Systemic Inflammatory Response After Cardiac Arrest: Potential Target for Therapy?* Brian W. Roberts, MD Department of Emergency Medicine Cooper University Hospital Cooper Medical School of Rowan University Camden, NJ Stephen Trzeciak, MD, MPH Department of Emergency Medicine; and Department of Medicine Division of Critical Care Medicine Cooper University Hospital Cooper Medical School of Rowan University Camden, NJ
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ut-of-hospital cardiac arrest (OHCA) is the most common lethal manifestation of cardiovascular disease with a mortality rate estimated to be as high as 89% (1). Even if return of spontaneous circulation (ROSC) is successfully achieved, 50% of patients do not survive to hospital discharge, and of those who do survive, the majority are functionally dependent, with more than half of these patients discharged to a long-term care facility (2). Identifying new post–cardiac arrest therapies to help improve clinical outcome is of the utmost importance to resuscitation science. In the post hoc analysis of a prospective multicenter randomized study in this issue of Critical Care Medicine, Bro-Jeppesen et al (3) aimed to test the association between the level of systemic inflammatory markers and mortality in patients who successfully achieved ROSC after OHCA. They found interleukin (IL)-6 at baseline was associated with mortality, and both IL-6 levels and procalcitonin levels at 24 hours after OHCA were associated with 30-day mortality. Using receiver operating characteristic curve analysis, the authors found the area under the curve for procalcitonin and IL-6 at 24 hours after OHCA to be 0.74 (95% CI, 0.64–0.83) and 0.63 (95% CI, 0.53–0.73), respectively. The authors concluded that IL-6 and procalcitonin at 24 hours after OHCA were modest predictors of 30-day mortality. We feel that one of the more important findings of this article is that procalcitonin and IL-6 (in addition to all inflammatory markers measured) increased over the initial 72 hours after ROSC. These findings support a theme in our previous work, which demonstrated that multiple organ dysfunction (MOD) worsens over *See also p. 1223. Key Words: anoxic brain injury; cardiac arrest; cardiopulmonary resuscitation; heart arrest; resuscitation The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001011
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the same 72-hour period (4). The authors also found an association between length of ischemia/reperfusion (I/R) injury (i.e., the administered dose of epinephrine and time to ROSC) and release of inflammatory markers. As pointed out by the authors in their conclusion, given the observational nature of this study, it remains unclear if inflammatory markers are simply indicators of the degree of I/R injury or actually exacerbate MOD. However, either way these findings provide additional support that the global I/R injury associated with cardiac arrest results in a “sepsis-like” state (5), and further support that therapies aimed at attenuating reperfusion injury, applied after cardiac arrest, could potentially decrease the systemic inflammatory response, prevent worsening MOD, and improve clinical outcomes. Ideal therapies would be simple and generalizable to all post–cardiac arrest patients. Accordingly, we believe that elements of conventional supportive critical care are especially attractive targets for attenuating reperfusion injury after ROSC. These include 1) optimization of mean arterial blood pressure (MAP), 2) avoidance of hyperoxia, and 3) avoidance of Paco2 derangements. It is also possible that not only does I/R injury result in a “sepsis-like” state but that a substantial proportion of these patients are actually septic or at least endotoxemic. Bowel I/R injury has been demonstrated to promote gut barrier failure and bacterial translocation, leading to sepsis and MOD (6). Although to our knowledge it has not been previous demonstrated in a clinical study, it would make sense that the global I/R injury, in addition to multiple doses of epinephrine during cardiopulmonary resuscitation (CPR), could also lead to bacterial translocation. In a recent retrospective study, it was found that 97.8% of patients with post–cardiac arrest syndrome (PCAS) had at least one marker for infection during the initial 72 hours after ROSC and that antibiotic administration was associated with survival, with a number needed to treat of five (7). Given a large proportion of PCAS are possibly septic or endotoxemic, it makes sense that maintaining adequate perfusion of vital organs is potentially beneficial. Previous literature has demonstrated an association between hypotension and poor outcome in PCAS (2); however, given the pathophysiological differences between sepsis and PCAS (with or without sepsis), it is unclear if increasing the MAP above the defined sepsis goal of 65 mm Hg is of any benefit. A recent study found an association between MAP more than 70 mm Hg and good neurological outcome in patients with PCAS, suggesting that the previous goal of MAP more than 65 mm Hg may be suboptimal for some patients with PCAS (8). Supplemental oxygen is frequently administered during the management of PCAS. Although it is intuitive that hypoxia can exacerbate cerebral ischemia, excessive oxygen delivery (hyperoxia) can also in theory exacerbate reperfusion injury through acceleration of oxygen-free radical formation. Hyperoxia has also been demonstrated to be associated with an increase in June 2015 • Volume 43 • Number 6
