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Evaluation of antiseptic-impregnated central venous catheters for prevention of catheter-related infection in intensive care unit patients
Diagnostic Microbiology and Infectious Disease 38 (2000) 1–5
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Bacteriology
Evaluation of antiseptic-impregnated central venous catheters for prevention of catheter-related infection in intensive care unit patients Wang-Huei Sheng, Wen-Je Ko, Jann-Tay Wang, Shan-Chwen Chang, Po-Ren Hsueh, Kwen-Tay Luh Department of Internal Medicine, Surgery and Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan Received 7 February 2000; accepted 6 June 2000
Abstract Central venous catheterization represents a significant medical advancement, particularly in the treatment of critical ill. However, there is a high risk of central venous catheters-related infection. A novel antiseptic central venous catheter, made of polyurethane and impregnated with chlorhexidine and silver sulfadiazine, was developed to reduce the risk of catheters-related infection. In this study, we did a randomized clinical study to determine the efficacy by using antiseptic catheters for the prevention of central venous catheters-related infection in the intensive care units. A total of 204 patients with 235 central venous catheters were studied at the surgical intensive care units at National Taiwan University Hospital between November 1998 and June 1999. Participants received either a standard triple-lumen polyurethane catheter or an antiseptic catheter (Arrow International, Reading, Pennsylvania, USA). Both were indistinguishable from each other. Compared to standard polyurethane catheters, antiseptic catheters were less likely to be colonized by microorganisms when they were cultured at the removal (8.0 versus 20.0 colonized catheters per 100 catheters; relative risk 0.34 [95% CI, 0.15 to 0.74]; p ⬍ 0.01). There was no significant differences between both groups in catheter-related infections (0.9 versus 4.9 infections per 100 catheters; relative risk 0.17 [95% CI, 0.03 to 1.15]; p ⫽ 0.07). Gram-positive cocci and fungi were more likely to colonize in the standard polyurethane catheters ( p ⫽ 0.06 and 0.04, compared to antiseptic catheters respectively). Two of our cases in the control group died directly due to catheter-related candidemia. No adverse reactions such as hypersensitivity or leukopenia were found in the antiseptic catheter group. Our study showed that central venous catheters with antiseptic coating were safe and had less risk of colonization of bacteria and fungi than standard catheters in the critically ill patients. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Central venous catheter, Antiseptic catheter, Catheter-related infection
1. Introduction Indwelling central venous catheters are used universally in the management of critically ill patients today. However, blood stream infection and bacterial colonization related to the use of central venous catheters are common and serious problems. In previous surveillance, central venous catheters account for 90% of all vascular catheter-related bloodstream infections (Banerjee et al. 1991; Taynes et al. 1991). Technologic innovations to block microbial access to the transcutaneous tract, such as use of topical application of potent antiseptics (Maki et al. 1991) or antimicrobials (Levin et al. 1991), or attachment of a subcutaneous silver-impregnated * Corresponding author. Tel.: ⫹886-2-23123456 ext. 5401; fax: ⫹8862-23971412. E-mail address: [email protected] (S.C. Chang).
cuff (Maki et al. 1988), have helped prevent catheter-related infection (CRI). An antiseptic central venous catheter, made of polyurethane and impregnated with chlorhexidine and silver sulfadiazine, was developed. The two antiseptics chlorhexidine and silver sulfadiazine, had exhibited both potent bactericidal and fungicidal activities in vitro (Carr et al. 1973; Hoffmann 1984; Quesnal et al. 1978; Schmitt et al. 1996). These cutaneous disinfection agents also had been used widely for decades to prevent burn wound or surgical wound infections (Gardner and Gray 1983; Sawhney et al. 1989). A prospective randomized study was conducted at National Taiwan University Hospital (NTUH), a tertiary medical center with 2000-bed capacity located in the northern Taiwan, to compare the effectiveness of antiseptic catheter versus standard central venous catheter in preventing CRI and colonization, and the safety of their use in Taiwanese critical ill patients.
