The Value of Early Administration of Antibiotics in Children With Presumed Severe Sepsis and Septic Shock* Philip Toltzis, MD Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, OH
Charles L. Sprung, MD, MCCM Department of Anesthesiology and Critical Care Medicine Hadassah Hebrew University Medical Center Jerusalem, Israel
he Surviving Sepsis Campaign (1) is an international initiative to reduce mortality from severe sepsis and septic shock by promulgating interventions shown to be effective in improving outcome. The Surviving Sepsis guide lines are multifarious but among the most important are those directed at care when the patient first presents, specifically, goal-directed correction of abnormalities in hemodynamics and oxygen delivery, and the administration of anti-infective therapy. The latter measure in particular mandates the admin istration of broad-spectrum antibiotics within 1 hour of pre sentation. This recommendation is based on studies that have demonstrated a progressive increase in in-hospital mortality among adult patients if effective antibiotics are delayed (2-4). The authors of the most recent iteration of the Surviv ing Sepsis Campaign guidelines, published in 2013 (1), were mostly adult physicians using data almost exclusively derived from adult populations. Pediatric guidelines for early inter vention in childhood sepsis were included in the Surviving Sepsis document by a pediatric subgroup (1), and additional guidelines have been published by some of the same authors including the management of childhood sepsis in developing countries (5). These pediatric-specific recommendations are considerably less evidence-based than those derived for adults, and as such, many are adopted from the adult paradigms despite the absence of supporting data, including the mandate to administer antibiotics within 1 hour of presentation. It was against this background that Weiss et al (6) performed their study testing the need for expeditious administration of antibiotics in children with severe sepsis and septic shock.
T
*See also p. 2409. Key Words: antimicrobial guidelines; antimicrobial timing; critically ill children; pediatric intensive care unit; sepsis Dr. Toltzis' institution received grant support from the Ohio Department of Health and Centers for Disease Control and Prevention. Dr. Sprung consulted for Asahi Kasei Pharma America Corporation (Data Safety and Monitoring Committee) and LeukoDX. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0000000000000582
Critical Care Medicine
Specifically, they examined whether a delay in the administra tion of antibiotics had a deleterious effect on survival in chil dren with sepsis. The study was conducted at a large quaternary care pediatric hospital and employed a retrospective observa tional design. One hundred thirty children hospitalized in 2012 for sepsis were examined, using data exported from electronic records. The duration of time between the recognition of sep sis and the administration of antibiotics was calculated, and its association with PICU mortality was assessed. The authors assigned the starting time of “sepsis recognition” as either the time that the patient was triaged in the emergency department or the time that the first sepsis-related intervention was ordered, depending on where the septic episode was initially identified. The results indicated that the risk of mortality progressively increased as each hour passed before appropriate antibiotics were administered, up to 3 hours (6). The association between delayed antibiotic administration and mortality was retained when the analyses were adjusted for possible confounders and for a propensity score composed of factors potentially associ ated with delayed antibiotic administration. Prima facie, one could imagine that the biological rationale underlying the early administration of antibiotics in children experiencing life-threatening infection is so obvious as to obvi ate the need for testing, but several considerations necessitate such an effort. First, although the majority of studies in adults demonstrate the benefit of early antibiotic therapy, not all of them do (7, 8). Hranjec et al (7), for example, performed a 2-year study in an adult surgical ICU. During the first study year, all patients with suspected infection were given antibiot ics immediately, whereas during the second year, therapy was initiated only after infection was confirmed by objective find ings. Those treated conservatively actually had a statistically significant lower mortality compared with those treated imme diately, even in the subgroup of patients requiring vasoactive support. Second, one literature review concluded that many studies testing the benefit of early administration of antibiotics in patients with presumed sepsis are beset by methodological issues, such as controlling for baseline severity of illness and defining appropriate versus inappropriate therapy, rendering it difficult to reach confident conclusions (9). Third, it can be argued that by the time the patient with sepsis becomes symp tomatic, many of the manifestations of sepsis are due to the endogenous mediator response rather than the organism per se. Hence, whether antibiotics are administered 1 hour after presentation or 3 or 4 hours may not make a significant differ ence. Fourth, mortality in children with severe sepsis or sep tic shock is a fraction of that seen in adults, less than 5% in one multicenter study (10). Any benefit gained by immediate antibiotic administration versus a more measured approach w w w .c c m jo u r n a l.o r g