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Editorials
inflammatory markers, including IL-6 in an animal model of cardiopulmonary bypass (9). Recent studies have demonstrated an association between excessively elevated Pao2 and poor outcome in patients with PCAS (10, 11), suggesting the potential benefit of achieving a Pao2 range which avoids both the ischemic injury of hypoxia and the free radical injury of hyperoxia. Finally, mechanical ventilation is typically required after successful resuscitation from cardiac arrest. Paco2 is a major regulator of cerebral blood flow after cerebral injury (12), and Paco2 levels are guided by the ventilator settings initiated by the treating clinician during mechanical ventilation. In addition, in an endotoxemia model, Co2 was demonstrated to modulate inflammatory marker levels, suggesting a possible role for Paco2 as a potential therapeutic modulator of the inflammatory response (13). Recent studies have found an association between Paco2 derangements and poor clinical outcome among patients suffering from PCAS (14, 15), although the optimal Paco2 range for PCAS patients remains unclear. The American Heart Association 2010 guidelines for CPR and Emergency Cardiovascular Care provide recommendations for targeting MAP, oxygenation, and ventilation during the initial post–cardiac arrest period (16). However, there is currently a paucity of data on which these recommendations are based, and the optimal targets for these variables remain unclear. We commend Bro-Jeppesen et al (3) on identifying the inflammatory response as a potential new target for future post–cardiac arrest therapies, and we propose that future well-designed clinical trials are warranted to test for the optimal goals for MAP, oxygenation, and ventilation after ROSC, as well as to investigate the efficacy of antibiotic administration after ROSC. Such trials have the potential to identify means to improve clinical outcomes through simple modifications of conventional care. As opposed to a novel (and expensive) therapeutic agent, such meaningful postresuscitation interventions could be simple, scalable, and generalizable to post–cardiac arrest patients worldwide.
REFERENCES
1. Roger VL, Go AS, Lloyd-Jones DM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics–2012 update: A report from the American Heart Association. Circulation 2012; 125:e2–e220
Critical Care Medicine
2. Trzeciak S, Jones AE, Kilgannon JH, et al: Significance of arterial hypotension after resuscitation from cardiac arrest. Crit Care Med 2009; 37:2895–2903; quiz 2904 3. Bro-Jeppesen J, Kjaergaard J, Wanscher M, et al: Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest: A Substudy of the Target Temperature Management Trial. Crit Care Med 2015; 43:1223–1232 4. Roberts BW, Kilgannon JH, Chansky ME, et al: Multiple organ dysfunction after return of spontaneous circulation in postcardiac arrest syndrome. Crit Care Med 2013; 41:1492–1501 5. Adrie C, Adib-Conquy M, Laurent I, et al: Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation 2002; 106:562–568 6. Sheng ZY, Dong YL, Wang XH: Bacterial translocation and multiple system organ failure in bowel ischemia and reperfusion. Chin Med J (Engl) 1991; 104:897–903 7. Davies KJ, Walters JH, Kerslake IM, et al: Early antibiotics improve survival following out-of hospital cardiac arrest. Resuscitation 2013; 84:616–619 8. Kilgannon JH, Roberts BW, Jones AE, et al: Arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest. Crit Care Med 2014; 42:2083–2091 9. Fujii Y, Shirai M, Tsuchimochi H, et al: Hyperoxic condition promotes an inflammatory response during cardiopulmonary bypass in a rat model. Artif Organs 2013; 37:1034–1040 10. Kilgannon JH, Jones AE, Parrillo JE, et al; Emergency Medicine Shock Research Network (EMShockNet) Investigators: Relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest. Circulation 2011; 123:2717–2722 11. Kilgannon JH, Jones AE, Shapiro NI, et al; Emergency Medicine Shock Research Network (EMShockNet) Investigators: Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA 2010; 303:2165–2171 12. Buunk G, van der Hoeven JG, Meinders AE: Cerebrovascular reactivity in comatose patients resuscitated from a cardiac arrest. Stroke 1997; 28:1569–1573 13. Kimura D, Totapally BR, Raszynski A, et al: The effects of CO2 on cytokine concentrations in endotoxin-stimulated human whole blood. Crit Care Med 2008; 36:2823–2827 14. Roberts BW, Kilgannon JH, Chansky ME, et al: Association between postresuscitation partial pressure of arterial carbon dioxide and neurological outcome in patients with post-cardiac arrest syndrome. Circulation 2013; 127:2107–2113 15. Schneider AG, Eastwood GM, Bellomo R, et al: Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest. Resuscitation 2013; 84:927–934 16. Peberdy MA, Callaway CW, Neumar RW, et al; American Heart Association: Part 9: Post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S768–S786