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W.H. Sheng et al. / Diagnostic Microbiology and Infectious Disease 38 (2000) 1–5
2. Materials and methods This study was conducted at the surgical intensive care units at NTUH between November 1998 and June 1999. All adult patients who were not allergic to chlorhexidine, silver, or sulfonamides and were scheduled to receive a central venous catheter were eligible to participate. Those who had known bacteremia or fungemia episodes within two weeks before the central venous catheter insertion were excluded. Febrile patients (oral temperature more than 38°C) and patients with sepsis syndrome within one week or at the time of catheter insertion were also excluded. Sepsis in these patients was defined as clinical evidence of infection plus at least two of the following systemic inflammatory responses: 1) oral temperature of ⱖ38°C or ⱕ36°C; 2) respiratory rate of ⱖ20 breaths/minute or PaCO2 of ⱕ32 torr; 3) heart rate of ⱖ90 beats/minute; 4) blood leukocyte ⱖ12000/mm3 or ⱕ4000/mm3 or band form of leukocyte ⱖ10% (American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee 1992). Two types of noncuffed, triple-lumen central venous catheters manufactured by Arrow International (Reading, PA, USA) were used in this study: the standard 16-G polyurethane catheter as control group and the antiseptic catheter of the same size as test group, which is impregnated with minute quantities of chlorhexidine gluconate (0.75 mg) and silver sulfadiazine (0.70 mg) on the external surface. The antiseptic catheter and the standard catheter were totally identical in the outlook and during the study, the users did not know which type of catheter was used. Catheters were inserted by senior residents in intensive care units or anesthesiologist in the operation room. All those who performed the insertion procedure must wear masks, sterile gloves, and surgical gowns. The insertion sites was disinfected with 10% povidone-iodine, applied with scrubbing for at least 30 seconds. The catheter was then inserted percutaneously using the Seldinger technique. Sites were dressed with sterile gauze and tape. Every 48 hours the dressing was removed, the site was inspected and cleansed with povidone-iodine, and a new dressing was applied. Each time a catheter was scheduled to be inserted in a study patient, it was randomly assigned to be a control or an antiseptic catheter. The insertion sites of central venous catheters were also randomized. The patients’ physicians and nurses, the investigators, and the laboratory technologists who processed the cultures were blinded to know which kind of catheter was used. Each study catheter was evaluated daily by a team of research nurses and infectious diseases specialist. When the dressings were changed and when the catheter was removed, the site was visually inspected for signs of inflammation (localized redness, swelling, heat, tenderness, and pus discharge or accumulation). The catheters were removed if one of the following conditions existed: 1) inflammation at the catheter site or local pus accumulation; 2) new episode of fever, leukocytosis that
no other infection foci could be attributed; 3) patient die; 4) bacteremia or fungemia identified; 5) no more need of central venous catheterization. When removed, a 5-cm segment of the catheter tip was cut down and sent for culture. If a patient needed continued central venous access after the first study catheter was removed, subsequent catheters were also studied at the time of insertion. The subsequent catheter was inserted into a different site and each catheter was assigned randomly to be a control or an antiseptic catheter. Insertion site infection was defined as either localized inflammation or pus accumulation over the insertion site plus more than 15 colony-forming units (CFUs) of microorganism colonization on the subsequent catheter tip or positive pus culture. Peripheral blood cultures were done for patients who had localized inflammation or any signs of sepsis. Data obtained for each catheter included the patient’s medical diagnoses and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score (Knaus et al. 1985) on the first catheter day. The use of other invasive devices, clinical and laboratory data pertaining to infection, the anatomical location and the duration of the catheter insertion were also recorded. According to the study design, some patients received more than one catheter, and an analysis with catheters as the experimental units makes an assumption of independence. All the baseline demographic data, risks, bacterial or fungal colonization, bloodstream infection, potential benefit of the antiseptic catheters were analyzed with the catheters as study unit. 2.1. Microbiological Tests For each catheter, the 5-cm segment of the tip was cultured by the semi-quantitative roll-plate culture method (Maki et al. 1977). Microorganisms were identified by conventional method (Lennette et al. 1980) and Vitek Auto Microbic System (bioMerieux Vitek, Hazelwood, MO, USA). Catheter-tip colonization was defined as a positive culture of the intravascular catheter segment with more than 15 CFUs of bacteria or fungi by semi-quantitative culture method (Maki 1994). Blood specimens were inoculated into BACTEC 6A and 7A media and processed by using BACTEC NR 860 blood culture system (Becton-Dickinson, Sparks, MD, USA). Catheter-related bloodstream infection was defined as isolation of the same strain from the catheter segment and from one or more peripheral blood cultures, and showed the same antimicrobial susceptibility pattern in a patient with clinical manifestations of sepsis and no other apparent source of bloodstream infection. 2.2. Statistical Analysis The significance of differences between the two study groups was determined by the chi-square test or Fisher’s exact test for categorical data. All p values
W.H. Sheng et al. / Diagnostic Microbiology and Infectious Disease 38 (2000) 1–5 Table 1 Clinical Characteristics and Demographic Data of Cases
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3. Results
Variable
Control group (n ⫽ 122)
Antiseptic group (n ⫽ 113)
Male sex, % Mean age ⫾ SD, y Host risk factors, % Recent surgery Azotemia Diabetes Therapeutic risk factors, % TPN Other invasive intravascular lines Urinary catheters Mechanical ventilation Prior antibiotic usage Mean laboratory variables Hb ⫾ SD, g/dL ALT ⫾ SD, U/L BUN ⫾ SD, mg/dL APACHE II ⫾ SD Catheters location, % Internal jugular vein Subclavian vein Femoral veina Mean duration of catheterization ⫾ SD, d
62 61 ⫾ 18
60 64 ⫾ 18
96 24 19
94 25 21
5 100
3 100
100 93 10
100 97 6
12.4 ⫾ 2.2 44.7 ⫾ 67.9 25.4 ⫾ 16.5 10.4 ⫾ 4.6
12.1 ⫾ 2.3 46.9 ⫾ 69.4 26.2 ⫾ 16.5 10.4 ⫾ 4.5
87 2 11 8.2 ⫾ 4.6
92 3 5 9.1 ⫾ 5.5
Abbreviation: ALT ⫽ alanine aminotransferase; APACHE II ⫽ acute physiology and chronic health evaluation II; BUN ⫽ blood urea nitrogen; Hb ⫽ hemoglobin; SD ⫽ standard deviation, TPN ⫽ total parenteral nutrition. a There was no statistical difference in femoral catheterization rates between the two groups (p ⫽ 0.13).
reported were based on two-tailed tests of significance. All 95% confidence intervals (CIs) were calculated by Epi Info, version 5.0 (USD, Inc., Stone Mountain, Georgia, USA).
