CHEST Systemic Inflammatory Response Syndrome After Cardiac Surgery Time for a Change n 1991, Bone et al defined the systemic inflammaItory response syndrome (SIRS) as a selected set of 1
physiologic and laboratory abnormalities occurring after a clinical insult. It was widely believed then that both infectious and noninfectious inflammation shared a pathophysiologic basis that might be amenable to early application of common treatments. By proposing the paradigm, his group aimed to (1) improve early detection and intervention, (2) improve prognostic assessment, and (3) standardize enrollment into clinical trials.1 The latter two goals were realized: In patients with SIRS from infection (sepsis), the relationship between an increasing number of SIRS criteria and worse prognosis was confirmed2; SIRS also became part of standard inclusion criteria for clinical trials of sepsis.3,4 However, the utility of SIRS to facilitate sepsis recognition never reached expectations, handicapped by oversensitivity and underspecificity.5,6 Highlighting the shortcomings of SIRS, in 1997, Jean-Louis Vincent5 famously wrote, “Dear SIRS, I’m sorry to say that I don’t like you,” a well-reasoned argument that SIRS did not offer practical help to the clinician. With some hyperbole, naysayers of SIRS point out that even modest exercise causes “SIRS” in healthy individuals. Because of these flaws, many physicians ascribe little importance to a patient meeting SIRS criteria. But is that correct? In this issue of CHEST (see page 1197), MacCallum et al7 make us rethink the predictive value of SIRS, using a large cohort of patients in a single ICU who had undergone cardiac surgery. Patient characteristics, organ dysfunction, outcomes, and detailed data on the number of SIRS criteria met during each hour from ICU admission to death or discharge were prospectively collected. They found the traditional definition of two or more SIRS criteria was met by almost 60% of patients in the first hour after surgery and by . 95% within the first day. The low positive predic-
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Editorials CHEST | Volume 145 | Number 6 | June 2014
tive value (PPV) for mortality associated with meeting two or more SIRS criteria in the first 24 h (PPV, 2.8%) was improved by modifying the definition to meeting three or more or four SIRS criteria (PPV, 4.2% and 10.2%, respectively), or to fulfilling two or more criteria for at least six consecutive hours on the first day (PPV range, 5.4%-7.0%). At first, these low predictive values for mortality might suggest SIRS criteria are not very useful, until one considers that cardiac surgery is rarely fatal, and essentially all patients with poor outcomes could be identified on the first ICU day by applying these reasonably simple modifications of the original SIRS criteria. The study has several limitations. It was conducted at a single center retrospectively. The rapid decrement in patients remaining in the ICU limits conclusions about the SIRS criteria after the first 24 h. Incomplete data regarding on-pump vs off-pump surgery, redo valves, and complex congenital heart disease may confound described predictive characteristics of the SIRS criteria if these factors are independently linked to both increased inflammation and worsened outcomes. Finally, the predictive factors examined in the study all occur after the onset of injury. Therapeutic studies targeting the high-risk subgroup identified in this fashion may encounter the same challenges experienced by therapies initiated after the onset of sepsis.3,8,9 Whether intervention in this population could change outcomes remains to be seen. Beyond enriching our understanding of the relationship between postsurgical inflammation and clinical outcomes suggested by prior investigations,10,11 the authors provide a unique picture of the evolution of SIRS after a discrete injury. Unlike prior studies, their detailed hourly data result from automatic electronic archiving of the output from routine ICU care and clearly demonstrate that prevalence of some SIRS parameters markedly differ over time. Abnormal temperature, seen in 80% of patients in the first hour, had , 10% prevalence at later times. Abnormal respiratory rate, observed in , 20% of patients in the cohort in the first hour, was present in almost three-quarters of cohort patients in the ICU in each hour after the first day. In contrast to the dramatic swings in the prevalence of abnormal temperature
CHEST / 145 / 6 / JUNE 2014
1181
and respiratory rate criteria, heart rate and WBC count criteria stayed abnormal in approximately onehalf of all study patients in the ICU at all times of observation. The availability of data with this level of granularity allows the authors to propose modifications of the SIRS criteria to include the dimension of time, an aspect of assessment routinely used by bedside clinicians but absent from the original SIRS definition. The improvements in predictive value by using the cumulative total hours or maximum number of consecutive hours during which criteria are met are modest, but then so is the deviation from the historical definition. Loosening the constraints further may more dramatically improve our insight into what these markers of inflammation signify. For example, it may be that a fever occurring in the first hour after surgery means something completely different than a fever occurring a day later. Because research into inflammation after cardiac surgery has the unique advantage of knowing “time zero,” the moment of injury, it may ultimately provide a picture of the temporal patterns of physiologic and laboratory abnormalities that will improve our understanding of systemic inflammation in the broader population. Even if the authors’ observations are not generalizable to medical and general surgical patients, their methods certainly are. The ICU environment today produces hundreds to thousands of physiologic, laboratory, and management data points each