www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
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O
ut-of-hospital cardiac arrest (OHCA) is the most common lethal manifestation of cardiovascular disease with a mortality rate estimated to be as high as 89% (1). Even if return of spontaneous circulation (ROSC) is successfully achieved, 50% of patients do not survive to hospital discharge, and of those who do survive, the majority are functionally dependent, with more than half of these patients discharged to a long-term care facility (2). Identifying new post–cardiac arrest therapies to help improve clinical outcome is of the utmost importance to resuscitation science. In the post hoc analysis of a prospective multicenter randomized study in this issue of Critical Care Medicine, Bro-Jeppesen et al (3) aimed to test the association between the level of systemic inflammatory markers and mortality in patients who successfully achieved ROSC after OHCA. They found interleukin (IL)-6 at baseline was associated with mortality, and both IL-6 levels and procalcitonin levels at 24 hours after OHCA were associated with 30-day mortality. Using receiver operating characteristic curve analysis, the authors found the area under the curve for procalcitonin and IL-6 at 24 hours after OHCA to be 0.74 (95% CI, 0.64–0.83) and 0.63 (95% CI, 0.53–0.73), respectively. The authors concluded that IL-6 and procalcitonin at 24 hours after OHCA were modest predictors of 30-day mortality. We feel that one of the more important findings of this article is that procalcitonin and IL-6 (in addition to all inflammatory markers measured) increased over the initial 72 hours after ROSC. These findings support a theme in our previous work, which demonstrated that multiple organ dysfunction (MOD) worsens over *See also p. 1223. Key Words: anoxic brain injury; cardiac arrest; cardiopulmonary resuscitation; heart arrest; resuscitation The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001011
1336
www.ccmjournal.org
the same 72-hour period (4). The authors also found an association between length of ischemia/reperfusion (I/R) injury (i.e., the administered dose of epinephrine and time to ROSC) and release of inflammatory markers. As pointed out by the authors in their conclusion, given the observational nature of this study, it remains unclear if inflammatory markers are simply indicators of the degree of I/R injury or actually exacerbate MOD. However, either way these findings provide additional support that the global I/R injury associated with cardiac arrest results in a “sepsis-like” state (5), and further support that therapies aimed at attenuating reperfusion injury, applied after cardiac arrest, could potentially decrease the systemic inflammatory response, prevent worsening MOD, and improve clinical outcomes. Ideal therapies would be simple and generalizable to all post–cardiac arrest patients. Accordingly, we believe that elements of conventional supportive critical care are especially attractive targets for attenuating reperfusion injury after ROSC. These include 1) optimization of mean arterial blood pressure (MAP), 2) avoidance of hyperoxia, and 3) avoidance of Paco2 derangements. It is also possible that not only does I/R injury result in a “sepsis-like” state but that a substantial proportion of these patients are actually septic or at least endotoxemic. Bowel I/R injury has been demonstrated to promote gut barrier failure and bacterial translocation, leading to sepsis and MOD (6). Although to our knowledge it has not been previous demonstrated in a clinical study, it would make sense that the global I/R injury, in addition to multiple doses of epinephrine during cardiopulmonary resuscitation (CPR), could also lead to bacterial translocation. In a recent retrospective study, it was found that 97.8% of patients with post–cardiac arrest syndrome (PCAS) had at least one marker for infection during the initial 72 hours after ROSC and that antibiotic administration was associated with survival, with a number needed to treat of five (7). Given a large proportion of PCAS are possibly septic or endotoxemic, it makes sense that maintaining adequate perfusion of vital organs is potentially beneficial. Previous literature has demonstrated an association between hypotension and poor outcome in PCAS (2); however, given the pathophysiological differences between sepsis and PCAS (with or without sepsis), it is unclear if increasing the MAP above the defined sepsis goal of 65 mm Hg is of any benefit. A recent study found an association between MAP more than 70 mm Hg and good neurological outcome in patients with PCAS, suggesting that the previous goal of MAP more than 65 mm Hg may be suboptimal for some patients with PCAS (8). Supplemental oxygen is frequently administered during the management of PCAS. Although it is intuitive that hypoxia can exacerbate cerebral ischemia, excessive oxygen delivery (hyperoxia) can also in theory exacerbate reperfusion injury through acceleration of oxygen-free radical formation. Hyperoxia has also been demonstrated to be associated with an increase in June 2015 • Volume 43 • Number 6