2455
Editorials
may be trivial. Finally, although virtually no authority denies the legitimacy of providing broad-spectrum antibiotics to the patient with sepsis, it should be noted that this rote practice is contrary to a competing mandate in the ICU, namely, to use antibiotics wisely in an effort to reduce the emergence of resis tant organisms, for which there may be few, if any, therapeutic options (11). Noninfectious conditions other than sepsis can initially appear like sepsis. Allowing the dust to settle before deciding to treat is a goal worthy, at least, of deliberation. Given these considerations, the importance of the results of the cur rent study becomes apparent: early antibiotic therapy in chil dren with sepsis does make a difference, and this is reflected in the most important outcome measure, mortality. That said, the study by Weiss et al (6) in this issue of Criti cal Care Medicine is vulnerable to criticisms common to any retrospective single-center study. The investigators were able to test only factors available through the medical record, and consequently, they may have missed important unmeasured confounders, and they were unable to determine the generalizability of their results. An additional issue that was peculiar to this study was the degree of accuracy in assigning a value to their independent variable, namely, the time elapsed prior to antibiotic administration. The authors chose two criteria to decide when the clock started, namely, triage time in the emergency department and time of ordering the first sepsisrelated intervention, both easily discernible through electronic records. The onset of signs and symptoms of sepsis, however, probably a more relevant starting point, doubtlessly occurred for variable times before each of these was recorded. These issues notwithstanding, the current study provides valuable evidence that rapid initiation of antimicrobial dosing in severe sepsis and septic shock in children is important, perhaps even life-saving, and, once confirmed, validates this key element of the Surviving Sepsis guidelines in the pediatric age group.
2456
w w w .c c m jo u rn a l.o rg
REFERENCES 1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580-637 2. Ferrer R, Artigas A, Suarez D, et al; Edusepsis Study Group: Effectiveness of treatments for severe sepsis: A prospective, mul ticenter, observational study. Am J Respir Crit Care Med 2009; 180:861-866 3. Gaieski DF, Mikkelsen ME, Band RA, et al: Impact of time to antibiot ics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency depart ment. Crit Care Med 2010; 38:1045-1053 4. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determi nant of survival in human septic shock. Crit Care Med 2006; 34: 1589-1596 5. Kissoon N, Carcillo JA, Espinosa V, et al; Global Sepsis Initiative Vanguard Center Contributors: World Federation of Pediatric Intensive Care and Critical Care Societies: Global sepsis initiative. Pediatr Crit Care Med 2011; 12:494-503 6. Weiss SL, Fitzgerald JC, Balamuth F, et al: Delayed Antimicrobial Therapy Increases Mortality and Organ Dysfunction Duration in Pediatric Sepsis. Crit Care Med 2014; 42:2409-2417 7. Hranjec T, Rosenberger LH, Swenson B, et al: Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgi cal patients with suspected intensive-care-unit-acquired infection: A quasi-experimental, before and after observational cohort study. Lancet Infect Dis 2012; 12:774-780 8. Vilella AL, Seifert CF: Timing and appropriateness of initial antibiotic therapy in newly presenting septic patients. Am J Emerg Med 2014; 32:7-13 9. McGregor JC, Rich SE, Harris AD, et al: A systematic review of the methods used to assess the association between appropriate anti biotic therapy and mortality in bacteremic patients. Clin Infect Dis 2007; 45:329-337 10. Odetola FO, Gebremariam A, Freed GL: Patient and hospital corre lates of clinical outcomes and resource utilization in severe pediatric sepsis. Pediatrics 2007; 119:487-494 11. Spellberg B, Guidos R, Gilbert D, et al; Infectious Diseases Society of America: The epidemic of antibiotic-resistant infections: A call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis 2008; 46:155-164
November 2014 • Volume 42 • Number 11
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.