hour and, as clearly seen in this study, the pattern of injury evolves over time. Accepting this complexity means accepting that a few easy-to-remember criteria evaluated intermittently by a clinician may not compete with complex, computer-applied algorithms of not just the original SIRS criteria12 or the 25 subsequently proposed sepsis criteria,6 but dozens or hundreds of other data points fluctuating over time. Future studies should forgo the limitations of using simple, memorable criteria and instead focus on putting the wealth of electronic data available in the ICU to work to find those patients at risk for adverse outcomes as early and accurately as possible, by any criteria necessary. Matthew W. Semler, MD Arthur P. Wheeler, MD, FCCP Nashville, TN Affiliations: From the Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Wheeler receives National Institutes of Health National Heart, Lung, and Blood Institute grant funding and royalties from a textbook that he coauthored, and serves as a paid consultant to Cumberland Pharmaceuticals Inc. Dr Semler has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Arthur P. Wheeler, MD, FCCP, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt Uni1182
versity Medical Center, T-1210 MCN, Nashville, TN 37232-2650; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0438
References 1. Bone RC, Balk RA, Cerra FB, et al; The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101(6):1644-1655. 2. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995; 273(2):117-123. 3. Abraham E, Wunderink R, Silverman H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA. 1995;273(12):934-941. 4. Bernard GR, Vincent JL, Laterre PF, et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. 5. Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med. 1997;25(2):372-374. 6. Levy MM, Fink MP, Marshall JC, et al; SCCM/ESICM/ ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003; 31(4):1250-1256. 7. MacCallum NS, Finney SJ, Gordon SE, Quinlan GJ, Evans TW. Modified criteria for the systemic inflammatory response syndrome improves their utility following cardiac surgery. Chest. 2014;145(6):1197-1203. 8. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317(11):653-658. 9. Opal SM, Laterre P-F, Francois B, et al; ACCESS Study Group. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013;309(11):1154-1162. 10. Cremer J, Martin M, Redl H, Bahrami S, Abraham C, Graeter T, Haverich A, Schlag G, Borst HG. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg. 1996;61(6):1714-1720. 11. Hirai S. Systemic inflammatory response syndrome after cardiac surgery under cardiopulmonary bypass. Ann Thorac Cardiovasc Surg. 2003;9(6):365-370. 12. Hooper MH, Weavind L, Wheeler AP, et al. Randomized trial of automated, electronic monitoring to facilitate early detection of sepsis in the intensive care unit*. Crit Care Med. 2012; 40(7):2096-2101.
Harm of In Utero Tobacco Smoke Exposure A Heritable Trait? harms of tobacco smoke exposure Thearesubstantial becoming increasingly well documented. In
utero tobacco smoke exposure is associated with an Editorials
physiologic and laboratory abnormalities occurring after a clinical insult. It was widely believed then that both infectious and noninfectious inflammation shared a pathophysiologic basis that might be amenable to early application of common treatments. By proposing the paradigm, his group aimed to (1) improve early detection and intervention, (2) improve prognostic assessment, and (3) standardize enrollment into clinical trials.1 The latter two goals were realized: In patients with SIRS from infection (sepsis), the relationship between an increasing number of SIRS criteria and worse prognosis was confirmed2; SIRS also became part of standard inclusion criteria for clinical trials of sepsis.3,4 However, the utility of SIRS to facilitate sepsis recognition never reached expectations, handicapped by oversensitivity and underspecificity.5,6 Highlighting the shortcomings of SIRS, in 1997, Jean-Louis Vincent5 famously wrote, “Dear SIRS, I’m sorry to say that I don’t like you,” a well-reasoned argument that SIRS did not offer practical help to the clinician. With some hyperbole, naysayers of SIRS point out that even modest exercise causes “SIRS” in healthy individuals. Because of these flaws, many physicians ascribe little importance to a patient meeting SIRS criteria. But is that correct? In this issue of CHEST (see page 1197), MacCallum et al7 make us rethink the predictive value of SIRS, using a large cohort of patients in a single ICU who had undergone cardiac surgery. Patient characteristics, organ dysfunction, outcomes, and detailed data on the number of SIRS criteria met during each hour from ICU admission to death or discharge were prospectively collected. They found the traditional definition of two or more SIRS criteria was met by almost 60% of patients in the first hour after surgery and by . 95% within the first day. The low positive predic-
journal.publications.chestnet.org
Editorials CHEST | Volume 145 | Number 6 | June 2014
tive value (PPV) for mortality associated with meeting two or more SIRS criteria in the first 24 h (PPV, 2.8%) was improved by modifying the definition to meeting three or more or four SIRS criteria (PPV, 4.2% and 10.2%, respectively), or to fulfilling two or more criteria for at least six consecutive hours on the first day (PPV range, 5.4%-7.0%). At first, these low predictive values for mortality might suggest SIRS criteria are not very useful, until one considers that cardiac surgery is rarely fatal, and essentially all patients with poor outcomes could be identified on the first ICU day by applying these reasonably simple modifications of the original SIRS criteria. The study has several limitations. It was conducted at a single center retrospectively. The rapid decrement in patients remaining in the ICU limits conclusions about the SIRS criteria after the first 24 h. Incomplete data regarding on-pump vs off-pump surgery, redo