ARTICLE IN PRESS American Journal of Infection Control ■■ (2016) ■■-■■
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
j o u r n a l h o m e p a g e : w w w. a j i c j o u r n a l . o r g
Major Article
Chlorhexidine-silver sulfadiazine-impregnated venous catheters are efficient even at subclavian sites without tracheostomy Leonardo Lorente MD, PhD a,*, María Lecuona MD, PhD b, Alejandro Jiménez PhD c, Judith Cabrera MD a, Ruth Santacreu MD a, Lisset Lorenzo MD a, Lorena Raja MD a, María L. Mora MD, PhD a a b c
Department of Critical Care, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain Department of Microbiology and Infection Control, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain Research Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
Key Words: Central venous catheter Bacteremia
Background: Chlorhexidine-silver sulfadiazine (CHSS)-impregnated catheters have been found to decrease the risk of catheter-related bloodstream infection (CRBSI) and central venous catheter (CVC)related costs. However, there are no published data about cost-effectiveness of the use of CHSS-impregnated catheters in subclavian venous access without the presence of tracheostomy (thus, with a very low risk of CRBSI). That was the objective of this study. Methods: This was a retrospective study of patients admitted to a mixed intensive care unit who underwent placement of subclavian venous catheters without the presence of tracheostomy. Results: Patients with standard catheters (n = 747) showed a higher CRBSI incidence density (0.95 vs 0/1,000 catheter-days; P = .02) and higher CVC-related cost per day ($3.78 ± $7.43 vs $3.31 ± $2.72; P < .001) than patients with a CHSS-impregnated catheter (n = 879). Exact logistic regression analysis showed that catheter duration (P = .02) and the type of catheter used (P = .01) were associated with the risk of CRBSI. Kaplan-Meier method showed that CHSS-impregnated catheters were associated with more prolonged CRBSI-free time than standard catheters (log-rank = 9.76; P = .002). Poisson regression analysis showed that CHSS-impregnated catheters were associated with a lower central venous catheter-related cost per day than standard catheters (odds ratio, 0.87; 95% confidence interval, 0.001-0.903; P < .001). Conclusions: The use of CHSS-impregnated catheters is an effective and efficient measure for the prevention of CRBSI even at subclavian venous access sites without the presence of tracheostomy. © 2016 Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc.
Catheter-related bloodstream infection (CRBSI) could lead to an increase in morbidity, mortality, and assistance costs.1-3 The use of antimicrobial-impregnated central venous catheters (CVCs) has been proposed for the prevention of CRBSI. The antimicrobial agent used for the impregnation of CVCs has been chlorhexidine-silver sulfadiazine (CHSS).4-7 In a meta-analysis by Veenstra et al,4 including 2,603 catheters from 11 randomized controlled trials, it was found that first-generation CHSS-impregnated catheters (ie, impregnated only on the external surface) reduced the incidence of CRBSI compared with nonimpregnated catheters. Afterward, in a meta-
* Address correspondence to Leonardo Lorente, MD, PhD, Department of Critical Care, Hospital Universitario de Canarias, Ofra s/n La Cuesta, La Laguna, 38320 Santa Cruz de Tenerife, Spain. E-mail address:
[email protected] (L. Lorente). Conflicts of Interest: None to report.
analysis by Hockenhull et al5 (including 1,176 patients from 3 randomized controlled trials) it was found that second-generation CHSS-impregnated catheters (impregnated on the external and internal surfaces) reduced the risk of CRBSI compared with nonimpregnated catheters. In addition, some cost-effectiveness analyses have found a reduction on the incidence of CRBSI and CVC-related cost with the use of CHSS-impregnated catheters.5-7 A limitation of all these costeffectiveness analyses was that CVC-related cost included the estimated cost that is attributed to the hospital stay increase. Thus, the mean additional cost attributed to CRBSI was approximately $10,000 per patient, although in some studies the mean additional cost attributed to CRBSI was $40,0008 and $71,000.9 To avoid that limitation, our team analyzed the cost-effectiveness of CHSSimpregnated catheters considering only the costs of diagnosis of CRBSI and antimicrobial agents for the treatment of CRBSI, and not including the estimated cost that is attributed to the hospital stay
0196-6553/© 2016 Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc. http://dx.doi.org/10.1016/j.ajic.2016.04.236
ARTICLE IN PRESS 2
L. Lorente et al. / American Journal of Infection Control ■■ (2016) ■■-■■
increase. We have found that CHSS-impregnated catheters decrease the risk of CRBSI and CVC-related costs in femoral10,11 and jugular sites,12 which are venous access sites with high risk of CRBSI.13,14 Later, we found that CHSS-impregnated catheters decrease the risk of CRBSI- and CVC-related costs for subclavian sites,15 which is a venous access site with lower risk of CRBSI than femoral and jugular sites.13,14 Another issue is that the presence of tracheostomy has been found to be a risk factor for CRBSI at subclavian and jugular venous access sites.16,17 Those studies included 1,211 and 1,392 catheters, respectively. This association could be due to the fact that respiratory secretions could contaminate more easily a CVC located at subclavian site in the presence of tracheostomy. Now arises the question of whether CHSS-impregnated catheters are also efficient in subclavian venous access without the presence of tracheostomy. To our knowledge, there are no published data about the cost-effectiveness of the use of CHSS-impregnated catheters in subclavian venous access sites without the presence of tracheostomy (thus, with a very low risk of CRBSI). Thus, the objective of this study was to determine whether the use of CHSS-impregnated catheters could be an effective and efficient measure for CRBSI prevention even in subclavian venous access without the presence of tracheostomy.