Charles L. Sprung, MD, MCCM Department of Anesthesiology and Critical Care Medicine Hadassah Hebrew University Medical Center Jerusalem, Israel
he Surviving Sepsis Campaign (1) is an international initiative to reduce mortality from severe sepsis and septic shock by promulgating interventions shown to be effective in improving outcome. The Surviving Sepsis guide lines are multifarious but among the most important are those directed at care when the patient first presents, specifically, goal-directed correction of abnormalities in hemodynamics and oxygen delivery, and the administration of anti-infective therapy. The latter measure in particular mandates the admin istration of broad-spectrum antibiotics within 1 hour of pre sentation. This recommendation is based on studies that have demonstrated a progressive increase in in-hospital mortality among adult patients if effective antibiotics are delayed (2-4). The authors of the most recent iteration of the Surviv ing Sepsis Campaign guidelines, published in 2013 (1), were mostly adult physicians using data almost exclusively derived from adult populations. Pediatric guidelines for early inter vention in childhood sepsis were included in the Surviving Sepsis document by a pediatric subgroup (1), and additional guidelines have been published by some of the same authors including the management of childhood sepsis in developing countries (5). These pediatric-specific recommendations are considerably less evidence-based than those derived for adults, and as such, many are adopted from the adult paradigms despite the absence of supporting data, including the mandate to administer antibiotics within 1 hour of presentation. It was against this background that Weiss et al (6) performed their study testing the need for expeditious administration of antibiotics in children with severe sepsis and septic shock.
T
*See also p. 2409. Key Words: antimicrobial guidelines; antimicrobial timing; critically ill children; pediatric intensive care unit; sepsis Dr. Toltzis' institution received grant support from the Ohio Department of Health and Centers for Disease Control and Prevention. Dr. Sprung consulted for Asahi Kasei Pharma America Corporation (Data Safety and Monitoring Committee) and LeukoDX. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0000000000000582
Critical Care Medicine
Specifically, they examined whether a delay in the administra tion of antibiotics had a deleterious effect on survival in chil dren with sepsis. The study was conducted at a large quaternary care pediatric hospital and employed a retrospective observa tional design. One hundred thirty children hospitalized in 2012 for sepsis were examined, using data exported from electronic records. The duration of time between the recognition of sep sis and the administration of antibiotics was calculated, and its association with PICU mortality was assessed. The authors assigned the starting time of “sepsis recognition” as either the time that the patient was triaged in the emergency department or the time that the first sepsis-related intervention was ordered, depending on where the septic episode was initially identified. The results indicated that the risk of mortality progressively increased as each hour passed before appropriate antibiotics were administered, up to 3 hours (6). The association between delayed antibiotic administration and mortality was retained when the analyses were adjusted for possible confounders and for a propensity score composed of factors potentially associ ated with delayed antibiotic administration. Prima facie, one could imagine that the biological rationale underlying the early administration of antibiotics in children experiencing life-threatening infection is so obvious as to obvi ate the need for testing, but several considerations necessitate such an effort. First, although the majority of studies in adults demonstrate the benefit of early antibiotic therapy, not all of them do (7, 8). Hranjec et al (7), for example, performed a 2-year study in an adult surgical ICU. During the first study year, all patients with suspected infection were given antibiot ics immediately, whereas during the second year, therapy was initiated only after infection was confirmed by objective find ings. Those treated conservatively actually had a statistically significant lower mortality compared with those treated imme diately, even in the subgroup of patients requiring vasoactive support. Second, one literature review concluded that many studies testing the benefit of early administration of antibiotics in patients with presumed sepsis are beset by methodological issues, such as controlling for baseline severity of illness and defining appropriate versus inappropriate therapy, rendering it difficult to reach confident conclusions (9). Third, it can be argued that by the time the patient with sepsis becomes symp tomatic, many of the manifestations of sepsis are due to the endogenous mediator response rather than the organism per se. Hence, whether antibiotics are administered 1 hour after presentation or 3 or 4 hours may not make a significant differ ence. Fourth, mortality in children with severe sepsis or sep tic shock is a fraction of that seen in adults, less than 5% in one multicenter study (10). Any benefit gained by immediate antibiotic administration versus a more measured approach w w w .c c m jo u r n a l.o r g
