Attributable Mortality of Central Line Associated Bloodstream Infection: Systematic Review and Meta-Analysis

Infection DOI 10.1007/s15010-014-0689-y

ORIGINAL PAPER

Attributable mortality of central line associated bloodstream infection: systematic review and meta-analysis

Matthew J. Ziegler • Daniela C. Pellegrini • Nasia Safdar

Received: 15 July 2014 / Accepted: 6 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract 2.75 (CI 1.86–4.07) and 1.51 (CI 1.08–2.09) in the sub- Purpose To identify the attributable mortality of central group of the ten matched studies. Those studies where line associated blood stream infections (CLABSI) through greater than 30 % of CLABSI were attributed to coagulase- meta-analysis. negative Staphylococcus had an odds ratio of death of 1.64 Methods Meta-analysis of case control and cohort stud- (95 % CI 1.02–2.65) compared with 4.71 (95 % CI ies, matched and unmatched, that reported on mortality of 1.54–14.39). patients with and without CLABSI was performed. MED- Conclusions CLABSI is associated with a significantly LINE, CENTRAL, CINAHL were searched. Non-inter- increased risk of death supporting the use of extensive ventional studies of all languages that reported mortality in efforts to reduce these infections. patients with CLABSI were included. Data were extracted on patient population, study setting, design, diagnostic Keywords Central line infection Á Mortality Á Intensive criteria for CLABSI, and mortality. Results from studies care unit Á Nosocomial infection comparing mortality due to CLABSI were pooled using a random effects model with assessment of heterogeneity. Heterogeneity of studies was assessed with an I2 statistic Introduction and a funnel plot was generated to assess for publication bias. Central line associated blood stream infections (CLABSI) Results Eighteen studies were included with 1,976 is increasingly recognized as a preventable health care CLABSI cases. Of the included studies, 17 took place in associated infection [1]. As of October 2008, the United intensive care unit settings, most involved a mixed popu- States Centers for Medicare and Medicaid Services has lation of medical and surgical patients, and ten were mat- ceased to reimburse healthcare institutions for these com- ched using an illness severity index. Our findings show an plications, driving home the need for effective strategies to odds ratio of in hospital death associated with CLABSI as prevent CLABSI [2, 3]. While it is clear that CLABSI have a number of adverse consequences such as increased antibiotic exposure for M. J. Ziegler Á D. C. Pellegrini Á N. Safdar treatment, length of stay and healthcare costs, not all William S. Middleton Memorial Veterans Hospital (NS), studies have demonstrated excess mortality [4–10]. This University of Wisconsin Medical School, Madison, WI, USA knowledge is important for clinical purposes as well as to appreciate the benefits that may be seen with specific M. J. Ziegler Á D. C. Pellegrini Á N. Safdar Section of Infectious Diseases, Department of Medicine, interventions to reduce CLABSI, thus we undertook a University of Wisconsin Medical School, Madison, WI, USA systematic review and meta-analysis to examine the attributable mortality of CLABSI [11]. Our study aims to & N. Safdar ( ) more clearly identify the associated adverse effects of these University of Wisconsin Hospital and Clinics, 1685 Highland Avenue, Madison, WI 53705, USA infections to be used in part for the assessment of their e-mail: [email protected] treatment and prevention. 123 M. J. Ziegler et al.

Materials and methods matching criteria, criteria for diagnosis of CLABSI, age, illness severity score, organism identified, data on mortal- This study was performed in accordance with the preferred ity, length of stay and attributable cost. Two authors MZ reporting items for systematic reviews and meta-analysis and DP independently reviewed each report identified by (PRISMA) [12]. Search terms were reviewed by a librarian the above mentioned search strategy. Disagreements and adjusted for a widely inclusive search. We searched among abstracters regarding values or analysis assignments MEDLINE, CENTRAL, and CINAHL using the terms: were resolved by discussion. (catheter or central line or peripherally inserted central We evaluated the included studies for methodological catheter and (bloodstream infection or bacteremia or sep- quality using the recommendations outlined in the Coch- ticemia) and (mortality or outcome or cost or morbidity or rane Handbook of Systematic Reviews [15]. The risk of attributable or excess or extra) with inclusion of MESH bias in each study was assessed by authors MZ and DP terms. The searches included citations from database using the Newcastle–Ottawa Scale [16]. inception until 07/01/2014 with no language restrictions. We manually searched bibliographies of recent reviews Statistical analysis and all relevant trials. The search was performed by one author (MZ). Attributable mortality was calculated by subtracting the mortality percentage of the control group from the CLABSI group. Results from the studies comparing mor- Inclusion criteria tality due to CLABSI were pooled using a random effects model with assessment of heterogeneity. We used Review A study was included if it compared mortality of patients Manager (RevMan version 5.2; Cochrane Collaboration) to with CLABSI to those without. Studies defined the perform the statistical analyses. Heterogeneity of studies microbiologic diagnosis of CLABSI using guidelines from was assessed with an I2 statistic and a funnel plot was the Centers for Disease Control (CDC) [13], Infectious generated to assess for publication bias. Disease Society of America (IDSA) [14] or individual criteria based on institution. Studies had to provide suffi- cient information to allow calculation of a risk ratio, either in the article or after contact with authors. We selected only case–control or cohort studies, both prospective and retrospective. We excluded surveillance studies, experimental studies, studies of pediatric patients, and studies that limited data to CLABSI by a specific organism. Interventional studies were excluded to prevent potential bias from altered patient care or Hawthorne effect.

