- Email: [email protected]
Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection
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MODEL
Infection, Disease & Health xxx (xxxx) xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.journals.elsevier.com/infectiondisease-and-health/
Research paper
Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection John F. McNamara a,b,*, Minyon Avent a,d, Adam Stewart a, Christopher Kwan a, David L. Paterson a,c a
University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia The Prince Charles Hospital, Brisbane, Queensland, Australia c Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia d Queensland Statewide Antimicrobial Stewardship Program, Queensland, Australia b
Received 5 November 2019; received in revised form 5 January 2020; accepted 6 January 2020
KEYWORDS: Bloodstream infection; Gram negative; qSOFA; SIRS; Antibiotic; Screening
Abstract Background: The quick sequential organ failure assessment (qSOFA) score predicts mortality in patients with suspected infection. We sought to understand how well qSOFA and the Systemic Inflammatory Response Syndrome (SIRS) criteria predict gram negative bacteraemia. Methods: We prospectively evaluated 99 patients with gram negative bloodstream infection from a single tertiary centre. We assessed the utility of SIRS and qSOFA for their rate of positivity and association with early delivery of antibiotics (<3 h). Results: The SIRS criteria had the highest positivity rate amongst patients with gram negative bacteraemia (85%) compared to the qSOFA criteria (25%) on the day of first positive culture. Positive SIRS criteria was the only score associated with delivery of antibiotics within 3 h (Relative risk 3.5, 95% Confidence interval 1.3 to 12.5, p Z < 0.02). Conclusion: In patients with gram negative bloodstream infection SIRS criteria was the most common positive risk score and had a higher association with early delivery of antibiotics when compared to qSOFA. ª 2020 Australasian College for Infection Prevention and Control. Published by Elsevier B.V. All rights reserved.
* Corresponding author. University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia. E-mail address: [email protected] (J.F. McNamara). https://doi.org/10.1016/j.idh.2020.01.003 2468-0451/ª 2020 Australasian College for Infection Prevention and Control. Published by Elsevier B.V. All rights reserved.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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J.F. McNamara et al. Highlights A positive SIRS criteria had the highest association with gram negative bloodstream infection in comparison to qSOFA. A positive SIRS criteria was also associated with delivery of antibiotics within 3 hours of culture collection Positive SIRS criteria provided a better early identification tool than qSOFA for gram negative bacteraemia.
Introduction Early recognition of patients with infections that have progressed to systemic involvement is essential to providing timely treatment [9]. The recognition of sepsis is difficult given its sometimes subtle clinical presentation [10]. Clinical risk scores serve as a prompt to consider sepsis in unwell patients and facilitate early appropriate care. The Sepsis-3 guideline proposed the quick Sequential Organ Failure Assessment (qSOFA) as a replacement for the systemic inflammatory response syndrome (SIRS) criteria which was deemed to have poor sensitivity and specificity in patients with sepsis [1]. It recommended qSOFA criteria should prompt clinicians to consider infection in patients not previously recognised as infected [2]. qSOFA has subsequently been shown to have a low sensitivity for identifying suspected infection when compared to hospital coding data for sepsis [3,4]. Gram negative bacteraemia has for a long time been considered synonymous with sepsis [5,6]. The estimated 28e30 day mortality from gram negative bloodstream infection is between 3.7 and 27% [7,8]. We sought to evaluate the SIRS and qSOFA criteria in patients who had blood cultures collected on the suspicion of infection, which was subsequently demonstrated to be positive for gram negative bacteria. We further evaluated the time to antibiotic delivery from the time the culture was drawn relative to SIRS and qSOFA scores.
