Improving Survival After Pédiatrie Cardiopulmonary Arrest: Pay Attention to the Details* Jamie McElrath Schwartz, MD Division of Critical Care Medicine Children's National Medical Center Washington, DC
who had hypotension and were treated with vasoactive infusions had no difference in outcome from those who had no recorded hypotension and were treated with vasoactive infusions. However, in children who did not receive vasoactive infusions, patients who had hypotension were more likely to die than those without hypotension (OR = 2.12). urvival from pédiatrie cardiopulmonary arrest (GPA) has Improved survival ftom in-hospital GPA can be attributed to increased dramatically in the last decade; risk-adjusted a greater emphasis on quality in each segment of the GPA consurvival to discharge for children who suffer in-hospital tinuum: recognition, GPR, and postresuscitation (4-8).Topjian arrest is 43% compared with less than 20% only 10 years ago ( 1et al's (9) findings focus on the postresuscitation phase of care, 3). It is notable that increased survival has not been associated when oxygen delivery maybe limited by acidosis, impaired autowith novel therapy but instead with increasing resuscitation regulation, and poor myocardial performance. Hypotension can quality: early recognition of GPA, refining chest compression be both causative of and additive to effects of poor oxygen delivtechnique to maximize cerebral and coronary perfusion during ery. In this study, children with early hypotension following GPA cardiopulmonary resuscitation (GPR), adherence to resuscitahad nearly double the risk of death or neurologic disability. tion guidelines, improved postarrest care, communication, and Although the data demonstrate an associative, not causal, teamwork (4-8). For pédiatrie patients with GPA, the focus of relationship between hypotension and poor outcomes, there is recent literature and bedside care is meticulous attention to physiologic basis to support careful monitoring of vital signs detail during resuscitation. and aggressive treatment of hypotension after GPA. Perfusion In this issue of Critical Care Medicine, Topjian et al (9) pressure to vital organs is dependent on blood pressure and present a study that highlights the importance of pédiatrie tenuous following GPA, when autoregulation may be unrelipostarrest management. They report a retrospective review of a large, multicenter database of children aged 1 day to 18 years able (10, 11). Additionally, the subgroup of patients who were not treated with vasoactive infusions despite hypotension was with GPA and subsequent return of spontaneous circulation more than two times likely to die when compared with patients (ROSG). Primary outcomes were systemic hypotension (blood without hypotension, further emphasizing the role of meticupressure less than fifth percentile for age) in the first 6 hours lous monitoring and treatment of patients following GPA to following GPA and in-hospital mortality. Secondary outcome improve outcomes. was neurologic disability as defined by Pédiatrie Gerebral PerThese findings are also consistent with other work that formance Score (PGPS) of less than 3 (moderate disability or documents the critically ill child's vulnerability to additional worse) or change in PGPS score more than or equal to 1. insult. Pigula et al (12) first reported that when children with They found that 56% of eligible patients (214 of 383) had at traumatic brain injury also have hypotension, even briefly, least one episode of hypotension following GPA; patients with there is a significantly increased risk of mortality and morbidhypotension were more likely to die prior to hospital discharge ity. Vavilala et al (13) expanded on these findings by retrospecthan those without hypotension (53% vs 41%, odds ratio [OR] = 1.61, p = 0.022). After controlling for patient and event tively examining the relationship between age-associated blood characteristics, hypotension in the first 6 hours after ROSG was pressure norms and outcomes in patients with traumatic brain associated with an increased risk of hospital mortality (OR = injury (TBI); children with TBI and blood pressure less than 75% for age had an adjusted OR of death = 4.2 when compared 1.71) and an unfavorable neurologic outcome (OR = 1.83). with children whose blood pressure was more than 75% for Additionally, Topjian et al (9) found that 41% of children age. These and other similar findings changed post-TBI care, (88 of 214) with postresuscitation hypotension received vasoprompting more careful attention to blood pressure manageactive infusions after ROSG; in subgroup analysis, patients ment. Topjian et al's (9) findings may prompt similar consideration of management after GPA. There are limitations to these data and its interpretation. *Seealso p. 1518. Although the database is large and multicentered, it is over 10 Key Words: oardiopulmonary resuscitation; children; hypotension; years old and was retrospectively reviewed. Important varioutcomes; postresuscitation care ables, such as duration of hypotension, number of hypotensive Dr. Schwartz provided expert testimony for Jeanne Stevens, LLC; lectured for the Amerioan Aoademy of Pediatrios; and reoeived support for the events, and treatments (other than vasoactive infusions), are development of educational presentations from University of Maryland not known. GPR practice and outcomes have changed in the Baltimore College. last 10 years. Finally, this work describes an association, not Copyright ® 2014 by the Society of Critical Care Medicine and Lippinoott causality; it is possible that early hypotension is associated with Williams & Wiikins greater degree of illness and thus poor outcomes. DOI:10.1097/CCM.0000000000000259
S
Critical Care Medicine
www.ccmjournal.org
1571
Editorials
However, the impact of this study should be interpreted in the context of current science of pericardiopulmonary arrest care; these flndings add to the fabric of understanding that meticulous attention to all aspects of CPA care may improve outcomes. The work by Topjian et al's (9) reminds us that although we work on a novel therapy for patients with CPA, we should pay attention to the details of therapies we have.