A total of 235 cases (122 cases of control group and 113 cases of antiseptic group) were included in this study. The age, sex, risk factors, and other clinical characteristics of these two groups were similar (Table 1). Most study cases were vulnerable to nosocomial infection, as shown by multiple invasive medical devices, recent surgery, and mechanical ventilation. More than 85% of the cases in each group had been inserted into internal jugular vein. Although a slightly more cases received femoral catheterization in the control group, there was no statistically significant difference in femoral catheterization rates between the two groups ( p ⫽ 0.13). Catheters remained in place for an average of 8.2 ⫾ 4.6 and 9.1 ⫾ 5.5 days, respectively (Table 1). No patient in either group experienced local or systemic hypersensitivity or toxicity ascribed to a study catheter. On the removal of the catheters, 34 cases (25 control cases and 9 antiseptic cases) were colonized by bacteria or fungi with more than 15 colony-forming units. Antiseptic group were less likely to be colonized than control group (8.0 versus 20.0 catheters colonized per 100 catheters; relative risk 0.34 [95% CI, 0.15 to 0.74]; p ⬍ 0.01) (Table 2). During the study period, six episodes of nosocomial bloodstream infection occurred in the control group and three in antiseptic group. Three bloodstream infections were catheter-related (two in the control group compared with one in the antiseptic group). Four of the control group and none of the antiseptic group had insertion site infection. Compared to the control group, the antiseptic group had nearly fivefold less likely to produce catheter-related infection. However, the p value of our analysis did not reveal a significant statistical difference (0.9 versus 4.9 infection per 100 catheters; relative risk 0.17 [95% CI, 0.03 to 1.15]; p ⫽ 0.07). There was no statistically significant difference in catheter-
Table 2 Outcomes of Catheter-Related Infection Variable
Deaths due to catheter-related infection, n (%) Catheter-related infection Catheter-related blood stream infectiona Catheter-related wound infection Colonized catheters, n (%) Gram-positive coccib Gram-negative bacillic Fungid a
Control group (n ⫽ 122) 2 (1.6) 6 (4.9) 2 4 25 (20.5) 14 4 7
Antiseptic group (n ⫽ 113)
Relative risk (95% CI)
0 (0) 1 (0.9) 1 0 9 (7.1) 6 2 1
p Value
0.27 0.17 (0.03–1.15)
0.34 (0.15–0.74)
0.07 0.53 0.71 0.006 0.06 0.84 0.04
Candida glabrata (one case) and Candida parapsilosis (1) in control group and methicillin-resistant Staphylococcus aureus (1) in antiseptic group. Including coagulase-negative Staphylococcus (4), Staphylococcus epidermidis (5), and Enterococcus species (5) in control group and coagulase-negative Staphylococcus (1), S. epidermidis (4), and methicillin-resistant S. aureus (1) in antiseptic group. c Including Enterobacter aerogenes (1), Enterobacter cloacae (1), Escherichia coli (1), and Pseudomonas aeruginosa (1) in control group and Enterobacter cloacae (1) and Proteus mirabilis (1) in antiseptic group. d Including Candida albicans (4), C. glabrata (2), and C. parapsilosis (1) in control group and C. albicans (1) in antiseptic group. b
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W.H. Sheng et al. / Diagnostic Microbiology and Infectious Disease 38 (2000) 1–5
related infections (including bacteremia) and colonizations between femoral sites and non-femoral sites of catheters ( p ⫽ 0.68 and 0.94, respectively). Gram-positive cocci, especially coagulase-negative staphylococci and Enterococcus species, and fungi were more likely to colonize in the control group ( p ⫽ 0.06 and 0.04, respectively). Two of the control group patients developed fungemia and died directly of the fungemia (Table 2). One was an 80-year-old man with multiple metastasis gastric cancer suffered from massive upper gastrointestinal tract bleeding and hypovolemic shock. He received central venous catheterization for transfusion. However, the patient developed multiple organ failure syndrome with catheter-related Candida glabrata bloodstream infection and died later. Another one was a 77-year-old man who had acute myocardial infarction with cardiogenic shock and developed catheter-related Candida parapsilosis bloodstream infection during stay in the ICU, then died of septic shock and multiple organ failure syndrome.
