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American National Standard

ANSI/AAMI RD52:2004

Dialysate for hemodialysis

The Objectives and Uses of AAMI Standards and Recommended Practices

It is most important that the objectives and potential uses of an AAMI product standard or recommended practice are clearly understood. The objectives of AAMI's technical development program derive from AAMI's overall mission: the advancement of medical instrumentation. Essential to such advancement are (1) a continued increase in the safe and effective application of current technologies to patient care, and (2) the encouragement of new technologies. It is AAMI's view that standards and recommended practices can contribute significantly to the advancement of medical instrumentation, provided that they are drafted with attention to these objectives and provided that arbitrary and restrictive uses are avoided. A voluntary standard for a medical device recommends to the manufacturer the information that should be provided with or on the product, basic safety and performance criteria that should be considered in qualifying the device for clinical use, and the measurement techniques that can be used to determine whether the device conforms with the safety and performance criteria and/or to compare the performance characteristics of different products. Some standards emphasize the information that should be provided with the device, including performance characteristics, instructions for use, warnings and precautions, and other data considered important in ensuring the safe and effective use of the device in the clinical environment. Recommending the disclosure of performance characteristics often necessitates the development of specialized test methods to facilitate uniformity in reporting; reaching consensus on these tests can represent a considerable part of committee work. When a drafting committee determines that clinical concerns warrant the establishment of minimum safety and performance criteria, referee tests must be provided and the reasons for establishing the criteria must be documented in the rationale. A recommended practice provides guidelines for the use, care, and/or processing of a medical device or system. A recommended practice does not address device performance per se, but rather procedures and practices that will help ensure that a device is used safely and effectively and that its performance will be maintained. Although a device standard is primarily directed to the manufacturer, it may also be of value to the potential purchaser or user of the device as a fume of reference for device evaluation. Similarly, even though a recommended practice is usually oriented towards health care professionals, it may be useful to the manufacturer in better understanding the environment in which a medical device will be used. Also, some recommended practices, while not addressing device performance criteria, provide guidelines to industrial personnel on such subjects as sterilization processing, methods of collecting data to establish safety and efficacy, human engineering, and other processing or evaluation techniques; such guidelines may be useful to health care professionals in understanding industrial practices. In determining whether an AAMI standard or recommended practice is relevant to the specific needs of a potential user of the document, several important concepts must be recognized: All AAMI standards and recommended practices are voluntary (unless, of course, they are adopted by government regulatory or procurement authorities). The application of a standard or recommended practice is solely within the discretion and professional judgment of the user of the document. Each AAMI standard or recommended practice reflects the collective expertise of a committee of health care professionals and industrial representatives, whose work has been reviewed nationally (and sometimes internationally). As such, the consensus recommendations embodied in a standard or recommended practice are intended to respond to clinical needs and, ultimately, to help ensure patient safety. A standard or recommended practice is limited, however, in the sense that it responds generally to perceived risks and conditions that may not always be relevant to specific situations. A standard or recommended practice is an important reference in responsible decision-making, but it should never replace responsible decisionmaking. Despite periodic review and revision (at least once every five years), a standard or recommended practice is necessarily a static document applied to a dynamic technology. Therefore, a standards user must carefully review the reasons why the document was initially developed and the specific rationale for each of its provisions. This review will reveal whether the document remains relevant to the specific needs of the user. Particular care should be taken in applying a product standard to existing devices and equipment, and in applying a recommended practice to current procedures and practices. While observed or potential risks with existing equipment typically form the basis for the safety and performance criteria defined in a standard, professional judgment must be used in applying these criteria to existing equipment. No single source of information will serve to identify a particular product as "unsafe". A voluntary standard can be used as one resource, but the ultimate decision as to product safety and efficacy must take into account the specifics of its utilization and, of course, cost-benefit considerations. Similarly, a recommended practice should be analyzed in the context of the specific needs and resources of the individual institution or firm. Again, the rationale accompanying each AAMI standard and recommended practice is an excellent guide to the reasoning and data underlying its provision. In summary, a standard or recommended practice is truly useful only when it is used in conjunction with other sources of information and policy guidance and in the context of professional experience and judgment.

INTERPRETATIONS OF AAMI STANDARDS AND RECOMMENDED PRACTICES

Requests for interpretations of AAMI standards and recommended practices must be made in writing, to the Manager for Technical Development. An official interpretation must be approved by letter ballot of the originating committee and subsequently reviewed and approved by the AAMI Standards Board. The interpretation will become official and representation of the Association only upon exhaustion of any appeals and upon publication of notice of interpretation in the "Standards Monitor" section of the AAMI News. The Association for the Advancement of Medical Instrumentation disclaims responsibility for any characterization or explanation of a standard or recommended practice which has not been developed and communicated in accordance with this procedure and which is not published, by appropriate notice, as an official interpretation in the AAMI News.

American National Standard

ANSI/AAMI RD52:2004

Dialysate for hemodialysis

Developed by Association for the Advancement of Medical Instrumentation Approved 9 August 2004 by American National Standards Institute, Inc.

Abstract:

This recommended practice covers the appropriate preparation of dialysate, handling of concentrates, operation of water treatment equipment and handling of its product water, monitoring of systems and the dialysate produced, and risks and hazards of dialysate preparation failure. dialysate, dialyzing fluid

Keywords:

AAMI Recommended Practice

This Association for the Advancement of Medical Instrumentation (AAMI) recommended practice implies a consensus of those substantially concerned with its scope and provisions. The existence of an AAMI recommended practice does not in any respect preclude anyone, whether they have approved the recommended practice or not, from manufacturing, marketing, purchasing, or using products, processes, or procedures not conforming to the recommended practice. AAMI recommended practices are subject to periodic review, and users are cautioned to obtain the latest editions. CAUTION NOTICE: This AAMI recommended practice may be revised or withdrawn at any time. AAMI procedures require that action be taken to reaffirm, revise, or withdraw this recommended practice no later than five years from the date of publication. Interested parties may obtain current information on all AAMI documents by calling or writing AAMI. All AAMI standards, recommended practices, technical information reports, and other types of technical documents developed by AAMI are voluntary, and their application is solely within the discretion and professional judgment of the user of the document. Occasionally, voluntary technical documents are adopted by government regulatory agencies or procurement authorities, in which case the adopting agency is responsible for enforcement of its rules and regulations.

Published by Association for the Advancement of Medical Instrumentation 1110 N. Glebe Road, Suite 220 Arlington, VA 22201-4795 © 2004 by the Association for the Advancement of Medical Instrumentation All Rights Reserved Publication, reproduction, photocopying, storage, or transmission, electronically or otherwise, of all or any part of this document without the prior written permission of the Association for the Advancement of Medical Instrumentation is strictly prohibited by law. It is illegal under federal law (17 U.S.C. § 101, et seq.) to make copies of all or any part of this document (whether internally or externally) without the prior written permission of the Association for the Advancement of Medical Instrumentation. Violators risk legal action, including civil and criminal penalties, and damages of $100,000 per offense. For permission regarding the use of all or any part of this document, contact AAMI at 1110 N. Glebe Road, Suite 220, Arlington, VA 22201-4795. Phone: (703) 525-4890; Fax: (703) 525-1067. Printed in the United States of America ISBN 1­57020­223­0

Contents

Page Glossary of equivalent standards .....................................................................................................................v Committee representation .............................................................................................................................. vii Foreword ....................................................................................................................................................... viii Introduction: Need for this AAMI recommended practice ................................................................................ ix 1 Scope........................................................................................................................................................1 1.1 1.2 1.3 2 3 4 General ..........................................................................................................................................1 Inclusions .......................................................................................................................................1 Exclusions ......................................................................................................................................1

Normative references................................................................................................................................1 Definitions .................................................................................................................................................2 Fluid quality...............................................................................................................................................5 4.1 4.2 4.3 Water .............................................................................................................................................5 4.1.1 Maximum level of chemical contaminants in water ..........................................................5 4.1.2 Bacteriology of water .......................................................................................................6 Concentrate....................................................................................................................................7 4.2.1 Maximum level of chemical contaminants in concentrate ................................................7 4.2.2 Bacteriology of concentrate..............................................................................................7 Dialysate ........................................................................................................................................7 4.3.1 Maximum level of chemical contaminants in dialysate .....................................................7 4.3.2 Bacteriology of dialysate ..................................................................................................7

5

Equipment.................................................................................................................................................8 5.1 5.2 General ..........................................................................................................................................8 Water purification systems .............................................................................................................8 5.2.1 General ............................................................................................................................8 5.2.2 Sediment filters ................................................................................................................8 5.2.3 Cartridge filters ................................................................................................................8 5.2.4 Softeners .........................................................................................................................9 5.2.5 Carbon adsorption ...........................................................................................................9 5.2.6 Chemical injection systems............................................................................................10 5.2.7 Reverse osmosis ...........................................................................................................10 5.2.8 Deionization ...................................................................................................................10 5.2.9 Ultrafiltration...................................................................................................................11 Water storage and distribution .....................................................................................................11 5.3.1 General ..........................................................................................................................11 5.3.2 Water storage ................................................................................................................11 5.3.3 Water distribution systems.............................................................................................12 5.3.4 Bacterial control devices ................................................................................................12 Concentrate preparation...............................................................................................................13 5.4.1 General ..........................................................................................................................13 5.4.2 Materials compatibility....................................................................................................14 5.4.3 Bulk storage tanks (acid concentrate)............................................................................14 5.4.4 Mixing systems ..............................................................................................................14 5.4.5 Additives ........................................................................................................................15 Concentrate distribution ...............................................................................................................15 5.5.1 Materials compatibility....................................................................................................15 5.5.2 System configurations....................................................................................................16 5.5.3 Acid concentrate distribution systems............................................................................16 5.5.4 Bicarbonate concentrate distribution systems................................................................16 5.5.5 Concentrate outlets........................................................................................................16 Dialysate proportioning.................................................................................................................17

5.3

5.4

5.5

5.6

6

Monitoring ...............................................................................................................................................18 6.1 6.2 General ........................................................................................................................................18 Water purification .........................................................................................................................19 6.2.1 General ..........................................................................................................................19 6.2.2 Sediment filters ..............................................................................................................20 6.2.3 Cartridge filters ..............................................................................................................20 6.2.4 Softeners .......................................................................................................................20 6.2.5 Carbon adsorption .........................................................................................................20 6.2.6 Chemical injection systems............................................................................................21 6.2.7 Reverse osmosis ...........................................................................................................21 6.2.8 Deionization ...................................................................................................................21 6.2.9 Ultrafiltration...................................................................................................................22 Water storage and distribution .....................................................................................................22 6.3.1 General ..........................................................................................................................22 6.3.2 Water storage ................................................................................................................22 6.3.3 Water distribution systems.............................................................................................22 6.3.4 Bacterial control devices ................................................................................................22 Concentrate preparation...............................................................................................................23 6.4.1 Mixing systems ..............................................................................................................23 6.4.2 Additives ........................................................................................................................23 Concentrate distribution ...............................................................................................................23 Dialysate proportioning.................................................................................................................23

6.3

6.4 6.5 6.6 7

Strategies for bacterial control ................................................................................................................24 7.1 7.2 General ........................................................................................................................................24 Microbial monitoring methods ......................................................................................................25 7.2.1 General ..........................................................................................................................25 7.2.2 Sample collection...........................................................................................................27 7.2.3 Heterotrophic plate count...............................................................................................27 7.2.4 Bacterial endotoxin test..................................................................................................27

8 9

Environment............................................................................................................................................28 Personnel................................................................................................................................................28

Annexes A B Rationale for the development and provisions of this recommended practice.........................................29 Bibliography ............................................................................................................................................39

Tables 1 2 3 4 Maximum allowable chemical contaminant levels in water used to prepare dialysate and concentrates from powder at a dialysis facility and to reprocess dialyzers for multiple uses.....................6 Compatibility of common disinfectants with piping materials used in water distribution systems ...........12 Symbols and color coding for different concentrate proportioning ratios .................................................17 Monitoring guidelines for water purification equipment and distribution systems and dialysate .............18

A.1 Lowest level of endotoxin detectable using assays of different sensitivity and with different sample dilutions of bicarbonate concentrate ...............................................................37 A.2 Maximum allowable sample dilution for detection of endotoxin concentrations of 1 EU/mL and 2 EU/mL as a function of assay sensitivity ....................................................................38 Figures 1 2 Example of decision tree that can be used to evaluate culture results and initiate corrective action, if necessary.............................................................................................................................................26 Example of a component label for a regenerable softener ......................................................................28

Glossary of equivalent standards

International Standards adopted in the United States may include normative references to other International Standards. For each International Standard that has been adopted by AAMI (and ANSI), the table below gives the corresponding U.S. designation and level of equivalency to the International Standard. (Note: Documents are sorted by international designation.) Other normatively referenced International Standards may be under consideration for U.S. adoption by AAMI; therefore, this list should not be considered exhaustive. International designation IEC 60601-1-2:2001 IEC 60601-2-04:2002 IEC 60601-2-21:1994 and Amendment 1:1996 IEC 60601-2-24:1998 IEC TR 60878:2003 IEC TR 62296:2003 ISO 5840:1996 ISO 7198:1998 ISO 7199:1996 ISO 10993-1:2003 ISO 10993-2:1992 ISO 10993-3:2003 ISO 10993-4:2002 ISO 10993-5:1999 ISO 10993-6:1994 ISO 10993-7:1995 ISO 10993-8:2000 ISO 10993-9:1999 ISO 10993-10:2002 ISO 10993-11:1993 ISO 10993-12:2002 ISO 10993-13:1998 ISO 10993-14:2001 ISO 10993-15:2000 ISO 10993-16:1997 ISO 10993-17:2002 ISO 11134:1994 ISO 11135:1994 ISO 11137:1995 and Amdt 1:2001 ISO 11138-1:1994 U.S. designation ANSI/AAMI/IEC 60601-1-2:2001 ANSI/AAMI DF80:2003 ANSI/AAMI/IEC 60601-2-21 & Amendment 1:2000 (consolidated texts) ANSI/AAMI ID26:1998 ANSI/AAMI/IEC TIR60878:2003 ANSI/AAMI/IEC TIR62296:2003 ANSI/AAMI/ISO 5840:1996 ANSI/AAMI/ISO 7198:1998/2001 ANSI/AAMI/ISO 7199:1996/(R)2002 ANSI/AAMI/ISO 10993-1:2003 ANSI/AAMI/ISO 10993-2:1993/(R)2001 ANSI/AAMI/ISO 10993-3:2003 ANSI/AAMI/ISO 10993-4:2002 ANSI/AAMI/ISO 10993-5:1999 ANSI/AAMI/ISO 10993-6:1995/(R)2001 ANSI/AAMI/ISO 10993-7:1995/(R)2001 ANSI/AAMI/ISO 10993-8:2000 ANSI/AAMI/ISO 10993-9:1999 ANSI/AAMI BE78:2002 ANSI/AAMI 10993-11:1993 ANSI/AAMI/ISO 10993-12:2002 ANSI/AAMI/ISO 10993-13:1999 ANSI/AAMI/ISO 10993-14:2001 ANSI/AAMI/ISO 10993-15:2000 ANSI/AAMI/ISO 10993-16:1997/(R)2003 ANSI/AAMI/ISO 10993-17:2002 ANSI/AAMI/ISO 11134:1993 ANSI/AAMI/ISO 11135:1994 ANSI/AAMI/ISO 11137:1994 and A1:2002 ANSI/AAMI ST59:1999 Equivalency Identical Major technical variations Identical Major technical variations Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Minor technical variations Minor technical variations Identical Identical Identical Identical Identical Identical Identical Identical Identical Major technical variations

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International designation ISO 11138-2:1994 ISO 11138-3:1995 ISO TS 11139:2001 ISO 11140-1:1995 and Technical Corrigendum 1:1998 ISO 11607:2003 ISO 11737-1:1995 ISO 11737-2:1998 ISO TR 13409:1996 ISO 13485:2003 ISO 13488:1996 ISO 14155-1:2003 ISO 14155-2:2003 ISO 14160:1998 ISO 14161: 2000 ISO 14937:2000 ISO TR 14969:2004

1

U.S. designation ANSI/AAMI ST21:1999 ANSI/AAMI ST19:1999 ANSI/AAMI/ISO 11139:2002 ANSI/AAMI ST60:1996 ANSI/AAMI/ISO 11607:2000 ANSI/AAMI/ISO 11737-1:1995 ANSI/AAMI/ISO 11737-2:1998 AAMI/ISO TIR13409:1996 ANSI/AAMI/ISO 13485:2003 ANSI/AAMI/ISO 13488:1996 ANSI/AAMI/ISO 14155-1:2003 ANSI/AAMI/ISO 14155-2:2003 ANSI/AAMI/ISO 14160:1998 ANSI/AAMI/ISO 14161:2000 ANSI/AAMI/ISO 14937:2000 ANSI/AAMI/ISO TIR14969:2004 ANSI/AAMI/ISO 14971:2000 and A1:2003 ANSI/AAMI/ISO 15223:2000 ANSI/AAMI/ISO 15223:2000/A1:2001 ANSI/AAMI/ISO 15223:2000/A2:2004 ANSI/AAMI/ISO 15225:2000 ANSI/AAMI/ISO 15225:2000/A1:2004 ANSI/AAMI/ISO 15674:2001 ANSI/AAMI/ISO 15675:2001 ANSI/AAMI/ISO TIR15843:2000 AAMI/ISO TIR15844:1998 ANSI/AAMI/ISO TIR16142:2000 ANSI/AAMI/ISO 25539-1:2003

Equivalency Major technical variations Major technical variations Identical Major technical variations Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical Identical

ISO 14971:2000 and A1:2003 ISO 15223:2000 ISO 15223/A1:2002 ISO 15223/A2:2004 ISO 15225:2000 ISO 15225/A1:2004 ISO 15674:2001 ISO 15675:2001 ISO TS 15843:2000 ISO TR 15844:1998 ISO TR 16142:1999 ISO 25539-1:2003

1

Year of publication estimated

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Committee representation

Association for the Advancement of Medical Instrumentation Renal Disease and Detoxification Committee This recommended practice was developed by the AAMI Renal Disease and Detoxification Committee. Committee approval of this recommended practice does not necessarily imply that all committee members voted for its approval. At the time this document was published, the AAMI Renal Disease and Detoxification Committee had the following members: Cochairs: Members: LeRoy J. Fischbach Richard A. Ward, PhD Steven Acres, MD, Carolina Regional Nephrology Associates Matthew J. Arduino, DrPH, U.S. Centers for Disease Control and Prevention Robert Berube, Church & Dwight Company, Inc. D. Michael Blankenship, MD, Texarkana Kidney Disease and Hypertension Center Danilo B. Concepcion, CHT, CCHT, St. Joseph Hospital Renal Center R. Barry Deeter, RN, MSN, University of Utah Dialysis Program Robert Dudek, US Filter Martin S. Favero, PhD, Johnson & Johnson Advanced Sterilization Products LeRoy J. Fischbach, Minntech Corporation Gema Gonzalez, U.S. Food and Drug Administration, Center for Devices and Radiological Health, Office of Device Evaluations Bertrand L. Jaber, MD, Tufts University School of Medicine, Caritas St. Elizabeth's Medical Center Jerome C. James III, PhD, Aksys Limited James M. Kaar, Baxter Healthcare Corporation Fei M. Law, Gambro Renal Products, Inc. Nathan W. Levin, MD, Renal Research Institute LLC John Lohr, PhD, Associates of Cape Cod, Inc. Douglas A. Luehmann, DaVita, Inc. Bruce H. Merriman, Central Florida Kidney Centers Glenda Payne, RN, MS, CNN, Centers for Medicare & Medicaid Services John A. Rickert, GE Osmonics Mark Rolston, Renal Care Group James D. Stewardson, Brighton, CO David S. Utterberg, Medisystems Services Corporation Richard A. Ward, PhD, Kidney Disease Program, University of Louisville Robert J. Chambers, Gambro BCT Inc. Christine Colon, Baxter Healthcare Corporation Conor Curtin, Fresenius Medical Care NA Dialysis Products Division Russell Dimmitt, AS, Renal Care Group Mark David Einzinger, BA, MS, Church & Dwight Company Inc. Barbara I. McCool, U.S. Food and Drug Administration, Center for Devices and Radiological Health, Office of Device Evaluations Gregory Montgomery, US Filter

Alternates:

NOTE--Participation by federal agency representatives in the development of this recommended practice does not constitute endorsement by the federal government or any of its agencies.

Acknowledgment

The AAMI Renal Disease and Detoxification Committee dedicates this recommended practice to the late Scott N. Walker of Fresenius USA for his outstanding contributions to AAMI dialysis standards work.