Methods This was a pilot observational study. All procedures followed were in accordance with the ethical standards of the Royal Brisbane and Women’s Hospital Human Ethics Review Board (Herston, Australia) approval number was HREC/11/ QRBW/257. All participants were 18 years of age or over and provided informed consent for participation in the study. During the period between January 2013 and March 2016 patients with gram-negative bacteria identified in a blood culture, were screened for eligibility and offered the opportunity to consent to participate in the study. The inclusion criteria: was the presence of gram negative bacteria identified in a blood culture, appropriate empirical antibiotics (ampicillin, piperacillin-tazobactam, ticarcillin-clavulanate, meropenem, ciprofloxacin,
ceftriaxone or an aminoglycoside) and consent within 72 h of culture collection. The exclusion criteria were: age less than 18 years, pregnancy, enrolled in a concurrent clinical trial, unable to provide consent, in palliative care, presence of a line related infection (defined as a patient with the same gram-negative organism isolated both from the line and peripheral blood culture), polymicrobial bloodstream infection, undergoing transfer to another hospital or receiving renal replacement therapy. Written consent was obtained from the patient or their substitute decision maker prior to being enrolled in the study. Acquisition of infection was defined as: hospital, healthcare associated or community acquired [11]. Hospital acquired bacteraemia was defined as occurring 48 h or more after admission and did not appear to be incubating at the time of admission. Healthcare associated was defined as bacteraemia that occurs in a previously non-hospitalized patient with extensive healthcare contact, as defined by one or more of the following: intravenous therapy, wound care, or intravenous chemotherapy within the prior 30 days, residence in a nursing home or other long-term care facility, hospitalization in an acute care hospital for two or more days within the prior 90 days or attendance at a hospital or haemodialysis clinic within the prior 30 days. Community acquired was defined as bacteraemia that occurred in individuals out of hospital (or have been in hospital for less than 48 h) and who are not significantly immunocompromised. Physiological and biochemical indices were collected during the first 7 days following the first positive blood culture. SIRS scores were evaluated prospectively and qSOFA scores were derived retrospectively from the previously collected physiological data (see appendix 1 for risk scores). The primary outcome was the proportion of patients with two or more SIRS and/or qSOFA criteria which defined a positive risk score. Participants who were discharged during the first 7 days following blood culture were assumed to have had normalisation of physiological indices. For any missing repeated variable used to define clinical resolution (e.g. daily white blood cell count), the last observation was carried forward until a new observation was recorded. Time to antibiotics was measured from the collection time of the first positive blood culture and expressed as either 3 h or <3 h and evaluated for association with positive risk score (qSOFA or SIRS) with Pearson’s Chi Squared or Fischer’s exact test as appropriate.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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qSOFA and SIRS in gram negative bloodstream infection.
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Figure. 1 Patient flow diagram describing the number of patients screened, those meeting exclusion criteria, the number of remaining patients which were eligible to participate and those who consented to participate.
Results In our study, 222 individuals with gram negative bloodstream infection were screened and 110 were eligible to participate. All 110 were approached to participate of which 99 consented as described in Fig. 1. The average age of the participants was 58 years (interquartile range 49e67 years). There were 36 females and 63 males included in the study. Median Charlson comorbidity score was 2 (interquartile 0 to 3 range). Patient characteristics are described in Table 1. The infections were acquired in hospital (48 of 99, 48%), community (34 of 99, 34%) and healthcare associated (17 of 99, 17%).
Table 1 Patient characteristics describing patients included in the study’s baseline characteristics, and source of acquisition. Patient characteristics
Counts
Age Median Average Range
60 58 21 to 94
Male Female
63 36
Charlson Comorbidity Index 0 1 2 3 or more
29 13 20 37
Acquisition Community Healthcare Associated Hospital Acquired
34 17 48
Haematology patient
25
The most common pathogen isolated from blood culture was Escherichia coli (45 of 99 blood cultures, 45%) with the most common focus of infection being the urinary tract (28 of 99 episodes, 28%), 21 of the urinary tract infections cultured E. coli. The type and frequency of gram negative bacteria causing infection and the presumed source of infection for the remaining episodes are described in Table 2. The proportion of participants that scored 2 or more for SIRS on day 1 was 85% compared to qSOFA which was positive in 25%. There was 15% of participants with a negative SIRS score on day 1 (0 or 1 SIRS criteria), 42% of those had 2 or more SIRS criteria by day 2. Of the 75% participants with a negative qSOFA score on day 1 (0 or 1) only an additional 9% had a positive qSOFA by day 2. The cumulative positive scoring of each of the scores is described in Fig. 2. Community, healthcare associated and hospital acquired BSI when assessed as subgroups showed similar rates of positive risk scores (SIRS positive: community 85%, healthcare 82%, hospital 85% and qSOFA positive: community 24%, healthcare 24%, hospital 27%). We assessed patients who were not on antibiotics at the time of blood culture collection and assessed the association of a positive risk score with delivery of antibiotics within 3 h. Positive SIRS criteria was the only score associated with delivery of antibiotics within 3 h (p Z 0.02) as shown in Fig. 3. The total mortality at 28 days in the cohort was 4% (n Z 4) and the median length of hospital stay following the positive blood culture was 9 days (average 17 days, interquartile range 5e17 days). All deaths had positive SIRS criteria on day one. qSOFA scores were positive in two of the four deaths on day one. There were two participants with missing 28-day mortality data.