MATERIALS AND METHODS This retrospective study was carried out in the mixed intensive care unit of the Hospital Universitario de Canarias (Tenerife, Spain). We included patients with subclavian venous catheters without the presence of tracheostomy. The study was approved by the institutional ethic review board. We used the following CVCs during the study: Arrow (Arrow; Reading, PA), which are standard CVC catheters without impregnation, and ARROWg+ard Blue (Arrow), which are CHSS-impregnated catheters (ie, impregnated on the external and internal surfaces). The patient’s physician decided the type of CVC for each patient. We used the following criteria for the definition of CRBSI: signs of systemic infection (eg, fever, chills, and/or hypotension), positive blood culture obtained from a peripheral vein, catheter-tip colonization (significant growth of a microorganism > 15 colony forming units) with the same organism as the blood culture (ie, the same species with identical antimicrobial susceptibility), and no apparent source of bacteremia except the catheter. We used the method described by Maki et al18 for the culture of each catheter tip. To calculate CVC-related cost we included only the cost of the CVC, the cost of cultures for diagnosis of CRBSI, and the cost of antimicrobial agents used for the treatment of CRBSI. All data about the costs were obtained from the hospital accounts department. The cost of CVCs was $17 for standard catheters and $30 for CHSSimpregnated catheters. We recorded the following variables for each patient: admission diagnostic, age, acute physiology and chronic health evaluation II score, use of chemotherapeutic agents, presence of chronic obstructive pulmonary disease or diabetes mellitus, duration of the catheter, female sex, presence of a hematologic tumor or solid tumor, use of steroid agents, use of antimicrobial agents, use of mechanical ventilation, use of paralytic agents, type of catheter, presence of CRBSI, and CVC-related cost. We reported categorical variables as frequencies and percentages, and continuous variables as means and standard deviations. We used Kruskal-Wallis test or Jonckeree-Terpstra test for the comparison of categorical variables, and Student t test for the comparison of continuous variables between both catheter groups (CHSSimpregnated or standard catheters).
