Bacterial Colonization of Thrombosed Dialysis Arteriovenous Grafts Gerald A. Beathard Lifeline Vasacular Access, Houston, Texas

ABSTRACT In the absence of obvious infection, an abandoned arteriovenous graft (AVG) is generally left in place. This has been thought to be the best solution in view of the surgical procedure that would be required for its removal. However, there are reports of occult infection in these retained AVGs that can lead to significant infectious complications. In addition, there is evidence that abandoned, retained AVGs may contribute to the inflamma-

tory state that exist in association with dialysis patients. This observational report of 100 cases of thrombosed AVG in which the thrombus was cultured at the time of thrombectomy demonstrated a significant degree of bacterial colonization in these cases without evidence of bacteremia. It is proposed that this could be the mechanism by which occult infection in an abandoned, retained AVGs occurs.

An arteriovenous dialysis access graft (AVG) has a limited life expectancy. Unless there are overt clinical signs or symptoms indicating the presence of infection, and AVG that is no longer being used for dialysis treatments is left in place. It is not unusual to see a patient who has been on dialysis for multiple years with several retained nonfunctioning AVGs. Unfortunately, these abandoned AVGs can harbor occult infection which can eventually lead to complications (1–6). Inflammation as indicated by an elevated C-reactive protein level as well as other acute phase reactants, is a prominent characteristic of patients undergoing hemodialysis treatments (7,8). In addition, it is been suggested that C-reactive protein may be a risk factor for cardiovascular and all-cause mortality in these patients (9–14). The etiology of the inflammation observed in association with these patients is variable and multifactorial (15). An unusual and potentially preventable cause is that of the occult infection in an abandoned, retained AVG (1–6). It has been suggested that the infection arising in a retained AVG was metastatic; the result of bacteria entering the bloodstream from other sites such as cannulation of a functioning arteriovenous access or from an infected central venous catheter (16).

The purpose of this report was to present an alternative hypothesis, i.e., that the AVG may have been colonized with bacteria at the time it was abandoned. The majority of these accesses are abandoned at the time of thrombosis. An AVG in poor condition is used as long as possible. When it becomes thrombosed, it is not salvaged. If the thrombus that is present is colonized with bacteria at that time, infection can continue to smolder until it becomes apparent for some reason. Methods This observational study was approved by the institutional review board and involved patients receiving thrice weekly in-center hemodialysis from multiple dialysis clinics. They received vascular access management care at a single interventional facility. To participate in the study, the patient was required to have a thrombosed AVG which was successfully treated. A thrombosed AVG was defined as one containing thrombus and having no blood flow by physical examination and angiographic evaluation. The thrombectomy procedure was considered successful if unobstructed flow through the access could be established sufficient and persistent enough to allow for one subsequent normal dialysis. Any clinical evidence or physical findings suggesting the presence of either a superficial or deep infection of the AVG was a disqualification for the study. A total of 100 patients were entered into the study. All cases were treated by a single interventionalist using a mechanical thrombectomy technique. This was a combined procedure involving

Address correspondence to: Gerald A. Beathard, Lifeline Vasacular Access, 9073 Briar Forest, Houston, TX 77024, e-mail: [email protected]. Seminars in Dialysis—Vol 28, No 4 (July–August) 2015 pp. 446–449 DOI: 10.1111/sdi.12360 © 2015 Wiley Periodicals, Inc. 446