Discussion This study assessed sepsis risk scores capacity to alert the clinician to the presence of a serious infection - gramnegative bloodstream infection. No scoring system identified all gram-negative bloodstream infections as at risk,
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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J.F. McNamara et al. Table 2 Table of pathogens isolated from patients included in the study and the presumed source of infection associated with bloodstream infection represents as counts. Pathogen
UTI
Unknown
Biliary
Linea
E.coli P.aeruginosa K.pneumoniae E.cloacae P.mirabillis E.aerogenes S.marcescens M.morganii K.oxytoca H.influenzae M.osloensis E.tarda A.baumannii Enterobacteraciae N.meningititis Polymicrobial Percentage source of infection
21 2 1
6 4 3 5
8 1 2
1 1 4 3 1 2
3
1
1
LRTI
Intra-abdominal
Wound
Post-partum
5
1
2
3 1
Misc.b 3
1
1 1
1 1 1
1 1 1 1
28
1 1 24
13
12
5
7
3
2
3
UTI Z urinary tract infection, LRTI Z lower respiratory tract infection a These infections were suspected to be line infections by the treating clinicians but did not meet full clinical criteria for a line related infection used as an exclusion criteria b 2 burns and 1 infusion related infection
Figure. 2 Cumulative proportion of gram negative BSI measuring as at risk by SIRS and qSOFA each day following first positive blood culture. Data is represented as counts with proportion of positive scoring participants represented on the y axis. Counts for each day for each risk score are displayed beneath.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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qSOFA and SIRS in gram negative bloodstream infection.
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Figure. 3 Association of positive risk scores with delivery of antibiotics within 3 h of blood culture collection. Blood culture collection time used as a marker of clinical suspicion of serious infection. Associations are represented as relative risk for antibiotic receipt within 3 h of culture collection, with 95% confidence interval and p value according to Fischer’s exact test. a) Systemic inflammatory response syndrome b) Quick sequential organ failure assessment. Histogram bars represent number of patients within each category.
though the SIRS criteria was the most commonly positive (85%) compared to qSOFA (25%). Mortality in the cohort was 4% at 28 days and was consistent with previous Australian studies of gram negative bloodstream infection [7]. A positive risk score by SIRS criteria on day one was present in all deaths. Prior studies examining the performance of have done so in large populations relying on the presumptive diagnosis of infection or defining sepsis according to hospital coding data. The diagnosis of infection in this context may be confounded by a positive physiological risk score. In these studies SIRS criteria has been shown to be sensitive rather than specific when compared to qSOFA for identifying patients with a clinical diagnosis of sepsis [3,4]. The differing sensitivity of the instruments may reflect the trajectory of the patient’s response to a systemic infection. The inflammatory (white cell count >12 or 10% immature bands) response occurs in response to the invading pathogen resulting in fever followed by alteration in the hypothalamic set point triggering skeletal muscle contractions to produce additional heat (rigours). Tachypnoea occurs partly from increased activation of the respiratory centre and a need to offset metabolic acidosis. Tachycardia (>90 bpm) to maintain perfusion in response to vasodilatation, reduced cardiac contractility and volume loss due to third spacing [12]. These compensatory mechanisms represented in the SIRS criteria occur in an attempt to mitigate physiological disaster. Failure of compensatory
mechanisms result in progression to sustained hypoperfusion at the capillary bed, hypotension and progressive altered level of consciousness. Failure of these compensatory mechanisms is reflected in the positive qSOFA criteria: altered level of consciousness and hypotension. The time to meet qSOFA criteria has been shown to be significantly longer than SIRS consistent with progression from compensatory physiology to failure [4]. We hypothesize that for most patients with gram negative bloodstream infection the compensatory mechanisms reflected in the SIRS criteria would occur early and the failure of compensation (ie hypotension and altered consciousness) reflected in qSOFA would occur late. In our cohort, a positive SIRS criteria had the strongest association with receipt of antibiotics within 3 h from culture collection (surrogate of suspected infection) in those patients not already on antibiotics at the time of collection. Part of this may be due to the widespread application of the SIRS criteria and a clinician’s familiarity with it as a marker of sepsis. However, the low capture rate of the qSOFA criteria (25% positive qSOFA on day of culture collection) would limit its efficacy to trigger early antibiotics in systemic infection at risk of subsequent organ failure. Early identification of sepsis is the first step towards timely delivery of antibiotics in patients at risk of poor outcomes and a sensitive risk assessment tool potentially provides benefits in early warning, although this may come with a decrease in diagnostic accuracy [13].
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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6 The strength of our study is the prospective, patient level examination of SIRS and qSOFA in patients who have a definitive rather than a presumptive or suspected diagnosis of infection. This study had a number of limitations. In the absence of a control group (ie., positive risk score and a negative blood culture) we were unable to assess specificity. The small prospective cohort in a single centre did not allow us to investigate the impact of co-morbidities or age on the likelihood of a positive risk score. Our study may not be representative of the larger population with severe infections due to ascertainment bias. The low mortality limits interrogation of mortality relative to risk scores. International guidelines have recommended aiming for a delivery target of 1 h to patient with sepsis [9]. We chose to evaluate antibiotic delivery within 3 h as we felt this better reflected what was achievable in clinical practice [13,14].
J.F. McNamara et al. Pharmaceuticals, personal fees from Bayer, personal fees from GlazoSmithKline, personal fees from Cubist, personal fees from Venatorx, personal fees from Accelerate, grants from Shionogi, grants from Merck (MSD), personal fees from Pfizer, outside the submitted work;.
Funding This study received no specific funding.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.idh.2020.01.003.
