexnayder SM, et al: Part 14: Pediatric advanced life support: 2010 American Heart Association Guidelines

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for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S876–S908 2. Crile G, Dolley DH: An experimental research into the resuscitation of dogs killed by anesthetics and asphyxia. J Exp Med 1906; 8:713–725 3. Kern KB, Ewy GA, Voorhees WD, et al: Myocardial perfusion pressure: A predictor of 24-hour survival during prolonged cardiac arrest in dogs. Resuscitation 1988; 16:241–250 4. Paradis NA, Martin GB, Rivers EP, et al: Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990; 263:1106–1113 5. Jude JR, Kouwenhoven WB, Knickerbocker GG: Cardiac arrest. Report of application of external cardiac massage on 118 patients. JAMA 1961; 178:1063–1070 6. Pytte M, Kramer-Johansen J, Eilevstjønn J, et al: Haemodynamic effects of adrenaline (epinephrine) depend on chest compression quality during cardiopulmonary resuscitation in pigs. Resuscitation 2006; 71:369–378 7. Wenzel V, Krismer AC, Arntz HR, et al; European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group: A comparison of vasopressin and epinephrine for outof-hospital cardiopulmonary resuscitation. N Engl J Med 2004; 350:105–113 8. Stiell IG, Hébert PC, Wells GA, et al: Vasopressin versus epinephrine for inhospital cardiac arrest: A randomised controlled trial. Lancet 2001; 358:105–109 9. Gueugniaud PY, David JS, Chanzy E, et al: Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med 2008; 359:21–30 10. Callaway CW, Hostler D, Doshi AA, et al: Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest. Am J Cardiol 2006; 98:1316–1321 11. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al: Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med 2009; 169:15–24 12. Mentzelopoulos SD, 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; 310:270–279 13. González R, Urbano J, Botrán M, et al: Adrenaline, Terlipressin, and Corticoids Versus Adrenaline in the Treatment of Experimental Pediatric Asphyxial Cardiac Arrest. Pediatr Crit Care Med 2014; 15:e280–e287 14. Carroll TG, Dimas VV, Raymond TT: Vasopressin rescue for in-pediatric intensive care unit cardiopulmonary arrest refractory to initial epinephrine dosing: A prospective feasibility pilot trial. Pediatr Crit Care Med 2012; 13:265–272 15. Sutton RM, Friess SH, Bhalala U, et al: Hemodynamic directed CPR improves short-term survival from asphyxia-associated cardiac arrest. Resuscitation 2013; 84:696–701 16. Friess SH, Sutton RM, Bhalala U, et al: Hemodynamic directed cardiopulmonary resuscitation improves short-term survival from ventricular fibrillation cardiac arrest. Crit Care Med 2013; 41:2698–2704 17. Berg RA, Sutton RM, Holubkov R, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network and for the American Heart Association’s Get With the GuidelinesResuscitation (formerly the National Registry of Cardiopulmonary Resuscitation) Investigators: Ratio of PICU versus ward cardiopulmonary resuscitation events is increasing. Crit Care Med 2013; 41:2292–2297

July 2014 • Volume 15 • Number 6