2455
Editorials
may be trivial. Finally, although virtually no authority denies the legitimacy of providing broad-spectrum antibiotics to the patient with sepsis, it should be noted that this rote practice is contrary to a competing mandate in the ICU, namely, to use antibiotics wisely in an effort to reduce the emergence of resis tant organisms, for which there may be few, if any, therapeutic options (11). Noninfectious conditions other than sepsis can initially appear like sepsis. Allowing the dust to settle before deciding to treat is a goal worthy, at least, of deliberation. Given these considerations, the importance of the results of the cur rent study becomes apparent: early antibiotic therapy in chil dren with sepsis does make a difference, and this is reflected in the most important outcome measure, mortality. That said, the study by Weiss et al (6) in this issue of Criti cal Care Medicine is vulnerable to criticisms common to any retrospective single-center study. The investigators were able to test only factors available through the medical record, and consequently, they may have missed important unmeasured confounders, and they were unable to determine the generalizability of their results. An additional issue that was peculiar to this study was the degree of accuracy in assigning a value to their independent variable, namely, the time elapsed prior to antibiotic administration. The authors chose two criteria to decide when the clock started, namely, triage time in the emergency department and time of ordering the first sepsisrelated intervention, both easily discernible through electronic records. The onset of signs and symptoms of sepsis, however, probably a more relevant starting point, doubtlessly occurred for variable times before each of these was recorded. These issues notwithstanding, the current study provides valuable evidence that rapid initiation of antimicrobial dosing in severe sepsis and septic shock in children is important, perhaps even life-saving, and, once confirmed, validates this key element of the Surviving Sepsis guidelines in the pediatric age group.
2456
w w w .c c m jo u rn a l.o rg
REFERENCES 1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580-637 2. Ferrer R, Artigas A, Suarez D, et al; Edusepsis Study Group: Effectiveness of treatments for severe sepsis: A prospective, mul ticenter, observational study. Am J Respir Crit Care Med 2009; 180:861-866 3. Gaieski DF, Mikkelsen ME, Band RA, et al: Impact of time to antibiot ics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency depart ment. Crit Care Med 2010; 38:1045-1053 4. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determi nant of survival in human septic shock. Crit Care Med 2006; 34: 1589-1596 5. Kissoon N, Carcillo JA, Espinosa V, et al; Global Sepsis Initiative Vanguard Center Contributors: World Federation of Pediatric Intensive Care and Critical Care Societies: Global sepsis initiative. Pediatr Crit Care Med 2011; 12:494-503 6. Weiss SL, Fitzgerald JC, Balamuth F, et al: Delayed Antimicrobial Therapy Increases Mortality and Organ Dysfunction Duration in Pediatric Sepsis. Crit Care Med 2014; 42:2409-2417 7. Hranjec T, Rosenberger LH, Swenson B, et al: Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgi cal patients with suspected intensive-care-unit-acquired infection: A quasi-experimental, before and after observational cohort study. Lancet Infect Dis 2012; 12:774-780 8. Vilella AL, Seifert CF: Timing and appropriateness of initial antibiotic therapy in newly presenting septic patients. Am J Emerg Med 2014; 32:7-13 9. McGregor JC, Rich SE, Harris AD, et al: A systematic review of the methods used to assess the association between appropriate anti biotic therapy and mortality in bacteremic patients. Clin Infect Dis 2007; 45:329-337 10. Odetola FO, Gebremariam A, Freed GL: Patient and hospital corre lates of clinical outcomes and resource utilization in severe pediatric sepsis. Pediatrics 2007; 119:487-494 11. Spellberg B, Guidos R, Gilbert D, et al; Infectious Diseases Society of America: The epidemic of antibiotic-resistant infections: A call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis 2008; 46:155-164
November 2014 • Volume 42 • Number 11
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.