References Conclusion qSOFA was positive in 1 of 4 g negative bloodstream infections suggesting it lacks suitable sensitivity to serve as a replacement for the SIRS criteria as a screening test. Earlier suspicion of infection and initiation of antibiotics is more likely to occur with the SIRS criteria.
Ethics All procedures followed were in accordance with the ethical standards of the Royal Brisbane and Women’s Hospital Human Ethics Review Board (Herston, Australia) approval number was HREC/11/QRBW/257.
Authorship statement DP, JM and MA conceptualised and designed the project. AS, CK, MA and JM collected and curated the data. JM and DP conducted the formal analysis of the paper. JM provided the original draft. MA, AS, CK and DP drafted and revised the manuscript. All authors should have made substantial contributions to all of the following [1]: the conception and design of the study, or acquisition of data, or analysis and interpretation of data [2], drafting the article or revising it critically for important intellectual content [3], final approval of the version to be submitted.
Declaration of Competing Interest Dr. McNamara has nothing to disclose. Dr. Avent has nothing to disclose. Dr. Stewart has nothing to disclose. Dr. Kwan has nothing to disclose. Dr. Paterson reports grants from National Health and Medical Research Council, non-financial support from Ecolab Pty Ltd, non-financial support from Whiteley Corporation, non-financial support from Kimberly-Clark Professional, during the conduct of the study; personal fees from Merck, personal fees from Shionogi, personal fees from Achaogen, personal fees from AstraZeneca, personal fees from Leo
[1] Freund Y, Lemachatti N, Krastinova E, Van Laer M, Claessens YE, Avondo A, et al. Prognostic accuracy of sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. J Am Med Assoc 2017 Jan 17;317(3):301e8. 2017. [2] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). J Am Med Assoc 2016 Feb 23;315(8):801 [Internet] [cited 2018 Nov 5]. Available from: http://jama.jamanetwork.com/article.aspx? doiZ10.1001/jama.2016.0287. [3] Anand V, Zhang Z, Kadri SS, Klompas M, Rhee C, CDC Prevention Epicenters Program. Epidemiology of quick sequential organ failure assessment criteria in undifferentiated patients and association with suspected infection and sepsis. Chest 2019 Aug;156(2):289e97 [Internet] [cited 2019 Dec 31]. Available from: https://linkinghub.elsevier.com/retrieve/pii/ S0012369219308219. [4] Haydar S, Spanier M, Weems P, Wood SST. Comparison of QSOFA score and SIRS criteria as screening mechanisms for emergency department sepsis. Am J Emerg Med 2017 Nov; 35(11):1730e3. 2017. [5] Waisbren BA. Bacteremia due to gram-negative bacilli other than the Salmonella; a clinical and therapeutic study. AMA Arch Intern Med 1951;88(4):467e88. [6] Coombs G, Bell JM, Daley D, Collignon P, Cooley L, Gottlieb T, et al. Sepsis outcome programs 2016 report. Aust Comm Qual Saf Heal Care; 2016. [7] Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, et al. Effect of piperacillin-tazobactam vs meropenem on 30day mortality for patients with e coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance. JAMA, J Am Med Assoc 2018 Sep 11;320(10):984e94 [Internet] [cited 2018 Dec 8]. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/30208454. [8] Al Hasan MN, Juhn YJ, Bang DW, Yang H-J, Baddour LM. External validation of bloodstream infection mortality risk score in a population-based cohort. Clin Microbiol Infect 2014 Sep;20(9):886e91 [Internet] [cited 2019 Apr 7]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1198743 X1465093X. [9] Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017 Mar 18;43(3):304e77 [Internet] [cited 2017 Aug 21]Available from: http://www.ncbi.nlm.nih.gov/ pubmed/28101605.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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qSOFA and SIRS in gram negative bloodstream infection. [10] Kaukonen KM, Bailey M, Pilcher D, Cooper DJBR. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015;372(17):1629e38. [11] Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002 Nov 19; 137(10):791e7 [Internet] [cited 2019 Mar 27]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12435215. [12] Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, Kurosawa S, Stepien D, Valentine CRD. Sepsis: multiple
7 abnormalities, heterogeneous responses, and evolving understanding. Physiol Rev 2013;93(3):1247e88. [13] Welker JA, Huston M, McCue JD. Antibiotic timing and errors in diagnosing pneumonia. Arch Intern Med 2008 Feb 25;168(4): 351e6 [cited 2017 Aug 21] [Internet]. Available from: http:// archinte.jamanetwork.com/article.aspx?doiZ10.1001/ archinternmed.2007.84. [14] Amaral AC, Fowler RA, Pinto R, Rubenfeld GD, Ellis P, Bookatz B, et al. Patient and organizational factors associated with delays in antimicrobial therapy for septic shock. Crit Care Med 2016;44(12):2145e53.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
MODEL
Infection, Disease & Health xxx (xxxx) xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.journals.elsevier.com/infectiondisease-and-health/
Research paper
Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection John F. McNamara a,b,*, Minyon Avent a,d, Adam Stewart a, Christopher Kwan a, David L. Paterson a,c a
University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia The Prince Charles Hospital, Brisbane, Queensland, Australia c Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia d Queensland Statewide Antimicrobial Stewardship Program, Queensland, Australia b
Received 5 November 2019; received in revised form 5 January 2020; accepted 6 January 2020
KEYWORDS: Bloodstream infection; Gram negative; qSOFA; SIRS; Antibiotic; Screening