REFERENCES 1. Matos RI, Watson RS, Nadkarni VM, et al; American Heart Association's Get With The Guidelines-Resuscitation (Formerly the National Registry of Cardiopulmonary Resuscitation) Investigators: Duration of cardiopulmonary resuscitation and illness category impact survival and neurologic outcomes for in-hospital pédiatrie cardiac arrests. Circulation 2013; 127:442-451 2. Girotra S, Spertus JA, Li Y, et al; American Heart Association Get With the Guidelines-Resuscitation Investigators: Survival trends in pédiatrie in-hospital cardiac arrests: An analysis from Get With the Guidelines-Resuscitation. C/rc Oardiovasc Oual Outcomes 2013; 6:42-49 3. Samson RA, Nadkarni VM, Meaney PA, et al; American Heart Association National Registry of CPR Investigators: Outcomes of in-hospital ventricular fibrillation in children. N EngI J Med 2006; 354:2328-2339 4. Sutton RM, Niles D, Nysaether J, et al: Quantitative analysis of CPR quality during in-hospital resuscitation of older children and adolescents. Pediatrics 2009; 124:494-499
5. Sutton RM, French B, Nishisaki A, et al: American Heart Association cardiopulmonary resuscitation quality targets are associated with improved arterial blood pressure during pédiatrie cardiac arrest. Resuscitation 2013; 84:168-172 6. Edelson DP, Abella BS, Kramer-Johansen J, et al: Effects of compression depth and pre-shock pauses predict defibrillation failure during cardiac arrest. Resuscitation 2006; 71:137-145 7 Idris AH, Guffey D, Aufderheide TP, et al; Resuscitation Outcomes Consortium (ROC) Investigators: Relationship between chest compression rates and outcomes from cardiac arrest. Circulation 2012; 125:3004-3012 8. Kleinman ME, Chameides L, Schexnayder SM, et al: Part 14: Pédiatrie advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergeney Cardiovaseular Care. Circulation 2010; 122:S876-S908 9. Topjian AA, Freneh B, Sutton RM, et al: Early Postresuseitation Hypotension Is Associated With Increased Mortality Following Pédiatrie Cardiac Arrest. Crit Care Med 2014; 42:1518-1523 10. Lee JK, Brady KM, Mytar JO, et al: Cerebral blood flow and cerebrovascular autoregulation in a swine model of pédiatrie eardiae arrest and hypothermia. Crit Care Med 2011 ; 39:2337-2345 11. Sundgreen C, Larsen FS, Herzog TM, et al: Autoregulation of eerebral blood flow in patients resuseitated from cardiac arrest. Stroke 2001 ; 32:128-132 12. Pigula FA, Wald SL, Shackford SR, et al: The eftect of hypotension and hypoxia on children with severe head injuries. J Pediatr Surg 1993; 28:310-314; discussion 315 13. Vavilala MS, Bowen A, Lam AM, et al: Blood pressure and outcome after severe pédiatrie traumatic brain injury. J Trauma 2003; 55:1039-1044
Nitric Oxide Synthase and Vascular Dysfunction in Sepsis: Should We Target Nitric Oxide Synthase 1, Nitric Oxide Synthase 2, Both, or Neither?* Mitchell P. Fink, MD Department of Surgery; and Department of Anesthesiology David Geffen School of Medicine at UCLA Los Angeles, CA
T
ogether with carbon monoxide and hydrogen sulfide, nitric oxide (NO) is recognized as being one of three gaseous molecules that play important roles as signaling agents in mammalian biology. NO is generated in cells via a reaction that uses the amino acid L-arginine and molecular oxygen as substrates. This reaction is catalyzed by a family of enzymes called "nitric oxide synthases" (NOSs). Three NOS
'See also p. e39i. Keywords: 7-nitroindazole; guanylyl cyclase; lipopolysaccharide; vasoplegia The author has disclosed that he does not have any potential eonflicts of Interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.00000000000003SS
1572
www.ccmjournal.org