Outcomes

The primary outcome measure was mortality. Mortality data was collected as hospital mortality, or intensive care unit (ICU) mortality. A priori subgroup analyses of primary outcomes included matched vs. unmatched studies. Analysis was performed using all studies and only studies which performed patient matching based on illness severity. A secondary ex post facto analysis was performed to determine if studies with high rates of (coagulase-negative Staphylococcus) CONS CLABSI were associated with lower mortality; we divided studies into subgroups using the arbitrary cut-off of those with greater or less than 30 % of participants with CONS as the causative organism. Data was extracted with a standardized form by both MZ and DP. The following data was collected when Fig. 1 Flow diagram of included studies. CLABSI central line available: study design, location, patient characteristics, associated blood stream infection 123 Attributable mortality of CLABSI

Results used IDSA criteria and 6 [7, 26–30] used individualized criteria without citation of guideline-based diagnosis. Of Selected studies the studies that did not cite previously established guidelines for the definition of CLABSI, three [7, 27, 30] iden- Our search criteria identified 4,094 citations. Figure 1 tified use of quantitative or semi-quantitative catheter details our process of selection which resulted in 18 studies culture with clinical signs of infection and without alter- which were included in final analysis. Tables 1 and 2 lists native infectious diagnosis, two [26, 28] used only semi- the characteristics of these studies including 1,976 case quantitative catheter culture and clinical signs of infection, patients and 9,222 controls. Of the included studies, 17 and one [29] study only used positive peripheral culture studied patients in the ICU; 10 involved a mixed popula- without other source of infection in presence of a catheter. tion of medical and surgical patients, two studied only Of the included studies, four [7, 21, 22, 30] identified surgical patients, one only trauma, one cardiac surgical strategies for addressing CONS; three [21, 22, 30] studies patients, and one a combination of ICU and general med- required a minimum of two positive cultures for diagnosis ical patients. Ten of the 18 studies were matched using of CONS CLABSI and one [7] study required identical varied criteria but all were based on a type of illness strains through the use of antibiogram. Eight [8, 10, 18, 22, severity index. Regarding diagnosis of CLABSI, 9 [10, 17– 25–27, 30] of the included studies identified the use of 24] of 18 studies used CDC definition criteria, 3 [8, 9, 25] semi-quantitative culture and no study identified

Table 1 Characteristics of included studies part 1 References Study location, ICU Country Study design Patient characteristics Matching Matching criteria

Blot [17] Medical-surgical Belgium Retrospective cohort Yes APACHE II ICU Cheewinmethasiri Surgical ICU Thailand Prospective case–control No N/A [8] Dimick [26] Surgical ICU USA Prospective cohort Projected No N/A stay C 3 days Hajjej [25] Medical-surgical Tunisia Prospective case–control No N/A ICU Higuera [18] Medical-surgical Mexico Prospective case–control LOS C 5 ICU days Yes ISS ICU Hsu [19] Medical-surgical USA Retrospective case– Yes Charlson Deyo ICU control Kumar [9] ICU India Prospective cohort No N/A Leistner [20] 10 ICUs Germany Prospective cohort Yes SAPS Olaechea [21] Medical-surgical Spain Retrospective case– Yes APACHE II ICU control Pawar [27] Cardiac Surgical India Prospective cohort Postoperative No N/A ICU Rello [7] Medical-surgical Spain Retrospective cohort LOS [ 48 h Yes APACHE II ICU Renaud [28] 15 ICUs France Prospective case–control LOS [ 48 h Yes SAPS II Rosenthal [22] Medical-surgical Argentina Prospective case–control LOS C 7 days Yes ASIS ICU Smith [29] Trauma ICU USA Retrospective cohort Yes ISS Stevens [23] ICU and Hospital USA Retrospective cohort No N/A Souﬁr [30] Medical-surgical France Prospective cohort Yes SAPS II ICU Warren [24] Medical-surgical USA Prospective cohort No N/A ICU Wittekamp [10] Medical-surgical Netherlands Prospective case–control ICU ICU intensive care unit, APACHE II acute physiology and chronic health evaluation II, ISS illness severity score, SAPS simpliﬁed acute physiology score, ASIS average severity of illness score