Abstract Background: The quick sequential organ failure assessment (qSOFA) score predicts mortality in patients with suspected infection. We sought to understand how well qSOFA and the Systemic Inflammatory Response Syndrome (SIRS) criteria predict gram negative bacteraemia. Methods: We prospectively evaluated 99 patients with gram negative bloodstream infection from a single tertiary centre. We assessed the utility of SIRS and qSOFA for their rate of positivity and association with early delivery of antibiotics (<3 h). Results: The SIRS criteria had the highest positivity rate amongst patients with gram negative bacteraemia (85%) compared to the qSOFA criteria (25%) on the day of first positive culture. Positive SIRS criteria was the only score associated with delivery of antibiotics within 3 h (Relative risk 3.5, 95% Confidence interval 1.3 to 12.5, p Z < 0.02). Conclusion: In patients with gram negative bloodstream infection SIRS criteria was the most common positive risk score and had a higher association with early delivery of antibiotics when compared to qSOFA. ª 2020 Australasian College for Infection Prevention and Control. Published by Elsevier B.V. All rights reserved.
* Corresponding author. University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia. E-mail address: [email protected] (J.F. McNamara). https://doi.org/10.1016/j.idh.2020.01.003 2468-0451/ª 2020 Australasian College for Infection Prevention and Control. Published by Elsevier B.V. All rights reserved.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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J.F. McNamara et al. Highlights A positive SIRS criteria had the highest association with gram negative bloodstream infection in comparison to qSOFA. A positive SIRS criteria was also associated with delivery of antibiotics within 3 hours of culture collection Positive SIRS criteria provided a better early identification tool than qSOFA for gram negative bacteraemia.
Introduction Early recognition of patients with infections that have progressed to systemic involvement is essential to providing timely treatment [9]. The recognition of sepsis is difficult given its sometimes subtle clinical presentation [10]. Clinical risk scores serve as a prompt to consider sepsis in unwell patients and facilitate early appropriate care. The Sepsis-3 guideline proposed the quick Sequential Organ Failure Assessment (qSOFA) as a replacement for the systemic inflammatory response syndrome (SIRS) criteria which was deemed to have poor sensitivity and specificity in patients with sepsis [1]. It recommended qSOFA criteria should prompt clinicians to consider infection in patients not previously recognised as infected [2]. qSOFA has subsequently been shown to have a low sensitivity for identifying suspected infection when compared to hospital coding data for sepsis [3,4]. Gram negative bacteraemia has for a long time been considered synonymous with sepsis [5,6]. The estimated 28e30 day mortality from gram negative bloodstream infection is between 3.7 and 27% [7,8]. We sought to evaluate the SIRS and qSOFA criteria in patients who had blood cultures collected on the suspicion of infection, which was subsequently demonstrated to be positive for gram negative bacteria. We further evaluated the time to antibiotic delivery from the time the culture was drawn relative to SIRS and qSOFA scores.
Methods This was a pilot observational study. All procedures followed were in accordance with the ethical standards of the Royal Brisbane and Women’s Hospital Human Ethics Review Board (Herston, Australia) approval number was HREC/11/ QRBW/257. All participants were 18 years of age or over and provided informed consent for participation in the study. During the period between January 2013 and March 2016 patients with gram-negative bacteria identified in a blood culture, were screened for eligibility and offered the opportunity to consent to participate in the study. The inclusion criteria: was the presence of gram negative bacteria identified in a blood culture, appropriate empirical antibiotics (ampicillin, piperacillin-tazobactam, ticarcillin-clavulanate, meropenem, ciprofloxacin,
ceftriaxone or an aminoglycoside) and consent within 72 h of culture collection. The exclusion criteria were: age less than 18 years, pregnancy, enrolled in a concurrent clinical trial, unable to provide consent, in palliative care, presence of a line related infection (defined as a patient with the same gram-negative organism isolated both from the line and peripheral blood culture), polymicrobial bloodstream infection, undergoing transfer to another hospital or receiving renal replacement therapy. Written consent was obtained from the patient or their substitute decision maker prior to being enrolled in the study. Acquisition of infection was defined as: hospital, healthcare associated or community acquired [11]. Hospital acquired bacteraemia was defined as occurring 48 h or more after admission and did not appear to be incubating at the time of admission. Healthcare associated was defined as bacteraemia that occurs in a previously non-hospitalized patient with extensive healthcare contact, as defined by one or more of the following: intravenous therapy, wound care, or intravenous chemotherapy within the prior 30 days, residence in a nursing home or other long-term care facility, hospitalization in an acute care hospital for two or more days within the prior 90 days or attendance at a hospital or haemodialysis clinic within the prior 30 days. Community acquired was defined as bacteraemia that occurred in individuals out of hospital (or have been in hospital for less than 48 h) and who are not significantly immunocompromised. Physiological and biochemical indices were collected during the first 7 days following the first positive blood culture. SIRS scores were evaluated prospectively and qSOFA scores were derived retrospectively from the previously collected physiological data (see appendix 1 for risk scores). The primary outcome was the proportion of patients with two or more SIRS and/or qSOFA criteria which defined a positive risk score. Participants who were discharged during the first 7 days following blood culture were assumed to have had normalisation of physiological indices. For any missing repeated variable used to define clinical resolution (e.g. daily white blood cell count), the last observation was carried forward until a new observation was recorded. Time to antibiotics was measured from the collection time of the first positive blood culture and expressed as either 3 h or <3 h and evaluated for association with positive risk score (qSOFA or SIRS) with Pearson’s Chi Squared or Fischer’s exact test as appropriate.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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qSOFA and SIRS in gram negative bloodstream infection.