4. Discussion Central venous catheters have been widely used throughout the world. However, catheter-related bloodstream infection is the most frequent serious complication seen with these catheters. According to the published data from other centers, the central venous catheter-related infection occurs with 3% to 7% of incidence (Maki 1994). In our study, the infection rate in control group was 4.9%, which was compatible with other studies. Strategies designed to block the major sources of microorganisms to colonize the percutaneously inserted catheters for preventing central venous catheter-related bloodstream infection should be a maximum benefit. Studies in animal models of vascular catheterrelated infection suggest that coating or impregnating a catheter with an antibiotic or antiseptic should be of benefit (Trooskin et al. 1985; Sheretz et al. 1993). The chlorhexidine and silver sulfadiazine incorporated into the external surface of the antiseptic catheter can be slowly released into the surrounding tissues and skin that exert inhibitory activity against a wide range of nosocomial pathogens encountered in vascular catheter-related infection (Maki et al. 1997). Previous studies had revealed the benefit of antiseptic catheters usage for prevention of catheterrelated infection (Maki et al. 1988; Maki et al. 1997). Similar results were found in our study, none of the patients using antiseptic catheter developed local inflammation or pus accumulation, but four in the control group had these complications. The antiseptic catheter reduced the risk of infection nearly fivefold, but this was not statistically significant ( p ⫽ 0.07). It may be due to that the incidence of catheter-related infection was low and the case number in this study was not large enough. The incidence of bacterial colonization of central venous catheters using a standard polyurethane catheter was 20.0 per 100 catheters compared
to 8.0 of the antiseptic group. The greatest benefit was seen for prevention of colonization caused by gram-positive cocci (especially coagulase-negative staphylococci and enterococci) and fungi. Chlorhexidine, a cationic biguanide, is a potent broad-spectrum antiseptic agent against many nosocomial-transmitted bacteria and yeasts, including Candida species (Gardner and Gray 1983; Freney et al. 1988). Silver sulfadiazine has also been used topically throughout the world for many years, mainly on burn wounds, where it delays colonization and substantially reduces the incidence of major infection (Hoffmann 1984; Sawhney et al. 1989; Carr et al. 1973). Moreover, the combination of the antiseptic chlorhexidine and antiseptic-antibiotic silver sulfadiazine exhibit synergistic effect in vitro and prevent the emergence of resistant bacteria (Quesnal et al. 1978). It is then no doubt that polyurethane central venous catheters impregnated with these agents will render them resistant to infection. The safety of chlorhexidine and silver sulfadiazine had been well established for many years. Toxicity of chlorhexidine and silver sulfadiazine, including hypersensitivity and leukopenia has been rarely reported (Terazawa et al. 1998), as in our patients, no one was found to have adverse effects. Use of antibiotics (minocycline/rifampin)-impregnated catheter was found to be associated with a lower rate of catheter-related bloodstream infection (CRBI) than the use of antiseptic (chlorhexidine/silver sulfadiazine)-coated catheter (Darouiche et al. 1999). However, residual antimicrobial activity in the removed catheter could sufficient prevent growth from the cultured catheter in the microbiology laboratory but does not eliminate the clinical syndrome of CRBI (Paterson 1999). Furthermore, the catheter of our study and currently being marketed is only coated on the external surface, which may explain why it was found to be inferior to the antibiotics (minocycline/rifampin)-impregnated catheter that is coated internally and externally. Drug-resistant bacteria may be emerged when a catheter coated with therapeutic agents was used. Continued surveillance for resistance is required when antibiotics-impregnated catheters are used routinely in every patient. On the contrary, previous studies did not find any appearance of chlorhexidine/silver sulfadiazine resistant grampositive organisms when chlorhexidine/silver sulfadiazine coated catheters were used (Collin 1999; Hannan et al. 1999). Some authors believe that if chlorhexidine/silver sulfadiazine was coated on both external and internal surface, there probably will be better effects in preventing colonization and/or catheter-related infection. Currently, a study of such kind of new chlorhexidine/silver sulfadiazine coated catheter is ongoing. In conclusion, patients using catheters impregnated with antiseptic agents (chlorhexidine and silver sulfadiazine) had less microorganism colonization compared with conventional catheters. Antiseptic catheters also exhibit antifungal activity and could potentially reduce the mortality of catheter-related fungemia. However, it requires a larger population study to
W.H. Sheng et al. / Diagnostic Microbiology and Infectious Disease 38 (2000) 1–5
confirm this preliminary finding. Adverse effects were not found in our patients, so it could be used safely.
References American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20, 864 –74. Banerjee, S., Emori, T., & Culver, D. (1991). Secular trends in nosocomial primary bloodstream infections in the United States, 1980 – 89. Am J Med 91 (3B): 86S– 89S. Carr, H. S., Wlodkowski, T. J., & Rozenkranz, H. S. (1973). Silver sulfadiazine: in vitro antibacterial activity. Antimicrob Agents Chermother 4, 585–590. Collin, G. R. (1999). Decreasing catheter colonization through the use of an antiseptic-impregnated catheter-a continuous quality improvement project. Chest 115, 1632–1640. Darouiche, R. D., Raad, I. I., Heard, S. O., Thornby, J. I., Wenker, O. C., Gabrielli, A., Berg, J., Khardori, N., Hanna, H., Hachem, R., Harris, R. L., & Mayhall, G. (1999). A comparison of two antimicrobialimpregnated central venous catheters. N Engl J Med 340, 1– 8. Freney, J., Husson, M. O., Gavini, F., Madier, S., Martra, A., Izard, D., Leclerc, H., & Fleurette, J. (1988). Susceptibilities to antibiotics and antiseptics of new species of the family Enterobacteriaceae. Antimicrob Agents Chemother 32, 873– 876. Gardner, J. F., & Gray, K. G. (1983). Chlorhexidine. In: Disinfection, sterilization and preservation. Ed, Block, S. S., Philadelphia: Lea & Febiger, pp. 251–270. Hannan, M., Juste, R. N., Umasanker, S., Glendenning, A., Nightingale, C., Azadian, B., & Soni, N. (1999). Antiseptic-bonded central venous catheters and bacterial colonization. Anaesthesia 54, 868 – 872. Hoffmann, S. (1984). Silver sulfadiazine: an antibacterial agent for topical use in burns. A review of the literature. Scand J Plast Reconstr Surg 18, 119 –126. Knaus, W. A., Draper, E. A., Wagner, D. P., & Zimmerman, J. E. (1985). APACHE II: a severity of disease classification system. Crit Care Med 13, 818 – 829. Lennette, E., Balows, A., Hausler, W., & Shadomy, H. (1980). Manual of Clinical Microbiology, 3rd ed. Washington, DC: American Society for Microbiology. Levin, A., Mason, A. J., Jindal, K. K., Fong, I. W., & Goldstein, M. B. (1991). Prevention of hemodialysis subclavian vein catheter infections by topical povidine-iodine. Kidney Int 40, 934 –938.