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Foreword

This recommended practice was developed by the AAMI Renal Disease and Detoxification Committee. The committee's objective is to provide rational guidelines for handling water and concentrates and for the production and monitoring of dialysate used for hemodialysis. The need for such guidelines is based on the critical role of dialysate quality in providing safe and effective hemodialysis, and the recognition that day-to-day dialysate quality is under the control of the health care professionals who deliver dialysis therapy. This recommended practice reflects the conscientious efforts of health care professionals, patients, medical device manufacturers, and representatives of federal agencies to develop recommendations for handling water and concentrates and for the production and monitoring of dialysate for hemodialysis. The document is intended as a guide for physicians, particularly the directors of dialysis facilities. The recommendations contained in this document may not be applicable in all circumstances and they are not intended for regulatory application. The term "should" as used in this document reflects the committee's intent to define goals, not requirements. The term "shall" as used here denotes quality recommendations and procedures that are required by applicable standards. The term "must" is used only to describe unavoidable situations, including those mandated by government regulation. The concepts incorporated in this recommended practice should not be considered inflexible or static. The recommendations presented here should be reviewed periodically in order to assimilate increased understanding of the role of dialysate purity in patient outcomes and technological developments. Suggestions for improving this recommended practice are invited and should be sent to: AAMI, Attn: Standards Department, 1110 N. Glebe Road, Suite 220, Arlington, VA 22201-4795. NOTE--This foreword does not contain provisions of the American National Standard ANSI/AAMI RD52:2004, Dialysate for hemodialysis.

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Introduction: Need for this AAMI recommended practice

The American National Standard Hemodialysis systems was first approved in May 1982 and was published under the designation ANSI/AAMI RD5:1981. In 1996, during the five-year review of RD5, the AAMI Renal Disease and Detoxification Committee determined that the hemodialysis community would be better served by this standard if it were divided into three parts: (1) hemodialysis concentrates, (2) water treatment equipment for hemodialysis, and (3) hemodialysis equipment. This decision resulted in the publication of ANSI/AAMI RD61:2000, Concentrates for hemodialysis; ANSI/AAMI RD62:2001, Water treatment equipment for hemodialysis applications; and ANSI/AAMI RD5:2003, Hemodialysis systems. These standards are addressed primarily to the manufacturers of equipment, although they also provide users with a basis for understanding the products and processes covered therein. The critical product resulting from the joint application of the devices addressed by the three standards is the dialysate, the fluid against which the patients' blood is balanced. Control of the dialysate characteristics is necessary in order to have safe and effective hemodialysis. Although hemodialysis machines are used to proportion concentrates and water to produce dialysate, the actual production and handling of dialysate is under the control of professional clinicians who care for the patients. Clinicians involved in providing hemodialysis may not be exposed to the technical aspects of water treatment for hemodialysis applications during their training. Therefore, the AAMI Renal Disease and Detoxification Committee undertook the development of this recommended practice to provide guidance to health care professionals. NOTE--This introduction does not contain provisions of the American National Standard ANSI/AAMI RD52:2004, Dialysate for hemodialysis.

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American National Standard

ANSI/AAMI RD52:2004

Dialysate for hemodialysis

1

1.1

Scope

General

The intent of this recommended practice is to provide dialysis practitioners with guidance on the preparation of dialysate for hemodialysis and related therapies, from the point at which municipal water enters their dialysis facility to the point at which the final dialysate enters the dialyzer. Included in the scope of the recommended practice are: (1) use, maintenance, and monitoring of equipment used to purify and distribute water used for the preparation of dialysate and other hemodialysis applications; (2) use, maintenance, and monitoring of equipment used to prepare concentrate from powder at a dialysis facility; and (3) preparation of the final dialysate from purified water and concentrate. The equipment used in the various stages of dialysate preparation is generally obtained from specialized vendors. This recommended practice provides a general description of the system components that these vendors may provide. These descriptions are intended to provide the user with a basis for understanding why certain equipment may be required and how it should be configured; they are not intended as detailed design standards. Dialysis practitioners are generally responsible for maintaining the equipment used to prepare dialysate following its installation. Therefore, this recommended practice provides guidance on monitoring and maintenance of the equipment to ensure that dialysate quality is acceptable at all times. At various places throughout this recommended practice, the user is advised to follow the manufacturer's instructions regarding the operation and maintenance of equipment. In those instances in which the equipment is not obtained from a specialized vendor, it is the responsibility of the user to validate the performance of the equipment in the hemodialysis setting and to ensure that appropriate operating and maintenance manuals are available. The guidance provided by this recommended practice should help protect hemodialysis patients from adverse effects arising from known chemical and microbial contaminants that may be found in improperly prepared dialysate. However, the physician in charge of dialysis has the ultimate responsibility for ensuring that the dialysate is correctly formulated and meets the requirements of all applicable quality standards. 1.2 Inclusions

This recommended practice addresses the user's responsibility for the dialysate once equipment has been delivered and installed. For the purposes of this recommended practice, the dialysate includes water used for the preparation of dialysate, water used for the preparation of concentrates at the user's facility, and water used for the preparation of ultrapure dialysate, as well as the final dialysate and concentrates. Because it is commonly prepared and distributed using the same equipment as the water used to prepare dialysate, water used to reprocess dialyzers is also covered by this recommended practice. 1.3 Exclusions

Excluded from the scope of this recommended practice are sorbent-based dialysate regeneration systems that regenerate and recirculate small volumes of dialysate, systems for continuous renal replacement therapy that use prepackaged solutions, and systems and solutions for peritoneal dialysis. This recommended practice excludes home hemodialysis, although this document may be of use to the home hemodialysis practitioner.

2

Normative references

The following documents contain provisions that, through reference in this text, constitute provisions of this recommended practice. At the time of publication, the editions indicated were valid. All standards are subject to revision. For this reason, it is recommended that the user obtain the most recent editions of the documents indicated below. The Association for the Advancement of Medical Instrumentation maintains a register of currently valid AAMI/American National Standards. 2.1 U.S. FOOD AND DRUG ADMINISTRATION. Guidance for the Content of Premarket Notifications for Water Purification Components and Systems for Hemodialysis. Rockville (MD): U.S. Food and Drug Administration, 1997. <http://www.fda.gov/cdrh/ode/hemodial.pdf> 2.2 ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL INSTRUMENTATION. Hemodialysis systems (ANSI/AAMI RD5:2003). Arlington (VA): AAMI, 2003. American National Standard.

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2.3 ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL INSTRUMENTATION. Water treatment equipment for hemodialysis applications (ANSI/AAMI RD62:2001). Arlington (VA): AAMI, 2001. American National Standard. 2.4 ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL INSTRUMENTATION. Concentrates for hemodialysis (ANSI/AAMI RD61:2000). Arlington (VA): AAMI, 2000. American National Standard. 2.5 UNITED STATES PHARMACOPEIAL CONVENTION, INC. United States Pharmacopoeia--National Formulary (USP-26-NF21). Rockville (MD): United States Pharmacopeial Convention Inc., 2003. 2.6 U.S. ENVIRONMENTAL PROTECTION AGENCY. Safe Drinking Water Act, 1996 (Public law 104­182). Washington (DC): EPA, 1996. (See also National Primary and Secondary Drinking Water Regulations. U.S. Environmental Protection Agency, Office of Ground Water and Drinking Water. <http://www.epa.gov/OGWDW/creg.html>) 2.7 ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL INSTRUMENTATION. Bacterial endotoxins--Test methodologies, routine monitoring, and alternatives to batch testing (ANSI/AAMI ST72:2002). Arlington (VA): AAMI, 2002. American National Standard.

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Definitions

For the purposes of this recommended practice, the following terms and definitions apply. 3.1 acetate concentrate: Concentrated solution of salts that may contain dextrose (sometimes referred to as "glucose"), which, when diluted with water, yields dialysate for use in dialysis. Sodium acetate is normally used as the buffer. This concentrate is used as a single concentrate. 3.2 acetate dialysate: Dialysate without bicarbonate, using acetate as a substitute for the bicarbonate buffer.

NOTE--Acetate dialyzing fluid is generally produced from a single concentrate. Acetate is metabolized by the patient to produce bicarbonate.

3.3 acid concentrate: Acidified concentrated solution of salts that may contain dextrose (sometimes referred to as "glucose"), which, when diluted with water and bicarbonate concentrate, yields dialysate for use in dialysis. The term "acid" refers to the small amount of acid (usually acetic acid) that is included in the concentrate to establish the buffer system in the final dialysate by reaction with a small amount of bicarbonate from the bicarbonate concentrate. 3.4 action level: Concentration of a contaminant at which steps should be taken to interrupt the trend toward higher, unacceptable levels. 3.5 3.6 3.7 anions: Ions carrying a negative charge. bacteriology: Area of study within the field of microbiology that deals with the study of bacteria. batch system: Apparatus in which the dialysate is prepared in bulk before each dialysis session.

3.8 bicarbonate concentrate: Concentrated solution of sodium bicarbonate that, when diluted with water and acid concentrate, makes dialysate used for dialysis. Some bicarbonate concentrates also contain sodium chloride. 3.9 bicarbonate dialysate: Dialysate containing physiological or higher concentrations of bicarbonate.

NOTE--Bicarbonate dialysate is generally produced from two concentrates: one containing bicarbonate and the other containing acid and other electrolytes (see acid concentrate and bicarbonate concentrate).

3.10 biofilm: Coating on surfaces that consists of microcolonies of bacteria embedded in a protective extracellular matrix. The matrix, a slimy material secreted by the cells, protects the bacteria from antibiotics and chemical disinfectants. 3.11 bulk delivery: Delivery of large volumes of concentrate in which the product is transferred (pumped) from the delivery container to a user's storage tank. Bulk delivery may include containers such as 55 gallon drums, which are pumped into a storage tank maintained at the user's facility. 3.12 3.13 cations: Ions carrying a positive charge. chlorine, combined: Chlorine that is chemically combined, such as in chloramine compounds.

NOTE--There is no direct test for measuring combined chlorine, but it can be measured indirectly by measuring both total and free chlorine and calculating the difference.

3.14

chlorine, free: Dissolved molecular chlorine.

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3.15 colony-forming unit (CFU): Organism capable of replicating to form a distinct, visible colony on a culture plate. In practice, a colony may be formed by a group of organisms. 3.16 concentrate generators: System in which the concentrate is delivered to the consumer as a powder in a container and then converted on-line into a saturated solution by a dialysis delivery machine. This solution is used by an individual proportioning system to make the final dialysate delivered to the dialyzer. 3.17 dialysate: Aqueous fluid containing electrolytes and, usually, dextrose, which is intended to exchange solutes with blood during hemodialysis. The word "dialysate" is used throughout this document to mean the fluid made from water and concentrates that is delivered to the dialyzer by the dialysate supply system. Such phrases as "dialyzing fluid" or "dialysis solution" may be used in place of dialysate. 3.18 dialysate supply system: Devices that: (1) prepare dialysate on-line from water and concentrates or that store and distribute premixed dialysate; (2) circulate the dialysate through the dialyzer; (3) monitor the dialysate for temperature, conductivity (or equivalent), pressure, flow, and blood leaks; and (4) prevent dialysis during disinfection or cleaning modes. The term includes reservoirs, conduits, proportioning devices for the dialysate, and monitors and associated alarms and controls assembled as a system for the characteristics listed above. The dialysate supply system is often an integral part of single-patient dialysis machines (see 2.2). 3.19 disinfection: Destruction of pathogenic and other kinds of microorganisms by thermal or chemical means. Disinfection is a less lethal process than sterilization, because it destroys most recognized pathogenic microorganisms but does not necessarily destroy all microbial forms. This definition of "disinfection" is equivalent to low-level disinfection in the Spalding classification. 3.20 electrolyte: Ion capable of transferring or exchanging electrons. In dialysate, the electrolytes are the charged ions that result from dissociation of salts when they are dissolved in water. These charged ions are responsible for the conductive property of dialysate. 3.21 empty-bed contact time (EBCT): Measure of how much contact occurs between particles, such as activated carbon, and water as the water flows through a bed of the particles. EBCT (minutes) is calculated from the following equation: EBCT = (7.48 x V)/Q where V is the volume of particles in the bed (ft3), Q is the flow rate of water through the bed (gal/min), and 7.48 is the conversion factor for gallons to ft3. 3.22 endotoxin: Major component of the outer cell wall of gram-negative bacteria. Endotoxins are lipopolysaccharides, which consist of a polysaccharide chain covalently bound to lipid A. Endotoxins can acutely activate both humoral and cellular host defenses, leading to a syndrome characterized by fever, shaking chills, hypotension, multiple organ failure, and even death if allowed to enter the circulation in a sufficient dose. (See also pyrogen.) 3.23 endotoxin units (EU): Units assayed by the Limulus amoebocyte lysate (LAL) method when testing for endotoxins. Because activity of endotoxins differs on a mass basis, their activity is referred to a standard E. coli endotoxin. The current standard (EC-6-1) is prepared from E. coli O:113:H10. The relationship between the mass of an endotoxin and its activity varies with both the lot of LAL and the lot of control standard endotoxin being used. Since standards for endotoxin were harmonized in 1983 with the introduction of EC-5, the relationship between mass and activity of endotoxin has been approximately 10 EU/ng.

NOTE--In some countries, endotoxin concentrations are expressed in international units (IU). Since the 1983 harmonization of endotoxin assays, EU and IU are equivalent.

3.24 3.25

feed water: Water supplied to a water treatment system or an individual component of the system. germicide: Agent that kills microorganisms.

3.26 hemodiafiltration: Form of renal replacement therapy in which waste solutes are removed from blood by a combination of diffusion and convection through a high-flux membrane. Diffusive solute removal is achieved using a dialysate stream as in hemodialysis. Convective solute removal is achieved by adding ultrafiltration in excess of that needed to obtain the desired weight loss; fluid balance is maintained by infusing a replacement solution into the blood either before the dialyzer (predilution hemodiafiltration) or after the dialyzer (postdilution hemodiafiltration). 3.27 hemodialysis: Form of renal replacement therapy in which waste solutes are removed primarily by diffusion from blood flowing on one side of a membrane into dialysate flowing on the other side. Fluid removal that is sufficient

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to obtain the desired weight loss is achieved by establishing a hydrostatic pressure gradient across the membrane. This fluid removal provides some additional waste solute removal, particularly for higher molecular weight solutes. 3.28 hemofiltration: Form of renal replacement therapy in which waste solutes are removed from blood by convection. Convective transport is achieved by ultrafiltration through a high-flux membrane. Fluid balance is maintained by infusing a replacement solution into the blood either before the hemofilter (pre-dilution hemofiltration) or after the hemofilter (post-dilution hemofiltration).

NOTE--There is no dialysate stream in hemofiltration.

3.29 Limulus amoebocyte lysate (LAL) test: Assay used to detect endotoxin. Exploits the immune response of the horseshoe crab to endotoxin (Limulus polyphemus). 3.30 manufacturer: Person who designs, manufactures, fabricates, assembles, or processes a finished device. Manufacturers include, but are not limited to, those who perform the functions of contract sterilization, installation, relabeling, remanufacturing, repacking, or specification development, and initial distributors of foreign entities performing these functions. 3.31 microbial: Referring to microscopic organisms, bacteria, fungi, and so forth. (See also bacteriology.)

3.32 microbiological contamination: Contamination with any form of microorganism (e.g., bacteria, yeast, fungi, and algae) or with the by-products of living or dead organisms such as endotoxins, exotoxins, and microcystin (derived from blue-green algae). 3.33 microfilter: Filter designed to remove particles in the range 0.1 µm to 3 µm in diameter. Microfilters have an absolute size cut-off and are available in both dead-end and cross-flow configurations. 3.34 3.35 product water: Water produced by a water treatment system or by an individual component of a system. proportioning system: Apparatus that proportions water and hemodialysis concentrate to prepare dialysate.

3.36 pyrogen: Fever-producing substance. Note that pyrogens are most often lipopolysaccharides of gramnegative bacterial origin. (See also endotoxin.) 3.37 spike: Small amount of a single chemical used to increase a constituent or constituents in the concentrate for a single patient's treatment.

NOTE--The spike may be in the form of a dry chemical or may be dissolved in water.

3.38 sterile: Free from all living organisms and viable spores, within the limits of tests for sterility, and maintained in that state by suitable means.

NOTE--For solutions used in hemodialysis and related therapies, "sterile" can be used to describe a packaged solution that was prepared using a terminal sterilization process that has been demonstrated to achieve a six log reduction in appropriate indicator microorganisms. Alternatively, "sterile" can be used to describe a solution prepared for immediate use by a continuous process that has been validated to produce a solution free of microorganisms when challenged with a defined test fluid and that is capable of meeting this challenge even with a single fault failure.

3.39 storage tank: Large tank at the user's facility for storage of purified water or concentrate from bulk deliveries, or for concentrate prepared in bulk at the user's facility from powder and purified water. 3.40 total dissolved solids (TDS): Sum of all ions in a solution, often approximated by means of electrical conductivity or resistivity measurements. TDS measurements are commonly used to assess the performance of reverse osmosis units. TDS values are often expressed in terms of CaCO3 or NaCl equivalents (ppm). 3.41 ultrafilter: Membrane filter with a pore size in the range 0.001 µm to 0.05 µm. Performance is usually rated in terms of a nominal molecular weight cut-off (MWCO), which is defined as the smallest molecular weight species for which the filter membrane has more than 90 % rejection. Depending on their nominal MWCO, ultrafilters may be used to remove particles and solutes as small as 1,000 dalton. Ultrafilters with a nominal MWCO of 20,000 or less are generally adequate for endotoxin removal.

NOTE--Ultrafilters are usually configured in a cross-flow mode. Some ultrafilters also remove endotoxins by adsorption.

3.42 ultrapure dialysate: Highly purified dialysate that can be used in place of conventional dialysate or as feed solution for further processing to create fluid intended for injection directly into the blood. The definition of "ultrapure dialysate" varies, but the recommendation used in the European Renal Association­European Dialysis and Transplant Association (ERA/EDTA) Best Practice Guidelines (ERA­EDTA, 2002) is < 0.1 CFU/mL and < 0.03 EU/mL. The endotoxin level may be reduced in the future as more sensitive tests become available.

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3.43 3.44

United States Pharmacopoeia (USP): The current version of this official compendium (see 2.5). user: Physician or physician's representative responsible for the actual production and handling of dialysate.

NOTE--This recommended practice is directed to the "user."

3.45 water treatment system: Collection of water purification devices and associated piping, pumps, valves, gauges, etc., that together produce purified water for hemodialysis applications and deliver it to the point of use.

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4.1

Fluid quality

Water

The requirements contained in clause 4.1 apply to the purified water as it enters the equipment used to prepare dialysate or concentrates from powder at a dialysis facility. As such, these requirements apply to the water treatment system as a whole and not to each of the devices that make up the system. However, collectively the individual devices shall produce water that, at a minimum, meets the requirements of this clause. 4.1.1 Maximum level of chemical contaminants in water Product water used to prepare dialysate or concentrates from powder at a dialysis facility, or to process dialyzers for reuse, shall not contain chemical contaminants at concentrations in excess of those listed in ANSI/AAMI RD62 (see 2.3), which is reproduced in Table 1 below. The manufacturer or supplier of a complete water treatment system should recommend a system that is capable of meeting the requirements of this clause given the analysis of the feed water. The system design should reflect possible seasonal variations in feed water quality. The manufacturer or supplier of a complete water treatment and distribution system shall demonstrate that the complete water treatment, storage, and distribution system is capable of meeting the requirements of RD62 at the time of installation. Following installation of a water treatment, storage, and distribution system, the user is responsible for continued monitoring of the levels of chemical contaminants in the water and for complying with the requirements of this standard.

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Table 1--Maximum allowable chemical contaminant levels in water used to prepare dialysate and concentrates from powder at a dialysis facility and to reprocess dialyzers for multiple uses (Reproduced from ANSI/AAMI RD62:2001)

Contaminant Calcium Magnesium Potassium Sodium Antimony Arsenic Barium Beryllium Cadmium Chromium Lead Mercury Selenium Silver Aluminum Chloramines Free Chlorine Copper Fluoride Nitrate (as N) Sulfate Thallium Zinc Maximum concentration (mg/L) 2 (0.1 mEq/L) 4 (0.3 mEq/L) 8 (0.2 mEq/L) 70 (3.0 mEq/L) 0.006 0.005 0.10 0.0004 0.001 0.014 0.005 0.0002 0.09 0.005 0.01 0.10 0.50 0.10 0.20 2.0 100 0.002 0.10

NOTE--American National Standards are revised every three to five years. Users should consult the most recent edition of ANSI/AAMI RD62 to ensure that the levels listed in this table are still valid.

4.1.2 Bacteriology of water Product water used to prepare dialysate or concentrates from powder at a dialysis facility, or to process dialyzers for reuse, shall contain a total viable microbial count lower than 200 CFU/mL and an endotoxin concentration lower than 2 EU/mL. The action level for the total viable microbial count in the product water shall be 50 CFU/mL, and the action level for the endotoxin concentration shall be 1 EU/mL. If those action levels are observed in the product water, corrective measures shall promptly be taken to reduce the levels. The manufacturer or supplier of a complete water treatment and distribution system shall demonstrate that the complete water treatment, storage, and distribution system is capable of meeting the requirements of RD52 at the time of installation. Following installation of a water treatment, storage, and distribution system, the user is responsible for continued monitoring of the water bacteriology of the system and for complying with the requirements of this standard, including those requirements related to action levels.