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Figure. 1 Patient flow diagram describing the number of patients screened, those meeting exclusion criteria, the number of remaining patients which were eligible to participate and those who consented to participate.
Results In our study, 222 individuals with gram negative bloodstream infection were screened and 110 were eligible to participate. All 110 were approached to participate of which 99 consented as described in Fig. 1. The average age of the participants was 58 years (interquartile range 49e67 years). There were 36 females and 63 males included in the study. Median Charlson comorbidity score was 2 (interquartile 0 to 3 range). Patient characteristics are described in Table 1. The infections were acquired in hospital (48 of 99, 48%), community (34 of 99, 34%) and healthcare associated (17 of 99, 17%).
Table 1 Patient characteristics describing patients included in the study’s baseline characteristics, and source of acquisition. Patient characteristics
Counts
Age Median Average Range
60 58 21 to 94
Male Female
63 36
Charlson Comorbidity Index 0 1 2 3 or more
29 13 20 37
Acquisition Community Healthcare Associated Hospital Acquired
34 17 48
Haematology patient
25
The most common pathogen isolated from blood culture was Escherichia coli (45 of 99 blood cultures, 45%) with the most common focus of infection being the urinary tract (28 of 99 episodes, 28%), 21 of the urinary tract infections cultured E. coli. The type and frequency of gram negative bacteria causing infection and the presumed source of infection for the remaining episodes are described in Table 2. The proportion of participants that scored 2 or more for SIRS on day 1 was 85% compared to qSOFA which was positive in 25%. There was 15% of participants with a negative SIRS score on day 1 (0 or 1 SIRS criteria), 42% of those had 2 or more SIRS criteria by day 2. Of the 75% participants with a negative qSOFA score on day 1 (0 or 1) only an additional 9% had a positive qSOFA by day 2. The cumulative positive scoring of each of the scores is described in Fig. 2. Community, healthcare associated and hospital acquired BSI when assessed as subgroups showed similar rates of positive risk scores (SIRS positive: community 85%, healthcare 82%, hospital 85% and qSOFA positive: community 24%, healthcare 24%, hospital 27%). We assessed patients who were not on antibiotics at the time of blood culture collection and assessed the association of a positive risk score with delivery of antibiotics within 3 h. Positive SIRS criteria was the only score associated with delivery of antibiotics within 3 h (p Z 0.02) as shown in Fig. 3. The total mortality at 28 days in the cohort was 4% (n Z 4) and the median length of hospital stay following the positive blood culture was 9 days (average 17 days, interquartile range 5e17 days). All deaths had positive SIRS criteria on day one. qSOFA scores were positive in two of the four deaths on day one. There were two participants with missing 28-day mortality data.
Discussion This study assessed sepsis risk scores capacity to alert the clinician to the presence of a serious infection - gramnegative bloodstream infection. No scoring system identified all gram-negative bloodstream infections as at risk,
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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J.F. McNamara et al. Table 2 Table of pathogens isolated from patients included in the study and the presumed source of infection associated with bloodstream infection represents as counts. Pathogen
UTI
Unknown
Biliary
Linea
E.coli P.aeruginosa K.pneumoniae E.cloacae P.mirabillis E.aerogenes S.marcescens M.morganii K.oxytoca H.influenzae M.osloensis E.tarda A.baumannii Enterobacteraciae N.meningititis Polymicrobial Percentage source of infection
21 2 1
6 4 3 5
8 1 2
1 1 4 3 1 2
3
1
1
LRTI
Intra-abdominal
Wound
Post-partum
5
1
2
3 1
Misc.b 3
1
1 1
1 1 1
1 1 1 1
28
1 1 24
13
12
5
7
3
2
3
UTI Z urinary tract infection, LRTI Z lower respiratory tract infection a These infections were suspected to be line infections by the treating clinicians but did not meet full clinical criteria for a line related infection used as an exclusion criteria b 2 burns and 1 infusion related infection
Figure. 2 Cumulative proportion of gram negative BSI measuring as at risk by SIRS and qSOFA each day following first positive blood culture. Data is represented as counts with proportion of positive scoring participants represented on the y axis. Counts for each day for each risk score are displayed beneath.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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qSOFA and SIRS in gram negative bloodstream infection.