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angiography to evaluate the anatomy and localize any stenotic lesions, balloon (Fogarty catheter)assisted thrombectomy with clot aspiration through a sheath using a 20-ml syringe, and angioplasty to treat any associated stenoses. Mechanical thrombectomy devices and lytic agents were not used. All thrombectomy procedures were all conducted in a surgery suite type procedure room using maximum barrier protection. The patient’s entire arm was prepped using 2% chlorhexidine in 70% alcohol and then draped with a sterile surgical drape. All personnel involved in the procedure wore surgical gowns, gloves, caps, and mask. A portion of the aspirated thrombus fragments was directly injected into aerobic and anaerobic blood culture bottles. The tip of the Fogarty catheter, the tip of the angioplasty balloon, and a sample of the flush solution (heparinized saline—1:100) were submitted for culture. In addition, the procedure table top was cultured using a sterile swab to sample its surface. The clinical lab was contacted the next morning to see if any of the thrombus cultures appeared to be positive. If any patient’s cultures were positive, their dialysis clinic was contacted to obtain a blood culture. Blood cultures were not performed on negative thrombus culture patients. All dialysis clinics referring patients to the interventional facility operated 6 days per week with three shifts of patients per day. These three shifts were designated as morning (7 AM), noon (12 noon) and evening (6 PM). In some instances, the patient would detect a thrombosed AVG before arriving at the dialysis clinic for their treatment. These patients were immediately referred to the interventional facility for treatment, generally the same day. Most patients with a thrombosed AVG were not detected until they arrived at the dialysis clinic for their regularly scheduled treatment. Patients presenting for the morning and noon shifts on Monday through Friday were immediately referred to the interventional facility and were treated that day. Patients presenting for the evening shift on Monday through Thursday were referred and treated the following day. Patients presenting for the Friday evening shift and all three shifts on Saturday were referred and treated the following Monday unless their clinical situation did not permit the delay. Due to this schedule, patients derived from six shifts were treated on Monday while patients derived from only three shifts were treated on Tuesday through Friday. Follow-up data were obtained on all patients 30 days following the index thrombectomy procedure to determine if any clinical evidence of access infection or bacteriemia had occurred during this period. Results Thrombus cultures were positive in 36 of the 100 cases (Table 1). All blood cultures obtained

the day following the positive thrombus culture where negative. These follow-up blood cultures were obtained in all except one case. In this instance, the patient died of a cause not related to the procedure prior to having a blood culture obtained. Cultures obtained from the tips of the Fogarty and angioplasty balloon catheters, the flush solution, and the swabs of the tabletop were all negative (Table 1). The organisms isolated from the positive cultures are shown in Table 2. Most of these were Staphylococcus (33 cases) with Staphylococcus epidermitis being the predominant organisms isolated (27 cases). Streptococcus viridans and diphtheroids were each isolated in two cases. Bacillus species was isolated from one case. In two cases, the bacterial isolate was mixed, Staphylococcus epidermidis with Streptococcus viridans in one instance and with bacillus species in the second instance. Both the number of AVG thrombectomy cases and the number of cases with positive thrombus cultures was not equal on each of the days of the week (Figs 1 and 2). A total of 32 cases (32%) were seen on Mondays. Of these, 50% (16) had positive thrombus cultures. This represented 44% of the total cases. The odds ratio (OR) for a positive thrombus culture for Monday cases was 2.4. The number of thrombosed cases seen on the other 4 days of the week ranged from 15 to 20 with a positive thrombus incidence ranging from 27% to 35%. The OR for a positive culture on Tuesday through Friday ranged from 0.49 to 0.85. No patient within this cohort developed clinical evidence of either bacteriemia or an access infection during the 30 days following their index thrombectomy procedure. TABLE 1. Culture results Category Thrombus Blood culture (at 24 hours) Fogarty catheter tip Angioplasty balloon tip Flush solution Table top

Negative

Positive

Total

64 99* 100 100 100 100

36 0 – – – –

100 99* 100 100 100 100

* One patient with a positive thrombus culture died before having a blood culture performed.

TABLE 2. Bacterial isolates from thrombus cultures Organism Staphylococcus epidermidis Staphylococcus aureus Staphylococcus hominis Staphylococcus auricularis Streptococcus viridans Diphtheroids Bacillus species Mixed

Number 27 1 4 1 2 2 1 2

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Fig. 1. Distribution of cases by day of week.

Discussion Approximately, 85% of AVG failure occurs at the time of thrombosis (17). A problematic AVG is generally used until it clots and cannot be salvaged, then it is abandoned and left in place. Surgical removal is generally not performed because of the procedure that would be required and it is not felt to be necessary. As a result many AVG-dependent patients have one or more abandoned, retained accesses. These have generally been thought of as being innocuous; however, several reports have shown that they may harbor an occult bacterial infection which can lead to complications (1–6). Nassar et al., (4) examined two groups of patients. The first group consisted of 20 patients with abandoned AVGs who presented with either fever or fever and clinical signs of sepsis. The source of infection was not clinically apparent in these cases. The patients were evaluated using an indium scan which showed uptake in and around the retained AVG in all 20 cases. Purulent material was obtained from the retained AVG in all 20 cases. Blood cultures were positive in 15 of the cases and corresponded to the organisms isolated from the AVG. The second group of patients which were evaluated consisted of 21 asymptomatic hemodialysis cases with abandoned, retained AVGs. Indium uptake was present in or around the retained AVG in 15 of these cases. Blood cultures were negative in