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4.2

Concentrate

4.2.1 Maximum level of chemical contaminants in concentrate Users do not have to test concentrates to demonstrate compliance with the requirements of this clause when using commercially available packaged chemicals intended for use in preparing liquid concentrates at a dialysis facility or when using commercially available liquid concentrates, provided that the concentrates are manufactured in accordance with the requirements of ANSI/AAMI RD61 (see 2.4). If a user purchases raw chemicals for the formulation of concentrate, all chemicals used shall meet the requirements of the current United States Pharmacopoeia--National Formulary, including all applicable portions of the General Notices and of the General Requirements for Tests and Assay (see 2.5). If all other requirements are met, monograph limits for sodium, potassium, calcium, magnesium, or pH may be exceeded provided that correction is made, if necessary, for the presence of those ions in the final formulation. Also, users need not comply with the USP labeling requirements that specify labeling for use in hemodialysis if the user performs testing to meet the USP requirements. Water used to prepare concentrates at a dialysis facility shall not contain chemical contaminants at concentrations in excess of those in Table 1. 4.2.2 Bacteriology of concentrate Water used to prepare concentrates at a dialysis facility shall meet the requirements of 4.1.2. Any concentrate prepared at a dialysis facility should be capable of allowing the dialysis machine to prepare dialysate meeting the recommendations of 4.3.2.1. No recommendations are made regarding the bacteriology of concentrate prepared at a dialysis facility. (See A.4.2.2 for further details.) 4.3 Dialysate

4.3.1 Maximum level of chemical contaminants in dialysate With the exception of those solutes normally present in dialysate (calcium, magnesium, potassium, and sodium), dialysate should not contain chemical contaminants at concentrations in excess of those in Table 1. 4.3.2 Bacteriology of dialysate The recommendations contained in this clause apply to the dialysate collected from a dialysate port of the dialyzer or from a sampling port in the inlet dialysate line that can be accessed using a syringe. 4.3.2.1 Bacteriology of conventional dialysate Conventional dialysate should contain a total viable microbial count lower than 200 CFU/mL and an endotoxin concentration of lower than 2 EU/mL. The action level for the total viable microbial count in conventional dialysate should be 50 CFU/mL and the action level for the endotoxin concentration should be 1 EU/mL. If levels exceeding the action levels are observed in the dialysate, corrective measures, such as disinfection and retesting, should promptly be taken to reduce the levels. 4.3.2.2 Bacteriology of ultrapure dialysate Ultrapure dialysate should contain a total viable microbial count lower than 0.1 CFU/mL and an endotoxin concentration lower than 0.03 EU/mL. If those limits are exceeded in ultrapure dialysate, corrective measures should be taken to reduce the levels into an acceptable range. The user is responsible for monitoring the dialysate bacteriology of the system following installation. It is incumbent on the user to establish a regular monitoring routine. 4.3.2.3 Bacteriology of dialysate for infusion The recommendations contained in this clause apply to highly purified dialysate as it enters the patient's blood. Dialysate for infusion may be used for substitution fluid in convective therapies, such as hemodiafiltration and hemofiltration, and may be produced on-line from dialysate by processes such as sequential ultrafiltration through bacteria- and endotoxin-retentive membranes. Dialysate for infusion should contain less than 10-6 CFU/mL (< 1 CFU/1000 L) and endotoxin concentration of lower than 0.03 EU/mL. Compliance with a maximum bacterial level of 10-6 CFU/mL cannot be demonstrated by culturing. Therefore, dialysate for infusion should be produced by a device or process that has been validated by the manufacturer to produce fluid meeting the above recommendations for a specified time or number of treatments when supplied with dialysate of a specified quality. For example, when dialysate for infusion is produced from conventional dialysate meeting the recommendations of 4.3.2.1, the process should be validated to provide at least a nine-log reduction in bacteria and at least a two-log reduction in endotoxin. The function of the validated system should be verified according to the manufacturer's instructions at the time of

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installation and confirmed by the user with a regular monitoring and maintenance schedule. The user should follow the manufacturer's instructions for use of the validated system, and the user's monitoring and maintenance schedule should be designed to confirm that the dialysate used to prepare the dialysate for infusion continues to meet the specifications of the manufacturer of the device or process.

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5.1

Equipment

General

This clause provides a brief description of the different components that may be included in a water purification and distribution system used for hemodialysis applications. Since feed water quality and product water requirements may vary from facility to facility, not all of the components described in the following clauses will be necessary in every purification and distribution system. Routine dialysis requires a well-functioning water purification and distribution system, since dialysis cannot be performed without an adequate supply of water. In addition, certain components of the water purification and distribution system are critical to its operation. An example of such a critical component is the circulating pump in an indirect feed system. A dialysis facility should develop contingency plans to cover the failure of its water purification and distribution system or a critical component of that system. Such contingency plans should describe how to deal with events that completely prevent dialysis from being performed, such as failure of the facility's municipal water supply or electrical service following a natural disaster or water main break. Other plans should address how to deal with sudden changes in municipal water quality, as well as with failure of a critical component of the water purification and distribution system. 5.2 Water purification systems

5.2.1 General Water purification systems consist of three basic sections: a pretreatment section that conditions the water supplied to the primary purification device, which may be followed by other devices that polish final water quality. The pre-treatment section commonly includes a sediment filter, cartridge filters capable of retaining particles of various sizes, a softener, and carbon adsorption beds. The primary purification process most commonly used is reverse osmosis, which may be followed by deionization and ultrafiltration for polishing the product water from the reverse osmosis system. Whether a particular device is included in an individual water purification system will be dictated by local conditions. 5.2.2 Sediment filters

NOTE--Requirements for sediment filters intended for use in hemodialysis applications can be found in subclause 4.3.8 of normative reference 2.3.

Permanent, backwashable sediment filters, also known as "bed filters," are frequently located at or near the beginning of hemodialysis water treatment systems and are intended to remove relatively coarse particulate materials from incoming water. Although a single filtration medium may be used, bed filters known as multimedia filters are more commonly selected. These units contain multiple layers, each layer retaining progressively smaller particles. In this way, the bed is used to its fullest extent; the largest particles are removed in the first layer contacted by the water and the smallest in the final layer. As the bed accumulates particulate material, open passages begin to clog and resistance to the water flowing through the filter increases. Ultimately, the increased resistance to flow will lead to a reduction in water supply to downstream components. To prevent this situation from occurring, bed filters are cleaned by periodic backwashing, which is accomplished either manually or by using a timer-activated control valve. Bed filters should be fitted with gauges to measure the hydrostatic pressure at the filters' inlet and outlet. These values can be used to determine the dynamic pressure drop across the filter (delta pressure or P), which serves as an index of resistance to flow and provides a basis for setting the frequency of backwashing. 5.2.3 Cartridge filters Cartridge filters consist of a cylindrical cartridge of the filter medium with a central drainage core. The cartridge is contained within an opaque filter housing with seals to separate the feed and product water streams. Although cartridge filters may be installed at the inlet to a water system, their usual application is as a final filtration step prior to reverse osmosis. As the cartridge accumulates particulate material, resistance to flow through the filter increases, as indicated by an increase in P. When the maximum P recommended by the filter manufacturer is reached, the cartridge should be replaced according to the manufacturer's instructions.

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5.2.4 Softeners

NOTE--Requirements for softeners intended for use in hemodialysis applications can be found in subclause 4.3.10 of normative reference 2.3.

Water that contains calcium or magnesium can form relatively hard deposits and is called "hard water." Water that has had these elements replaced by sodium ion exchange is called "soft water," hence, the term "softener." Softeners also remove other polyvalent cations, most notably iron and manganese, although they are somewhat limited in this regard. The primary use of softeners in hemodialysis water systems is to prevent hard water deposits from damaging sensitive reverse osmosis membranes. A softener is a cylinder or vessel that contains insoluble spheres or beads, called "resin," to which sodium ions are attached. During operation, exchangeable sodium ions in the resin are progressively replaced by calcium and magnesium ions. When all the sodium ions have been used, the resin bed has reached a condition referred to as "exhaustion." Prior to exhaustion, softeners should be restored; that is, new exchangeable sodium ions are placed on the resin by a process known as "regeneration," which involves exposure of the resin bed to a saturated sodium chloride solution. Softeners that automatically regenerate also include a brine tank, from which saturated sodium chloride solution is drawn during regeneration, and a control valve that regulates regeneration and service cycles. 5.2.5 Carbon adsorption

NOTE--Requirements for carbon adsorption beds intended for use in hemodialysis applications can be found in subclause 4.3.9 of normative reference 2.3.

Carbon adsorption systems, often referred to as carbon filters, are the principal means of removing both free chlorine and chloramine. Removal of free chlorine to a maximum level of 0.5 mg/L and chloramine to a maximum level of 0.1 mg/L is necessary to protect hemodialysis patients from red cell hemolysis. In addition, free chlorine may also degrade some reverse osmosis membranes, depending on the membrane material. In addition to removing free chlorine and chloramine, carbon also adsorbs a wide variety of other substances, including both naturally occurring and synthetic organic compounds. The capacity of carbon to remove free chlorine and chloramine may be reduced when other substances "mask" reactive sites on the carbon media. In addition, the efficiency of free chlorine and chloramine removal is reduced as pH increases or as temperature decreases. The net effect of those variables is that the finite capacity of carbon beds to remove free chlorine and chloramine cannot be predicted with any certainty. Therefore, their performance needs to be monitored frequently. For free chlorine and chloramine removal, carbon adsorption systems and carbon media should be selected and configured as described in ANSI/AAMI RD62:2001 (see 2.3). That is, two carbon beds shall be installed in series with a sample port following the first bed. A sample port should also be installed following the second bed for use in the event of free chlorine or chloramine breaking through the first bed. When samples from the first sampling port are positive for chlorine or chloramine, operation may be continued for a short time (up to 72 hours) until a replacement bed is installed, provided that samples from the second sampling port remain negative. The replacement bed should be placed in the second position, and the existing second bed should be moved to the first position to replace the exhausted bed. If it is not possible to rotate the position of the beds, both beds should be replaced. Carbon beds are sometimes arranged as series-connected pairs of beds so that they need not be overly large. The beds within each pair are of equal size and water flows through them are parallel. In this situation, each pair of beds should have a minimum empty bed contact time of 5 minutes at the maximum flow rate through the bed. When seriesconnected pairs of beds are used, the piping should be designed to minimize differences in the resistance to flow from inlet and outlet between each parallel series of beds to ensure that an equal volume of water flows through all beds. When granular activated carbon is used as the media, it shall have a minimum iodine number of 900, and each bed shall have a minimum empty bed contact time of 5 minutes at the maximum flow rate through the bed. Other forms of carbon should not be used unless there is performance data to demonstrate that each adsorption bed has the capacity to reduce the chloramine concentration in the feed water to less than 0.1 mg/L when operating at the maximum anticipated flow rate for the maximum time interval between scheduled testing of the product water for chloramines. Regenerated carbon shall not be used for hemodialysis applications. Some granular activated carbon contains aluminum, which can elute from the carbon and add to the burden of aluminum to be removed by reverse osmosis or ion exchange. The use of acid-washed carbon minimizes this source of aluminum in the water. In some circumstances, carbon adsorption may not adequately remove chloramines from water. High pH of feed water, the occurrence of N-chloramines, and the use of orthophosphate or polyphosphate for corrosion control have been associated with a decrease in the removal of chloramines by carbon adsorption. In those situations, carbon adsorption may need to be supplemented with other methods of chloramine removal.

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5.2.6 Chemical injection systems Chemical injection systems may be used in the pretreatment section of a water purification system to supplement the physical purification processes described in the previous clauses. Applications of chemical injection include the addition of sodium metabisulfite to remove chloramines and the addition of acid to adjust pH. Chemical injection systems consist of a reservoir that contains the chemical to be injected, a metering pump, and a mixing chamber located in the main water line. Chemical injection systems also include some means of regulating the metering pump to control the addition of a chemical. This system should be designed to tightly control the addition of the chemical. The control system should ensure that a chemical is added only when water is flowing through the pretreatment cascade and that it is added in fixed proportion to the water flow or based on some continuously monitored parameter, such as pH, using an automated control system. If an automated control system is used to inject the chemical, the controlling parameter should be independently monitored. There should also be a means of verifying that the concentrations of any residuals arising from the chemical added to the water are reduced to a safe level before the water reaches its point of use. When acid is added to adjust pH, a mineral acid should be used; organic acids may act as a nutrient and allow bacteria to proliferate. 5.2.7 Reverse osmosis

NOTE--Requirements for reverse osmosis systems intended for use in hemodialysis applications can be found in subclause 4.3.7 of normative reference 2.3.

Reverse osmosis (RO) systems have become widely used in hemodialysis water purification systems, largely because these devices remove dissolved inorganic solutes as well as bacteria and bacterial endotoxins. The RO membrane separation process components are a semipermeable membrane, typically in a spiral-wound configuration, a pump, and various flow and pressure controls to direct the flow of water through the system. In operation, feed water is pressurized by the RO pump and is then directed along the surface of the semipermeable membrane. A portion of the water is forced through the membrane, a process that removes inorganic salts, bacteria, and bacterial endotoxins. The remainder of the water continues along the membrane surface and is directed to drain. Water passing through the membrane is referred to as "product water" or "permeate." The water that flows along the membrane surface and to the drain is known as "reject water" or "concentrate." This flow configuration, known as "cross-flow filtration," prevents a progressive build-up of materials on the membrane surface that would eventually lead to fouling and membrane failure. In some reverse osmosis systems, a portion of the reject water stream is recycled to the feed water stream. This recycling allows higher velocities across the membrane surface, which may help reduce membrane fouling, as well as allowing higher overall use of water. RO systems usually operate in a single-stage configuration. However, if a higher level of purification is required, a two-stage RO can be used. In a twostage RO, the product water from the first stage acts as the feed water for the second stage. Depending on membrane configuration and materials of construction, RO systems are sensitive to various feed water conditions that may lead to diminished performance or premature failure. To avoid such problems, users should carefully follow the manufacturer's instructions for feed water treatment and monitoring to ensure that the RO is operated within its design parameters. RO systems should be fitted with a variety of sensors to monitor the system's performance. Conductivity or total dissolved solids (TDS) sensors in the feed water and product water streams are used to monitor the membrane's ability to remove dissolved inorganic solutes. Flow meters, usually in the product water and reject water streams, are used to monitor the output of the RO system. RO systems are also fitted with gauges to monitor the pressure at various points in the system. Although not indicative of treated water quality, monitoring flow rates and pressures can help ensure that the system is operating within the manufacturer's specifications and thus will help ensure RO reliability. 5.2.8 Deionization

NOTE--Requirements for deionizers intended for use in hemodialysis applications can be found in subclause 4.3.10 of normative reference 2.3.

Deionization (DI) is an ion exchange process that removes both anions (negatively charged ions) and cations (positively charged ions) from water. During the exchange process, hydroxyl ions replace other feed water anions, and hydrogen ions replace other feed water cations; the hydroxyl and hydrogen ions then combine to form pure water. Water treated by DI may be very high quality with regard to ionized contaminants, but the process does not remove nonionized substances, including bacteria and bacterial endotoxins. DI systems may contain anion and cation resin in separate vessels, known as "dual-bed systems," or have may both resin types mixed together in a single vessel, known as "mixed-bed" or "unibed systems."

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Systems that include deionizers as a component shall also contain carbon adsorption and ultrafiltration. In such systems, carbon is placed upstream of the deionizer to avoid formation of carcinogenic nitrosamines, and ultrafiltration is placed downstream of the deionizer to remove bacteria and endotoxins. The usual application for a deionizer is as a polisher following reverse osmosis or as a standby process if the reverse osmosis system fails. Use of deionization as the primary means of purification is not recommended because of the inability of deionization and ultrafiltration to remove certain low-molecular-weight toxic bacterial products, such as microcystins. In all instances, deionizers shall be followed by an ultrafilter or other bacteria- and endotoxin-reducing device to remove microbiological contaminants that may originate in the deionizer resin bed. DI has a finite capacity that, when exceeded, will cause dangerously high levels of contaminants in the product water. Fortunately, the quality of product water from DI is easily monitored by resistivity monitors that, when used as specified in ANSI/AAMI RD62:2001 (see 2.3) (minimum resistivity 1 megohm-cm or greater), can prevent inadvertent operation of an exhausted deionization system. Specifically, the resistivity monitor following the final deionizer bed shall be connected to an audible and visible alarm in the dialysis treatment area, and the DI system shall divert product water to drain or otherwise prevent product water from entering the distribution system should an alarm condition occur. Under no circumstances shall DI be used when the product water of the final bed has a resistivity below 1 megohm-cm. The most common configuration for DI is to have two mixed beds in series, with resistivity monitors being placed downstream of each bed. Upon exhaustion of the first bed, reliance for water of sufficiently high resistivity shifts to the second bed, and dialysis operations may be continued for a short time (up to 72 hours) until a replacement bed is installed. 5.2.9 Ultrafiltration

NOTE--Requirements for ultrafilters intended for use in hemodialysis applications can be found in subclause 4.3.12 of normative reference 2.3.

Ultrafilters are membrane-based separation devices that may be used to remove particles as small as 1,000 dalton and are thus well suited to remove both bacteria and endotoxins. Endotoxin-retentive ultrafilters should be placed in dialysis water systems at locations downstream of deionization, if deionization is the last process in a water treatment system (see subclause 4.3.6 of normative reference 2.3) or following ultraviolet irradiation (see subclause 4.3.13 of normative reference 2.3). Ultrafiltration membranes used for dialysis applications are typically in either a spiral-wound configuration or in a hollow-fiber configuration. Spiral-wound ultrafilters are usually operated in a cross-flow mode, with a fraction of the feed water being forced through the membrane and the remainder being directed along the membrane surface to drain. As with reverse osmosis, cross-flow filtration is intended to minimize membrane fouling. Hollow-fiber ultrafilters are typically housed in vessels similar to those used for cartridge sediment filters and these are operated in a deadend (no cross-flow) mode. Ultrafilters should be fitted with pressure gauges on the inlet and outlet water lines to monitor the pressure drop (P) across the membrane. Such monitoring will indicate when membrane fouling has progressed to the point at which membrane replacement or cleaning is needed. Monitoring also ensures that the device is being operated in accordance with the manufacturer's instructions. Ultrafilters should be included in routine disinfection procedures to prevent uncontrolled proliferation of bacteria in the feed water compartment of the filter. If bacterial proliferation is not controlled, bacteria may "grow through" the membrane and contaminate the product water compartment of the filter. Ultrafilters operated in the cross-flow mode should also be fitted with a flow meter to monitor the flow rate of water being directed to drain. 5.3 Water storage and distribution

5.3.1 General The function of the water storage and distribution system is to distribute product water from the purification cascade to its points of use, including individual hemodialysis machines, hemodialyzer reprocessing equipment, and concentrate preparation systems. A water storage and distribution system typically contains a large volume of water exposed to a large surface area of piping and storage tank walls. Because chlorine and chloramines are removed in the purification process, the water does not contain a bacteriostatic agent. This combination of circumstances predisposes wetted surfaces to bacterial proliferation and biofilm formation. Therefore, a water storage and distribution system should be designed specifically to facilitate bacterial control, including measures to prevent bacterial colonization and to allow for easy and frequent disinfection. 5.3.2 Water storage When used, storage tanks should have a conical or bowl-shaped base and should drain from the lowest point of the base. Storage tanks should have a tight-fitting lid and be vented through a hydrophobic 0.2 µm air filter. The filter

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should be changed on a regular schedule according to the manufacturer's instructions. A means shall be provided to effectively disinfect any storage tank installed in a water distribution system. Internal spray mechanisms can facilitate effective disinfection and rinsing of a storage tank. 5.3.3 Water distribution systems Two types of water distribution systems are used: direct feed systems and indirect feed systems. In a direct feed system, water flows directly from the last stage of the purification cascade to the points of use. In an indirect feed system, water flows from the end of the purification cascade to a storage tank. From there, it is distributed to the points of use. In general, direct feed systems offer the least favorable environment for bacterial proliferation. However, with a direct feed system the purification cascade must be sized to provide sufficient water to meet the peak demand, and the system must have sufficient pressure at the end of the purification cascade to distribute the water to the points of use. Those two requirements often preclude the use of a direct feed system. Whichever type of system is used, water distribution systems should be configured as a continuous loop and designed to minimize bacterial proliferation and biofilm formation (see clause 7). A centrifugal pump made of inert materials is necessary to distribute the purified water and aid in effective disinfection. A multistage centrifugal pump is preferred for this purpose. Product water distribution systems shall be constructed of materials that do not contribute chemicals, such as aluminum, copper, lead, and zinc, or bacterial contaminants to the purified water. The choice of materials used for a water distribution system will also depend on the proposed method of disinfection. Table 2 provides some guidance on the compatibility of different materials and disinfection agents. Whatever material is used, care should be taken to select a product with properties that provide the least favorable environment for bacterial proliferation, such as smooth internal surfaces.

Table 2--Compatibility of common disinfectants with piping materials used in water distribution systems

Material PVC CPVC PVDF PEX SS PP PE ABS PTFE Glass X X X X Bleach X X X X Peracetic acid X X X X X X X X X X X X X X X X Formaldehyde X X X X X X X X X X X X X X Hot water Ozone

PVC = polyvinylchloride, CPVC = chlorinated polyvinylchloride, PVDF = polyvinylidene fluoride, PEX = cross-linked polyethylene, SS = stainless steel, PP = polypropylene, PE = polyethylene, ABS = acrylonitrile butadiene styrene, PTFE = polytetrafluoroethylene. NOTE--Table 2 is not intended as an exhaustive compilation of all possible compatible combinations of piping material and disinfectant. Users should verify compatibility between a given germicide and the materials of a piping system with the supplier of that piping system before using the germicide. Considerations of compatibility should include any joint materials and pipe fittings, as well as the actual piping material. The concentration of germicide and the duration and frequency of exposure also should be taken into account.