valves, and complex congenital heart disease may confound described predictive characteristics of the SIRS criteria if these factors are independently linked to both increased inflammation and worsened outcomes. Finally, the predictive factors examined in the study all occur after the onset of injury. Therapeutic studies targeting the high-risk subgroup identified in this fashion may encounter the same challenges experienced by therapies initiated after the onset of sepsis.3,8,9 Whether intervention in this population could change outcomes remains to be seen. Beyond enriching our understanding of the relationship between postsurgical inflammation and clinical outcomes suggested by prior investigations,10,11 the authors provide a unique picture of the evolution of SIRS after a discrete injury. Unlike prior studies, their detailed hourly data result from automatic electronic archiving of the output from routine ICU care and clearly demonstrate that prevalence of some SIRS parameters markedly differ over time. Abnormal temperature, seen in 80% of patients in the first hour, had , 10% prevalence at later times. Abnormal respiratory rate, observed in , 20% of patients in the cohort in the first hour, was present in almost three-quarters of cohort patients in the ICU in each hour after the first day. In contrast to the dramatic swings in the prevalence of abnormal temperature
CHEST / 145 / 6 / JUNE 2014
1181
and respiratory rate criteria, heart rate and WBC count criteria stayed abnormal in approximately onehalf of all study patients in the ICU at all times of observation. The availability of data with this level of granularity allows the authors to propose modifications of the SIRS criteria to include the dimension of time, an aspect of assessment routinely used by bedside clinicians but absent from the original SIRS definition. The improvements in predictive value by using the cumulative total hours or maximum number of consecutive hours during which criteria are met are modest, but then so is the deviation from the historical definition. Loosening the constraints further may more dramatically improve our insight into what these markers of inflammation signify. For example, it may be that a fever occurring in the first hour after surgery means something completely different than a fever occurring a day later. Because research into inflammation after cardiac surgery has the unique advantage of knowing “time zero,” the moment of injury, it may ultimately provide a picture of the temporal patterns of physiologic and laboratory abnormalities that will improve our understanding of systemic inflammation in the broader population. Even if the authors’ observations are not generalizable to medical and general surgical patients, their methods certainly are. The ICU environment today produces hundreds to thousands of physiologic, laboratory, and management data points each hour and, as clearly seen in this study, the pattern of injury evolves over time. Accepting this complexity means accepting that a few easy-to-remember criteria evaluated intermittently by a clinician may not compete with complex, computer-applied algorithms of not just the original SIRS criteria12 or the 25 subsequently proposed sepsis criteria,6 but dozens or hundreds of other data points fluctuating over time. Future studies should forgo the limitations of using simple, memorable criteria and instead focus on putting the wealth of electronic data available in the ICU to work to find those patients at risk for adverse outcomes as early and accurately as possible, by any criteria necessary. Matthew W. Semler, MD Arthur P. Wheeler, MD, FCCP Nashville, TN Affiliations: From the Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Wheeler receives National Institutes of Health National Heart, Lung, and Blood Institute grant funding and royalties from a textbook that he coauthored, and serves as a paid consultant to Cumberland Pharmaceuticals Inc. Dr Semler has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Arthur P. Wheeler, MD, FCCP, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt Uni1182
versity Medical Center, T-1210 MCN, Nashville, TN 37232-2650; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0438
References 1. Bone RC, Balk RA, Cerra FB, et al; The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101(6):1644-1655. 2. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995; 273(2):117-123. 3. Abraham E, Wunderink R, Silverman H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA. 1995;273(12):934-941. 4. Bernard GR, Vincent JL, Laterre PF, et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. 5. Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med. 1997;25(2):372-374. 6. Levy MM, Fink MP, Marshall JC, et al; SCCM/ESICM/ ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003; 31(4):1250-1256. 7. MacCallum NS, Finney SJ, Gordon SE, Quinlan GJ, Evans TW. Modified criteria for the systemic inflammatory response syndrome improves their utility following cardiac surgery. Chest. 2014;145(6):1197-1203. 8. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317(11):653-658. 9. Opal SM, Laterre P-F, Francois B, et al; ACCESS Study Group. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013;309(11):1154-1162. 10. Cremer J, Martin M, Redl H, Bahrami S, Abraham C, Graeter T, Haverich A, Schlag G, Borst HG. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg. 1996;61(6):1714-1720. 11. Hirai S. Systemic inflammatory response syndrome after cardiac surgery under cardiopulmonary bypass. Ann Thorac Cardiovasc Surg. 2003;9(6):365-370. 12. Hooper MH, Weavind L, Wheeler AP, et al. Randomized trial of automated, electronic monitoring to facilitate early detection of sepsis in the intensive care unit*. Crit Care Med. 2012; 40(7):2096-2101.
Harm of In Utero Tobacco Smoke Exposure A Heritable Trait? harms of tobacco smoke exposure Thearesubstantial becoming increasingly well documented. In
utero tobacco smoke exposure is associated with an Editorials