123 M. J. Ziegler et al.

Table 2 Characteristics of References Age (case, Severity of illness (case, Criteria of CLABSI Organism included studies part 2 control) control) diagnosis identiﬁed (%) Gram S positive aureus

Blot [17] 56, 57 21 APACHE II CDC 64.5 10.1 Cheewinmethasiri 47, 62 36, 20 APACHE II IDSA 36 20 [8] Dimick [26] 65 64 APACHE III Other 75 5 Hajjej [25] 56, 51 24, 14 APACHE II IDSA 18.5 Higuera [18] 46, 43 3.98, 3.49 Severity of CDC Illness Score Hsu [19] 55, 61 3.12, 2.74 Charlson CDC Deyo Kumar [9] 50, 46 IDSA 18 7 Leistner [20] 63, 67 40, 43 SAPS CDC 6 Olaechea [21] 57 18.36, 18.19 APACHE CDC 70.6 10.3 II Pawar [27] 60.2, 58.3 10.8, 6.8 APACHE II Other 17.5 11.7 Rello [7] 60.3, 58.4 15.5, 15.2 APACHE II Other 77.4 10.2 ICU intensive care unit, APACHE II acute physiology Renaud [28] 60.3, 62.9 35.1, 45.9 SAPS II Other 41 13.7 and chronic health evaluation II, Rosenthal [22] 70, 68.8 3.30, 3.09 ASIS CDC ISS illness severity score, SAPS Smith [29] 49, 40 32.5, 29.8 ISS Other simpliﬁed acute physiology Stevens [23] 58, 59 14, 11 APACHE II CDC 64 6.6 score, ASIS average severity of illness score, CDC Centers for Souﬁr [30] 63, 64 50.2, 49.3 SAPS II Other 63 55 Disease Control, IDSA Warren [24] 71, 70 25, 24 APACHE II CDC 68 7 Infectious Diseases Society of Wittekamp [10] 62 21 APACHE II CDC America

Table 3 Study outcomes References Patient population Hospital mortality % Attributable regarding mortality CLABSI No CLABSI CLABSI No CLABSI

Blot [17] 176 315 27.84 26.03 1.81 Cheewinmethasiri [8] 44 129 20.45 22.48 -2.02 Dimick [26] 9 251 55.56 21.12 34.44 Hajjej [25] 32 120 21.87 13.54 8.33 Higuera [18] 55 55 41.82 21.82 20.00 Hsu [19] 16 64 43.75 18.75 25.00 Kumar [9] 28 72 7.14 0 7.14 Leistner [20] 40 40 17.50 7.50 10.00 Olaechea [21] 1011 4044 25.91 19.09 6.82 Pawar [27] 35 1279 22.86 0.23 22.62 Rello [7] 49 49 22.45 34.69 -12.24 Renaud [28] 26 26 38.46 26.92 11.54 Rosenthal [22] 142 142 54.23 29.58 24.65 Smith [29] 35 105 11.43 11.43 0.00 Stevens [23] 197 201 28.42 8.95 19.47 Souﬁr [30] 38 75 52.63 26.67 25.96 Warren [24] 41 1091 51.22 27.59 23.63 CLABSI central line associated Wittekamp [10] 2 216 50.00 27.31 22.68 blood stream infection

123 Attributable mortality of CLABSI quantitative culture use. Of the studies which reported organisms identified, seven of 12 identified a predominance of gram positive organisms. The percentage of S aureus was between 5 and 13 % except in Soufir et al. [30] which identified 55 % of CLABSI cultures as S aureus. There was

limited reporting of the types of central lines used, removal Total Non-response rate of central lines upon infection, and treatment of CLABSI (Table 3).