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Maki, D. G. (1994). Infections caused by intravascular devices used for infusion therapy: pathogenesis, prevention, and management. In: Infections Associated with Indwelling Medical Devices, 2nd Ed. Eds, Bistro, A., and Waldvogel, F. A. Washington, DC: ASM Pr, pp. 155–205. Maki, D. G., Cobb, L., Garman, J. K., Shapiro, J. M., Ringer, M., & Helgerson, R. B. (1988). An attachable silver-impregnated cuff for prevention of infection with central venous catheters: a prospective randomized multi-center trial. Am J Med 85, 307–314. Maki, D. G., Ringer, M., & Alvarado, C. J. (1991). Prospective randomized trial of povidine-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet 338, 339 –343. Maki, D. G., Stolz, A. M., Wheeler, S., & Mermel, L. A. (1997). Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter. Ann Intern Med 127, 257–266. Maki, D. G., Weise, C. E., & Sarafin, H. W. (1977). A semiquantitative culture method for identifying intravenous-catheter-related infection. N Engl J Med 296, 1305–1309. Paterson, D. L. (1999). Antimicrobial-impregnated central venous catheters. N Engl J Med 340, 1761–1762. Quesnal, L. B., Al-Najjar, A. R., & Buddhavudhikrai, P. (1978). Synergism between chlorhexidine and sulphadiazine. J Appl Bacteriol 45, 397– 403. Sawhney, C. P., Sharma, R. K., Rao, K. R., & Kaushish, R. (1989). Long-term experience with 1 percent topical silver sulphadiazine cream in the management of burn wounds. Burns 15, 403– 406. Schmitt, S. K., Knapp, C., Hall, G. S., Longworth, D. L., McMahon, J. T., & Washington, J. A. (1996). Impact of chlorhexidine-silver sulfadiazine-impregnated central venous catheters on the in vitro quantitation of catheter-associated bacteria. J Clin Microbiol 34, 508 –511. Sheretz, R. J., Carruth, W. A., Hampton, A. A., Byron, M. P., & Solomon, D. D. (1993). Efficacy of antibiotic-coated catheters in preventing subcutaneous Staphylococcus aureus infection in rabbits. J Infect Dis 167, 98 –106. Taynes, R., Culver, D., & Emori, T. (1991). The National Nosocomial Infections Surveillance System: Plans for the 1990s and beyond. Am J Med 91 (3B): 116S–120S. Terazawa, E., Shimonaka, H., Nagase, K., Masue, T., & Dohi, S. (1998). Severe anaphylactic reaction due to a chlorhexidine-impregnated central venous catheter. Anesthesiol 89, 1296 –1298. Trooskin, S. Z., Donetz, A. P., Harvey, R. A., & Greco, R. S. (1985). Prevention of catheter sepsis by antibiotic bonding. Surgery 97, 547– 551.
www.elsevier.com/locate/diagmicrobio
Bacteriology
Evaluation of antiseptic-impregnated central venous catheters for prevention of catheter-related infection in intensive care unit patients Wang-Huei Sheng, Wen-Je Ko, Jann-Tay Wang, Shan-Chwen Chang, Po-Ren Hsueh, Kwen-Tay Luh Department of Internal Medicine, Surgery and Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan Received 7 February 2000; accepted 6 June 2000
Abstract Central venous catheterization represents a significant medical advancement, particularly in the treatment of critical ill. However, there is a high risk of central venous catheters-related infection. A novel antiseptic central venous catheter, made of polyurethane and impregnated with chlorhexidine and silver sulfadiazine, was developed to reduce the risk of catheters-related infection. In this study, we did a randomized clinical study to determine the efficacy by using antiseptic catheters for the prevention of central venous catheters-related infection in the intensive care units. A total of 204 patients with 235 central venous catheters were studied at the surgical intensive care units at National Taiwan University Hospital between November 1998 and June 1999. Participants received either a standard triple-lumen polyurethane catheter or an antiseptic catheter (Arrow International, Reading, Pennsylvania, USA). Both were indistinguishable from each other. Compared to standard polyurethane catheters, antiseptic catheters were less likely to be colonized by microorganisms when they were cultured at the removal (8.0 versus 20.0 colonized catheters per 100 catheters; relative risk 0.34 [95% CI, 0.15 to 0.74]; p ⬍ 0.01). There was no significant differences between both groups in catheter-related infections (0.9 versus 4.9 infections per 100 catheters; relative risk 0.17 [95% CI, 0.03 to 1.15]; p ⫽ 0.07). Gram-positive cocci and fungi were more likely to colonize in the standard polyurethane catheters ( p ⫽ 0.06 and 0.04, compared to antiseptic catheters respectively). Two of our cases in the control group died directly due to catheter-related candidemia. No adverse reactions such as hypersensitivity or leukopenia were found in the antiseptic catheter group. Our study showed that central venous catheters with antiseptic coating were safe and had less risk of colonization of bacteria and fungi than standard catheters in the critically ill patients. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Central venous catheter, Antiseptic catheter, Catheter-related infection
1. Introduction Indwelling central venous catheters are used universally in the management of critically ill patients today. However, blood stream infection and bacterial colonization related to the use of central venous catheters are common and serious problems. In previous surveillance, central venous catheters account for 90% of all vascular catheter-related bloodstream infections (Banerjee et al. 1991; Taynes et al. 1991). Technologic innovations to block microbial access to the transcutaneous tract, such as use of topical application of potent antiseptics (Maki et al. 1991) or antimicrobials (Levin et al. 1991), or attachment of a subcutaneous silver-impregnated * Corresponding author. Tel.: ⫹886-2-23123456 ext. 5401; fax: ⫹8862-23971412. E-mail address: [email protected] (S.C. Chang).