We used exact logistic regression analysis to determine whether the type of catheter (CHSS or standard) and duration of catheter were associated with the occurrence of CRBSI. Exact nonparametric inference, also known as permutational inference, allowed us to make reliable inferences by exact methods when data were sparse and the accuracy of the corresponding large sample theory was in doubt.19 We used the exact regression method, so the point estimates, the confidence intervals (including infinite limits), and P values do exist in our study, although the asymptotic ones do not.20 Poisson regression analysis was carried out to test the influence of the type of catheter (CHSS-impregnated or standard) on the CVCrelated cost per catheter-day. Odds ratio and 95% confidence interval were used to express the magnitude of the effect. We carried out a survival analysis using CRBSI as the event, type of catheter (CHSS or standard) as the independent variable, and catheter duration as the dependent variable. Curves were represented using the KaplanMeier method and to compare distributions of CRBSI-free time between groups we used log-rank tests. All P values < .05 were considered statistically significant. We used SPSS 17.0 (IBM-SPSS Inc, Armonk, NY), LogXact 4.1, (Cytel Co, Cambridge, MA), and StatXact 5.0.3 (Cytel Co) for the statistical analysis. RESULTS A total of 214 out of 1,093 CHSS-impregnated catheters (19.6%) and 143 out of 890 standard catheters (16.1%) were located at subclavian venous access sites in the presence of tracheostomy. Table 1 shows the comparison of characteristics of patients with CHSSimpregnated (n = 879) or standard catheters (n = 747) at subclavian venous access sites without the presence of tracheostomy. There were no significant differences between CHSS-impregnated or standard catheters on admission diagnostic, age, acute physiology and chronic health evaluation II score, use of chemotherapeutic agents, presence of chronic obstructive pulmonary disease or diabetes mellitus, female sex, presence of a hematologic tumor, presence of a solid tumor, use of steroid agents, use of antimicrobial agents, use of mechanical ventilation, and use of paralytic agents. We found that
Table 1 Characteristics of patients receiving chlorhexidine-silver sulfadiazine (CHSS)impregnated or standard catheter CHSS (n = 879)
Standard (n = 747)
Admission diagnostic Cardiac surgery 103 (11.7) 80 (10.7) Cardiology 92 (10.5) 71 (9.5) Respiratory 187 (21.3) 150 (20.1) Digestive 171 (19.5) 152 (20.3) Neurologic 157 (17.9) 142 (19.0) Traumatology 86 (9.8) 80 (10.7) Intoxication 33 (3.8) 21 (2.8) Others 50 (5.7) 51 (6.8) Age (y) 59.60 ± 16.47 59.54 ± 16.64 APACHE II score 17.06 ± 7.53 16.96 ± 11.26 Chemotherapeutic agents 55 (6.3) 45 (6.0) Chronic obstructive pulmonary disease 110 (12.5) 90 (12.0) Diabetes mellitus 252 (28.7) 205 (27.4) Duration of the catheter 8.95 ± 4.05 5.62 ± 4.03 Female sex 317 (36.1) 274 (36.7) Hematologic tumor 39 (4.4) 31 (4.1) Solid tumor 107 (12.2) 89 (11.9) Steroid agents 101 (11.5) 82 (11.0) Use of antimicrobial agents 814 (92.6) 698 (93.4) Use of mechanical ventilation 687 (78.2) 580 (77.6) Use of paralytic agents 92 (10.5) 68 (9.1) NOTE. Values are presented as n (%) or mean ± standard deviation. APACHE, acute physiology and chronic health evaluation.
P value .81
.94 .80 .92 .82 .62 < .001 .84 .81 .88 .75 .56 .81 .40
ARTICLE IN PRESS L. Lorente et al. / American Journal of Infection Control ■■ (2016) ■■-■■
Table 2 Catheter-related bloodstream infection (CRBSI) and central venous catheter (CVC)related cost using chlorhexidine-silver sulfadiazine (CHSS)-impregnated or standard catheter
CRBSI Number CRBSI/1,000 catheter-days CVC-related cost ($/d)
Standard (n = 747) (4,196 d)
CHSS (n = 879) (7,863 d)
P value
4 (0.5) 0.95 3.78 ± 7.43
0 0 3.31 ± 2.72
.04 .02 < .001
NOTE. Values are presented as n (%) or mean ± standard deviation.
Table 3 Exact logistic regression analysis to estimate the risk of catheter-related bloodstream infection
Duration of catheter insertion (d) Type of catheter*
Odds ratio
95% Confidence interval
P value
1.17 0.10
1.029-∞ ∞-0.79
.02 .01
*Chlorhexidine-silver sulfadiazine-impregnated catheter versus standard catheter.
Fig 1. Catheter-related bloodstream infection (CRBSI)-free time in subclavian venous access sites without tracheostomy using chlorhexidine-silver sulfadiazine (CHSS)impregnated and standard catheters.
patients with CHSS-impregnated catheters showed a higher duration of catheter dwell than patients with standard catheters (P < .001). Table 2 shows the comparison on CRBSI incidence and CVCrelated cost using CHSS-impregnated or standard catheters. We diagnosed 4 CRBSIs in 747 patients with standard catheters during 4,196 days of catheter-dwell and no CRBSI in 879 patients with CHSSimpregnated catheters during 7,863 days of catheter-dwell. Patients with standard catheters showed a higher incidence density of CRBSI (P = .02), and higher CVC-related cost per day (P < .001) than patients with a CHSS-impregnated catheter. The costs of the 4 CRBSIs was $2,872; the mean cost for each CRBSI was $718 ± $144. Exact logistic regression analysis showed that catheter duration (P = .02) and the type of catheter used (P = .01) were associated with the risk of CRBSI (Table 3). The Kaplan-Meier method showed than CHSS-impregnated catheters were associated with more prolonged CRBSI-free time than standard catheters (log-rank = 9.76; P = .002) (Fig 1). Figure 1 shows a lack of benefit in short-duration catheter insertions; that is, when duration of catheter dwell was less than 6 days.