Study quality

Study quality was assessed using the Newcastle–Ottawa ascertainment for cases and controls Scale [16]. This scale can be used to assess both case– control and cohort studies where stars are allocated in categories of selection, comparability, and exposure/ outcome. A greater number of stars suggests a higher quality study. For the purpose of this analysis, we assessed that case-definition was adequate if studies of exposure utilized CDC definitions, IDSA definitions or a method that used both clinical signs and microbiologic data. Adequate follow-up was defined as \10 % lost to follow-up. The consensus results of the quality of assessment are presented in Tables 4 and 5, demonstrating an average score of 6.5/8 (range 4–8) in the case control studies and 6.3/10 (range 5–7) in the cohort studies. Illness severity Age Ascertainment Comparability Exposure Same method of Between authors MZ and DP similar interpretations on study quality were obtained in 13 of 18 studies and 93 % of total star allocation, and consensus interpretation was obtained in all cases. Definition of controls

Primary endpoints

All studies included in the meta-analysis reported on

mortality [7–10, 17–30]. Our meta-analysis shows an odds Selection of controls ratio of in hospital death associated with CLABSI as 2.75 (95 % confidence interval 1.86–4.07) (Fig. 2). Significant heterogeneity was identified with an I2 of 80 %. A funnel plot was created for this endpoint (Fig. 3) which demon- strates asymmetry suggesting publication bias. Using the subgroup of the 10 matched studies [7, 17–22, 28–30]we identified an odds ratio of in hospital death of 1.51 asso- Representativeness of the cases ciated with CLABSI (CI 1.08–2.09) with an I2 of 61 %. Using the 5 studies where ICU mortality [7, 10, 26, 28, 30] was reported we found an odds ratio of ICU death associated with CLABSI as 2.15 (95 % CI 0.83–5.56) with an 2 I of 67 %. case definition adequate ] * * * * * * 6 of 9 Secondary endpoints 8 ]* * * * * 4of9 ]* * * * ** * 7of9 ]* * * * ** * 7of9 10 ] * * * * * * * * 8 of 9 ]* * * * *** 7of9 22

A secondary analysis was performed comparing the sub- 21 ] * * * * * * 6 of 9 18 Quality assessment using Newcastle–Ottawa scale: case control studies 28 ]* * ***** 7of9 group of studies where identiﬁed organism was CONS in 25 greater or less than 30 %. Using the 5 studies [7, 17, 21, 23, 19 Cheewinmethasiri [ Hajjej [ Higuera [ Hsu [ Olaechea [ Renaud [ Rosenthal [ Wittekamp [ 24] where greater than 30 % of cases were attributed to Table 4 Title Selection, 123 M. J. Ziegler et al.

Table 5 Quality assessment using Newcastle–Ottawa scale: cohort studies Title Selection Selection of Ascertainment Outcome Comparability Outcome Follow Total the non of exposure not present up long Representativeness exposed at start Illness Age Ascertainment enough? Adequate of the cohort cohort severity of outcome follow-up of cohorts

Blot [17]* * * * * * *7of9 Dimick [26] * * * * * * 5 of 9 Kumar [9]* * * * * * * 7of9 Leistner [20]* * * * * * * 7of9 Pawar [27]* * * * * 5of9 Rello [7]* * * * * * *7of9 Smith [29]*****5of9 Stevens [23]* * * * * * * 7of9 Souﬁr [30]* * * * * * * 7of9 Warren [24] * * * * * * 6 of 9

CLABSI Control Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI

Blott 2005 49 176 82 315 8.1% 1.10 [0.72, 1.66] Cheewinmethasiri 2014 9 44 29 129 6.3% 0.89 [0.38, 2.06] Dimick 2001 5 9 53 251 4.3% 4.67 [1.21, 18.00] Hajjej 2014 7 32 10 120 5.4% 3.08 [1.07, 8.88] Higuera 2007 23 55 12 55 6.3% 2.58 [1.12, 5.93] Hsu 2013 7 16 12 64 4.9% 3.37 [1.05, 10.86] Kumar 2014 2 28 0 72 1.4% 13.68 [0.64, 294.32] Leistner 2013 7 40 3 40 4.1% 2.62 [0.63, 10.95] Olaechea 2013 262 1011 772 4044 8.7% 1.48 [1.26, 1.74] Pawar 2004 8 35 3 1279 4.2% 126.02 [31.69, 501.22] Rello 2000 11 49 17 49 6.1% 0.54 [0.22, 1.33] Renaud 2001 10 26 7 26 4.9% 1.70 [0.53, 5.48] Rosenthal 2003 77 142 42 142 7.8% 2.82 [1.73, 4.60] Smith 2011 4 35 12 1050 4.9% 11.16 [3.41, 36.56] Soufir 1999 20 38 20 75 6.4% 3.06 [1.35, 6.92] Stevens 2013 56 197 18 201 7.4% 4.04 [2.27, 7.17] Warren 2006 21 41 301 1091 7.2% 2.76 [1.47, 5.16] Wittekamp 2013 1 2 59 219 1.6% 2.71 [0.17, 44.06]

