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Factors affecting the safety of infusing recirculated saline or blood in hemodialysis.

Recirculation of saline is a routine part of preparing a new hemodialysis system and generally occurs shortly before dialysis initiation. However, sometimes there is a time lag between preparation of a new hemodialysis system and the availability of the patient for treatment initiation. How much recirculation time can elapse before the system can "safely" be used for a patient? Additionally, a problem with vascular access may require blood to be recirculated within the circuit if it cannot be immediately reinfused. In those instances, how much time can elapse before the blood must be returned to the patient? How long does the blood remain "safe" for reinfusion?

These questions have been considered by members of the ANNA Research Committee and also by nurses participating in the online ANNA Hemodialysis Specialty Practice Network (SPN) this past summer. Nurses responded to initial SPN queries provided by other members with information related to their dialysis unit policies. Much of this practice is rooted in professional judgment and experience, but the evidence supporting these policies is elusive. For these reasons, this topic was chosen for inclusion in this "Exploring the Evidence" section of the journal.

The literature search for publications related to these questions utilized the CINAFIL, Medline, and Academic Search Complete databases, as well as the Cochrane Database of Systematic Reviews. Key words of hemodialysis, system, recirculation, saline, and blood were used in different combinations to find research articles that could answer these questions. Unfortunately, no relevant articles were retrieved, and most articles found about "recirculation" referred to vascular access recirculation. With no published articles on the topic, a different focus was chosen --that of identifying those factors affecting the quality of fluids or blood infused to a patient from an extracorporeal dialysis system. Several articles address issues relating to the bacteriologic and pyrogenic quality of dialysis systems; additional articles address factors that can affect thrombogenicity, or tendency to clot, of blood once it is outside the patient's vascular system. A review of this literature can help to identify dialysis components and practices that affect the quality of the extracorporeal system and the safety of infusing these fluids to the person being dialyzed.

It is also important to note the terminology used in the literature reviewed and referenced in this article. Some research identifies the problematic material that passes through dialyzer membrane directly as endotoxin, the byproduct of bacteria and the substance stimulating the physiological symptoms of inflammation. Other articles refer to these particles as pyrogens, a more general term denoting any substance leading to symptoms, such as increased temperature, fever, and chills. For the purposes of this review, these terms can be used interchangeably, although there are other less well-known bacteria-derived products also implicated in transmembrane passage (Canaud, Bose, Leray, Morena, & Stec, 2000). These bacterial products result in the body's synthesis of pro-inflammatory cytokines, leading to the inflammatory response seen in the patient (Canaud et al., 2000). These terms are often seen in scientific research articles about the dialyzer-blood interaction and can be confusing to clinicians outside of this narrow research field.

Quality of Recirculated Saline in Dialysis Systems

Although the primed dialysis system is considered sterile, the literature identifies several ways in which bacterial contamination can occur and the consequences for patients. In addition to the danger of direct intravenous bacterial inoculation, the small molecular size of endotoxin and endotoxin fragments produced by bacteria enables them to pass through the semipermeable membrane of a dialyzer from the dialysate compartment. This can cause pyrogenic reactions characterized by fever, chills, and/or hypotension (Bommer, Becker, & Urbaschek, 1996). The possibility of endotoxin passage through the membrane occurs in all dialyzers used in studies on this topic despite differences in material used in dialyzer production or permeability. Specific results for different dialyzers studied in the literature are summarized later in this article.

Even in the absence of clinically obvious symptoms, endotoxin-induced leukocyte activation can lead to increased levels of acute phase proteins, such as C-reactive protein, and trigger a chronic inflammatory state (Lonnemann, Sereni, Lemke, & Tetta, 2001). Continued exposure to this process has been implicated in the development of complications, such as amyloidosis and carpal tunnel syndrome, experienced by persons receiving chronic hemodialysis treatments (Bommer et al., 2001). Bacterial contamination of the dialysis circuit has been identified through operator error during the priming process, contamination of equipment in contact with the dialysis bloodlines, contaminated machines or dialysate, or the type of dialyzer used.

Technical Errors

Preparation of the dialysis circuit prior to the beginning of dialysis requires strict aseptic technique to avoid inadvertent contamination of the priming saline. Practices, such as preliminary removal of protective caps on saline bags, dialysis tubing, and dialyzers in advance of immediate connection with another system component, jeopardizes the sterility of the dialysis circuit. Appropriate training and retraining of personnel who perform this function are essential. If dialysis personnel cannot recognize when the ends of bloodline or other sterile components are being contaminated by contact with a nonsterile object, the principle of asepsis may not be safely incorporated into practice. This issue has been identified as a problem by investigators who have written about outbreaks of bloodstream infections (BSIs) in patients on hemodialysis (Arnow et al., 1998).