3
Poisson regression analysis showed that CHSS-impregnated catheters were associated with a lower CVC-related cost per day than standard catheters (odds ratio, 0.87; 95% confidence interval, 0.0010.903; P < .001).
DISCUSSION To our knowledge, this is the first study reporting that CHSSimpregnated catheters at subclavian venous sites without the presence of tracheostomy reduce the incidence of CRBSI- and CVCrelated costs. The findings of our study are in consonance with those of previous meta-analyses showing that CHSS-impregnated catheters reduce the incidence of CRBSI4,5 and lower CVC-related costs.5-7 An interesting point of our study was that in our cost-effectiveness analysis we included only the costs of diagnosis and treatment of CRBSI; thus, there were no other potential costs attributed to CRBSI (eg, hospital stay increase, mechanical ventilation duration increase, laboratory determinations, and other costs). In addition, the findings of our study are in consonance with those of our previous studies10-12 that found that CHSS-impregnated catheters reduce CVC-related costs in femoral and jugular access sites (using the same approach; ie, considering only the costs of diagnosis and treatment of CRBSI, and not including the cost of hospital stay). Besides, we found that the duration of catheter insertion is another risk factor for the development of CRBSI. Therefore, we suggest the removal of the intravascular catheter as soon as it is no longer needed, such as in the current guidelines for CRBSI prevention.21 A key point of our current study is that CHSS-impregnated catheters reduce the incidence of CRBSI and reduce CVC-related costs even at the subclavian venous site without the presence of tracheostomy. Previously we found that CHSS-impregnated CVCs decreased the risk of CRBSI and CVC-related costs in femoral10,11 and jugular venous access sites,12 which are venous access sites with high risk of CRBSI,13,14 and also in subclavian venous access sites,15 which is a venous access site with lower risk of CRBSI than femoral and jugular sites. In addition, the presence of tracheostomy has been associated with higher risk of CRBSI.16,17 Thus, the novel findings of our study suggest that the use of CHSSimpregnated catheters could be an effective and efficient measure for CRBSI prevention even at subclavian venous sites without the presence of tracheostomy. CRBSI prevention guidelines recommend using CHSS-impregnated catheters in patients expecting a duration of catheter dwell time longer than 5 days, and if the rate of CRBSI has not been reduced by the implementation of a comprehensive strategy.21 However, there are no recommendations about the use of impregnated catheters according to venous site or the presence or not of tracheostomy. A potential risk in the use of CHSS-impregnated catheters is the possibility of allergic reactions to the antimicrobial agent used in the impregnation. However, we have not found any allergic reaction.22-25 The present study has certain limitations. First, this was a singlecenter study. In other institutions the CVC-related costs could be different. Second, this was a retrospective study and the use of CHSSimpregnated or standard catheters was not randomly assigned.
CONCLUSIONS The use of CHSS-impregnated catheters is an effective and efficient measure for the prevention of CRBSI, even at subclavian venous access sites without the presence of tracheostomy.