cuff (Maki et al. 1988), have helped prevent catheter-related infection (CRI). An antiseptic central venous catheter, made of polyurethane and impregnated with chlorhexidine and silver sulfadiazine, was developed. The two antiseptics chlorhexidine and silver sulfadiazine, had exhibited both potent bactericidal and fungicidal activities in vitro (Carr et al. 1973; Hoffmann 1984; Quesnal et al. 1978; Schmitt et al. 1996). These cutaneous disinfection agents also had been used widely for decades to prevent burn wound or surgical wound infections (Gardner and Gray 1983; Sawhney et al. 1989). A prospective randomized study was conducted at National Taiwan University Hospital (NTUH), a tertiary medical center with 2000-bed capacity located in the northern Taiwan, to compare the effectiveness of antiseptic catheter versus standard central venous catheter in preventing CRI and colonization, and the safety of their use in Taiwanese critical ill patients.
0732-8893/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 2 - 8 8 9 3 ( 0 0 ) 0 0 1 6 6 - 8
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W.H. Sheng et al. / Diagnostic Microbiology and Infectious Disease 38 (2000) 1–5
2. Materials and methods This study was conducted at the surgical intensive care units at NTUH between November 1998 and June 1999. All adult patients who were not allergic to chlorhexidine, silver, or sulfonamides and were scheduled to receive a central venous catheter were eligible to participate. Those who had known bacteremia or fungemia episodes within two weeks before the central venous catheter insertion were excluded. Febrile patients (oral temperature more than 38°C) and patients with sepsis syndrome within one week or at the time of catheter insertion were also excluded. Sepsis in these patients was defined as clinical evidence of infection plus at least two of the following systemic inflammatory responses: 1) oral temperature of ⱖ38°C or ⱕ36°C; 2) respiratory rate of ⱖ20 breaths/minute or PaCO2 of ⱕ32 torr; 3) heart rate of ⱖ90 beats/minute; 4) blood leukocyte ⱖ12000/mm3 or ⱕ4000/mm3 or band form of leukocyte ⱖ10% (American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee 1992). Two types of noncuffed, triple-lumen central venous catheters manufactured by Arrow International (Reading, PA, USA) were used in this study: the standard 16-G polyurethane catheter as control group and the antiseptic catheter of the same size as test group, which is impregnated with minute quantities of chlorhexidine gluconate (0.75 mg) and silver sulfadiazine (0.70 mg) on the external surface. The antiseptic catheter and the standard catheter were totally identical in the outlook and during the study, the users did not know which type of catheter was used. Catheters were inserted by senior residents in intensive care units or anesthesiologist in the operation room. All those who performed the insertion procedure must wear masks, sterile gloves, and surgical gowns. The insertion sites was disinfected with 10% povidone-iodine, applied with scrubbing for at least 30 seconds. The catheter was then inserted percutaneously using the Seldinger technique. Sites were dressed with sterile gauze and tape. Every 48 hours the dressing was removed, the site was inspected and cleansed with povidone-iodine, and a new dressing was applied. Each time a catheter was scheduled to be inserted in a study patient, it was randomly assigned to be a control or an antiseptic catheter. The insertion sites of central venous catheters were also randomized. The patients’ physicians and nurses, the investigators, and the laboratory technologists who processed the cultures were blinded to know which kind of catheter was used. Each study catheter was evaluated daily by a team of research nurses and infectious diseases specialist. When the dressings were changed and when the catheter was removed, the site was visually inspected for signs of inflammation (localized redness, swelling, heat, tenderness, and pus discharge or accumulation). The catheters were removed if one of the following conditions existed: 1) inflammation at the catheter site or local pus accumulation; 2) new episode of fever, leukocytosis that
no other infection foci could be attributed; 3) patient die; 4) bacteremia or fungemia identified; 5) no more need of central venous catheterization. When removed, a 5-cm segment of the catheter tip was cut down and sent for culture. If a patient needed continued central venous access after the first study catheter was removed, subsequent catheters were also studied at the time of insertion. The subsequent catheter was inserted into a different site and each catheter was assigned randomly to be a control or an antiseptic catheter. Insertion site infection was defined as either localized inflammation or pus accumulation over the insertion site plus more than 15 colony-forming units (CFUs) of microorganism colonization on the subsequent catheter tip or positive pus culture. Peripheral blood cultures were done for patients who had localized inflammation or any signs of sepsis. Data obtained for each catheter included the patient’s medical diagnoses and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score (Knaus et al. 1985) on the first catheter day. The use of other invasive devices, clinical and laboratory data pertaining to infection, the anatomical location and the duration of the catheter insertion were also recorded. According to the study design, some patients received more than one catheter, and an analysis with catheters as the experimental units makes an assumption of independence. All the baseline demographic data, risks, bacterial or fungal colonization, bloodstream infection, potential benefit of the antiseptic catheters were analyzed with the catheters as study unit. 2.1. Microbiological Tests For each catheter, the 5-cm segment of the tip was cultured by the semi-quantitative roll-plate culture method (Maki et al. 1977). Microorganisms were identified by conventional method (Lennette et al. 1980) and Vitek Auto Microbic System (bioMerieux Vitek, Hazelwood, MO, USA). Catheter-tip colonization was defined as a positive culture of the intravascular catheter segment with more than 15 CFUs of bacteria or fungi by semi-quantitative culture method (Maki 1994). Blood specimens were inoculated into BACTEC 6A and 7A media and processed by using BACTEC NR 860 blood culture system (Becton-Dickinson, Sparks, MD, USA). Catheter-related bloodstream infection was defined as isolation of the same strain from the catheter segment and from one or more peripheral blood cultures, and showed the same antimicrobial susceptibility pattern in a patient with clinical manifestations of sepsis and no other apparent source of bloodstream infection. 2.2. Statistical Analysis The significance of differences between the two study groups was determined by the chi-square test or Fisher’s exact test for categorical data. All p values