Equipment Contamination

Bacteria or endotoxin can also enter the sterile saline-primed dialysis circuit either through direct contact with a contaminated surface or through the semipermeable membrane of a dialyzer. Arnow et al. (1998) described the outcome of an epidemiological investigation after 29 patients on chronic dialysis developed BSIs due to 16 different pathogens. The primary problem leading to these adverse outcomes was the use of a commercially marketed attachment for disposal of spent priming saline that connected directly to the arterial line. Contamination occurred through inadequate cleaning of the disposal ports and use of the same-gloved hands to connect tubing ends for recirculation that had been contaminated when the tubing was disconnected from the waste disposal port. Changes in priming procedures and disinfection protocols were necessary to reduce the incidence of sepsis. It is noteworthy that most of the infections in this patient population occurred in patients with a hemodialysis catheter access. The investigators surmised that the catheter lumen allowed bacteria introduced through the priming procedure to sequester and replicate between treatments. Patients with fistulas and grafts may have also been infected, but these could have been silent cases with few symptoms and resolved without treatment.

Contaminated Machines or Dialysate

Several articles implicated contaminated dialysate as the cause of infection or pyrogenic reactions because bacterial or endotoxin fragments can pass through all cellulose-based or synthetic membranes that constitute dialyzers currently in use (Bommer, 2001; Bommer et al., 1996; Canaud et al., 2000; Goetz, Yu, Hanchett, & Rihs, 1983; Lonnemann et al., 1992). Sodium bicarbonate, used as the chemical buffer in dialysate, provides an environment that enhances proliferation of water-borne bacteria present in the dialysate circuit. Warming of the dialysate, typically to 37[degrees] C, also enables bacteria to multiply when already present (Canaud et al., 2000). Pseudomonas strains may be present in the tap water used to produce dialysate and may also exist in dialysis machines that have been inadequately disinfected or stagnant for a period of time (Bommer, 2001). The use of ultrafilters in the dialysate circuit is recommended as one way to reduce bacterial contamination in prepared dialysate before communication with the dialyzer occurs (Ledobo & Blankestijn, 2010). Some nephology practitioners recommend the use of two or more ultrafilters in a series, demonstrating that the probability of bacteria passing through the dialysate system is substantially reduced each time water is filtered through one of them (Canaud et al., 2000). The production of "ultrapure" water for use in dialysis is suggested by some as one way to decrease the morbidity of patients due to endotoxin exposure (Bommer, 2001).

Dialyzer Type

As the dialysis membranes used to enhance solute removal become thinner and more permeable, back-filtration of fluid from the dialysate to the blood compartment can occur, increasing the incidence of bacterial or pyrogen contamination in blood or saline. These changes in dialyzer design provide an additional argument by some practitioners for using as close to sterile dialysate as possible (Bommer, 2001).

Although all current hollow fiber dialyzers increase the potential of fluid transfer across the dialyzer membrane with resultant immune response to pyrogens, some investigators have identified differences in the type of membrane used. In 1992, Lonnemann and colleagues demonstrated that a pro-inflammatory substance, tumor necrosis factor (TNF), was generated by whole blood samples exposed to pyrogens from the dialysate side of the membrane in dialyzers produced from regenerated cellulose, cellulose triacetate, and polyacrylonitrate. No increase in TNF activity was seen when dialyzers composed of polyamide or polysulfone were used. The conclusion was that the physiochemical nature of the membrane rather than its pore size was responsible for the differences in results.

A similar study conducted by Lonnemann and colleagues in 2001 measured levels of two cytokines, TNF, and interleukin-IB production in blood exposed to recirculating dialysate contaminated with Pseudomonas aeruginosa across two types of synthetic dialyzers. They concluded that polysulfone dialyzers were more effective in preventing detectable cytokine-producing reactions than dialyzers produced from polyethersulfone. An additional interesting finding in this study was the difference in results as recirculating time increased. Although initial blood samples demonstrated a significant difference in cytokine response after 30 minutes of recirculation, differences were no longer detectable after 60 minutes. This indicated that pyrogens adsorbed to the dialysate side of the dialyzer membrane as time passed and prevented further pyrogen transfer. This study illustrates that dialyzers produced from specific synthetic polymers vary in their ability to prevent the passage of bacterial products derived from dialysate, an important implication for choice of dialyzer. Even among dialyzers produced using the same type of membrane, differences in endotoxin transfer can occur. Bommer and colleagues (1996) demonstrated differences in endotoxin transfer in three different types of polysulfone dialyzers, and indicated that manufacturers need to evaluate this property in commercially available dialyzers.