ARTICLE IN PRESS 4
L. Lorente et al. / American Journal of Infection Control ■■ (2016) ■■-■■
References 1. Siempos II, Kopterides P, Tsangaris I, Dimopoulou I, Armaganidis AE. Impact of catheter-related bloodstream infections on the mortality of critically ill patients: a meta-analysis. Crit Care Med 2009;37:2283-9. 2. Lambert ML, Suetens C, Savey A, Palomar M, Hiesmayr M, Morales I, et al. Clinical outcomes of health-care-associated infections and antimicrobial resistance in patients admitted to European intensive-care units: a cohort study. Lancet Infect Dis 2011;11:30-8. 3. Laupland KB, Lee H, Gregson DB, Manns BJ. Cost of intensive care unit-acquired bloodstream infections. J Hosp Infect 2006;63:124-32. 4. Veenstra DL, Saint S, Saha S, Lumley T, Sullivan SD. Efficacy of antisepticimpregnated central venous catheters in preventing catheter-related bloodstream infection: a meta-analysis. JAMA 1999;281:261-7. 5. Hockenhull JC, Dwan K, Boland A, Smith G, Bagust A, Dundar Y, et al. The clinical effectiveness and cost-effectiveness of central venous catheters treated with anti-infective agents in preventing bloodstream infections: a systematic review and economic evaluation. Health Technol Assess 2008;12:1-154. 6. Veenstra DL, Saint S, Sullivan SD. Cost-effectiveness of antiseptic-impregnated central venous catheters for the prevention of catheter-related bloodstream infection. JAMA 1999;282:554-60. 7. Shorr AF, Humphreys CW, Helman DL. New choices for central venous catheters: potential financial implications. Chest 2003;124:275-84. 8. Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, extra costs, and attributable mortality. JAMA 1994;271:1598-601. 9. Dimick JB, Pelz RK, Consunji R, Swoboda SM, Hendrix CW, Lipsett PA. Increased resource use associated with catheter-related bloodstream infection in the surgical intensive care unit. Arch Surg 2001;136:229-34. 10. Lorente L, Lecuona M, Jiménez A, Santacreu R, Raja L, González O, et al. Chlorhexidine-silver sulfadiazine-impregnated venous catheters save costs. Am J Infect Control 2014;42:321-4. 11. Lorente L, Lecuona M, Jiménez A, Raja L, Cabrera J, Gonzalez O, et al. Chlorhexidine-silver sulfadiazine or rifampicin-miconazol impregnated venous catheters decrease the risk of catheter-related bloodstream infection similarly. Am J Infect Control 2015;2015:doi:10.1016/j.ajic.2015.08.014; pii: S01966553(15)00931-1, Epub ahead of print. 12. Lorente L, Lecuona M, Jiménez A, Lorenzo L, Diosdado S, Marca L, et al. Cost/ benefit analysis of chlorhexidine-silver sulfadiazine-impregnated venous catheters for femoral access. Am J Infect Control 2014;42:1130-2.
13. Lorente L, Henry C, Martín MM, Jimenez A, Mora ML. Central venous catheterrelated infection in a prospective and observational study of 2595 catheters. Crit Care 2005;9:631-5. 14. Parienti JJ, Mongardon N, Mégarbane B, Mira JP, Kalfon P, Gros A, et al. Intravascular complications of central venous catheterization by insertion site. N Engl J Med 2015;373:1220-9. 15. Lorente L, Lecuona M, Jiménez A, Lorenzo L, Santacreu R, Ramos S, et al. Efficiency of chlorhexidine-silver sulfadiazine-impregnated venous catheters at subclavian site. Am J Infect Control 2015;43:711-4. 16. Garnacho-Montero J, Aldabó-Pallás T, Palomar-Martínez M, Vallés J, Almirante B, Garcés R, et al. Risk factors and prognosis of catheter-related bloodstream infection in critically ill patients: a multicenter study. Intensive Care Med 2008;34:2185-93. 17. Lorente L, Jiménez A, Martín MM, Castedo J, Galván R, García C, et al. Influence of tracheostomy on the incidence of central venous catheter-related bacteremia. Eur J Clin Microbiol Infect Dis 2009;28:1141-5. 18. Maki DG, Weise CE, Sarafin HW. A semiquantitative culture method for identifying intravenous catheter-related infection. N Engl J Med 1977;296: 1305-9. 19. Mehta C, Patel N. Preface. In: StatXact. 5th ed. Cambridge, MA. USA: Cytel Co; 2001:i-iv. 20. Mehta C, Patel N. A logXact tutorial. In: LogXact. 4th ed. Cambridge, MA. USA: Cytel Co; 2000:15-36. 21. O’Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control 2011;39:S1-34. 22. Stephens R, Mythen M, Kallis P, Davies DW, Egner W, Rickards A. Two episodes of life-threatening anaphylaxis in the same patient to a chlorhexidinesulphadiazine-coated central venous catheter. Br J Anaesth 2001;87: 306-8. 23. Terazawa E, Shimonaka H, Nagase K, Masue T, Dohi S. Severe anaphylactic reaction due to a chlorhexidine-impregnated central venous catheter. Anesthesiology 1998;89:1296-8. 24. Oda T, Hamasaki J, Kanda N, Mikami K. Anaphylactic shock induced by an antiseptic-coated central venous [correction of nervous] catheter. Anesthesiology 1997;87:1242-4. 25. Jee R, Nel L, Gnanakumaran G, Williams A, Eren E. Four cases of anaphylaxis to chlorhexidine impregnated central venous catheters: a case cluster or the tip of the iceberg? Br J Anaesth 2009;103:614-5.