5.3.4 Bacterial control devices 5.3.4.1 Ultraviolet irradiators

NOTE--Requirements for ultraviolet (UV) irradiators intended for use in hemodialysis applications can be found in subclause 4.3.13 of normative reference 2.3. The recommendations provided in this clause concern UV irradiators used specifically for bacterial

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control. UV irradiators also may be used for other applications in a water purification and distribution system (see 5.3.4.2 and A.5.2.5).

Ultraviolet irradiators (also known as UV lights) may be used to control bacterial proliferation in purified water storage and distribution systems. UV irradiators contain a low-pressure mercury lamp that emits ultraviolet light at a wavelength of 254 nm. The lamp is housed in a transparent quartz sleeve that isolates it from direct contact with the water. If the irradiator is not fitted with a calibrated ultraviolet intensity meter that is filtered to restrict its sensitivity to the disinfection spectrum and that is installed in the wall of the disinfection chamber at the point of greatest water depth from the lamp, the dose of radiant energy provided by the lamp shall be at least 30 milliwatt-sec/cm2. If the irradiator includes a meter as described above, the minimum dose of radiant energy should be at least 16 milliwattsec/cm2. Ultraviolet irradiation also can be used to control bacteria in the pretreatment section of a water purification system, such as following carbon adsorption beds to reduce the bacterial burden presented to a reverse osmosis unit. Because using UV irradiation to kill bacteria increases the level of endotoxins in the water, UV irradiators should be followed by a means of reducing endotoxin concentrations, such as an ultrafilter in the purified water distribution system or reverse osmosis in the pretreatment cascade. To prevent the use of sublethal doses of radiation that may lead to the development of resistant strains of bacteria, UV irradiators shall be equipped with a calibrated ultraviolet intensity meter, as described above, or with an on-line monitor of radiant energy output that activates a visible alarm, which indicates that the lamp should be replaced. Alternatively, the lamp should be replaced on a predetermined schedule according to the manufacturer's instructions to maintain the recommended radiant energy output. 5.3.4.2 Ozone generators

NOTE--Requirements for ozone generators intended for use in hemodialysis applications can be found in subclause 4.3.15 of normative reference 2.3.

Ozone may be used to control bacterial proliferation in water storage and distribution systems. Ozone may also degrade endotoxins. Ozone generators convert oxygen in air to ozone using a corona discharge or ultraviolet irradiation. The ozonated air is then injected into the water stream. An ozone concentration of 0.2 mg/L to 0.5 mg/L, combined with a contact time of 10 minutes, is capable of killing bacteria, bacterial spores, and viruses in water. Destruction of established biofilm may require longer exposure times and/or higher concentrations of ozone. Ozone may degrade many plastic materials, including PVC and elastomeric O-rings and seals. Therefore, ozone can be used for bacterial control only in systems constructed from ozone-resistant materials (see 5.3.3 for suitable piping materials). 5.3.4.3 Hot water disinfection systems

NOTE--Requirements for hot water disinfection systems intended for use in hemodialysis applications can be found in subclause 4.3.14 of normative reference 2.3.

Hot water ( 80 °C) may be used to control bacterial proliferation in water storage and distribution systems. The manufacturer's instructions for using hot water disinfection systems should be followed. If no manufacturer's instructions are available, the effectiveness of the system can be demonstrated by verifying that the system maintains a specified temperature for a specified time and by performing ongoing surveillance with bacterial cultures and endotoxin testing. Bacterial kill studies are not required. Hot water disinfection systems can be used only in systems constructed from heat-resistant materials, such as crosslinked polyethylene, polypropylene, and stainless steel (see 5.3.3). 5.4 Concentrate preparation

5.4.1 General Dialysate is customarily prepared from two concentrates: the bicarbonate concentrate, which contains sodium bicarbonate (and sometimes additional sodium chloride), and the acid concentrate, which contains all remaining ions, acetic acid, and sometimes glucose. Dialysate also can be prepared from a single concentrate that contains acetate. The buffer is provided to the patient in the form of acetate, which is subsequently metabolized to yield bicarbonate. Acetate-containing dialysate is now rarely used in clinical practice. In general, acetate-containing concentrate is handled in a similar manner to that of acid concentrate (see 5.5.3 and 5.5.5), except that acetate-containing concentrate systems are color-coded white. Acid concentrate can be supplied by the manufacturer in bulk (usually in 55 gallons drums) or in gallon containers. In some cases, the manufacturer will pump the acid concentrate from the 55 gallon drums into a holding tank at the

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dialysis facility. Systems have recently been introduced that allow a user at a dialysis facility to prepare acid concentrate from packaged powder and purified water using a mixer. Acid concentrates supplied in 55 gallon drums or gallon containers by the manufacturer are the responsibility of that manufacturer (see 2.4). If the acid concentrate is pumped into a bulk storage tank at the dialysis facility, the user is responsible for maintaining the concentrate in its original state and to ensure that the correct formula is used according to the patient's prescription. Acid concentrate prepared at the dialysis facility from powder and water is also the responsibility of the user. Bicarbonate concentrate can be supplied by the manufacturer in one of three ways: (1) in gallon containers, (2) as packaged powder that is mixed with purified water at the dialysis facility, and (3) in powder cartridges that are used to prepare concentrate on-line at the time of dialysis. 5.4.2 Materials compatibility All components used in concentrate preparation systems (including mixing and storage tanks, pumps, valves, and piping) shall be fabricated from materials (e.g., plastics or appropriate stainless steel) that do not interact chemically or physically with the concentrate so as to affect its purity, or with the germicides or germicidal procedure used to disinfect the equipment. The use of materials that are known to cause toxicity in hemodialysis, such as copper, brass, galvanized material, and aluminum, are specifically prohibited. 5.4.3 Bulk storage tanks (acid concentrate) Procedures should be in place to control the transfer of the acid concentrate from the delivery container to the storage tank to prevent the inadvertent mixing of different concentrate formulations. If possible, the tank and associated plumbing should form an integral system to prevent contamination of the acid concentrate. The storage tanks and inlet and outlet connections, if remote from the tank, should be secure and labeled clearly. 5.4.4 Mixing systems 5.4.4.1 General Concentrate mixing systems require a purified water source (see 2.3), a suitable drain, and a ground fault protected electrical outlet. Protective measures should be used to ensure a safe work environment. For example, ventilation and personal protective equipment should be used to handle any residual dust that is introduced into the atmosphere as powdered concentrates are added to the system and to handle any additional heat produced by the device. Structural issues, such as the facility's weight-bearing capacity, should be addressed if systems are to be installed above ground level. Operators should at all times use appropriate personal protective equipment, such as face shields, masks, gloves, gowns, and shoe protectors, as recommended by the manufacturer. If a concentrate mixing system is used, the preparer should follow the manufacturer's instructions for mixing the powder with the correct amount of water. The number of bags or the weight of powder added should be determined and recorded. Labeling strategies should permit positive identification by anyone using the contents of mixing tanks, bulk storage/dispensing tanks, and small containers intended for use with a single hemodialysis machine. Requirements for such positive identification will vary among facilities, depending on the differences between concentrate formulations used and on whether single or multiple dialysate proportioning ratios are used. (The use of multiple dialysate proportioning ratios in a single facility is strongly discouraged.) Although it is the responsibility of facilities to develop and use labeling to positively identify the contents of mixing tanks, bulk storage/dispensing tanks, and concentrate jugs, the following guidelines are suggested. Mixing tanks: Prior to batch preparation, a label should be affixed to the mixing tank that includes the date of preparation and the chemical composition or formulation of the concentrate being prepared. This labeling should remain on the mixing tank until the tank has been emptied. Using a photocopy of the concentrate manufacturer's package label provides a convenient and comprehensive means of identifying the chemical composition or formulation of the concentrate; however, the lot number and expiration date should be marked out because they apply only to the dry powder. Bulk storage/dispensing tanks: These tanks should be permanently labeled to identify the chemical composition or formulation of their contents. As with mixing tanks, bulk storage/dispensing tank labeling can be conveniently accomplished by affixing a copy of the concentrate manufacturer's package label. Concentrate jugs: Concentrate jugs are typically nondisposable vessels provided by hemodialysis machine manufacturers and having a capacity sufficient for one or two hemodialysis sessions. The extent of labeling for these containers depends on the variety of concentrate formulations used and on whether the facility uses dialysis machines with different proportioning ratios (a practice that is strongly discouraged). At a minimum, concentrate jugs should be labeled with sufficient information to differentiate the contents from other concentrate formulations used at the facility. If a chemical spike is added to an individual container to increase the concentration of an electrolyte, the

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label should show the added electrolyte, the date and time added, and the name of the person making the addition (see 5.4.5). The additional information may be simple or extensive, but in all cases it should permit users to positively identify the container's contents. In addition to container labeling, there should be permanent records of batches produced. These records should include the concentrate formula produced, the volume of the batch, the lot numbers of powdered concentrate packages, the manufacturer of the powdered concentrate, the date and time of mixing, any test results, the person performing the mixing, the person verifying mixing and test results, and the expiration date (if applicable). Manufacturer's recommendations should be followed regarding any preventive maintenance and sanitization procedures. Records should be maintained indicating the date, time, person performing the procedure, and results (if applicable). 5.4.4.2 Acid concentrate mixing systems Acid concentrate mixing tanks should be designed to allow the inside of the tank to be completely emptied and rinsed according to the manufacturer's instructions when concentrate formulas are changed. Use of a tank with a sloping bottom that drains from the lowest point is one means of facilitating this process. Because concentrate solutions are highly corrosive, mixing systems should be designed and maintained to prevent corrosion. Acid concentrate mixing tanks should be emptied completely before mixing another batch of concentrate. 5.4.4.3 Bicarbonate concentrate mixing systems Bicarbonate concentrate mixing tanks should be designed to drain completely; for example, they should have a sloping bottom and a drain at the lowest point. High- and low-level alarms can prevent overfilling and air damage to the pump. Because concentrate solutions are highly corrosive, mixing systems should be designed and maintained to prevent corrosion. Mixing tanks should have a tight-fitting lid and should be designed to allow all internal surfaces to be disinfected and rinsed. A translucent tank allows users to see the liquid level; the use of sight tubes is not recommended because of the potential for microbial growth, such as bacteria, algae, and fungi. Once mixed, bicarbonate concentrate should be used within the time specified by the manufacturer of the concentrate. The concentrate shall be shown to routinely produce dialysate meeting the recommendations of 4.3.2.1. Overagitating or overmixing of bicarbonate concentrate should be avoided, as this can cause CO2 loss and can increase pH. (Systems designed for mixing dry acid concentrates may use methods that are too vigorous for dissolving dry bicarbonate.) The mixing tank should be either (1) completely emptied and disinfected according to the manufacturer's instructions, or (2) disinfected using a procedure demonstrated by the facility to be effective in routinely producing concentrate that allows the recommendations of 4.3.2.1 to be met. 5.4.5 Additives Manufacturers provide acid concentrates with a wide range of electrolyte compositions for different proportioning ratios. Most typical dialysate prescriptions can be obtained by using one or more of these commercially available concentrates. If particular formulations are not available, manufacturers provide additives that can be used to adjust the level of potassium or calcium in the dialysate. These additives are commonly referred to as "spikes." Concentrate additives should be mixed with liquid acid concentrates according to the manufacturer's instructions, taking care to ensure that the additive is formulated for use in concentrates of the appropriate dilution ratio. When liquid additives are used, the volume contributed by the additive should be considered when calculating the effect of dilution on the concentration of the other components in the resulting concentrate. When powder additives are used, care should be taken to ensure that the additive is completely dissolved and mixed before the concentrate is used. Containers should be labeled to indicate the final concentration of the added electrolyte, the date and time mixed, and the person mixing the concentrate. This information should also be recorded in a permanent record. Labels should be affixed to the containers when the mixing process begins. 5.5 Concentrate distribution

5.5.1 Materials compatibility All components used in concentrate distribution systems (including concentrate jugs, storage tanks, and piping) that contact the fluid shall be fabricated from nonreactive materials (e.g., plastics or appropriate stainless steel) that do not interact chemically or physically with the concentrate so as to affect its purity. The use of materials that are known to cause toxicity in hemodialysis, such as copper, brass, galvanized material, and aluminum, are specifically prohibited.

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5.5.2 System configurations Concentrate may be distributed from a central preparation point using reusable concentrate jugs that contain sufficient concentrate for one to two treatments, or it may be distributed through a piping system that provides concentrate connections at each treatment station. A combination of these two systems may also be used, with some concentrates distributed by concentrate jug and others through a piping system. Two common configurations used for distributing concentrate through a piping system are gravity feed and pressurized. Gravity feed systems require an elevated tank; pressurized systems deliver the concentrate using a pump and motor and do not require an elevated tank. The maximum allowable concentrate delivery pressure is specified by the manufacturer of the dialysate delivery machine and should not be exceeded. Elevated tanks are usually smaller than those used for preparing concentrates. Elevated tanks for bicarbonate concentrate distribution should be equipped with conical or bowl-shaped bottoms, tight-fitting lids, a spray mechanism, and high- and low-level alarms. Any air vents should have 0.2 µm hydrophobic vent filters. 5.5.3 Acid concentrate distribution systems Acid concentrate delivery piping should be labeled and color-coded red at the point of use (at the jug filling station or the dialysis machine connection). More than one type of acid concentrate may be delivered, and each line should clearly indicate the type of acid concentrate it contains. All joints should be sealed to prevent leakage of concentrate. Acid concentrate is not susceptible to bacteria contamination, but every effort should be made to keep the system closed to prevent nonbacterial contamination and evaporation. If the acid system remains intact, no rinsing or disinfection is necessary. 5.5.4 Bicarbonate concentrate distribution systems Bicarbonate concentrate delivery piping should be color-coded blue at the point of use (at the jug filling station or dialysis machine connection). All joints should be sealed to prevent leakage of concentrate. Because bicarbonate concentrates provide excellent media for bacterial proliferation, bicarbonate concentrate delivery systems should be disinfected on a regular basis to ensure that the dialysate routinely achieves the level of bacteriological purity recommended in 4.3.2.1. The manufacturer's instructions can provide an initial disinfection schedule. However, this schedule may need to be adjusted on the basis of the user's bacteriological monitoring. For piped distribution systems, the entire system, including patient station ports, should be purged of bicarbonate concentrate before disinfection. Each patient station port should be opened and flushed with disinfectant and then rinsed; otherwise, it would be a "dead leg" in the system. When reusable concentrate jugs are used to distribute bicarbonate concentrate, they should be rinsed free of residual concentrate before disinfection. All chemical disinfectants (e.g., bleach and peracetic acid products) that are compatible with dialysis machines can be used to disinfect bicarbonate concentrate delivery systems. However, some disinfectants attack biofilm better than others. Appropriate dwell times and concentrations should be used as recommended by the manufacturer of the concentrate system. If this information is not available, bleach may be used at a dilution of 1:100 and proprietary disinfectants at the concentration recommended by the manufacturer for disinfecting piping systems. In the event that precipitation or salt build-up impedes flow through a piping system, cleaning with a 1:34 solution of 5 % acetic acid (e.g., distilled white vinegar) is recommended. Some manufacturers supply bicarbonate concentrate systems with UV irradiation or ozone systems for bacterial control. UV irradiation devices that are used to control bacteria proliferation in the pipes of bicarbonate concentrate distribution systems should be fitted with a low-pressure mercury lamp that emits light at a wavelength of 254 nm and provides a dose of radiant energy of 30 milliwatt-sec/cm2. The device should be sized for the maximum anticipated flow rate according to the manufacturer's instructions and be equipped with an on-line monitor of radiant energy output that activates a visual alarm indicating that the lamp should be replaced. Alternatively, the lamp should be replaced on a predetermined schedule according to the manufacturer's instructions to maintain the recommended radiant energy output. It is recommended that UV irradiators be followed by an ultrafilter. Disinfection of the bicarbonate concentrate distribution system should continue to be performed routinely. When used to disinfect the pipes of a bicarbonate concentrate delivery system, an ozone generator should be capable of delivering ozone at the concentration and for the exposure time specified by the manufacturer. When ozone disinfection systems are used, ambient air should be monitored for ozone as required by the U.S. Occupational Safety and Health Administration (OSHA). 5.5.5 Concentrate outlets For piped concentrate distribution systems, each treatment station is equipped with a concentrate outlet for bicarbonate, one or more outlets for acid concentrate, and a product water outlet for connection to the inlet line of the dialysis machine. To prevent mix-ups with delivery of two or more types of acid concentrate, each concentrate should have its own outlet. Concentrate outlets should be compatible with the dialysis machine and have a means of

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minimizing the risk that the wrong concentrate will be connected to an outlet. The dispensing outlets should be labeled with the appropriate symbol (see Table 3) indicating the proportioning ratio for the dialysis machine and should be color-coded blue for bicarbonate, red for acid. 5.6 Dialysate proportioning

Essentially, all dialysate is produced with three fluid streams: water, acid concentrate, and bicarbonate concentrate. This three-stream combination produces a highly buffered dialysate with a pH between 6.9 and 7.6. Dialysate can also be prepared from a single concentrate that contains acetate to provide a dialysate in which buffer is provided to the patient in the form of acetate, which is subsequently metabolized to yield bicarbonate. However, acetatecontaining dialysate is now rarely used in clinical practice. Different manufacturers of dialysis machines use different methods of controlling the proportions of the concentrates. These can be generally grouped into two categories: "fixed proportioning" and "servo control." With both methods, the operator can select a desired sodium and bicarbonate level, and the machine will make the necessary adjustments to achieve the selected levels. Both types use a redundant system of controls and monitoring. With fixed proportioning systems, the pumps are set to established volumes, and the final conductivity is verified. With servo control machines, the individual concentrates are added until the conductivity achieves the expected value. A final redundant conductivity monitor verifies the mixture. Some machines may also monitor the pH of the dialysate as an additional safeguard against gross errors in dialysate formulation. A different type of machine with a batch tank and dedicated concentrates is also available. It is important that the acid and bicarbonate concentrates be matched with respect to the proportioning ratio and with the model and setup configuration of the dialysis machine. Several types of three-stream concentrates are available, with different ratios of acid concentrate to bicarbonate concentrate to water (see Table 3). The different proportioning types are not compatible with one another. Generally, bicarbonate is available in one or two forms for each proportioning type (in liquid, cartridge, or dry powder, and in various sizes). Each proportioning type has numerous acid concentrate formulations ("codes") with different amounts of potassium, calcium, and magnesium ions, plus dextrose. To help differentiate between concentrates of different proportioning types, AAMI recommends that the manufacturer include a geometric symbol on the labels along with acid/base color coding.

Table 3--Symbols and color coding for different concentrate proportioning ratios

Concentrate type 35X 36.83X 45X 36.1X Acid proportioning ratio (Red color coding) 1:34 1:35.83 1:44 1:35.1 Geometric symbol Square Circle Triangle Hexagon Bicarbonate concentrate (Blue color coding) Dry, liquid, or cartridge Dry or liquid Dry, liquid, or cartridge Cartridge Powder cartridges may be used for other proportioning ratios, except for 36.83X, in which the bicarbonate concentrate also contains NaCl. Bicarbonate concentrate contains some NaCl.

Comments

NOTE 1--The acid proportioning ratio refers to acid concentrate:water + bicarbonate concentrate. NOTE 2--Acetate-containing concentrate is color-coded white.

Some models of dialysis machines can use concentrates of only one type of proportioning ratio, but others may be set up or calibrated for use with concentrates of more than one proportioning type. (Note that changing from one proportioning ratio to another requires recalibration for some models of dialysis machines.) Thus, for those machines, the type of concentrate should be labeled on the machine or clearly indicated by the machine display. It is strongly recommended that facilities configure every machine to use only one type of concentrate. Injuries related to improper dialysate are rare, but they can and do happen when all procedures are not followed. Frequently, when the error occurs, several patients have been exposed before the facility recognizes the mistake. For example, because one of the concentrates is quite acidic and the other is basic, connecting the wrong concentrates to the machine could result in dialysate that could harm the patient. Thus, it is necessary for the operator to follow the manufacturer's instructions regarding dialysate conductivity and to measure approximate pH with an independent method before starting the treatment of the next patient.

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Even though a single concentrate is used to prepare acetate dialysate, conductivity and pH should be checked, because certain mix-ups involving acid concentrate and other chemicals can result in an acceptable conductivity and very low pH.

6

6.1

Monitoring

General

Quality control and quality assurance procedures should be established to ensure ongoing conformance to policies and procedures regarding dialysate quality. This clause defines some of the monitoring activities to be conducted at the dialysis facility as part of the quality assurance process. The paragraph numbers in 6.2 and 6.3 correspond to the paragraph numbers in 5.2 and 5.3. The test methods described in 6.2 do not represent the only acceptable methods available, but are intended to provide examples of acceptable methods. The frequency of monitoring is generally recommended by the equipment manufacturer. Table 4 can be used as a guideline for setting up a quality assurance monitoring program in the absence of a manufacturer's recommendations or to supplement those recommendations.

Table 4--Monitoring guidelines for water purification equipment and distribution systems and dialysate

NOTE--Refer to footnote for an explanation of the use of Xs in the Specification column.