Additional importance lies in the donor-dependent variation in response to cytokines by the blood samples used in the study conducted by Lonnemann et al. (2001). Because there were significantly different immune responses in samples from three different blood donors, the authors concluded that there may be "high responders" as contrasted with "low responders," distinguished by the varying levels of cytokine response to pryogen exposure. Because each donor's blood demonstrated the same result on different days, this reproducible difference indicates a possible genetic variability in how individuals react to pyrogen exposure.

Quality of Recirculated Blood in Dialysis Systems

All of the same possible problems with the quality of recirculated saline exist when the extracorporeal system is filled with the patient's blood, but they are further complicated by the possibility of thrombosis developing in any portion of the system. Thrombosis can stop the recirculating process from proceeding as blockage occurs in the system, but it can also diminish blood clearance as dialyzer fibers selectively clot. It is preferable to reinfuse dialyzed blood rather than recirculate it as several participants in the ANNA Hemodialysis SPN communications identified; however, it may not be possible when the vascular access is suddenly not able to be used. Is it ever safe to reinfuse recirculated blood, and how long can it remain in the extracorporeal system?

The research to date does not answer these questions but has begun to identify some of the complex factors leading to thrombogenicity, or tendency to clot, in individuals on chronic hemodialysis. Available literature on the topic identifies the contact between blood and the dialyzer as the primary trigger for the coagulation cascade during hemodialysis (Frank et al., 2001; Kourtzelis et al., 2010). The process by which this occurs continues to be under investigation, especially because ongoing blood cell stimulation may lead to repeated vascular access thrombosis in some individuals undergoing hemodialysis (Kourtzelis et al., 2010). Frank et al. (2001) studied various components of the complex coagulation process and their stimulation by contact with three types of hemodialyzers. They demonstrated generation of thrombin-antithrombin complexes with all three dialyzers (cuprophan, polysulfone, and AN69) using blood from the same donor. It is notable that using the same donor blood was critical in this study because it had already been demonstrated that there is considerable variability in the response to prothrombotic stimuli and anticoagulants by different individuals.

Two conclusions of this study are relevant to the question of thrombus formation in the dialyzer. First, the authors hypothesize that clotting during extracorporeal circulation may be enhanced by less inhibition of thrombin formation that usually occurs in the antithrombotic vascular endothelium. Second, triggers leading to thrombus formation may involve stimulation of monocytes in the blood that lead to activation of factor X, an important enzyme in the coagulation cascade. Thus, the physiological process related to inflammation may also be a factor in eventual development of clot formation (Frank et al., 2001).

This conclusion is seconded by results of a later study demonstrating generation of tissue factor (TF), a major trigger of coagulation when serum from patients with end stage renal disease (ESRD) during dialysis was analyzed (Kourtzelis et al., 2010). Polysulfone dialyzers and standard bloodlines were used in this experiment. An increase in procoagulant properties was seen immediately after hemodialysis was started, reaching a maximum at 15 minutes and returning to predialysis levels after four hours. Analysis of several components in the dialyzed blood showed complement activation triggered by recurrent contact of blood with the dialyzer and lines. The complex interaction between blood components and the dialysis system is yet to be fully understood, but initial studies point to numerous factors as significant in promoting coagulation soon after dialysis is initiated. Factors, such as the effect of varying levels of uremia on blood component activity, and alterations in other body systems, such as the liver, may affect the probability of clotting in any one person undergoing hemodialysis.

Summary and Conclusions

It is not surprising that there is no documented evidence supporting a standard for safe infusion of recirculated saline or blood in hemodialysis. A number of factors affect the bacteriologic and pyrogenic quality of recirculated saline and how individuals will physiologically respond to the final product. Attention to strict asepsis when preparing the dialysis circuit, bacterial quality of the dialysate, characteristics of the dialyzer used, and individual physiological response to the presence of endotoxins all play a part in whether individuals being dialyzed experience a pyrogenic response. Those who depend on chronic hemodialysis utilizing catheter access may be especially vulnerable due to the possibility of continued bacterial growth in the catheter lumen. Unit policy regarding the length of time a primed dialysis system can be considered safe for use should consider all of these factors. It may not be possible to create experimental situations in which all relevant factors leading to high quality of primed saline can replicate any one actual experience in a hemodialysis unit. However, practices that decrease the probability of bacterial contamination of priming saline or dialysate can help prevent adverse patient responses.