isoforms are known: NOSl (neuronal NOS); NOS2 (inducible NOS); and N0S3 (endothelial NOS). The enzymatic activity of NOSl and NOS3 is controlled by changes in intracellular calcium ion (Ca^+) concentration. By contrast, the enzymatic activity of NOS2 is independent of Ca'^ concentration. NOSl and N0S3 are expressed constitutively although the expression of these proteins can be up-regulated under certain conditions (1, 2). NOS2 is an inducible protein and its expression in macrophages and other cell types can be triggered by various proinflammatory mediators. N0S3-dependent production of NO in endothelial cells promotes dilation of resistance and capacitance blood vessels (3). This process depends on diffusion of NO from the endothelium into nearby vascular smooth cells wherein a heme-containing enzyme, soluble guanylyl cyclase, is activated by the formation of a chemical bond between the diatomic gas and an iron atom, which is in the -1-2 (ferrous) oxidation state, in the heme moiety. After being activated, soluble guanylyl cyclase catalyzes the conversion of the purine nucleotide, guanosine triphosphate, into 3',5'-cyclic guanosine monophosphate (cCMP). This "second messenger" activates a protein June 2014 • Volume 42 • Number 6
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
who had hypotension and were treated with vasoactive infusions had no difference in outcome from those who had no recorded hypotension and were treated with vasoactive infusions. However, in children who did not receive vasoactive infusions, patients who had hypotension were more likely to die than those without hypotension (OR = 2.12). urvival from pédiatrie cardiopulmonary arrest (GPA) has Improved survival ftom in-hospital GPA can be attributed to increased dramatically in the last decade; risk-adjusted a greater emphasis on quality in each segment of the GPA consurvival to discharge for children who suffer in-hospital tinuum: recognition, GPR, and postresuscitation (4-8).Topjian arrest is 43% compared with less than 20% only 10 years ago ( 1et al's (9) findings focus on the postresuscitation phase of care, 3). It is notable that increased survival has not been associated when oxygen delivery maybe limited by acidosis, impaired autowith novel therapy but instead with increasing resuscitation regulation, and poor myocardial performance. Hypotension can quality: early recognition of GPA, refining chest compression be both causative of and additive to effects of poor oxygen delivtechnique to maximize cerebral and coronary perfusion during ery. In this study, children with early hypotension following GPA cardiopulmonary resuscitation (GPR), adherence to resuscitahad nearly double the risk of death or neurologic disability. tion guidelines, improved postarrest care, communication, and Although the data demonstrate an associative, not causal, teamwork (4-8). For pédiatrie patients with GPA, the focus of relationship between hypotension and poor outcomes, there is recent literature and bedside care is meticulous attention to physiologic basis to support careful monitoring of vital signs detail during resuscitation. and aggressive treatment of hypotension after GPA. Perfusion In this issue of Critical Care Medicine, Topjian et al (9) pressure to vital organs is dependent on blood pressure and present a study that highlights the importance of pédiatrie tenuous following GPA, when autoregulation may be unrelipostarrest management. They report a retrospective review of a large, multicenter database of children aged 1 day to 18 years able (10, 11). Additionally, the subgroup of patients who were not treated with vasoactive infusions despite hypotension