Item to monitor Sediment filter Sediment filter backwashing cycle Cartridge filter Water softener

What to monitor Pressure drop across the filter Backwash cycle timer setting Pressure drop across the filter Product water softness

Special interval NA NA

Normal interval Daily Daily--beginning of the day Daily Daily--end of the day

Specification Pressure drop less than XXXX Backwash clock set to XX:XX

NA NA

Pressure drop less than XXXX Hardness as calcium carbonate less than 1 grain/gal, unless otherwise specified by the manufacturer of the reverse osmosis equipment Salt level at XXX Softener timer set to XX:XX

Water softener brine tank Water softener regeneration cycle Carbon adsorption beds Chemical injection system

Level of undissolved salt in tank Regeneration cycle timer setting Product water free chlorine and/or total chlorine between the beds Level of chemical in the reservoir, injector function, value of the controlling parameter (e.g., pH) Product water conductivity, total dissolved solids (TDS), or resistivity and calculated rejection

NA NA

Daily--end of the day Daily--beginning of the day Prior to beginning each patient shift

NA

< 0.1 mg/L of total chlorine

NA

Daily

Chemical level in reservoir XXX; controlling parameter in range XX­XX

Reverse osmosis

NA

According to the manufacturer's recommendations (continuous monitors)

Rejection XX%

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Table 4 (continued) Item to monitor Reverse osmosis Deionizers Ultrafilters Water storage tanks Special interval NA

What to monitor Product and reject flow rates, and calculated recovery Product water resistivity Pressure drop across the filter Bacterial growth and pyrogens

Normal interval Daily (continuous monitors) Continuous Daily NA

Specification Product water flow rate > X.X gpm; recovery in the range XX­XX % Resistivity > 1 megohm-cm Pressure drop less than XXXX Bacterial count 50 CFU/mL; endotoxin 1 EU/mL

NA NA Weekly, until a pattern of consistent compliance with limits can be demonstrated Weekly, until a pattern of consistent compliance with limits can be demonstrated NA NA NA

Water distribution piping system

Bacterial growth and pyrogens

Monthly

Bacterial count 50 CFU/mL; endotoxin 1 EU/mL

UV light sources Ozone generators Hot water disinfection systems Dialysate

Energy output Concentration in the water Temperature and time of exposure of the system to hot water Bacterial growth and endotoxin in the dialysate

Monthly During each disinfection During each disinfection

Light output > XXX Ozone concentration > XXX Temperature not less than XX °C; minimum exposure time at temperature XX minutes Bacterial growth 50 CFU/mL; endotoxin 1 EU/mL

NA

Monthly, rotated among machines so that at least two machines are tested each month and so that each machine is tested at least once per year Each treatment

Dialysate

Conductivity and pH

NA

Conductivity within ± 5% of the nominal machine value; pH in the range 6.9­7.6

NOTE--It is not possible to specify universally acceptable operating ranges for each device listed in the table, since some of these values will be system-specific. In those cases (denoted by Xs in the Specification column of the table), the facility should define an acceptable operating range based on manufacturer's instructions or measurements of system performance.

6.2

Water purification

6.2.1 General The recommendations below apply.

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6.2.2 Sediment filters Sediment filters should be monitored on a periodic basis. There is no easy test to determine the effectiveness of a sediment filter; however, pressure drop (P) across the filter can be used to determine when the filter is retaining particulate matter to the point that the filter will no longer allow the required water flow without an excessive reduction in pressure at the outlet of the filter. A backwash cycle is used to remove particulate matter from the sediment filter. The frequency of backwashing should follow the manufacturer's recommendations. Sediment filter monitoring should include verification that the timer used to initiate backwashing cycles is set to the correct time of day. A log sheet should be developed to record the pressure drop measurements and timer verifications. 6.2.3 Cartridge filters Cartridge filters should be monitored on a periodic basis. There is no easy test to determine the effectiveness of a cartridge filter; however, pressure drop (P) across the filter can be used to determine when the filter is retaining particulate matter to the point that the filter will no longer allow the required water flow without an excessive reduction in pressure at the outlet of the filter. A marked decrease in P without a corresponding decrease in flow rate may indicate a loss of filter integrity. Follow the manufacturer's recommendations concerning when to replace cartridge filters. Replacement of the cartridge will usually be indicated by an increase in P to some specified value. A log sheet should be developed to record the pressure drop measurements. 6.2.4 Softeners Softener monitoring, which should be done each treatment day, consists of testing effluent water for total hardness to ensure that limits established by the reverse osmosis machine manufacturer are not exceeded. In the case of automatically regenerating softeners, monitoring also includes verification that the brine tank contains a sufficient supply of undissolved sodium chloride and that the control valve timer, when present, indicates the correct time of day. Testing for hardness should be performed using an ethylenediaminetetracetic acid (EDTA) titration test, with "dip and read" test strips, or a similar method. Regardless of the method chosen, users should ensure that test accuracy and sensitivity are sufficient to satisfy the total hardness monitoring requirements of the reverse osmosis machine manufacturer. It is recommended that the total hardness of the water exiting the water softener be measured at the end of each treatment day. The hardness test at the end of the day will indicate the overall effectiveness of the water softener under worst case conditions and will ensure that the softener is sized properly--that is, that it has sufficient capacity expressed in grains of calcium carbonate. The softener brine tank should be monitored daily to ensure that a saturated salt solution exists in the brine tank. Salt pellets should fill at least half the tank. Salt designated as rock salt should not be used for softener regeneration since it is not refined and typically contains sediments and other impurities that may damage O-rings and pistons and clog orifices in the softener control head. Timers should be checked at the beginning of each day and should be interlocked with the RO system so that RO is stopped when a softener regeneration cycle is initiated. Water hardness test results should be recorded in a water softener log. 6.2.5 Carbon adsorption Carbon adsorption performance is monitored by measuring free chlorine and/or chloramine concentrations in the water exiting the first carbon bed of a series-connected pair. It should be noted that sampling for total chlorine (the sum of free chlorine and chloramine), allowing a maximum level of 0.1 mg/L of total chlorine, is often simpler than analyzing for free chlorine and chloramine separately. Testing for free chlorine, chloramine, or total chlorine can be accomplished using the N.N-diethyl-p-phenylene-diamine (DPD) based test kits or dip-and-read test strips. On-line monitors can be used to measure chloramine concentrations. Whichever test system is used, it should have sufficient sensitivity and specificity to resolve the maximum levels described in 4.1.1 (Table 1). Testing for free chlorine, chloramine, or total chlorine should be performed at the beginning of each treatment day prior to patients initiating treatment and again prior to the beginning of each patient shift. If there are no set patient shifts, testing should be performed approximately every 4 hours. More frequent monitoring may be appropriate during temporary operation with a single carbon bed, which can occur following breakthrough of the first bed. In such instances, testing is performed on water exiting the second carbon bed in a series-connected pair. The decision to increase the frequency of monitoring should be based on the past performance of the system and on whether changes in feed water quality have occurred. Samples should be drawn when the system has been operating for at least 15 minutes. The analysis should be performed on-site, since chloramine levels will decrease if the sample is not assayed promptly. Results of monitoring of free chlorine, chloramine, or total chlorine should be recorded in a log sheet.

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6.2.6 Chemical injection systems Systems for chemical injection should be monitored according to the manufacturer's instructions. If a facility designs its own system, procedures should be developed to ensure proper preparation of the chemical, adequate mixing of the injected chemical with the water flowing through the pretreatment cascade, and reduction to a safe level of the concentration of any chemical residuals before the point of water use. The facility should also verify that the injected chemical does not degrade the performance of downstream devices, including the primary purification process. The adequacy of these procedures should be verified using an independent laboratory. Verification can be accomplished by testing samples from the chemical reservoir and the water line after the point of injection for at least three batches of chemical. When the chemical to be injected is prepared at a facility from powder or by dilution of a liquid concentrate, the chemical injection reservoir should be labeled with the name of the chemical and its concentration, the date the solution was prepared, and the name of the person who mixed the solution. Each batch of chemical should be tested for correct formulation before use. A batch of chemical should not be used or transferred to the injection system reservoir until all tests are completed. The test results--and verification that they meet all applicable criteria--should be recorded and signed by the individual performing the tests. Protective clothing and an appropriate environment, including ventilation adequate to meet applicable OSHA environmental exposure limits, should be provided when chemicals for injection are prepared in a dialysis facility. 6.2.7 Reverse osmosis Reverse osmosis systems should be monitored daily using continuous-reading monitors that measure product water conductivity (or total dissolved solids (TDS)). The measurements can be used to calculate rejection of solutes by the RO membrane and provide a measure of equipment performance. Percent rejection is calculated using the following formula: Rejection (%) = Feed water conductivi ty - Permeate conductivi ty × 100 Feed water conductivi ty

Newer RO systems may have a direct reading for percent rejection. Other parameters that should be measured daily include product and reject stream flow rates and various internal pressures to the extent permitted by RO instrumentation. Although these parameters are not directly indicative of treated water quality, monitoring them can help ensure that the system is operating within the manufacturer's specifications and thus will aid in maintaining the performance of the RO membranes. Flow rates can be used to calculate the percent recovery of the RO using the following formula: Recovery (%) = Permeate water flow rate × 100 Permeate water flow rate + Reject water flow rate

NOTE--The percent recovery is also known as the "water conversion factor." The terms are equivalent if none of the reject water stream is recycled to the feed water stream (see 5.2.7). If some of the reject water stream is recycled, the equation given above provides a measure of overall water utilization by the reverse osmosis system, rather than the recovery of water during a single pass through the membrane module.

RO systems are not equipped with instrumentation that permits measurement of product water levels of bacteria, endotoxins, or the individual contaminants listed in 4.1. Chemical analysis for the contaminants listed in 4.1.1 (Table 1) should be done when the RO system is installed, when membranes are replaced, and at not less than annual intervals thereafter to ensure that the limits specified in 4.1.1 are met (see Table 1). It is further recommended that chemical analyses be done when seasonal variations in source water suggest worsening quality or when rejection rates fall below 90 %. All results of measurements of RO performance should be recorded daily in an operating log that permits trending and historical review. 6.2.8 Deionization Deionizers shall be monitored continuously using resistivity monitors that compensate for temperature and are equipped with audible and visual alarms. Resistivity monitors shall have a minimum sensitivity of 1.0 megohm-cm. Patients shall not be dialyzed on deionized water with resistivity less than 1.0 megohm-cm measured at the output of the deionizer. When deionization is employed as the primary method for removing inorganic contaminants (reverse osmosis is not employed), or when deionization is necessary to polish RO-treated water, chemical analyses to ensure that the requirements of 4.1.1 (Table 1) are met should be performed when the system is installed and at annual intervals thereafter. Resistivity monitor readings should be recorded on a log sheet twice each treatment day.

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6.2.9 Ultrafiltration The performance of ultrafilters can be monitored by testing the water that is directly exiting the ultrafilter for bacteria and endotoxins. Bacteria and endotoxin levels should be measured as specified in ANSI/AAMI RD62:2001 (see 2.3). The pressure drop across the ultrafilter (P) should be measured using simple inlet and outlet pressure gauges. Such monitoring will indicate when membrane fouling has progressed to the point that membrane replacement or cleaning is needed. Monitoring is also necessary to ensure that the device is being operated in accordance with the manufacturer's instructions. Ultrafilters operated in the cross-flow mode should also be monitored in terms of the flow rate of water being directed to drain (concentrate). Results of pressure measurements and bacteria and endotoxin levels should be recorded in a log. 6.3 Water storage and distribution

6.3.1 General The recommendations below apply. 6.3.2 Water storage Routine monitoring of water storage tanks for bacteria and endotoxin levels is generally accomplished indirectly by monitoring the water at the first outlet to the distribution loop (see 6.3.3). If direct monitoring of a water storage tank is performed as part of a troubleshooting process, bacteria and endotoxin levels shall be measured as specified in ANSI/AAMI RD62:2001 (see 2.3). All bacteria and endotoxin results should be recorded on a log sheet. 6.3.3 Water distribution systems Water distribution piping systems should be monitored for bacteria and endotoxin levels. Bacteria and endotoxins shall not exceed the levels specified in 4.1.2. Monitoring should be accomplished by taking samples from the first and last outlets of the water distribution loop and the outlets supplying reuse equipment and bicarbonate concentrate mixing tanks. If the results of this testing are unsatisfactory, additional testing (e.g., ultrafilter inlet and outlet, RO product water, and storage tank outlet) should be undertaken as a troubleshooting strategy to identify the source of contamination, after which appropriate corrective actions can be taken. Bacteria and endotoxin levels shall be measured as specified in ANSI/AAMI RD62:2001 (see 2.3). Bacteria and endotoxin testing should be conducted at least monthly. For a newly-installed water distribution piping system, or when a change has been made to an existing system, it is recommended that weekly testing be conducted for 1 month to verify that bacteria or endotoxin levels are consistently within the allowed limits. All bacteria and endotoxin results should be recorded on a log sheet to identify trends that may indicate the need for corrective action. 6.3.4 Bacterial control devices 6.3.4.1 Ultraviolet irradiators Ultraviolet irradiators intended for use as a direct means of bacterial control shall be monitored for radiant energy output. UV irradiators are available equipped with radiant energy intensity sensors. A visual alarm or an output meter is acceptable for determining if the UV lamp is emitting sufficient radiant energy. UV irradiators should be monitored at the frequency recommended by the manufacturer. Because the radiant energy decreases with time, annual lamp replacement is typically required. Periodic cleaning of the quartz sleeve may also be required, depending on the water quality. A log sheet should be used to indicate that monitoring has been performed. 6.3.4.2 Ozone generators Ozone generators should be monitored for ozone output at a level specified by the manufacturer. The output of the ozone generator should be measured by the ozone concentration in the water. A test based on indigo trisulfonate chemistry, or the equivalent, should be used to measure the ozone concentration. It is recommended that ozone concentration be measured each time disinfection is performed. An ozone-in-ambient-air test should be conducted on a periodic basis, as recommended by the manufacturer, to ensure compliance with the OSHA permissible exposure limit of 0.1 ppm. A log sheet should be used to indicate that monitoring has been performed. 6.3.4.3 Hot water disinfection systems Hot water disinfection systems should be monitored for temperature and time of exposure to hot water as specified by the manufacturer. Also, hot water disinfection should be performed at least as often as recommended by the manufacturer. The temperature of the water should be recorded at a point farthest from the water heater--that is, where the lowest water temperature is likely to occur. It is recommended that the water temperature be measured each time a disinfection cycle is performed. A record that verifies successful completion of the heat disinfection should be maintained. Successful completion is defined as meeting temperature and time requirements specified by the equipment manufacturer.

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6.4

Concentrate preparation

6.4.1 Mixing systems Systems for preparing either bicarbonate or acid concentrate from powder should be monitored according to the manufacturer's instructions. If a facility designs its own system, procedures should be developed and demonstrated to ensure proper mixing of the concentrate, including establishment of acceptable limits for tests of proper concentration. The adequacy of those procedures should be verified using an independent laboratory that is capable of meeting the requirements of ANSI/AAMI RD61:2000 (see 2.4). Verification can be accomplished by testing a sample from each batch prepared over a 3-day period. Acid and bicarbonate concentrates may be tested by using conductivity or by using a hydrometer. Although not required, some manufacturers may provide allowable ranges for either the conductivity or the specific gravity of concentrates prepared from their powder. The use of pH as an indicator of proper dissolution is inappropriate for both acid and bicarbonate concentrates, because large variations in concentration do not produce significant changes in pH. Concentrates should not be used or transferred to holding tanks or distribution systems until all tests are completed. The test results and verification that they meet all applicable criteria should be recorded and signed by the individuals performing the tests. Concentrate mixing equipment should be either: (1) completely emptied, cleaned, and disinfected according to the manufacturer's instructions; or (2) cleaned and disinfected using a procedure demonstrated by the facility to be effective in routinely producing concentrate that allows the recommendations of 4.3.2.1 to be met. The mixing and disinfection data should be recorded for each mix and disinfection cycle using a dedicated log. 6.4.2 Additives When additives are used to increase concentrations of specific electrolytes in the acid concentrate, mixing procedures should be followed as specified by the additive manufacturer. When additives are prescribed for a specific patient, the container holding the prescribed acid concentrate should be labeled with the name of the patient, the final concentration of the added electrolyte, the date on which the prescribed concentrate was made, and the name of the person who mixed the additive. 6.5 Concentrate distribution

A daily check to ensure that the appropriate acid and bicarbonate concentrate is connected to the corresponding concentrate delivery line is recommended if the storage tank is not permanently connected to its distribution piping. Piped bicarbonate concentrate distribution systems should be disinfected either according to the manufacturer's instructions or using a procedure that has been demonstrated by the facility to be effective in routinely producing concentrate and that allows the recommendations of 4.3.2.1 to be met. It is recommended that the interval between disinfections not exceed 1 week. If the manufacturer does not supply disinfection procedures, the user should develop and validate a disinfection protocol. It is recommended that monitoring of concentrate distribution systems be performed on a routine basis. When reusable concentrate jugs are used to distribute bicarbonate concentrate, they should be disinfected at least weekly. Bicarbonate concentrate jugs should be rinsed with treated water and stored inverted at the end of each treatment day. Pick-up tubes should also be rinsed with treated water and allowed to air dry at the end of each treatment day. Once a bicarbonate distribution system has been activated, dialysate should be monitored weekly until sufficient data has been obtained to demonstrate consistent compliance with acceptable levels of contamination. The frequency of monitoring may then be reduced, but monitoring should be performed at least monthly. If elevated bacteria or endotoxin levels are found in the dialysate, all systems involved in dialysate preparation, including the bicarbonate concentrate distribution system should be evaluated and appropriate action, such as disinfection, should be taken. The frequency of monitoring should then be increased until it can be demonstrated that the problem has been resolved. Because acid concentrate distribution systems have been shown not to be subject to bacterial proliferation, it is not necessary to perform bacteria and endotoxin testing on those systems. 6.6 Dialysate proportioning

Dialysate proportioning should be monitored following the procedures specified by the equipment manufacturer. The user should maintain a record of critical parameters such as conductivity and approximate pH. When the user has specific requirements for monitoring dialysate proportioning, such as when dialysis machine settings are changed to allow the use of concentrates with a different proportioning ratio, the user should develop procedures for routine monitoring of dialysate electrolyte values.