Considering the limited evidence about reasons for thrombosis of blood in dialysis systems, very few conclusions can be drawn about the safety of infusing recirculated blood. The possible interactions of the dialysis system and individual physiological factors are limitless and are probably impossible to predict. The available literature identifies that the coagulation process begins immediately as blood interacts with the dialyzer and can be exacerbated if complement is activated. Combining this probability with the effects of possible pyrogen exposure, it is safe to say that considerable risk may exist the longer blood in the extracorporeal system is recirculated. Weighing these risks with the possible benefits of returning recirculated blood to a person on hemodialysis must be an individual decision each time the situation presents itself.

Key Words: Recirculated saline, hemodialysis, blood, safety, system, thrombogenicity, clotting.

Exploring the Evidence is a department in the Nephrology Nursing Journal designed to provide a summary of evidence-based research reports related to contemporary nephrology nursing practice issues. Content for this department is provided by members of the ANNA Research Committee. Committee members review the current literature related to a clinical practice topic and provide a summary of the evidence and implications for best practice. Readers are invited to submit questions or topic areas that pertain to evidence-based nephrology practice issues. Address correspondence to: Tamara Kear, Exploring the Evidence Department Editor, ANNA National Office, East Holly Avenue/Box 56, Pitman, NJ 08071-0056; (856) 256-2320; or via e-mail at NNJEvidence@ajj.com. The opinions and assertions contained herein are the private views of the contributors and do not necessarily reflect the views of the American Nephrology Nurses' Association.

References

Arnow, P.M., Garcia-Houchins, S., Neagle, M.B., Bova, J.L. Dillon, JJ., & Chou, T. (1998). An outbreak of bloodstream infections arising from hemodialysis equipment. The Journal of Infectious Diseases, 178, 783-791.

Bommer, J. (2001). Sterile filtration of dialysate: Is it really of no use? Nephrology Dialysis Transplantation, 16, 1992-1994.

Bommer, J., Becker, K.P., & Urbaschek, R. (1996). Potential transfer of endotoxin across high-flux polysulfone membranes. Journal of the American Society of Nephrology, 7(6), 883-888.

Canaud, B., Bose, J.Y., Leray, H,. Morena, M., & Stec, F. (2000). Microbiologic purity of dialysate: Rationale and technical aspects. Blood Purification, 18, 200-213.

Frank, R.D., Weber, J., Dresbach, H., Thelen, H., Weiss, C., & Florege, J. (2001). Role of contact system activation in hemodialyzer-induced thrombogenicity. Kidney International, 60, 1972-1981.

Goetz, A., Yu, V.L., Hanchett, J.E., & Rihs, J.D. (1983). Pseudomonas stutzeri bacteremia associated with hemodialysis. Archives of Internal Medicine, 143, 1909-1912.

Kourtzelis, I., Markiewski, M.M., Doumas, M., Rafail, S., Kambas, K., Mitroulis, I., ... Lambris, J.D. (2010). Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood, 116(4), 631-639. doi: 10.1182/ blood-2010-01-264051

Ledebo, I., & Blankestijn, PJ. (2010). Haemodiafiltration--Optimal efficiency and safety. Nephrology Dialysis Transplantation Plus, 3(1), 8-16. doi:10.1093/ndtplus/sfpl49

Lonnemann, G., Behme, T.C., Lenzner, B., Floege, J., Schulze, M., Colton, C.K., ... Shaldon, S. (1992). Permeability of dialyzer membranes to TNF-a-inducing substances derived from water bacteria. Kidney International, 42, 61-68.

Lonnemann, G., Sereni, L., Lemke, H., & Tetta, C. (2001). Pyrogen retention by highly permeable synthetic membranes during in vitro dialysis. Artificial Organs, 25(12), 951-960.

Tamara Rear, Department Editor

Christine M. Schrauf, PhD, RN, MBA, is an Associate Professor, School of Nursing, Elms College, Chicopee, MA, a Hemodialysis Staff Member, Hartford Hospital, Hartford, CT, and a member of ANNA's Colonial Chapter. She may be contacted directly via email at schraufc@elms.edu
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Title Annotation:Exploring the Evidence
Author:Schrauf, Christine M.
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:Mar 1, 2014
Words:3075
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