5
Figure. 3 Association of positive risk scores with delivery of antibiotics within 3 h of blood culture collection. Blood culture collection time used as a marker of clinical suspicion of serious infection. Associations are represented as relative risk for antibiotic receipt within 3 h of culture collection, with 95% confidence interval and p value according to Fischer’s exact test. a) Systemic inflammatory response syndrome b) Quick sequential organ failure assessment. Histogram bars represent number of patients within each category.
though the SIRS criteria was the most commonly positive (85%) compared to qSOFA (25%). Mortality in the cohort was 4% at 28 days and was consistent with previous Australian studies of gram negative bloodstream infection [7]. A positive risk score by SIRS criteria on day one was present in all deaths. Prior studies examining the performance of have done so in large populations relying on the presumptive diagnosis of infection or defining sepsis according to hospital coding data. The diagnosis of infection in this context may be confounded by a positive physiological risk score. In these studies SIRS criteria has been shown to be sensitive rather than specific when compared to qSOFA for identifying patients with a clinical diagnosis of sepsis [3,4]. The differing sensitivity of the instruments may reflect the trajectory of the patient’s response to a systemic infection. The inflammatory (white cell count >12 or 10% immature bands) response occurs in response to the invading pathogen resulting in fever followed by alteration in the hypothalamic set point triggering skeletal muscle contractions to produce additional heat (rigours). Tachypnoea occurs partly from increased activation of the respiratory centre and a need to offset metabolic acidosis. Tachycardia (>90 bpm) to maintain perfusion in response to vasodilatation, reduced cardiac contractility and volume loss due to third spacing [12]. These compensatory mechanisms represented in the SIRS criteria occur in an attempt to mitigate physiological disaster. Failure of compensatory
mechanisms result in progression to sustained hypoperfusion at the capillary bed, hypotension and progressive altered level of consciousness. Failure of these compensatory mechanisms is reflected in the positive qSOFA criteria: altered level of consciousness and hypotension. The time to meet qSOFA criteria has been shown to be significantly longer than SIRS consistent with progression from compensatory physiology to failure [4]. We hypothesize that for most patients with gram negative bloodstream infection the compensatory mechanisms reflected in the SIRS criteria would occur early and the failure of compensation (ie hypotension and altered consciousness) reflected in qSOFA would occur late. In our cohort, a positive SIRS criteria had the strongest association with receipt of antibiotics within 3 h from culture collection (surrogate of suspected infection) in those patients not already on antibiotics at the time of collection. Part of this may be due to the widespread application of the SIRS criteria and a clinician’s familiarity with it as a marker of sepsis. However, the low capture rate of the qSOFA criteria (25% positive qSOFA on day of culture collection) would limit its efficacy to trigger early antibiotics in systemic infection at risk of subsequent organ failure. Early identification of sepsis is the first step towards timely delivery of antibiotics in patients at risk of poor outcomes and a sensitive risk assessment tool potentially provides benefits in early warning, although this may come with a decrease in diagnostic accuracy [13].
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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6 The strength of our study is the prospective, patient level examination of SIRS and qSOFA in patients who have a definitive rather than a presumptive or suspected diagnosis of infection. This study had a number of limitations. In the absence of a control group (ie., positive risk score and a negative blood culture) we were unable to assess specificity. The small prospective cohort in a single centre did not allow us to investigate the impact of co-morbidities or age on the likelihood of a positive risk score. Our study may not be representative of the larger population with severe infections due to ascertainment bias. The low mortality limits interrogation of mortality relative to risk scores. International guidelines have recommended aiming for a delivery target of 1 h to patient with sepsis [9]. We chose to evaluate antibiotic delivery within 3 h as we felt this better reflected what was achievable in clinical practice [13,14].
J.F. McNamara et al. Pharmaceuticals, personal fees from Bayer, personal fees from GlazoSmithKline, personal fees from Cubist, personal fees from Venatorx, personal fees from Accelerate, grants from Shionogi, grants from Merck (MSD), personal fees from Pfizer, outside the submitted work;.
Funding This study received no specific funding.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.idh.2020.01.003.
References Conclusion qSOFA was positive in 1 of 4 g negative bloodstream infections suggesting it lacks suitable sensitivity to serve as a replacement for the SIRS criteria as a screening test. Earlier suspicion of infection and initiation of antibiotics is more likely to occur with the SIRS criteria.