W.H. Sheng et al. / Diagnostic Microbiology and Infectious Disease 38 (2000) 1–5 Table 1 Clinical Characteristics and Demographic Data of Cases
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3. Results
Variable
Control group (n ⫽ 122)
Antiseptic group (n ⫽ 113)
Male sex, % Mean age ⫾ SD, y Host risk factors, % Recent surgery Azotemia Diabetes Therapeutic risk factors, % TPN Other invasive intravascular lines Urinary catheters Mechanical ventilation Prior antibiotic usage Mean laboratory variables Hb ⫾ SD, g/dL ALT ⫾ SD, U/L BUN ⫾ SD, mg/dL APACHE II ⫾ SD Catheters location, % Internal jugular vein Subclavian vein Femoral veina Mean duration of catheterization ⫾ SD, d
62 61 ⫾ 18
60 64 ⫾ 18
96 24 19
94 25 21
5 100
3 100
100 93 10
100 97 6
12.4 ⫾ 2.2 44.7 ⫾ 67.9 25.4 ⫾ 16.5 10.4 ⫾ 4.6
12.1 ⫾ 2.3 46.9 ⫾ 69.4 26.2 ⫾ 16.5 10.4 ⫾ 4.5
87 2 11 8.2 ⫾ 4.6
92 3 5 9.1 ⫾ 5.5
Abbreviation: ALT ⫽ alanine aminotransferase; APACHE II ⫽ acute physiology and chronic health evaluation II; BUN ⫽ blood urea nitrogen; Hb ⫽ hemoglobin; SD ⫽ standard deviation, TPN ⫽ total parenteral nutrition. a There was no statistical difference in femoral catheterization rates between the two groups (p ⫽ 0.13).
reported were based on two-tailed tests of significance. All 95% confidence intervals (CIs) were calculated by Epi Info, version 5.0 (USD, Inc., Stone Mountain, Georgia, USA).
A total of 235 cases (122 cases of control group and 113 cases of antiseptic group) were included in this study. The age, sex, risk factors, and other clinical characteristics of these two groups were similar (Table 1). Most study cases were vulnerable to nosocomial infection, as shown by multiple invasive medical devices, recent surgery, and mechanical ventilation. More than 85% of the cases in each group had been inserted into internal jugular vein. Although a slightly more cases received femoral catheterization in the control group, there was no statistically significant difference in femoral catheterization rates between the two groups ( p ⫽ 0.13). Catheters remained in place for an average of 8.2 ⫾ 4.6 and 9.1 ⫾ 5.5 days, respectively (Table 1). No patient in either group experienced local or systemic hypersensitivity or toxicity ascribed to a study catheter. On the removal of the catheters, 34 cases (25 control cases and 9 antiseptic cases) were colonized by bacteria or fungi with more than 15 colony-forming units. Antiseptic group were less likely to be colonized than control group (8.0 versus 20.0 catheters colonized per 100 catheters; relative risk 0.34 [95% CI, 0.15 to 0.74]; p ⬍ 0.01) (Table 2). During the study period, six episodes of nosocomial bloodstream infection occurred in the control group and three in antiseptic group. Three bloodstream infections were catheter-related (two in the control group compared with one in the antiseptic group). Four of the control group and none of the antiseptic group had insertion site infection. Compared to the control group, the antiseptic group had nearly fivefold less likely to produce catheter-related infection. However, the p value of our analysis did not reveal a significant statistical difference (0.9 versus 4.9 infection per 100 catheters; relative risk 0.17 [95% CI, 0.03 to 1.15]; p ⫽ 0.07). There was no statistically significant difference in catheter-
Table 2 Outcomes of Catheter-Related Infection Variable
Deaths due to catheter-related infection, n (%) Catheter-related infection Catheter-related blood stream infectiona Catheter-related wound infection Colonized catheters, n (%) Gram-positive coccib Gram-negative bacillic Fungid a
Control group (n ⫽ 122) 2 (1.6) 6 (4.9) 2 4 25 (20.5) 14 4 7
Antiseptic group (n ⫽ 113)
Relative risk (95% CI)
0 (0) 1 (0.9) 1 0 9 (7.1) 6 2 1
p Value
0.27 0.17 (0.03–1.15)
0.34 (0.15–0.74)
0.07 0.53 0.71 0.006 0.06 0.84 0.04
Candida glabrata (one case) and Candida parapsilosis (1) in control group and methicillin-resistant Staphylococcus aureus (1) in antiseptic group. Including coagulase-negative Staphylococcus (4), Staphylococcus epidermidis (5), and Enterococcus species (5) in control group and coagulase-negative Staphylococcus (1), S. epidermidis (4), and methicillin-resistant S. aureus (1) in antiseptic group. c Including Enterobacter aerogenes (1), Enterobacter cloacae (1), Escherichia coli (1), and Pseudomonas aeruginosa (1) in control group and Enterobacter cloacae (1) and Proteus mirabilis (1) in antiseptic group. d Including Candida albicans (4), C. glabrata (2), and C. parapsilosis (1) in control group and C. albicans (1) in antiseptic group. b
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W.H. Sheng et al. / Diagnostic Microbiology and Infectious Disease 38 (2000) 1–5
related infections (including bacteremia) and colonizations between femoral sites and non-femoral sites of catheters ( p ⫽ 0.68 and 0.94, respectively). Gram-positive cocci, especially coagulase-negative staphylococci and Enterococcus species, and fungi were more likely to colonize in the control group ( p ⫽ 0.06 and 0.04, respectively). Two of the control group patients developed fungemia and died directly of the fungemia (Table 2). One was an 80-year-old man with multiple metastasis gastric cancer suffered from massive upper gastrointestinal tract bleeding and hypovolemic shock. He received central venous catheterization for transfusion. However, the patient developed multiple organ failure syndrome with catheter-related Candida glabrata bloodstream infection and died later. Another one was a 77-year-old man who had acute myocardial infarction with cardiogenic shock and developed catheter-related Candida parapsilosis bloodstream infection during stay in the ICU, then died of septic shock and multiple organ failure syndrome.