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7

7.1

Strategies for bacterial control

General

The strategy for controlling the proliferation of microorganisms in hemodialysis systems primarily involves proper system design and operation, and regular disinfection of water treatment system and hemodialysis machines. A key concept in ensuring compliance with the requirements of 4.1.2 is that disinfection schedules should be designed to prevent bacterial proliferation, rather than being designed to eliminate bacteria once they have proliferated to an unacceptable level (i.e., above the action level). With this strategy, monitoring levels of bacteria and endotoxin serves to demonstrate that the disinfection program is effective, not to indicate when disinfection should be performed. Gram-negative water bacteria, their associated lipopolysaccharides (bacterial endotoxins), and nontuberculous mycobacteria (NTM) most frequently come from the community water supply, and levels of those bacteria can be amplified depending on the water treatment system, dialysate distribution system, type of dialysis machine, and method of disinfection. Two components of hemodialysis water distribution systems--pipes and storage tanks--can serve as reservoirs of microbial contamination. Hemodialysis systems frequently use pipes that are of larger diameter and longer than are needed to handle the required flow. Oversized piping slows the fluid velocity and increases both the total fluid volume and the wetted surface area of the system. Gram-negative bacteria in fluids remaining in pipes overnight multiply rapidly and colonize the wet surfaces, thus producing bacterial populations and endotoxin quantities in proportion to the volume and surface area. Such colonization results in the formation of protective biofilm that is difficult to remove once formed and that provides a barrier between the bacteria and germicide during disinfection. Biofilms are communities of microorganisms attached to surfaces. They form just about anywhere a nonsterile fluid flows over a surface. Biofilm increases the ability of microorganisms to compete for nutrients and other resources. The complexity of biofilm depends on the degree of water or fluid movement and the availability of nutrients. Thicker biofilm, and usually a greater diversity of microorganisms, will form in slower moving waters; in faster moving waters, it is harder for microorganisms to become (and remain) attached to the surface, so biofilm formation takes longer. Organisms living within biofilm are shielded by an extracellular polymer or glycocalyx. This glycocalyx provides the bacteria with some protection from the action of disinfectants. Biofilm may exist throughout a hemodialysis distribution system. Once established in a distribution system or dialysis machine, biofilm can be difficult to eradicate. Bleach and ozone are generally the most effective agents for biofilm removal, and their use may be more efficacious if the pipes are treated first with a descaling agent. However, in some cases, complete or partial replacement of the distribution system may be the only way to eliminate biofilm. Routine low-level disinfection of the pipes should be performed to control bacterial contamination of the distribution system. The frequency of disinfection will vary with the design of the system and the extent to which biofilm has already formed in existing systems, but disinfection should be performed at least monthly. To minimize biofilm formation, there should always be flow in a piping system. A minimum velocity of 3 ft/sec in the distal portion of the loop of an indirect feed system and a minimum velocity of 1.5 ft/s in the distal portion of a direct feed system are recommended when the system is operating under conditions of peak demand. Other measures can also help protect pipes from contamination. A mechanism should be incorporated in the distribution system to ensure that disinfectant does not drain from pipes during the disinfection period. Dead-end pipes and unused branches and taps that can trap fluid should be eliminated because they act as reservoirs of bacteria and are capable of continuously inoculating the entire volume of the system. Joints between sections of piping and between piping and fittings should be formed in a manner that minimizes the formation of crevices and other voids that may serve as sites for bacterial colonization. Pipes should not be cut with a hacksaw. Any burrs should be removed before the joint is formed. These measures also minimize the possibility that pockets of residual disinfectant could remain in the piping system after disinfection. A storage tank in the distribution system greatly increases the volume of fluid and surface area available and can serve as a niche for water bacteria. Storage tanks are therefore not recommended for use in dialysis systems unless they are frequently drained and adequately disinfected. It may be necessary for the user to scrub the sides of the tank to remove bacterial biofilm if the tank design and maintenance are not adequate to prevent bacterial proliferation. An ultrafilter, distal to the storage tank, or some other form of bacterial control device is recommended. For most dialysis machines, routine disinfection with hot water or with a chemical germicide connected to a disinfection port on the machine does not disinfect the line between the outlet from the water distribution system and the back of the dialysis machine. Users should establish a procedure for regular disinfection of this line. One approach is to rinse the dialysis machines with water containing germicide or hot water when the water distribution loop is disinfected. If this procedure is used with a chemical germicide, each dialysis machine should be rinsed and tested for the absence of residual germicide following disinfection. Storage times for bicarbonate concentrate should be minimized, as well as the mixing of fresh bicarbonate concentrate with unused portions of concentrate from a previous batch. The manufacturer's instructions should be followed if they are available. Facilities that reuse concentrate jugs for bicarbonate concentrate should disinfect the

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jugs at least weekly. Bicarbonate concentrate can support prolific growth of microorganisms. Jugs can be disinfected with household bleach solutions (300 mg to 600 mg free chlorine, or 30 mL to 60 mL of 6.15 % household bleach per gallon of water) with a contact time of about 30 minutes or another EPA-registered disinfectant according to the manufacturer's instructions. Following disinfection, jugs should be drained, rinsed, and inverted to dry. 7.2 Microbial monitoring methods

7.2.1 General The microbial quality of water should be monitored at least monthly to validate the effectiveness of the disinfection program. Monitoring can be accomplished by direct plate counts, in conjunction with the measurement of bacterial endotoxin. Samples of water should be collected from several places to give an indication of the microbial quality of the water throughout the water distribution system. In general, samples should be collected in the following areas: from the first and last outlets of the water distribution loop, where water enters equipment used to reprocess dialyzers, and where water enters equipment used to prepare bicarbonate concentrate or from the bicarbonate concentrate mixing tank. Additional testing, such as at the end of the water purification cascade and at the outlet of the storage tank, if one is used, may be necessary during initial qualification of a system or when troubleshooting the cause of contamination within the distribution loop. Dialysate samples should also be collected from at least two machines monthly and from enough machines so that each machine is tested at least once per year. If testing of any dialysis machine reveals a level of contamination above the action level, an investigation should be conducted that includes retesting the offending machine, reviewing compliance with disinfection and sampling procedures, and evaluating microbiological data for the previous 3 months to look for trends. The medical director also should be notified. An example of a decision tree for this process is given in Figure 1. Cultures should be repeated when bacterial counts exceed the allowable levels. If culture growth exceeds permissible standards, the water system and dialysis machines should be cultured weekly until acceptable results are obtained. Additional samples should be collected when there is a clinical indication of a pyrogenic reaction or septicemia, and following a specific request by the clinician or the infection control practitioner. Samples should always be collected before sanitization/disinfection of the water treatment system and dialysis machines. If repeat cultures are performed after the system has been disinfected (e.g., with formaldehyde, hydrogen peroxide, chlorine, or peracetic acid), the system should be flushed completely before collecting samples. Drain and flush storage tanks and the distribution system until residual disinfectant is no longer detected before collecting samples. Culture water and dialysis fluid weekly for new systems until a pattern has been established. For established systems, culture monthly unless a greater frequency is dictated by historical data at a given institution. If bacterial contamination is suspected, but water cultures are negative, it may be necessary to check for the presence of biofilm (see 7.2.3).

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Review dialysate culture results

Results < 50 CFU/mL?

Results 50--199 CFU/mL ?

Results 200 CFU/mL?

Notify Facility Manager & Biomedical Technician

Notify Medical Director, Facility Manager & Biomedical Technician

Review culture & disinfection logs

Review culture & disinfection logs

Disinfect equipment or water system if necessary

No

Disinfect equipment or water system if necessary

Redraw sample Redraw sample

Yes Yes

Results < 50 CFU/mL?

Results < 50 CFU/mL?

Repeat this site in next regular monthly sample collection

No Yes Notify Medical Director, Facility Manager & Biomedical Manager

Initiate troubleshooting protocol Determine whether equipment should be removed from patient use -Evaluate/correct sample collection technique -Evaluate/correct bicarbonate preparation/ distribution technique -Evaluate/correct water system components -Evaluate/replace equipment ultrafilters -Evaluate/implement biofilm removal protocols

Resume/Continue Routine Monthly Testing

Yes

Notify Medical Director, Facility Manager & Biomedical Manager No

Results < 50 CFU/mL?

Redraw sample

Figure 1--Example of decision tree that can be used to evaluate culture results and initiate corrective action, if necessary

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7.2.2 Sample collection Water samples should be collected directly from outlet taps situated in different parts of the water distribution system. In general, the sample taps should be opened and the water should be allowed to run for at least 60 seconds before a sample is collected in a sterile, endotoxin-free container. (All new sterile plasticware is endotoxin-free because of the high temperatures involved in the manufacturing process.) A minimum of 50 mL of water, or the volume specified by the laboratory performing the test, should be collected. Sample taps should not be disinfected. Users who insist on disinfecting sample taps should use sterile gauze saturated with alcohol to wipe the sample tap. The sample should not be collected until all the alcohol has evaporated so as to leave no disinfectant residual in the sample. Bleach or other disinfectant solutions should not be used. Dialysate samples should be collected from a dialysate port of the dialyzer, if possible. In some newer dialysis machines, dialysate flow stops when the effluent line is disconnected from the port. In these instances, the machines are equipped with dialysate sampling ports that can be accessed using a syringe. Sample ports may be disinfected with alcohol and allowed to air dry. A 30 mL sterile syringe should then be used to aspirate dialysate out of and into the port before filling the syringe. The filled syringe should be discarded, and a fresh sample of dialysate collected using a new sterile syringe. At least 25 mL of fluid, or the volume specified by the laboratory performing the test, should be collected in sterile endotoxin-free specimen containers. 7.2.3 Heterotrophic plate count Samples that cannot be cultured within 1 to 2 hours can be refrigerated for up to 24 hours. The reference method for culturing is the membrane filtration technique. With this method, a known volume of sample or diluted sample is filtered through a 0.45 µm membrane filter and the membrane filter is aseptically transferred to the surface of an agar plate. Trypticase soy agar (TSA, a soybean casein digest agar) is the medium of choice for culturing water and dialysate; other acceptable media include standard methods agar and plate count agar (also known as TGYE). Blood and chocolate agars are not appropriate for this test. The spread plate technique may also be used. With this method, an inoculum of at least 0.5 mL of sample is spread equally over the surface of the agar plate. Use of a calibrated loop to apply the sample to the agar plate is NOT permitted. Dip samplers may be used for bacterial surveillance. However, they should be used only in conjunction with a quality assurance program designed to ensure their appropriate use. Elements of the quality assurance program should include staff training in areas such as the correct methods of inoculation, incubation, and interpretation, and verification involving duplicate samples sent to a certified laboratory on at least an annual basis. Plates shall be incubated at 35 °C for 48 hours. (This method is an indicator of water quality only and is not to be confused with total heterotrophic plate counts, which require much longer incubation times at 28 °C). Colonies should be counted using a magnifying device. If a more accurate count from plates containing fewer than 30 or more than 300 colonies is desired, larger or smaller volumes may be cultured. Smaller volumes can be obtained by making 1:10 serial dilutions in sterile phosphate buffer. If larger volumes are required, the membrane filtration method should generally be used. Biofilm is likely to form in water storage and distribution systems even when levels of bacterial contamination are low. Heterotrophic plate counts may not provide a good measure of the presence of biofilm, since the bacteria in biofilm are sessile and not free swimming. Erratic colony counts, however, may indicate the presence of biofilm since sloughing of biofilm may occur with release of bacteria into the water. Currently, few practical methods are available for the routine detection of biofilm. The methods that are available include installing side streams (biofilm sampling devices) with removable coupons or rings that can be analyzed, and scraping or swabbing the internal surfaces of pipes. Biofilm is usually detected by a combination of laboratory procedures that includes viability staining (fluorescent staining) of surfaces and fluorescent, confocal, or scanning electron microscopy. Scrapings and removed sections of pipe can be sonicated and cultured using conventional methods (membrane filtration or spread plate techniques). If careful attention is paid to routine disinfection of the water treatment and distribution system, routine monitoring for biofilm is not necessary. However, when contamination persists in spite of frequent and aggressive disinfection, it may be necessary to determine if biofilm is present in the system using the methods described above. 7.2.4 Bacterial endotoxin test Bacterial endotoxin testing is done using the Limulus amoebocyte lysate (LAL) assay. Two basic types of assay can be performed. The first is a kinetic assay, which is available in a colorimetric or turbidimetric format, and the second is a gel-clot assay. The kinetic LAL assay uses control standard endotoxin to generate a standard curve to which unknowns are compared and concentrations are determined using linear regression. The kinetic assays employed in laboratories generally use a computer-driven spectrophotometer that automatically calculates the amount of endotoxin on the basis of color development or onset times for gel formation.

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The gel-clot LAL assay is not as sensitive as the kinetic assay and provides only a positive or negative result; that is, it shows if endotoxin is present--or not--at a particular concentration. Single tube gel-clot tubes are available from several commercial sources, and kits with the following sensitivities are available: 0.015 EU, 0.03 EU, 0.06 EU, 0.125 EU, 0.25 EU, and 0.5 EU. At a minimum, two tubes should be run each time the assay is performed. The first tube contains LAL reagent and the sample to be tested. The second tube contains LAL reagent, a known amount of endotoxin, and the sample to be tested. The second tube acts as a positive control to confirm the absence of any interference that might lead to a false negative result. Positive control tubes are available from the suppliers of commercial LAL assays. More sophisticated testing protocols involving reagent controls may also be used (see 2.7), but their use is optional in this application.

8

Environment

The water purification and storage system should be located in a secure area that is readily accessible to authorized users. The location should be chosen with a view to minimizing the length and complexity of the distribution system. Access to the purification system should be restricted to those individuals responsible for monitoring and maintenance of the system. The layout of the water purification system should provide easy access to all components of the system, including all meters, gauges, and sampling ports used for monitoring system performance. An area for processing samples and performing on-site tests is also recommended. Critical alarms, such as those associated with deionizer exhaustion or low water levels in a storage tank, should be configured to sound in the patient treatment area, as well as in the water treatment room. Water systems should include schematic diagrams that identify components, valves, sample ports, and flow direction. Additionally, piping should be labeled to indicate the contents of the pipe and direction of flow. The use of text labels, such as "RO Water," and color-coded "arrow tape" provides a convenient means of identifying pipe content and flow direction. If water system manufacturers have not done so, users should label major water system components in a manner that not only identifies a device but also describes its function, how performance is verified, and what actions to take in the event performance is not within an acceptable range. An example of such labeling for a regenerable softener is given in Figure 2.

WATER SOFTENER: System protects RO membrane by removing calcium and magnesium "hardness ions," adding sodium ions in their place. -- Using sample port #4 [varies from system to system], test water hardness at end of each treatment day. Result must be 1 grain/gallon or less. -- Check brine tank daily to be sure the tank is at least half filled with salt, adding salt pellets if necessary. Water may become "hard" if salt pellet level is low. -- Check timer daily to verify that it shows the correct time of day. Incorrect timer settings may cause the softener to regenerate during dialysis and can result in automatic shutdown of the RO. -- Notify charge nurse and facility technician if hardness test is greater than 1 grain/gallon or if timer does not show correct time of day.

Figure 2--Example of a component label for a regenerable softener

9

Personnel

Policies and procedures that are understandable and accessible are mandatory, along with a training program that includes quality testing, the risks and hazards of improperly prepared concentrate, and bacterial issues. Operators should be trained in the use of the equipment by the manufacturer or should be trained using materials provided by the manufacturer. The training should be specific to the functions performed (i.e., mixing, disinfection, maintenance, and repairs). Periodic audits of the operators' compliance with procedures should be performed. The user should establish an ongoing training program designed to maintain the operator's knowledge and skills.

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Annex A (informative) Rationale for the development and provisions of this recommended practice

A.1 Scope

It has long been known that chemical and microbiological contamination of dialysate places hemodialysis patients at risk of acute and chronic adverse events. As a result, the first edition of the American National Standard Hemodialysis systems (ANSI/AAMI RD5:1981) included chemical and microbiological quality requirements for the water used to prepare dialysate, as well as microbiological quality requirements for the final dialysate. From the beginning, the AAMI Renal Disease and Detoxification Committee recognized a problem with including fluid quality requirements in a standard directed at manufacturers of dialysis equipment. Although the manufacturer is responsible for providing equipment that, when assembled as a system, provides water that meets the quality requirements of the standard, the manufacturer has no control over that system once it is installed. Purified water quality may change if the system is not well maintained or if there is some change in the municipal water feeding the system. The day-to-day responsibility for maintaining water quality lies with the health care professionals at each dialysis facility under the leadership of the facility's medical director. For this reason, ANSI/AAMI RD5 included an appendix (Appendix B) that provided users with guidelines for monitoring water purity and with criteria for selecting water treatment equipment. The water and dialysate quality provisions of ANSI/AAMI RD5, as well as the guidelines provided in Annex B, were subsequently adopted by the Centers for Medicare and Medicaid Services (CMS, formerly the Health Care Financing Administration (HCFA)) as part of their conditions for coverage of end-stage renal disease services. In 1996, during a 5-year review of ANSI/AAMI RD5, the AAMI Renal Disease and Detoxification Committee determined that the hemodialysis community would be better served if ANSI/AAMI RD5 were divided into three parts: (1) hemodialysis concentrates, (2) water treatment equipment for hemodialysis applications, and (3) hemodialysis systems. This decision resulted in the publication of ANSI/AAMI RD61:2000, Concentrates for hemodialysis; ANSI/AAMI RD62:2001, Water treatment equipment for hemodialysis applications; and ANSI/AAMI RD5:2003, Hemodialysis systems. These standards are addressed to the manufacturers of equipment, although they also provide users with a basis for understanding the products and processes they cover. In the process of creating the three new standards, Appendix B of the original ANSI/AAMI RD5 was eliminated. The critical product resulting from the joint application of the devices addressed by ANSI/AAMI RD61:2000, ANSI/AAMI RD62:2001, and ANSI/AAMI RD5:2003 is the dialysate, the fluid against which the patients' blood is balanced. Although the proportioning of concentrates and water to produce dialysate is usually accomplished by a hemodialysis machine, the actual production and handling of dialysate is under the control of health care professionals who care for these dialysis patients. To fill the void left by the elimination of Appendix B from ANSI/AAMI RD5, the AAMI Renal Disease and Detoxification Committee undertook the development of this recommended practice. This recommended practice expands the guidelines originally included in Appendix B of ANSI/AAMI RD5 to include all aspects of the selection and care of the systems involved in the preparation of dialysate for hemodialysis. Those systems include water purification and distribution systems, concentrate preparation and distribution systems, and dialysate proportioning systems. The recommended practice also includes recommendations for the chemical and microbiological quality of the dialysate. The information provided in this recommended practice is intended to complement the equipment standards set forth in ANSI/AAMI RD61:2000, ANSI/AAMI RD62:2001, and ANSI/AAMI RD5:2003.

A.2 A.3 A.4

Normative references Definitions Fluid quality

For the purposes of this recommended practice, the references cited in clause 2 apply.

For the purposes of this recommended practice, the definitions given in clause 3 apply.

A.4.1 Water The water quality recommendations contained in this recommended practice are the same as those set forth in ANSI/AAMI RD62:2001 (see 2.3).

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A.4.1.1 Maximum level of chemical contaminants in water ANSI/AAMI RD62:2001 sets forth maximum levels of chemical contaminants in three categories: chemicals known to have particular toxicity for hemodialysis patients, chemicals included in the U.S. Environmental Protection Agency's Safe Drinking Water Act (see 2.6), and physiological substances that can adversely affect the patient if present in the dialysate in excessive amounts. Several chemicals have been clearly shown to be toxic to dialysis patients at concentrations that are not necessarily toxic to the general population. Those chemicals include aluminum, copper, chloramines, fluoride, nitrate, sulfate, and zinc. Uptake of aluminum from the dialysate is associated with bone disease (Ward, et al., 1978), anemia (Kaiser and Schwartz, 1985), and the dialysis encephalopathy syndrome, which is usually fatal (Alfrey, et al., 1976). The suggested maximum aluminum level has been specified to prevent accumulation of this toxic metal in the patient (Kovalchik, et al., 1978). Aluminum is particularly likely to increase suddenly to high levels as a result of changing the method of water treatment to include aluminum-containing compounds (Simoes, et al., 1994). Chloramines damage red blood cells by oxidizing hemoglobin to methemoglobin and by inhibiting antioxidant pathways (Eaton, et al., 1973). Their toxicity in hemodialysis patients is undisputed (Ward, 1996). Although the role of free chlorine in oxidative blood damage is unclear, its high oxidation potential and its ability to form chloramines suggest that the use of highly chlorinated water in preparation of dialysate should be avoided. High levels (> 20 ppm) of fluoride in the water used to prepare dialysate are clearly toxic to hemodialysis patients, and have resulted in patient deaths (CDC, 1980; Arnow, et al., 1994). Such high levels of fluoride have resulted from accidental overfluoridation of a municipal water supply (CDC, 1980), as well as from deionizer exhaustion (Arnow, et al., 1994). Toxicity of fluoride in dialysis patients is questionable at the levels usually associated with fluoridated water (1 ppm). However, in the absence of a consensus on its role in uremic bone disease (Rao and Friedman, 1975), the committee thought it prudent to restrict the fluoride level of dialysate. Nitrates are a marker for bacterial contamination and fertilizer runoff and have caused methemoglobinemia (Carlson and Shapiro, 1970). Nitrates should, therefore, be permitted only at very low levels. Sulfate at levels above 200 mg/L has been related to nausea, vomiting, and metabolic acidosis. The symptoms disappear when the level remains below 100 mg/L (Comty, et al., 1974). Both copper and zinc toxicity have been demonstrated when those substances are present in dialysate at levels below those permitted by the EPA standard (Ivanovich, et al., 1969; Petrie and Row, 1977). Hence, a lower level has been chosen. The second group of chemical contaminants included in ANSI/AAMI RD62:2001 is based on the U.S. Environmental Protection Agency's Safe Drinking Water Act (see 2.6). The standard specifies maximum allowable limits for most contaminants in this group at 1/10 of the EPA maximum allowable limit. The lower levels were chosen because the volume of water used for dialysis far exceeds that used for drinking water, because protein binding of these solutes may occur in the blood, and because there is reduced renal excretion of these substances. Selenium and chromium levels were set at the "no-transfer" level (Klein, et al., 1979). The no-transfer level was chosen even though it is above the EPA limit for selenium and 28 % of the EPA limit for chromium, because there is no need for a restriction below the level at which there is no passage from the dialysate to the blood. The third group of substances included in ANSI/AAMI RD62:2001 consists of physiological substances that can adversely affect the patient if they are present in the dialysate in excessive amounts. Calcium, potassium, and sodium are examples of those substances. The chemical contaminants regulated by ANSI/AAMI RD62:2001 and reproduced in Table 1 of this recommended practice should not be taken as a definitive list of harmful substances; they are only a partial listing of the contaminants that might reasonably be expected to be present and have clinical implications. Iron is not included because it does not enter the patient's blood in sufficient quantities to cause toxicity. However, iron may cause fouling of water purification devices or dialysate proportioning systems. Furthermore, municipal water supplies are dynamic systems, which may change with the seasons or in response to new regulations from the EPA. When the water quality requirements included in ANSI/AAMI RD5:1981 were originally developed, limits could not be set for toxic organic substances or for radioactive materials (Keshaviah, et al., 1980). However, the committee noted that the EPA drinking water standard (see 2.6) lists maximum contaminant levels (MCLs) for more than 50 toxic organic substances. Following the rationale used in establishing levels for other potentially toxic contaminants that have not been shown to be harmful to dialysis patients (see above), it is reasonable that those levels should be reduced tenfold if they are monitored. This data is provided for information purposes only, since those substances represent only some of a vast number of contaminants that occur in tap water, all of whose toxic effects are largely unknown (Keshaviah, et al., 1980). The committee also agreed with the Keshaviah report that systems that include reverse osmosis and carbon filtration would adequately remove most organics.