Ethics All procedures followed were in accordance with the ethical standards of the Royal Brisbane and Women’s Hospital Human Ethics Review Board (Herston, Australia) approval number was HREC/11/QRBW/257.
Authorship statement DP, JM and MA conceptualised and designed the project. AS, CK, MA and JM collected and curated the data. JM and DP conducted the formal analysis of the paper. JM provided the original draft. MA, AS, CK and DP drafted and revised the manuscript. All authors should have made substantial contributions to all of the following [1]: the conception and design of the study, or acquisition of data, or analysis and interpretation of data [2], drafting the article or revising it critically for important intellectual content [3], final approval of the version to be submitted.
Declaration of Competing Interest Dr. McNamara has nothing to disclose. Dr. Avent has nothing to disclose. Dr. Stewart has nothing to disclose. Dr. Kwan has nothing to disclose. Dr. Paterson reports grants from National Health and Medical Research Council, non-financial support from Ecolab Pty Ltd, non-financial support from Whiteley Corporation, non-financial support from Kimberly-Clark Professional, during the conduct of the study; personal fees from Merck, personal fees from Shionogi, personal fees from Achaogen, personal fees from AstraZeneca, personal fees from Leo
[1] Freund Y, Lemachatti N, Krastinova E, Van Laer M, Claessens YE, Avondo A, et al. Prognostic accuracy of sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. J Am Med Assoc 2017 Jan 17;317(3):301e8. 2017. [2] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). J Am Med Assoc 2016 Feb 23;315(8):801 [Internet] [cited 2018 Nov 5]. Available from: http://jama.jamanetwork.com/article.aspx? doiZ10.1001/jama.2016.0287. [3] Anand V, Zhang Z, Kadri SS, Klompas M, Rhee C, CDC Prevention Epicenters Program. Epidemiology of quick sequential organ failure assessment criteria in undifferentiated patients and association with suspected infection and sepsis. Chest 2019 Aug;156(2):289e97 [Internet] [cited 2019 Dec 31]. Available from: https://linkinghub.elsevier.com/retrieve/pii/ S0012369219308219. [4] Haydar S, Spanier M, Weems P, Wood SST. Comparison of QSOFA score and SIRS criteria as screening mechanisms for emergency department sepsis. Am J Emerg Med 2017 Nov; 35(11):1730e3. 2017. [5] Waisbren BA. Bacteremia due to gram-negative bacilli other than the Salmonella; a clinical and therapeutic study. AMA Arch Intern Med 1951;88(4):467e88. [6] Coombs G, Bell JM, Daley D, Collignon P, Cooley L, Gottlieb T, et al. Sepsis outcome programs 2016 report. Aust Comm Qual Saf Heal Care; 2016. [7] Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, et al. Effect of piperacillin-tazobactam vs meropenem on 30day mortality for patients with e coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance. JAMA, J Am Med Assoc 2018 Sep 11;320(10):984e94 [Internet] [cited 2018 Dec 8]. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/30208454. [8] Al Hasan MN, Juhn YJ, Bang DW, Yang H-J, Baddour LM. External validation of bloodstream infection mortality risk score in a population-based cohort. Clin Microbiol Infect 2014 Sep;20(9):886e91 [Internet] [cited 2019 Apr 7]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1198743 X1465093X. [9] Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017 Mar 18;43(3):304e77 [Internet] [cited 2017 Aug 21]Available from: http://www.ncbi.nlm.nih.gov/ pubmed/28101605.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003
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qSOFA and SIRS in gram negative bloodstream infection. [10] Kaukonen KM, Bailey M, Pilcher D, Cooper DJBR. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015;372(17):1629e38. [11] Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002 Nov 19; 137(10):791e7 [Internet] [cited 2019 Mar 27]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12435215. [12] Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, Kurosawa S, Stepien D, Valentine CRD. Sepsis: multiple
7 abnormalities, heterogeneous responses, and evolving understanding. Physiol Rev 2013;93(3):1247e88. [13] Welker JA, Huston M, McCue JD. Antibiotic timing and errors in diagnosing pneumonia. Arch Intern Med 2008 Feb 25;168(4): 351e6 [cited 2017 Aug 21] [Internet]. Available from: http:// archinte.jamanetwork.com/article.aspx?doiZ10.1001/ archinternmed.2007.84. [14] Amaral AC, Fowler RA, Pinto R, Rubenfeld GD, Ellis P, Bookatz B, et al. Patient and organizational factors associated with delays in antimicrobial therapy for septic shock. Crit Care Med 2016;44(12):2145e53.
Please cite this article as: McNamara JF et al., Evaluation of quick sequential organ failure assessment and systemic inflammatory response syndrome in patients with gram negative bloodstream infection, Infection, Disease & Health, https://doi.org/10.1016/ j.idh.2020.01.003