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Editorials
inflammatory markers, including IL-6 in an animal model of cardiopulmonary bypass (9). Recent studies have demonstrated an association between excessively elevated Pao2 and poor outcome in patients with PCAS (10, 11), suggesting the potential benefit of achieving a Pao2 range which avoids both the ischemic injury of hypoxia and the free radical injury of hyperoxia. Finally, mechanical ventilation is typically required after successful resuscitation from cardiac arrest. Paco2 is a major regulator of cerebral blood flow after cerebral injury (12), and Paco2 levels are guided by the ventilator settings initiated by the treating clinician during mechanical ventilation. In addition, in an endotoxemia model, Co2 was demonstrated to modulate inflammatory marker levels, suggesting a possible role for Paco2 as a potential therapeutic modulator of the inflammatory response (13). Recent studies have found an association between Paco2 derangements and poor clinical outcome among patients suffering from PCAS (14, 15), although the optimal Paco2 range for PCAS patients remains unclear. The American Heart Association 2010 guidelines for CPR and Emergency Cardiovascular Care provide recommendations for targeting MAP, oxygenation, and ventilation during the initial post–cardiac arrest period (16). However, there is currently a paucity of data on which these recommendations are based, and the optimal targets for these variables remain unclear. We commend Bro-Jeppesen et al (3) on identifying the inflammatory response as a potential new target for future post–cardiac arrest therapies, and we propose that future well-designed clinical trials are warranted to test for the optimal goals for MAP, oxygenation, and ventilation after ROSC, as well as to investigate the efficacy of antibiotic administration after ROSC. Such trials have the potential to identify means to improve clinical outcomes through simple modifications of conventional care. As opposed to a novel (and expensive) therapeutic agent, such meaningful postresuscitation interventions could be simple, scalable, and generalizable to post–cardiac arrest patients worldwide.
REFERENCES
1. Roger VL, Go AS, Lloyd-Jones DM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics–2012 update: A report from the American Heart Association. Circulation 2012; 125:e2–e220
Critical Care Medicine
2. Trzeciak S, Jones AE, Kilgannon JH, et al: Significance of arterial hypotension after resuscitation from cardiac arrest. Crit Care Med 2009; 37:2895–2903; quiz 2904 3. Bro-Jeppesen J, Kjaergaard J, Wanscher M, et al: Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest: A Substudy of the Target Temperature Management Trial. Crit Care Med 2015; 43:1223–1232 4. Roberts BW, Kilgannon JH, Chansky ME, et al: Multiple organ dysfunction after return of spontaneous circulation in postcardiac arrest syndrome. Crit Care Med 2013; 41:1492–1501 5. Adrie C, Adib-Conquy M, Laurent I, et al: Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation 2002; 106:562–568 6. Sheng ZY, Dong YL, Wang XH: Bacterial translocation and multiple system organ failure in bowel ischemia and reperfusion. Chin Med J (Engl) 1991; 104:897–903 7. Davies KJ, Walters JH, Kerslake IM, et al: Early antibiotics improve survival following out-of hospital cardiac arrest. Resuscitation 2013; 84:616–619 8. Kilgannon JH, Roberts BW, Jones AE, et al: Arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest. Crit Care Med 2014; 42:2083–2091 9. Fujii Y, Shirai M, Tsuchimochi H, et al: Hyperoxic condition promotes an inflammatory response during cardiopulmonary bypass in a rat model. Artif Organs 2013; 37:1034–1040 10. Kilgannon JH, Jones AE, Parrillo JE, et al; Emergency Medicine Shock Research Network (EMShockNet) Investigators: Relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest. Circulation 2011; 123:2717–2722 11. Kilgannon JH, Jones AE, Shapiro NI, et al; Emergency Medicine Shock Research Network (EMShockNet) Investigators: Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA 2010; 303:2165–2171 12. Buunk G, van der Hoeven JG, Meinders AE: Cerebrovascular reactivity in comatose patients resuscitated from a cardiac arrest. Stroke 1997; 28:1569–1573 13. Kimura D, Totapally BR, Raszynski A, et al: The effects of CO2 on cytokine concentrations in endotoxin-stimulated human whole blood. Crit Care Med 2008; 36:2823–2827 14. Roberts BW, Kilgannon JH, Chansky ME, et al: Association between postresuscitation partial pressure of arterial carbon dioxide and neurological outcome in patients with post-cardiac arrest syndrome. Circulation 2013; 127:2107–2113 15. Schneider AG, Eastwood GM, Bellomo R, et al: Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest. Resuscitation 2013; 84:927–934 16. Peberdy MA, Callaway CW, Neumar RW, et al; American Heart Association: Part 9: Post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S768–S786
www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
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