Total (95% CI) 1976 9222 100.0% 2.75 [1.86, 4.07]

Total events 579 1452 Heterogeneity: Tau² = 0.45; Chi² = 87.14, df = 17 (P < 0.00001); I² = 80% 0.01 0.1 1 10 100 Test for overall effect: Z = 5.06 (P < 0.00001) Favours [experimental] Favours [control]

Fig. 2 Mortality of CLABSI compared to No CLABSI, forest Plot. CLABSI central line associated blood stream infection

CONS we found an odds ratio of hospital death associated Discussion with CLABSI as 1.64 (95 % CI 1.02–2.65) with an I2 of 82 %. In the 7 studies [8, 9, 25–28, 30] where less than The effects of CLABSI have been previously evaluated 30 % of cases were attributed to CONS we found an odds for both cost and mortality with repeated evidence of ratio of death of 4.71 (95 % CI 1.54–14.39) with an I2 of increased associated cost but varied reports of mortality 84 %. [11, 17, 24, 26]. While several studies have

123 Attributable mortality of CLABSI

This study had 35 cases compared to 1,279 controls, and on univariate analysis those with CLABSI had a significantly increased APACHE II score; 10.8 compared with 6.8 in controls. Our study re-demonstrated a decreased mortality in the subgroup of matched studies, which suggests that illness severity is a significant variable in the non-matched groups. We additionally demonstrated that those studies where CONS was frequently identified as the causative organism (arbitrarily defined as [30 %) were associated with a decreased mortality. This likely reflects absence of true infection or the lower virulence of this organism. Our study had several limitations. Regarding selection of studies, we were interested in obtaining results from a broader demographic of patients with central lines including peripherally inserted central catheters, but were only able to identify one study which met criteria outside of the ICU. Additionally, statistical analyses in our study Fig. 3 Mortality of CLABSI compared to No CLABSI, funnel. SE were limited by the information available in the included standard error, OR odds ratio studies. Of the included studies, there were varied definitions used for CLABSI, as well as differences in microbiologic diagnoses and methods for addressing demonstrated varying degrees of excess mortality, four CONS. The heterogeneity of definition likely resulted studies that we identified did not show a statistically from both the historically available definitions and the significant difference in mortality with CLABSI [7, 17, variation in collected data of each study. Additionally, 20, 28]. A previous meta-analysis, Siempos et al. 2009 studies with more rigorous methods evaluating for undertook a meta-analysis focusing on ICU studies to potential skin contaminates could theoretically give more identify the mortality of CLABSI using both a matched accurate mortality estimates, however, this was not clearly and unmatched cohort [31]. Our review provides an defined in all studies. Finally, the studies used in meta- update of this data with 18 compared with 8 included analysis showed significant clinical and statistical heter- studies with a total of 1,976 CLABSI compared with ogeneity most likely secondary to the diverse settings 536. included; both in the various countries included and the Our review indicates that CLABSI is associated with different hospital settings. Despite attempts to explain significantly increased odds of death with our calculated heterogeneity using subgroup analyses, much of the het- odds ratio of 2.75 (CI 1.86–4.07). Our findings are in erogeneity could not be explained; thus the pooled esti- keeping with the previous meta-analysis by Siempos et al. mates should be viewed with caution. which found an odds ratio of 1.96 and 1.65 (CI 1.28–2.13) for ICU mortality in matched studies [31]. The differences that we see in our results are most likely due to a greater Conclusion number of studies included rather than a significantly different patient population. The addition of more studies with Overall we found that CLABSI has a substantial attribut- the resultant large sample size also allows us to generate able mortality. We anticipate that our results can be used more precise estimates. for further assessments of measures aimed to reduce these Of the included studies, only two of 18 studies showed a infections. Additional studies to examine the attributable trend toward decreased mortality [7, 8] and seven showed no mortality of CLABSI in the non ICU inpatient setting are statistically significant difference in mortality with CLABSI needed with rigorous attention to study design, setting, and [7–10, 17, 20, 28]. Those studies that demonstrate an odds severity of illness measures. ratio favoring CLABSI ranged from 1.10 to 13.68 and an outlier of 126.02. This outlying study, Pawar et al. [27], Acknowledgments Thanks to Nestor Anguiano, MD for his assis- investigated CLABSI in patients undergoing cardiac opera- tance in translating Spanish language studies. tions. It is likely that this outlier was the result of the low case Conflict of interest All authors report no conflicts of interest rele- number in addition to greater illness severity in the cases. vant to this article.

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