Fig. 2. Percentage of total cases observed by day of week.

all of these asymptomatic patients. Purulent material was aspirated from the retained AVG in 13 of the 15 cases having a positive scan. The cultures were predominately Staphylococcus. The natural history of abandoned, retained AVGs colonized with bacteria has not been fully explored. This cluster of reports (1–6) provides evidence that they can cause infectious problems. There is also evidence to suggest that they may cause noninfectious problems by contributing to the chronic inflammatory state that is associated with dialysis patients. In a study (6) designed to investigate this relationship, 20 hemodialysis patients were identified with the chronic inflammatory state based on erythropoietin resistance, low serum albumin, and elevated C-reactive protein. Eight of these patients had abandoned, retained AVGs. An indium scan was positive in six of these cases. The surgically resected AVG contained purulent material which grew Staphylococcus aureus. Follow-up data at 2 months on these cases showed a marked improvement in the previously abnormal parameters compared to preresection values. This prospective data were compared with retrospectively collected data on 22 patients who had had surgical resection of an old abandoned, retained AVG which had clinically proven occult infection. All of these cases had shown marked anemia, hypoalbuminemia and erythropoietin resistance prior to AVG removal. Laboratory evaluation done at 3 months postsurgery also showed a marked improvement in hemoglobin and albumin levels, and a fall in erythropoietin requirements in these cases. This relationship between abandoned, retained AVGs and the chronic inflammatory state associated with dialysis patients was also suggested by a study illustrating that the severity of inflammation as judged by plasma levels of C-reactive protein, interleukin-6, tumor necrosis factor alpha and albumin was associated with the number of retained AVGs that were present (16). In this study, the thrombus in a thrombosed AVG was colonized with bacteria even though there was no evidence of overt infection and blood cultures were negative. The most frequently encountered organism was Staphylococcus epidermidis. The source of this bacterial contamination was not apparent. However, transient bacteriemia is a frequent occurrence in the dialysis patient and can arise from a variety of sources (18). Some of these cases could simply represent a prelude in the development of an AVG infection. However, the incidence of colonization noted in this cohort is considerably in excess of the typically reported incidence of AVG infection (18). This disparity suggests that at least a large portion of these cases represent a simple colonization. Poor technique at the time of cannulation is often quoted as the major risk factor in the development of AVG infection (18,19). It is not known how many of cases represented in this cohort had an

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attempt at cannulation prior to being referred for a thrombosed access. Based upon knowledge of the practices of the various referring dialysis clinics, it is probable that at least some of the cases did. It is probable that thrombus of different ages was present to varying degree in cases within this cohort. Judging by the elapsed time from successful use of the AVG until the initiation of the thrombectomy procedure, the maximum possible age of the thrombus present in these cases varied between approximately 48 and 60 hours. This thrombus would still be judged as fresh but would certainly have time for bacterial growth and proliferation to occur. The presence of pseudoaneurysms was not recorded for this cohort; however, judging by the frequency with which these occur, their presence within this cohort can be assumed to have been significant. These structures commonly contain old thrombus in varying degrees of organization. These could serve as a nidus for bacterial colonization on a more chronic basis. Based upon the number of dialysis shifts providing patients to the interventional facility on each of the days of the week, the number of thrombectomy patients per shift ranged from 5 to 6.7; however, a disproportionate number of thrombus-positive cases were seen on Mondays. The question as to how long an AVG has been thrombosed prior to its treatment is of some importance. If the initiating event for colonization is bacterial contamination, the longer it has to grow and proliferate the greater the chance that it will be detected in an aspirated sample. The exact timing of thrombosis is not possible to accurately identify, however, the maximum possible duration can be determined from the end of the previous dialysis treatment at which the AVG was patent and functional. For those cases treated on Tuesday through Friday, this would be approximately 36 hours. For cases treated on Monday, in some instances their previous treatment ended on the previous Friday evening, a time period of approximately 60 hours. This additional time would provide more opportunity for growth and proliferation of bacterial contamination; however, this is only speculative. It is of considerable interest that none of these patients had positive blood cultures and no cases of clinically apparent bacteremia or access infection occurred within the 30 days subsequent to the index thrombectomy procedure. All of these cases of AVG thrombosis were salvaged. If any of those with positive thrombus cultures had been abandoned and left in place they would have served as a continuing nidus for smoldering inflammation and possible infection similar to that which has been described with abandoned retained AVGs. This