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A.4.1.2 Bacteriology of water When ANSI/AAMI RD5:1981 was initially developed, it was generally considered that the water used to prepare dialysate need not be sterile. However, studies had demonstrated that the incidence of pyrogenic reactions was related directly to the number of bacteria in dialysate (Dawids and Vejlsgaard, 1976; Favero, et al., 1974). It was also known that a dialysate delivery system could amplify the level of bacteria in the water used to supply the system. Those studies provided the rationale for setting a recommended maximum concentration of 200 bacteria per mL in the water used to prepare dialysate. Several groups of investigators have shown convincingly that pyrogenic reactions are caused by lipopolysaccharides or endotoxins associated with gram-negative bacteria. Gram-negative water bacteria are able to multiply rapidly in the chemically pure water used to supply hemodialysis systems. Furthermore, it has been demonstrated clearly that endotoxins and endotoxin fragments can cross both low-flux and high-flux hemodialysis membranes (see A.4.3.2.1). Consequently, when ANSI/AAMI RD62:2001 was being developed, it was thought prudent to recommend an upper limit on the endotoxin content (endotoxin units, or EU) of the water. A level of 2 EU/mL was chosen, since that level is easily achieved with contemporary water treatment systems using reverse osmosis, ultrafiltration, or both. Because 48 hours can elapse between sampling water to determine microbial contamination and receiving results, and because bacterial proliferation can be rapid, action levels for microbial counts and endotoxin concentrations were also included in ANSI/AAMI RD62:2001. Those action levels allow the user to initiate corrective action before levels exceed the recommended maximum levels. Unlike cultures, endotoxin testing does not require extended incubation times. Endotoxin testing, if performed in the dialysis facility, can give results in about 1 hour, eliminating the long delay between sampling and obtaining a result. During the development of this recommended practice, the committee was asked to recommend levels of bacteria and endotoxin above which the water should not be used for dialysis applications. In making the recommendations set forth in 4.1.2, the committee understood that dialysis would be continued at contaminant levels above the action level but below the recommended maximum level. Establishing a recommended maximum level of contamination at which dialysis should be stopped immediately is difficult, because the risk of adverse events, such as pyrogenic reactions, must be balanced against the risks of uremia if a patient is not dialyzed. The balance between those two risks will depend on the level of contamination and time of exposure on the one hand, and the medical condition of the patient on the other hand. Because this balance will almost certainly vary from circumstance to circumstance, the committee felt that there was insufficient data on which to base levels of bacteria and endotoxins above which dialysis should not be performed. The final decision of whether to discontinue dialysis rests with the medical director of a facility. Whatever decision is made, the committee recommends that the water treatment and distribution system be disinfected promptly any time the levels of bacteria or endotoxins exceed the action levels recommended in 4.1.2. In addition, it may be prudent to discontinue dialyzer reuse if the levels of bacteria or endotoxins exceed the recommended maximum levels set forth in 4.1.2, since the water is introduced directly into the blood compartment of the dialyzer. A.4.2 Concentrate The concentrate quality recommendations contained in this recommended practice are the same as those set forward in ANSI/AAMI RD61:2000 (see 2.4). A.4.2.2 Bacteriology of concentrate Although ANSI/AAMI RD61:2000 (see 2.4) sets limits on bacteria and endotoxins in bicarbonate concentrate, the committee decided not to recommend limits for concentrate prepared at a dialysis facility. This decision was based on the difficulty of performing cultures and endotoxin assays in samples with high concentrations of salts. High concentrations of bicarbonate require special culturing techniques and are inhibitory in the LAL assay. The committee determined that it was unreasonable to require an individual dialysis facility to meet the special conditions required for proper testing of bicarbonate concentrate and that patients would be adequately safeguarded by the quality recommendations for the water used to prepare the concentrate and for the final dialysate. For users who are interested in determining bacterial levels and endotoxin concentrations as part of a troubleshooting investigation, guidelines on performing cultures and endotoxin assays in bicarbonate concentrate are included in A.7.2.3 and A.7.2.4. A.4.3 Dialysate A.4.3.1 Maximum level of chemical contaminants in dialysate The recommended maximum levels of chemical contaminants in dialysate are the same as those for the water used to prepare the dialysate. The long-standing recognition that some metal ions are toxic to dialysis patients has resulted in the elimination of all sources of these metal ions from dialysate proportioning systems, in compliance with ANSI/AAMI RD5:2003, Hemodialysis systems (see 2.2).

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A.4.3.2 Bacteriology of dialysate A.4.3.2.1 Bacteriology of conventional dialysate ANSI/AAMI RD5:1981 established a maximum level of 2,000 CFU/mL for bacteria in the dialysate; no maximum level was set for endotoxins. The maximum allowable level of bacteria was based on limited epidemiological data that showed a relationship between the number of bacteria in the dialysate and the incidence of pyrogenic reactions (Dawids and Vejlsgaard, 1976; Favero, et al., 1974). High levels of bacteria in the dialysate were associated with poorly designed and maintained water purification systems, as well as the now obsolete central systems for batch preparation of dialysate and recirculating single-pass dialysate delivery systems. Studies in the 1960s (Jones, et al., 1970; Kidd, 1964) showed that bacteria growing in dialysate produced products that could cross dialysis membranes. Other investigators (Gazenfeldt-Gazit and Eliahou, 1969; Raij, et al., 1973) showed that gram-negative bacteria growing in dialysate produced endotoxins that stimulated the production of antiendotoxin antibodies in hemodialysis patients. The introduction of high-flux membranes was thought to increase the likelihood of passage of endotoxins or endotoxin fragments into the blood path. Several findings supported this concern. Vanholder, et al. (1992) observed an increase in plasma endotoxin concentrations during dialysis against dialysate containing 103 to 104 CFU/mL Pseudomonas species, and patients treated with high-flux membranes were reported to have higher levels of anti-endotoxin antibodies than normal subjects or patients treated with conventional low-flux membranes (Yamagami, et al., 1990). Furthermore, in vitro studies using both radiolabeled lipopolysaccharide and biological assays demonstrated that biologically active substances derived from bacteria found in dialysate were able to cross some dialysis membranes (Laude-Sharp, et al., 1990; Evans and Holmes, 1991; Lonnemann, et al., 1992; Ureña, et al., 1992; Bommer, et al., 1996). Finally, the Centers for Disease Control and Prevention reported that the use of high-flux dialyzers was a significant risk factor for pyrogenic reactions (Tokars, et al., 1996). Other investigators, however, were unable to demonstrate endotoxin transfer across dialysis membranes (Bernick, et al., 1979; Bommer, et al., 1987; Tielemans, et al., 1996). More recent studies (Schindler, et al., 2001; Lonnemann, et al., 2001) may explain these conflicting findings. Those studies show that the ability of in vitro systems to detect the transfer of biologically active substances across a dialysis membrane depends on the nature of the microbiological challenge, the choice of membrane, and the test fluid used in the blood compartment, Overall, it is now clear that endotoxins, endotoxin fragments, or other bacterial products cross at least some membranes under some operating conditions. In addition to the risk of acute pyrogenic reactions, indirect evidence increasingly shows that chronic exposure to low amounts of endotoxin may play a role in some of the long-term complications of hemodialysis therapy. Patients treated with ultrafiltered dialysate have demonstrated a decrease in serum 2-microglobulin concentrations (Quellhorst, 1998), a decrease in markers of inflammation (Schindler, et al., 1994; Sitter, et al., 2000; Schiffl, et al., 2001), and an increased responsiveness to erythropoietin (Sitter, et al., 2000; Spittle, 2001; Matsuhashi and Yoshioka, 2002). In longer-term studies, use of microbiologically ultrapure dialysate has been associated with a decreased incidence of 2-microglobulin-associated amyloidosis (Baz, et al., 1991; Kleophas, et al., 1998; Schiffl, et al., 2000), better preservation of residual renal function (McKane, et al., 2002; Schiffl, et al., 2002), and improved nutritional status (Schiffl, et al., 2001). For those reasons, the committee reduced the recommended maximum microbial count in the dialysate to 200 CFU/mL and added a recommendation that the endotoxin concentration not exceed 2 EU/mL. The values are the same as those for water used to prepare the dialysate (ANSI/AAMI RD62:2001), implying that the dialysate proportioning system should not add significantly to the microbiological burden in the water. Although the committee did not review supporting data, it considered contemporary dialysate delivery systems to be fully capable of performing at this level provided that the user followed the manufacturer's instructions on cleaning and disinfecting the system, including disinfection of the line between the water distribution system and the concentrate mixing chambers of the dialysate proportioning system. Some members of the committee supported recommending a lower level of endotoxin contamination, such as 0.25 EU/mL, either immediately or after a period of 2 to 3 years. The argument for a lower endotoxin level is based on the hypothesis that bacterial products from the dialysate promote a microinflammatory state, which contributes to long-term morbidity in hemodialysis patients (Stenvinkel, et al., 1999). Indeed, the committee recognized that essentially all of the clinical outcome studies showing a benefit from the use of dialysate of high microbiological purity have been conducted with dialysate ultrafiltered at the point of use so that it contains very low levels of endotoxin, generally < 0.03 EU/mL. Only one study (Schiffl, et al., 2000) that reported a benefit of improving dialysate quality was conducted using dialysate meeting the quality recommendations set forth in 4.3.2.1. However, the committee was concerned that recommending the use of ultrapure dialysate without an adequate transition period would place an undue burden on some dialysis facilities. Furthermore, some committee members were not convinced that the clinical outcome data referred to above was sufficiently convincing to justify the lower endotoxin concentration. Therefore, the committee opted to recommend the levels of quality stated in 4.3.2.1. This topic is an active area of research and, until additional information from this research confirms the need for lower levels of endotoxins in the dialysate, the recommendations of 4.3.2.1 are reasonable and achievable.

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A.4.3.2.2 Bacteriology of ultrapure dialysate Although the net movement of water in hemodialysis is from the blood to the dialysate, there may be local movement of water from the dialysate to the blood through the phenomenon of back-filtration, particularly in dialyzers with highly permeable membranes (Leypoldt, et al., 1991; Ronco, et al., 1998). The concern that back-filtration and backdiffusion may facilitate the transfer of endotoxins and endotoxin fragments across high-flux membranes has given rise to the concept of ultrapure dialysate for use in dialysis applications. Ultrapure dialysate is defined as one having a bacterial content of less than 0.1 CFU/mL and an endotoxin content of less than 0.03 EU/mL using sensitive assays (Ledebo and Nystrand, 1999). This definition is now widely accepted, particularly in Europe, and use of ultrapure dialysate is considered a requirement for on-line convective therapies (see A.4.3.2.3). Ultrapure dialysate is prepared by sequential ultrafiltration of dialysate prepared from purified water meeting the requirements of 4.1 and concentrates. Dry powder cartridges are frequently used for on-line preparation of the bicarbonate concentrate to minimize the potential for the bicarbonate concentrate to contribute high levels of bacteria and endotoxin to the dialysate. A.4.3.2.3 Bacteriology of dialysate for infusion Convective therapies, such as hemofiltration and hemodiafiltration, require the infusion of large volumes of electrolyte solution (20 L to 70 L) into the blood to replace the volume of plasma water removed in providing solute clearance. Increasingly, this electrolyte solution is being prepared on-line from water and concentrate. To be acceptable for direct infusion into the blood, the solution (often referred to as "substitution fluid" or "replacement solution") should contain less than 10­6 CFU/mL and less than 0.03 EU/mL of endotoxin. In on-line therapies, this requirement is met using a process of sequential ultrafiltration of dialysate prepared from water and concentrate meeting the requirements of 4.1 and 4.2. To produce dialysate for injection from water and concentrate containing 200 CFU/mL and 2 EU/mL of endotoxin, such a process should be capable of reducing the bacterial burden in the water by a factor of 109 and the endotoxin level by a factor of 102. The process should have sufficient redundancy to ensure that the quality of the dialysate for infusion is maintained in the event of a single-fault failure, since testing will only disclose a process failure retrospectively. Because on-line therapies use the infusion solution as it is produced, the traditional methods used by the manufacturers of infusion fluids and pharmaceuticals cannot be used to confirm that the solutions meet the quality requirements for bacteria and endotoxins. Instead, the quality of the solutions is ensured by using a process that has been validated by the manufacturer of the equipment (Ledebo, 2002). Once a validated process has been installed and its performance verified by the manufacturer, it is the responsibility of the user to implement a regular monitoring and maintenance program to ensure that the quality of the dialysate for infusion is maintained. At a minimum, testing, disinfection, and maintenance should be performed according to the manufacturer's instructions, including maintaining the specified quality of the water and concentrate used to prepare the dialysate, replacing the filter, and disinfecting the system. Verifying that the endotoxin concentration in the final dialysate for infusion is less than 0.03 EU/mL can be achieved by testing; however, testing to verify that the final dialysate for infusion contains less than 10­6 CFU/mL (1 CFU/1,000 L) is not feasible. One approach to monitoring bacterial levels is to demonstrate that the level of bacteria in the water immediately prior to the final dialysate filter is less than 10 CFU/100 mL. The recommended test methodology is to collect 500 mL of dialysate and subject it to culturing using the membrane filtration method. Some manufacturers provide 500 mL collection bags specifically for this purpose. Electrolyte solutions prepared on-line may also be used to prime the extracorporeal blood circuit before dialysis, as infusion fluid administered in response to a hypotensive episode during dialysis, or to periodically back-flush the dialyzer during dialysis. Dialysate for infusion that meets the recommendations of 4.3.2.3 can be used for this purpose. Some manufacturers have also demonstrated that small volumes of fluid containing less than 0.1 CFU/mL and less than 0.25 EU/mL of endotoxin can also be used safely for this purpose.

A.5

Equipment

A.5.2 Water purification systems Subclause 5.2 provides a brief description of the principal equipment used to purify water used in hemodialysis applications. Devices used to purify water for hemodialysis should comply with the requirements of ANSI/AAMI RD62:2001 (see 2.3). ANSI/AAMI RD62:2001 includes certain design and performance specifications for individual water treatment devices. The rationale for those requirements can be found in Annex A of ANSI/AAMI RD62:2001, and the reader is encouraged to consult that document for further information. Devices used to purify water for hemodialysis are also subject to the U.S. Food and Drug Administration's 510(k) approval process. The FDA has published guidelines for water purification devices used in hemodialysis (Guidance for the Content of Premarket Notifications for Water Purification Components and Systems for Hemodialysis; see 2.1). The committee attempted to ensure compatibility between the requirements of ANSI/AAMI RD62:2001 and the FDA guidance document, although not all of the FDA's requirements were included in ANSI/AAMI RD62:2001. Water purification devices used in hemodialysis applications must be approved by the FDA, and users should ensure that devices obtained from vendors have been approved by the FDA.

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The subclauses of 5.2 provide general information. Design and instrumentation of individual purification devices may vary from these general descriptions. For example, softeners may be configured as a single resin bed that is regenerated outside the normal operating hours of the dialysis unit, or they may have a dual-bed configuration that allows one bed to be regenerated while the other is used to provide water for normal dialysis operations. Depending on the feed water quality and product water requirements, not every component in 5.2 may be required in a given facility. Likewise, additional components may be required in certain circumstances. For example, carbon adsorption may not provide adequate chloramine removal if the water contains substances, such as polyphosphates, that mask the reactive sites on the carbon particles. In those circumstances, other processes, such as infusion of sodium metabisulfite, may be required to achieve product water that meets the requirements of 4.1.1. Users are encouraged to obtain detailed descriptions of all purification processes, together with operating manuals and maintenance procedures, from the manufacturer or the vendor providing the water purification and distribution system. A.5.2.5 Carbon adsorption Although treatment of water by carbon adsorption is the method usually used to meet the requirement of 4.1.1 for chloramines, the committee recognized that in certain situations carbon adsorption might not adequately remove chloramines. Inadequate removal of chloramines may occur when the chloramines are in the form of naturally occurring N-chloramines or when practices such as the use of high pH or the inclusion of orthophosphate or polyphosphates are used to comply with the EPA's lead and copper rule. In other situations, such as acute dialysis with portable water treatment systems, it may not be practical to use the volume of carbon required to ensure adequate chloramine removal. In such circumstances, other strategies for chloramine removal may be needed to supplement carbon adsorption. The committee is aware that adding sodium metabisulfite prior to the reverse osmosis system has been successful in eliminating chloramine in hemodialysis applications. Ascorbic acid has also been added to the acid concentrate used to eliminate chloramine from the final dialysate (Ward, 1996). It should be noted that some minimum contact time is required for ascorbic acid to neutralize chloramine in water. If ascorbic acid is being used to neutralize chloramine and if unexplained red cell destruction or anemia occurs, the effectiveness of the ascorbic acid neutralization of chloramine should be investigated. Other means of removing chloramines, such as redox alloy media and ultraviolet irradiation at 185 nm, are used in the pharmaceutical and electronics industries. These processes are currently being evaluated for hemodialysis applications. The final choice of a system for chloramine removal in hemodialysis settings will depend on local conditions and may need to include more than one of the processes outlined above. The committee recognized that it might not be practical to rotate the bed positions in installations that use large, backwashable carbon beds. However, there was concern that the capacity of the second bed might decrease unpredictably and no longer provide adequate backup if there was breakthrough of the first bed. For this reason, the committee recommended replacing both beds if bed rotation was not possible. A.5.2.6 Chemical injection systems The committee expressed reservations about the addition of chemicals to the water. However, it recognized that the addition of chemicals may be necessary in some circumstances if a facility is to meet the maximum contaminant levels set forth in 4.1.1. For example, if the municipal water contains high levels of N-chloramines or chloramine in the presence of orthophosphate or polyphosphate, injection of sodium metabisulfite may be one of the few options available for chloramine removal. If chemical injection is used in the pretreatment cascade, users should ensure that the addition of the chemical does not interfere with the operation of subsequent purification processes, including the primary purification process. For example, the performance of thin-film composite reverse osmosis membranes may be affected by the pH of the feed water. At pH levels below 7, the rejection of fluoride may be substantially reduced, compared to its rejection at a pH of 8. A.5.2.8 Deionization Deionizers are an effective means of removing ionic contaminants from water. However, they do not remove nonionic species, and they may contribute bacterial contaminants to the water rather than remove them. The inability of deionizers to remove nonionic contaminants may limit aluminum removal by deionization, since aluminum is an amphoteric substance that changes from cationic to anionic as the pH varies from acidic to basic (Stumm and Morgan, 1996). At neutral pH, aluminum is present mostly as colloidal aluminum, which does not carry a charge and is not removed by deionization (Parkinson, et al., 1981). Furthermore, deionizers have a finite capacity for contaminant removal. Once the deionizer is depleted of hydrogen and hydroxyl ions, the next least avidly bound ions will be displaced by more avidly bound ions. For example, once the hydroxyl ions are depleted, anionic contaminants in the water will displace fluoride ions from the anion exchange resin (Bland, et al., 1996). This phenomenon has led to high levels of fluoride in the product water, with subsequent patient injury and death (Arnow, et al., 1994; Johnson

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and Taves, 1974). For the above reasons, use of deionization as the primary means of purification is strongly discouraged. Deionization may be used to polish product water from a reverse osmosis system or may be used as a standby if the reverse osmosis system fails. Some members of the committee believe that a two-stage reverse osmosis system is preferable to a combination of reverse osmosis and deionization. Deionizers offer a large surface area for bacterial proliferation and deionizers generally contribute to the bioburden in the water. Therefore, the committee strongly recommends that deionizers be followed by an ultrafilter. The tendency for deionizers to contribute bacterial contaminants to the water is greater when deionizers are kept as a backup for a reverse osmosis system, particularly if there is no flow through the deionizers. Some facilities counter this tendency by connecting the deionizers in parallel to the main water line and by maintaining a low flow through them. An alternative approach is to contract with a local vendor to provide backup deionizers on demand. A.5.3 Water storage and distribution The design of the water storage and distribution system is a critical element in preventing bacterial proliferation that may otherwise lead to water and dialysate not meeting the quality requirements of clause 4. The water storage and distribution system should be designed to provide the simplest possible flow path and to contain the smallest volume of water consistent with the operating needs of the dialysis unit. The simplest system is generally a direct feed system, in which purified water is piped directly from the last stage of the purification system to the points of use. However, direct feed systems are frequently impractical. For example, the pressure at the end of the purification cascade may be insufficient to provide adequate flow and pressure at the points of use without a booster pump. In this circumstance, an indirect feed system with a storage tank is required. Since storage tanks provide a large surface area for potential biofilm formation, their volume should be kept to a minimum in order to maximize water turnover in the tank. One consequence of the increased attention being paid to bacterial control in the water storage and distribution system is an interest in alternatives to traditional chemical disinfection. Two approaches have been developed, one based on ozone and the other on hot water. Both techniques may allow more frequent disinfection of the water storage and distribution system, because prolonged rinsing is not needed to remove residual disinfectant from the system before dialysis is recommenced. The use of ozone or hot water is possible only if the systems are constructed from appropriately resistant materials. This limitation applies not only to the piping and any storage tank that may be in the system, but also to all pumps, valves, and other fittings, including any O-rings and seals they may contain. Direct feed water distribution systems typically return unused water to the feed side of the reverse osmosis unit. If the pressure at the end of the distribution loop decreases to a value below the water pressure at the inlet to the reverse osmosis pressurizing pump, retrograde flow of nonpurified water into the distribution loop can occur. To minimize this risk, the committee recommends that dual check valves be used to prevent retrograde flow and that the pressure at the end of the distribution loop be monitored. A.5.4 Concentrate preparation A.5.4.4.3 Bicarbonate concentrate mixing systems Bicarbonate concentrates have been shown to support bacterial growth and to provide another source of initial bioburden capable of rapidly increasing after dilution (Ebben, et al., 1987; Bland, et al., 1987). Therefore, additional precautions should be taken when preparing and handling bicarbonate concentrate to avoid excess growth of haloduric organisms. Also, prompt use of bicarbonate concentrates prepared in dialysis facilities from powder and purified water is strongly recommended. Overagitation or mixing of bicarbonate concentrate may result in loss of CO2 from the solution. Loss of CO2 results in an increase in pH and favors the formation of carbonate that can lead to precipitation of calcium and magnesium carbonate in the fluid pathways of the dialysis machine following dialysate proportioning. A.5.6 Dialysate proportioning Dialysate is usually prepared by a proportioning system that sequentially adds acid concentrate and bicarbonate concentrate to purified water. These systems produce a buffered physiologic dialysate with a pH between 6.9 and 7.6. Current dialysis machines are also capable of supplying acetate dialysate. For acetate dialysate, purified water is mixed with a single acetate concentrate to produce the dialysate. This system is not buffered, so the pH can vary depending on the supply water. More recently, systems have been developed that use three concentrates (bicarbonate, sodium chloride, and an acid concentrate containing the remaining electrolytes) to allow more sophisticated variation of the dialysate composition during dialysis.