was with GPA and subsequent return of spontaneous circulation more than two times likely to die when compared with patients (ROSG). Primary outcomes were systemic hypotension (blood without hypotension, further emphasizing the role of meticupressure less than fifth percentile for age) in the first 6 hours lous monitoring and treatment of patients following GPA to following GPA and in-hospital mortality. Secondary outcome improve outcomes. was neurologic disability as defined by Pédiatrie Gerebral PerThese findings are also consistent with other work that formance Score (PGPS) of less than 3 (moderate disability or documents the critically ill child's vulnerability to additional worse) or change in PGPS score more than or equal to 1. insult. Pigula et al (12) first reported that when children with They found that 56% of eligible patients (214 of 383) had at traumatic brain injury also have hypotension, even briefly, least one episode of hypotension following GPA; patients with there is a significantly increased risk of mortality and morbidhypotension were more likely to die prior to hospital discharge ity. Vavilala et al (13) expanded on these findings by retrospecthan those without hypotension (53% vs 41%, odds ratio [OR] = 1.61, p = 0.022). After controlling for patient and event tively examining the relationship between age-associated blood characteristics, hypotension in the first 6 hours after ROSG was pressure norms and outcomes in patients with traumatic brain associated with an increased risk of hospital mortality (OR = injury (TBI); children with TBI and blood pressure less than 75% for age had an adjusted OR of death = 4.2 when compared 1.71) and an unfavorable neurologic outcome (OR = 1.83). with children whose blood pressure was more than 75% for Additionally, Topjian et al (9) found that 41% of children age. These and other similar findings changed post-TBI care, (88 of 214) with postresuscitation hypotension received vasoprompting more careful attention to blood pressure manageactive infusions after ROSG; in subgroup analysis, patients ment. Topjian et al's (9) findings may prompt similar consideration of management after GPA. There are limitations to these data and its interpretation. *Seealso p. 1518. Although the database is large and multicentered, it is over 10 Key Words: oardiopulmonary resuscitation; children; hypotension; years old and was retrospectively reviewed. Important varioutcomes; postresuscitation care ables, such as duration of hypotension, number of hypotensive Dr. Schwartz provided expert testimony for Jeanne Stevens, LLC; lectured for the Amerioan Aoademy of Pediatrios; and reoeived support for the events, and treatments (other than vasoactive infusions), are development of educational presentations from University of Maryland not known. GPR practice and outcomes have changed in the Baltimore College. last 10 years. Finally, this work describes an association, not Copyright ® 2014 by the Society of Critical Care Medicine and Lippinoott causality; it is possible that early hypotension is associated with Williams & Wiikins greater degree of illness and thus poor outcomes. DOI:10.1097/CCM.0000000000000259
S
Critical Care Medicine
www.ccmjournal.org
1571
Editorials
However, the impact of this study should be interpreted in the context of current science of pericardiopulmonary arrest care; these flndings add to the fabric of understanding that meticulous attention to all aspects of CPA care may improve outcomes. The work by Topjian et al's (9) reminds us that although we work on a novel therapy for patients with CPA, we should pay attention to the details of therapies we have.