possibility is a more plausible explanation for this phenomenon than the possibility that the closed impermeable lumen of an abandoned AVG might become seeded by a later occurring bacteremia. As has been pointed out (4), it is unlikely that antibiotic therapy would have any effect on these sequestered areas of bacterial colonization because of the closed structure of the abandoned, retained AVG. This factor also makes it unlikely that colonization occurs after it is abandoned. References 1. Ayus JC, Sheikh-Hamad D: Silent infection in clotted hemodialysis access grafts. J Am Soc Nephrol 9:1314, 1998 2. Sheikh-Hamad D, Ayus JC: The patient with a clotted PTFE graft developing fever. Nephrol Dial Transplant 13:2392, 1998 3. Fishbane S, Maesaka J: Occult nonfunctioning AV graft infection as a cause of refractory anemia and low serum albumin in hemodialysis patients [abstract]. J Am Soc Nephrol 10:278A, 1999 4. Nassar GM, Ayus JC: Clotted arteriovenous grafts: a silent source of infection. Semin Dial 13:1, 2000 5. Nassar GM, Ayus JC: Infectious complications of the hemodialysis access. Kidney Int 60:1, 2001 6. Nassar GM, Fishbane S, Ayus JC: Occult infection of old nonfunctioning arteriovenous grafts: a novel cause of erythropoietin resistance and chronic inflammation in hemodialysis patients. Kidney Int Suppl 80:49, 2002 7. Stenvinkel P: Inflammation in end-stage renal failure: could it be treated? Nephrol Dial Transplant 17(Suppl. 8):33, 2002 8. Kaysen GA, Eiserich JP: Characteristics and effects of inflammation in end-stage renal disease. Semin Dial 16:438, 2003 9. Kimmel PL, Phillips TM, Simmens SJ, Peterson RA, Weihs KL, Alleyne S, Cruz I, Yanovski JA, Veis JH: Immunologic function and survival in hemodialysis patients. Kidney Int 54:236, 1998 10. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C: Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 55:648, 1999 11. Yeun JY, Levine RA, Mantadilok V, Kaysen GA: C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 35:469, 2000 12. Qureshi AR, Alvestrand A, Divino-Filho JC, Gutierrez A, Heimburger O, Lindholm B, Bergstrom J: Inflammation, malnutrition, and cardiac disease as predictors of mortality in hemodialysis patients. J Am Soc Nephrol 13(Suppl. 1):S28, 2002 13. Selim G, Stojceva-Taneva O, Zafirovska K, Sikole A, Gelev S, Dzekova P, Stefanovski K, Koloska V, Polenakovic M: Inflammation predicts all-cause and cardiovascular mortality in haemodialysis patients. Prilozi 27:133, 2006 14. Kawaguchi T, Tong L, Robinson BM, Sen A, Fukuhara S, Kurokawa K, Canaud B, Lameire N, Port FK, Pisoni RL: C-reactive protein and mortality in hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephron Clin Pract 117:c167, 2011 15. Kaysen GA, Kumar V: Inflammation in ESRD: causes and potential consequences. J Ren Nutr 13:158, 2003 16. Wasse H, Cardarelli F, De Staercke C, Hooper WC, Long Q: Accumulation of retained nonfunctional arteriovenous grafts correlates with severity of inflammation in asymptomatic ESRD patients. Nephrol Dial Transplant 28:991, 2013 17. Beathard G: Complications of Vascular Access. New York, NY: Marcel Dekker, Inc., 2000 18. Fysaraki M, Samonis G, Valachis A, Daphnis E, Karageorgopoulos DE, Falagas ME, Stylianou K, Kofteridis DP: Incidence, clinical, microbiological features and outcome of bloodstream infections in patients undergoing hemodialysis. Int J Med Sci 10:1632, 2013 19. Bachleda P, Utikal P, Kalinova L, K€ ocher M, Cerna M, Kolar M, Zadrazil J: Infectious complications of arteriovenous ePTFE grafts for hemodialysis. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154:13, 2010

Bacterial Colonization of Thrombosed Dialysis Arteriovenous Grafts.

In the absence of obvious infection, an abandoned arteriovenous graft (AVG) is generally left in place. This has been thought to be the best solution ...
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