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A.6

Monitoring

A.6.2.5 Carbon adsorption Intensive monitoring of carbon adsorption beds is recommended because of the long history of adverse events related to chloramine contamination of dialysate (Ward, 1996). Chloramine concentrations in municipal water may change from day to day and the capacity of carbon adsorption beds to remove chloramine can vary with the pH and temperature of the water, the nature of the chloramine compounds present, and the presence of other substances in the water. The dependence of chloramine removal on multiple factors makes the performance of carbon adsorption beds unpredictable. Therefore, patient safety can only be ensured by intensively monitoring the performance of the carbon adsorption bed. Configuring carbon adsorption beds in series and sampling from a port located between the two beds provides one margin of protection against chloramine breakthrough. When chloramine is first detected in the effluent from the first adsorption bed, essentially the full capacity of the second bed remains available for chloramine removal. This reserve capacity allows the user to conveniently replace the exhausted bed without risk to patients. The exhausted bed is discarded, the second bed is moved into the first position, and a new bed is placed in the second position. A new bed of virgin carbon shall be used for replacement. Carbon cannot be regenerated in a dialysis facility, and the use of regenerated carbon is prohibited by ANSI/AAMI RD62:2001 (see 2.3). Backwashing of carbon beds does not regenerate the carbon, although it may allow more efficient use of the bed's capacity by removing channels that can form in the bed during routine operation. The recommendation that the water purification system should operate for at least 15 minutes before samples are drawn is to guard against inadvertently sampling water that has been in the bed for an extended period.

A.7

Strategies for bacterial control

A.7.2.3 Heterotrophic plate count Sensitive culturing methods must be used to measure the low total viable microbial counts permitted for water used for hemodialysis applications under the provisions of ANSI/AAMI RD62:2001 and recommended for dialysate in this recommended practice. The membrane filter technique is particularly suited for this application because it permits large volumes of water to be assayed. Because the membrane filter technique may not be readily available in clinical laboratories, the spread plate assay can be used as an alternative (Bland, 1995). However, if the spread plate assay is used, a calibrated loop shall not be used to apply sample to the plate. The sensitivity of an assay performed with a calibrated loop is low. A standard calibrated loop transfers 0.001 mL of sample to the culture medium, so that the minimum sensitivity of the assay is 1,000 CFU/mL. This sensitivity is unacceptable when the maximum allowable limit for microorganisms is 200 CFU/mL. Therefore, when the spread plate method is used, a pipette should be used to place 0.1 mL to 0.5 mL of water on the culture medium. The original clinical observations on which the microbiological requirements of ANSI/AAMI RD62:2001 were based used standard methods agar (SMA), a medium containing relatively few nutrients (Favero, et al., 1974). Later, the use of trypticase soy agar (TSA), a general purpose medium for isolating and cultivating fastidious organisms, was recommended because it was thought to be more appropriate for culturing bicarbonate-containing dialysate. However, several studies have shown that the use of nutrient-poor media, such as R2A or tryptone glucose extract agar (TGEA), results in an increased recovery of bacteria from water (Ledebo and Nystrand, 1999; van der Linde, et al, 1999; Pass, et al., 1996; Reasoner and Geldreich, 1985). ANSI/AAMI RD62:2001 also specifies incubation for 48 hours at 35 °C to 37 °C before enumeration of bacterial colonies. Extending the culturing time up to 168 hours and using incubation temperatures of 23 °C to 28 °C also have been shown to increase the recovery of bacteria (Ledebo and Nystrand, 1999; Pass, et al., 1996; Reasoner and Geldreich, 1985). For those reasons, culture results obtained using the methods outlined in ANSI/AAMI RD62:2001 and reiterated in 7.2.3 are only a relative indicator of the bioburden in the water or dialysate and do not provide a measure of the absolute bacterial burden. When monitoring for microbial contamination in water to be used for the preparation of ultrapure dialysate or dialysate for infusion, use of the alternative test methods will aid in the detection of contaminating organisms. Culturing should be performed using the membrane filtration method with a minimum of 125 mL of water being passed through the filter. The use of larger volumes (up to 1000 mL) will provide greater sensitivity, but the improved sensitivity needs to be balanced against the increased risk of contamination in collecting and handling the sample. The same culturing conditions can be used for ultrapure dialysate; however, the addition of 2 % to 8 % sodium bicarbonate to the medium may enhance the recovery of organisms. Even with these more sensitive techniques, compliance with the stringent requirements for dialysate for infusion (< 10­6 CFU/mL) cannot be demonstrated by culturing; it has to be ensured by use of a validated process. Monitoring of the production of dialysate for infusion will depend on the production system and should be performed according to the manufacturer's instructions. Furthermore, the culturing conditions recommended in ANSI/AAMI RD62:2001 and reiterated in 7.2.3 may fail to identify the presence of some organisms. Specifically, the recommended method may not detect the presence of various nontuberculous mycobacteria that have been associated with several outbreaks of infection in dialysis units (Bolan, et al., 1985; Lowry, et al., 1990). Also, the recommended method will not detect fungi and yeast, which have been shown to contaminate water used for hemodialysis applications (Klein, et al., 1990).

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The microbiological purity of packaged liquid concentrates and dry powder cartridges is the responsibility of the manufacturer (see 2.4). Monitoring of bicarbonate concentrate produced at a dialysis facility from powder and water, though not required routinely, may be undertaken as part of a troubleshooting investigation. The sodium content of TSA is sufficient for use in culturing bicarbonate concentrate without supplementation. However, if Reasoner's 2A or TGEA is used to monitor microbial contamination in bicarbonate concentrate, it may be necessary to supplement the media with 4 % sodium bicarbonate. A.7.2.4 Bacterial endotoxin test Bicarbonate concentrate inhibits the LAL assay. Inhibition is caused by the high concentration of solutes in the concentrate and the pH. In the gel-clot assay, this inhibition results in a failure of the positive control to clot. In kinetic assays, inhibition results in a failure to recover the "spike" (product positive control) to within ­50 % to +200 % of the nominal value. Dilution of the bicarbonate concentrate with water is the usual method for overcoming inhibition. A minimum dilution of 1:16 is necessary; however, higher dilutions are recommended for more sensitive assays: for example, a 1:20 dilution is recommended when using an assay with a sensitivity of 0.03 EU/mL. In kinetic methods, the sensitivity is the lowest concentration used to construct the standard curve. Standard gel-clot tests are incubated at 37 °C for 1 hour. At the end of 1 hour, the tubes are inverted to detect the presence of a clot. A positive test will have a clot, which will remain in the end of the tube as long as it is not shaken or bumped. A negative test will not have a clot and will tend to flow out of the tube. A clot that is semisolid and flows slowly is classified as a negative clot. For example, when bicarbonate concentrate is tested using a gel-clot assay with a sensitivity of 0.03 EU/mL and the concentrate is diluted 1:20 (1.0 mL concentrate plus 19 mL LAL reagent water or equivalent), the positive control sample should clot, indicating that there is no inhibition of the assay. If the diluted bicarbonate concentrate sample clots, it indicates that the sample contains at least 0.6 EU/mL of endotoxin. (To test at the 1.0 EU/mL action level using an assay with a sensitivity of 0.03 EU/mL, the concentrate is diluted 1:32, or 1 mL concentrate plus 31 mL LAL reagent water or equivalent.) A new version of the gel-clot assay has a matched positive control, which simplifies the testing and increases the reliability of the results. Tables A.1 and A.2 show the relationship between assay sensitivity, sample dilution, and the lowest level of endotoxin that can be detected. Table A.1 shows the lowest level of endotoxin (EU/mL) that can be detected using an assay of a given sensitivity and a specified dilution of a bicarbonate concentrate sample. Table A.2 shows the maximum sample dilution that can be used with an assay of a given sensitivity if the objective is to detect endotoxin concentrations as low as 1 EU/mL or 2 EU/mL.

Table A.1--Lowest level of endotoxin detectable using assays of different sensitivity and with different sample dilutions of bicarbonate concentrate

Sample dilution Assay sensitivity 0.015 0.03 0.06 0.125 0.25 1:16 0.25 0.5 1.0 2.0 NA 1:20 0.3 0.6 1.2 NA NA 1:32 0.5 1.0 2.0 NA NA

NA = not applicable. An assay with this sensitivity cannot be used to determine endotoxin concentrations 2 EU/mL at this dilution.

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37

Table A.2--Maximum allowable sample dilution for detection of endotoxin concentrations of 1 EU/mL and 2 EU/mL as a function of assay sensitivity

Detection limit Assay sensitivity (EU/mL) 0.015 0.03 0.06 0.125 0.25 0.5 1 EU/mL 1:64 1:32 1:16 1:8* 1:4* 1:2* 2 EU/mL 1:128 1:64 1:32 1:16 1:8* 1:4*

* The requirement that bicarbonate concentrate needs to be diluted at least 1:16 to avoid inhibition of the assay by high solute concentrations precludes the use of this combination of assay sensitivity and detection limit for testing bicarbonate concentrate.

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Annex B (informative) Bibliography

Alfrey AC, LeGendre GR, and Kaehny WD. The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 294:184­188, 1976. Arnow PM, Bland LA, Garcia-Houchins S, et al. An outbreak of fatal fluoride intoxication in a long-term hemodialysis unit. Ann Intern Med 121:339­344, 1994. Baz M, Durand C, Ragon A, et al. Using ultrapure water in hemodialysis delays carpal tunnel syndrome. Int J Artif Organs 14:681­685, 1991. Bernick JJ, Port FK, Favero MS, and Brown DG. Bacterial and endotoxin permeability of hemodialysis membranes. Kidney Int 16:491­496, 1979. Bland LA. Microbiological and endotoxin assays of hemodialysis fluids. Adv Renal Replacement Ther 2:70­79, 1995. Bland LA, Arnow PM, Arduino MJ, et al. Potential hazards of deionization systems used for water purification in hemodialysis. Artif Organs 20:2­7, 1996. Bland LA, Ridgeway MR, Aguero SM, et al. Potential bacteriologic and endotoxin hazards associated with liquid bicarbonate concentrate. Trans Am Soc Artif Int Organs 33:542­545, 1987. Bolan G, Reingold AL, Carson LA, et al. Infections with Mycobacterium chelonei in patients receiving dialysis and using reprocessed dialyzers. J Infect Dis 152:1013­1019, 1985. Bommer J, Becker KP, and Urbaschek R. Potential transfer of endotoxin across high-flux polysulfone membranes. J Am Soc Nephrol 7:883­888, 1996. Bommer J, Becker KP, Urbaschek R, et al. No evidence for endotoxin transfer across high-flux polysulfone membranes. Clin Nephrol 27:278­282, 1987. Carlson DJ and Shapiro FL. Methemoglobin from well water nitrates. A complication of hemodialysis. Ann Int Med 73:757­759, 1970. Centers for Disease Control and Prevention (CDC). Fluoride intoxication in a dialysis unit--Maryland. Morbidity and Mortality Weekly, 29:134, 1980. Comty C, Luehmann D, Wathen R, and Shapiro F. Prescription water for chronic hemodialysis. Trans Am Soc Artif Int Organs 20:189­196, 1974. Dawids SG and Vejlsgaard R. Bacteriological and clinical evaluation of different dialysate delivery systems. Acta Med Scand 199:151­155, 1976. Eaton JW, Koplin CF, Swofford HS, et al. Chlorinated urban water: A cause of dialysis-induced hemolytic anemia. Science 181:463­464, 1973. Ebben JP, Hirsch DN, Luehmann DA, et al. Microbiologic contamination of liquid bicarbonate concentrate for hemodialysis. Trans Am Soc Artif Int Organs 33:269­273, 1987. European Renal Association­European Dialysis and Transplant Association. European Best Practice Guidelines for Haemodialysis (Part 1), Section IV: Dialysis Fluid Purity. Nephrol Dial Transplant: 17 [Suppl. 7] 45­62, 2002. Evans RC and Holmes CJ. In vitro study of the transfer of cytokine-inducing substances across selected high-flux hemodialysis membranes. Blood Purif 9:92­101, 1991. Favero MS, Peterson NJ, Boyer KM, et al. Microbial contamination of renal dialysis systems and associated risks. Trans Am Soc Artif Int Organs 20:175­183, 1974. Gazenfeldt-Gazit E and Eliahou HE. Endotoxin antibodies in patients on maintenance hemodialysis. Israel J Med Sci 5:1032­1036, 1969.

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Ivanovich PA, Manzler A, and Drake R. Acute hemolysis following hemodialysis. Trans Am Soc Artif Int Organs 15:316­320, 1969. Johnson WJ and Taves DR. Exposure to excessive fluoride during hemodialysis. Kidney Int 5:451­454, 1974. Jones DM, Tobin BM, Harlow GR, et al. Bacteriological studies of the modified Kiil dialyzer. Brit Med J 3:135­137, 1970. Kaiser L and Schwartz KA. Aluminum-induced anemia. Am J Kidney Dis 6:348­352, 1985. Keshaviah P, Luehmann D, Shapiro F, et al. Investigation of the Risks and Hazards Associated with Hemodialysis Systems. Technical report, Contract #223-78-5046. Silver Spring (MD): U.S. Dept. of Health and Human Services, Public Health Service/Food and Drug Administration/Bureau of Medical Devices, June 1980. Kidd EE. Bacterial contamination of dialyzing fluid of artificial kidney. Brit Med J 880­882, 1964. Klein E, Holland FF, Gidden H, et al. Membrane and Material Evaluation. Annual progress report, N01-8M-2221, PB299021-AS. Gulf South Research Institute, March 15, 1979. Klein E, Pass T, Harding GB, et al. Microbial and endotoxin contamination in water and dialysate in the central United States. Artif Organs 14:85­94, 1990. Kleophas W, Haastert B, Backus G, et al. Long-term experience with an ultrapure individual dialysis fluid with a batch type machine. Nephrol Dial Transplant 13:3118­3125, 1998. Kovalchik MT, Kaehny WD, Higg AP, et al. Aluminum kinetics during hemodialysis. J Lab Clin Med 92:712­720, 1978. Laude-Sharp M, Caroff M, Simard L, et al. Induction of IL-1 during hemodialysis: Transmembrane passage of intact endotoxin (LPS). Kidney Int 38:1089­1094, 1990. Ledebo I. On-line preparation of solutions for dialysis: Practical aspects versus safety and regulations. J Am Soc Nephrol 13:S78­S83, 2002. Ledebo I and Nystrand R. Defining the microbiological quality of dialysis fluid. Artif Organs 23:37­43, 1999. Leypoldt JK, Schmidt B, and Gurland HJ. Measurement of backfiltration rates during hemodialysis with highly permeable membranes. Blood Purif 9:74­84, 1991. Lonnemann G, Behme TC, Lenzer B, et al. Permeability of dialyzer membranes to TNF-inducing substances derived from water bacteria. Kidney Int 42:61­68, 1992. Lonnemann G, Sereni L, Lemke HD, and Tetta C. Pyrogen retention by highly permeable synthetic membranes during in vitro dialysis. Artif Organs 25:951­960, 2001. Lowry PW, Beck-Sague CM, Bland LA, et al. Mycobacterium chelonae infection among patients receiving high-flux dialysis in a hemodialysis clinic in California. J Infect Dis 161:85­90, 1990. Matsuhashi N and Yoshioka T. Endotoxin-free dialysate improves response to erythropoietin in hemodialysis patients. Nephron 92:601­604, 2002. McKane W, Chandna SM, Tattersall JE, Greenwood RN, and Farrington K. Identical decline of residual renal function in high-flux biocompatible hemodialysis and CAPD. Kidney Int 61:256­265, 2002. Parkinson IS, Ward MK, and Kerr DNS. Dialysis encephalopathy, bone disease and anaemia: The aluminium intoxication syndrome during regular haemodialysis. J Clin Pathol 34:1285­1294, 1981. Pass T, Wright R, Sharp B, and Harding GB. Culture of dialysis fluids on nutrient-rich media for short periods at elevated temperatures underestimates microbial contamination. Blood Purif 14:136­145, 1996. Petrie JJB and Row PG. Dialysis anemia caused by subacute zinc toxicity. Lancet 1:1178­1180, 1977. Quellhorst E. Methods of hemodialysis. Nieren u Hochdruck 27:35­41, 1998. Raij L, Shapiro FL, and Michael AF. Endotoxemia in febrile reactions during hemodialysis. Kidney Int 4:57­60, 1973. Rao RKS and Friedman EA. Fluoride and bone disease in uremia. Kidney Int 7:125­129, 1975.

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Reasoner DJ and Geldreich EE. A new medium for the enumeration and subculture of bacteria from potable water. Appl Environ Microbiol 49:1­7, 1985. Ronco C, Orlandini G, Brendolan A, et al. Enhancement of convective transport by internal filtration in a modified experimental hemodialyzer. Kidney Int 54:979­985, 1998. Schiffl H, Fischer R, Lang SM, and Mangel E. Clinical manifestations of AB-amyloidosis: Effects of biocompatibility and flux. Nephrol Dial Transplant 15:840­845, 2000. Schiffl H, Lang SM, and Fischer R. Ultrapure dialysis fluid slows loss of residual renal function in new dialysis patients. Nephrol Dial Transplant 17:1814­1818, 2002. Schiffl H, Lang SM, Stratakis D, and Fischer R. Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters. Nephrol Dial Transplant 16:1863­1869, 2001. Schindler R, Eichert F, Lepenies J, and Frei U. Blood components influence cytokine induction by bacterial substances. Blood Purif 19:380­387, 2001. Schindler R, Lonnemann G, Schäffer J, et al. The effect of ultrafiltered dialysate on the cellular content of interleukin-1 receptor antagonist in patients on chronic hemodialysis. Nephron 68:229­233, 1994. Simoes J, Barata JD, D'Haese PC, and De Broe ME. Aluminium intoxication only happens in the other nephrologist's dialysis center. Nephrol Dial Transplant 9:67­68, 1994. Sitter T, Bergner A, and Schiffl H. Dialysate related cytokine induction and response to recombinant human erythropoietin in haemodialysis patients. Nephrol Dial Transplant 15:1207­1211, 2000. Spittle MA. Chronic inflammation and water quality in hemodialysis patients. Nephrol News Issues 15(May):24­28, 2001. Stenvinkel P, Heimbürger O, Paultre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 55:1899­1911, 1999. Stumm W and Morgan JJ. Aquatic Chemistry. Chemical Equilibria and Rates in Natural Waters (3ed.). New York: John Wiley & Sons, 1996, pp. 272­275. Tielemans C, Husson C, Schurmans T, et al. Effects of ultrapure and non-sterile dialysate on the inflammatory response during in vitro hemodialysis. Kidney Int 49:236­243, 1996. Tokars JI, Alter MJ, Favero MS, et al. National surveillance of dialysis associated diseases in the United States, 1993. ASAIO J 42:219­229, 1996. Ureña P, Herbelin A, Zingraff J, et al. Permeability of cellulosic and non-cellulosic membranes to endotoxin subunits and cytokine production during in-vitro haemodialysis. Nephrol Dial Transplant 7:16­28, 1992. van der Linde K, Lim BT, Rondeel JMM, et al. Improved bacteriological surveillance of haemodialysis fluids: A comparison between tryptic soy agar and Reasoner's 2A media. Nephrol Dial Transplant 14:2433­2437, 1999. Vanholder R, Van Haecke E, Veys N, et al. Endotoxin transfer through dialysis membranes: Small- versus large-pore membranes. Nephrol Dial Transplant 7:333­339, 1992. Ward DM. Chloramine removal from water used in hemodialysis. Adv Renal Replacement Ther 3:337­347, 1996. Ward MK, Feest TG, Ellis HA, Parkinson IS, et al. Osteomalacic dialysis osteodystrophy: Evidence for a water-borne aetiological agent, probably aluminium. Lancet 1:841­845, 1978. Yamagami S, Adachi T, Sugimura T, et al. Detection of endotoxin antibody in long-term dialysis patients. Int J Artif Organs 13:205­210, 1990.

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