4. Discussion Central venous catheters have been widely used throughout the world. However, catheter-related bloodstream infection is the most frequent serious complication seen with these catheters. According to the published data from other centers, the central venous catheter-related infection occurs with 3% to 7% of incidence (Maki 1994). In our study, the infection rate in control group was 4.9%, which was compatible with other studies. Strategies designed to block the major sources of microorganisms to colonize the percutaneously inserted catheters for preventing central venous catheter-related bloodstream infection should be a maximum benefit. Studies in animal models of vascular catheterrelated infection suggest that coating or impregnating a catheter with an antibiotic or antiseptic should be of benefit (Trooskin et al. 1985; Sheretz et al. 1993). The chlorhexidine and silver sulfadiazine incorporated into the external surface of the antiseptic catheter can be slowly released into the surrounding tissues and skin that exert inhibitory activity against a wide range of nosocomial pathogens encountered in vascular catheter-related infection (Maki et al. 1997). Previous studies had revealed the benefit of antiseptic catheters usage for prevention of catheterrelated infection (Maki et al. 1988; Maki et al. 1997). Similar results were found in our study, none of the patients using antiseptic catheter developed local inflammation or pus accumulation, but four in the control group had these complications. The antiseptic catheter reduced the risk of infection nearly fivefold, but this was not statistically significant ( p ⫽ 0.07). It may be due to that the incidence of catheter-related infection was low and the case number in this study was not large enough. The incidence of bacterial colonization of central venous catheters using a standard polyurethane catheter was 20.0 per 100 catheters compared
to 8.0 of the antiseptic group. The greatest benefit was seen for prevention of colonization caused by gram-positive cocci (especially coagulase-negative staphylococci and enterococci) and fungi. Chlorhexidine, a cationic biguanide, is a potent broad-spectrum antiseptic agent against many nosocomial-transmitted bacteria and yeasts, including Candida species (Gardner and Gray 1983; Freney et al. 1988). Silver sulfadiazine has also been used topically throughout the world for many years, mainly on burn wounds, where it delays colonization and substantially reduces the incidence of major infection (Hoffmann 1984; Sawhney et al. 1989; Carr et al. 1973). Moreover, the combination of the antiseptic chlorhexidine and antiseptic-antibiotic silver sulfadiazine exhibit synergistic effect in vitro and prevent the emergence of resistant bacteria (Quesnal et al. 1978). It is then no doubt that polyurethane central venous catheters impregnated with these agents will render them resistant to infection. The safety of chlorhexidine and silver sulfadiazine had been well established for many years. Toxicity of chlorhexidine and silver sulfadiazine, including hypersensitivity and leukopenia has been rarely reported (Terazawa et al. 1998), as in our patients, no one was found to have adverse effects. Use of antibiotics (minocycline/rifampin)-impregnated catheter was found to be associated with a lower rate of catheter-related bloodstream infection (CRBI) than the use of antiseptic (chlorhexidine/silver sulfadiazine)-coated catheter (Darouiche et al. 1999). However, residual antimicrobial activity in the removed catheter could sufficient prevent growth from the cultured catheter in the microbiology laboratory but does not eliminate the clinical syndrome of CRBI (Paterson 1999). Furthermore, the catheter of our study and currently being marketed is only coated on the external surface, which may explain why it was found to be inferior to the antibiotics (minocycline/rifampin)-impregnated catheter that is coated internally and externally. Drug-resistant bacteria may be emerged when a catheter coated with therapeutic agents was used. Continued surveillance for resistance is required when antibiotics-impregnated catheters are used routinely in every patient. On the contrary, previous studies did not find any appearance of chlorhexidine/silver sulfadiazine resistant grampositive organisms when chlorhexidine/silver sulfadiazine coated catheters were used (Collin 1999; Hannan et al. 1999). Some authors believe that if chlorhexidine/silver sulfadiazine was coated on both external and internal surface, there probably will be better effects in preventing colonization and/or catheter-related infection. Currently, a study of such kind of new chlorhexidine/silver sulfadiazine coated catheter is ongoing. In conclusion, patients using catheters impregnated with antiseptic agents (chlorhexidine and silver sulfadiazine) had less microorganism colonization compared with conventional catheters. Antiseptic catheters also exhibit antifungal activity and could potentially reduce the mortality of catheter-related fungemia. However, it requires a larger population study to
W.H. Sheng et al. / Diagnostic Microbiology and Infectious Disease 38 (2000) 1–5
confirm this preliminary finding. Adverse effects were not found in our patients, so it could be used safely.
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