REFERENCES 1. Matos RI, Watson RS, Nadkarni VM, et al; American Heart Association's Get With The Guidelines-Resuscitation (Formerly the National Registry of Cardiopulmonary Resuscitation) Investigators: Duration of cardiopulmonary resuscitation and illness category impact survival and neurologic outcomes for in-hospital pédiatrie cardiac arrests. Circulation 2013; 127:442-451 2. Girotra S, Spertus JA, Li Y, et al; American Heart Association Get With the Guidelines-Resuscitation Investigators: Survival trends in pédiatrie in-hospital cardiac arrests: An analysis from Get With the Guidelines-Resuscitation. C/rc Oardiovasc Oual Outcomes 2013; 6:42-49 3. Samson RA, Nadkarni VM, Meaney PA, et al; American Heart Association National Registry of CPR Investigators: Outcomes of in-hospital ventricular fibrillation in children. N EngI J Med 2006; 354:2328-2339 4. Sutton RM, Niles D, Nysaether J, et al: Quantitative analysis of CPR quality during in-hospital resuscitation of older children and adolescents. Pediatrics 2009; 124:494-499
5. Sutton RM, French B, Nishisaki A, et al: American Heart Association cardiopulmonary resuscitation quality targets are associated with improved arterial blood pressure during pédiatrie cardiac arrest. Resuscitation 2013; 84:168-172 6. Edelson DP, Abella BS, Kramer-Johansen J, et al: Effects of compression depth and pre-shock pauses predict defibrillation failure during cardiac arrest. Resuscitation 2006; 71:137-145 7 Idris AH, Guffey D, Aufderheide TP, et al; Resuscitation Outcomes Consortium (ROC) Investigators: Relationship between chest compression rates and outcomes from cardiac arrest. Circulation 2012; 125:3004-3012 8. Kleinman ME, Chameides L, Schexnayder SM, et al: Part 14: Pédiatrie advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergeney Cardiovaseular Care. Circulation 2010; 122:S876-S908 9. Topjian AA, Freneh B, Sutton RM, et al: Early Postresuseitation Hypotension Is Associated With Increased Mortality Following Pédiatrie Cardiac Arrest. Crit Care Med 2014; 42:1518-1523 10. Lee JK, Brady KM, Mytar JO, et al: Cerebral blood flow and cerebrovascular autoregulation in a swine model of pédiatrie eardiae arrest and hypothermia. Crit Care Med 2011 ; 39:2337-2345 11. Sundgreen C, Larsen FS, Herzog TM, et al: Autoregulation of eerebral blood flow in patients resuseitated from cardiac arrest. Stroke 2001 ; 32:128-132 12. Pigula FA, Wald SL, Shackford SR, et al: The eftect of hypotension and hypoxia on children with severe head injuries. J Pediatr Surg 1993; 28:310-314; discussion 315 13. Vavilala MS, Bowen A, Lam AM, et al: Blood pressure and outcome after severe pédiatrie traumatic brain injury. J Trauma 2003; 55:1039-1044
Nitric Oxide Synthase and Vascular Dysfunction in Sepsis: Should We Target Nitric Oxide Synthase 1, Nitric Oxide Synthase 2, Both, or Neither?* Mitchell P. Fink, MD Department of Surgery; and Department of Anesthesiology David Geffen School of Medicine at UCLA Los Angeles, CA
T
ogether with carbon monoxide and hydrogen sulfide, nitric oxide (NO) is recognized as being one of three gaseous molecules that play important roles as signaling agents in mammalian biology. NO is generated in cells via a reaction that uses the amino acid L-arginine and molecular oxygen as substrates. This reaction is catalyzed by a family of enzymes called "nitric oxide synthases" (NOSs). Three NOS
'See also p. e39i. Keywords: 7-nitroindazole; guanylyl cyclase; lipopolysaccharide; vasoplegia The author has disclosed that he does not have any potential eonflicts of Interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.00000000000003SS
1572
www.ccmjournal.org
isoforms are known: NOSl (neuronal NOS); NOS2 (inducible NOS); and N0S3 (endothelial NOS). The enzymatic activity of NOSl and NOS3 is controlled by changes in intracellular calcium ion (Ca^+) concentration. By contrast, the enzymatic activity of NOS2 is independent of Ca'^ concentration. NOSl and N0S3 are expressed constitutively although the expression of these proteins can be up-regulated under certain conditions (1, 2). NOS2 is an inducible protein and its expression in macrophages and other cell types can be triggered by various proinflammatory mediators. N0S3-dependent production of NO in endothelial cells promotes dilation of resistance and capacitance blood vessels (3). This process depends on diffusion of NO from the endothelium into nearby vascular smooth cells wherein a heme-containing enzyme, soluble guanylyl cyclase, is activated by the formation of a chemical bond between the diatomic gas and an iron atom, which is in the -1-2 (ferrous) oxidation state, in the heme moiety. After being activated, soluble guanylyl cyclase catalyzes the conversion of the purine nucleotide, guanosine triphosphate, into 3',5'-cyclic guanosine monophosphate (cCMP). This "second messenger" activates a protein June 2014 • Volume 42 • Number 6
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
