id
stringlengths 32
40
| source
stringclasses 46
values | title
stringlengths 3
245
| clean_text
stringlengths 280
1.63M
| raw_text
stringlengths 4
1.63M
| url
stringlengths 4
285
| overview
stringclasses 216
values |
|---|---|---|---|---|---|---|
cd9f1df66dfe4a4eb97264bbd8701592
|
2012+WHO技术规范
|
冷冻治疗用于治疗宫颈癌前病变以及宫颈癌预防
|
# WHO technical specificationsCryosurgical equipment forthe treatment of precancerouscervical lesions and preventionof cervical cancer.
# .
# WHO technical specifications.
Cryosurgical equipment for the treatment of precancerous cervical lesions and prevention of cervical cancer.
# WHO Library Cataloguing- in- Publication Data.
WHO technical specifications: cryosurgical equipment for the treatment of precancerous cervical lesions and prevention of cervical cancer.. 1. Cryosurgery - instrumentation.
2.Uterine cervical diseases - surgery.
3.Precancerous conditions - therapy.
4.Uterine cervical neoplasms - prevention and control. I.World Health Organization.. ISBN 978 92 4 150456 0. (NLM classification: WP 480). \mathfrak{G}. All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e- mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications - whether for sale or for noncommercial distribution - should be addressed to WHO Press through the WHO web site (. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.. Printed by the WHO Document Production Services, Geneva, Switzerland.
# Acknowledgements.
AcknowledgementsThis document is the result of a review of the latest available evidence and an extensive consultative process on the treatment of precancerous cervical lesions by cryosurgery. WHO, UNFPA, and PATH organized a joint meeting of clinical experts in cryosurgery in Seattle, March 30- April 1, 2009. The goal of the meeting was to build consensus on approaches to improving cryosurgical service delivery to prevent cervical cancer. The meeting had two areas of focus: to discuss clinical recommendations in the use of cryosurgery for cervical cancer prevention and to initiate development of technical specifications to facilitate country procurement. Meeting attendees included experts from different countries on obstetrics and gynaecology, and the use of cryosurgery to treat cervical precancerous lesions. Representatives from NGOs and advocacy groups, and representatives from two cryotherapy device manufacturers, Wallach and MedGyn, also attended the meeting.. The first meeting identified several key issues relating to technical specifications for cryosurgery equipment which required follow- up and further development. These included procurement, performance, and maintenance of cryosurgical devices and related equipment, such as gas cylinders and connectors. At that time a framework was developed to address these issues, including the formation of a technical specification working group.. A second meeting re- convened key members from the technical specification working group to finalize the technical basis and make recommendations for the development of a procurement specification to guide the purchase, use, and maintenance of cryosurgical devices. This document is based on the output of the second meeting, together with input from members of the technical specification working group and other experts listed below.. WHO, UNFPA, and PATH have all supported the development of this document and would like to gratefully acknowledge the contributions of the following people and organizations:. Co-authors. Co- authorsWilliam Potter (Consultant/WHO Technical Adviser) drafted the technical specification and supporting documents, with core contributions from Siavoche Mohadjer (WHO Consultant), Margaret Usher- Patel (WHO), Jennifer L. Winkler (PATH), Jered Singleton (PATH), Keith Neroutsos (PATH), and Nathalie Broutet (WHO).. Primary reviewers. Primary reviewersAgnes Chidanyika (UNFPA), Hugo de Vuyst (International Agency for Research on Cancer), Paul Blumenthal (Stanford University School of Medicine), Ricky Lu (Jhpiego), Carlos Santos (Instituto Nacional de Enfermedades Neoplásicas), Jose Jeronimo (PATH), Lisa Hedman (WHO), and Ingegerd Nordin (UNFPA) who provided detailed feedback on the draft documents with input from equipment manufacturers Wallach, Cooper Surgical, ERBE, and CryoPen Inc. In addition, feedback was received from field staff who were asked to comment on issues related to gas used for cryotherapy and to review from a programmatic perspective: Shumet Adnew (Pathfinder), Min Zaw (PSI), Matts Boxshall (PSI), Edward Kumakech (PATH), and Wame Baravilala (UNFPA).. Meeting participants and members of the technical specification working group. Meeting participants and members of the technical specification working groupLinda Alexander (Qiagen), Laura Bell (Qiagen), Paul Blumenthal (Stanford University School of Medicine), Nathalie Broutet (WHO), Linda Cella (Wallach), Agnes Chidanyika (UNFPA), Craig Citron (Wallach), Hugo de Vuyst (International Agency for Research on Cancer), Lauren Ditzian (Basic Health International), Francisco Garcia (American Cancer Society), Lisa Hedman (WHO), Judith Henninger (WHO), Arnynah Janmohamed (PATH), Jose Jeronimo (PATH), Greg Kinley (MedGyn International), Ricky Lu (Jhpiego), Silvana Luciani (WHO), Rachel Masch (Beth Israel Medical Center), Mutsumi Metzler (PATH), Siavoche Mohadjer (WHO Consultant), Katie Richey (WHO), Carlos Santos (Instituto Nacional de Enfermedades Neoplásicas), Jered Singleton (PATH), Gene Spahija (MedGyn International), Maggie Usher- Patel (WHO), and Jennifer Winkler (PATH).. Editing and layoutGreen Ink (www.greenink.co.uk).
# iv Cryosurgical equipment for the treatment of precancerous cervical lesions and prevention of cervical cancer.
# Contents.
ContentsAcknowledgements iiiExecutive Summary viiIntroduction 1Chapter 1. Generic specification of cryosurgical equipment for the treatment of precancerous cervical lesions 3Chapter 2. Advice and guidance regarding gas supplies for cryosurgical treatment of precancerous cervical lesions 10Chapter 3. Recommendations for handling gas cylinders 19Chapter 4. Procurement guidance 22Annex 1. Glossary of terms 27Annex 2. Technical Basis Paper: Cryosurgical equipment for the treatment of precancerous cervical lesions 29Annex 3. WHO guidelines on cryotherapy 38Annex 4. WHO universal precautions for infection prevention 42Annex 5. Details of gas fittings and suppliers by country 46. Figures. FiguresFigure 1: A typical cryosurgical unit 5Figure 2: Illustration of dimensions of cryotips suggested for cryosurgical treatment of precancerous cervical lesions 7Figure 3: Range of high pressure gas cylinder sizes 14Figure 4: Examples of pin- indexed cylinder valves 15Figure 5: The stages of procurement 22Figure A1: A typical cryosurgical unit 31Figure A2: Illustration of dimensions of cryotips suggested for cryosurgery of precancerous cervical lesions 32. Tables. TablesTable 1: Suppliers of cryosurgical equipment suitable for cervical lesions 4Table 2: Values of 1 Bar of pressure in commonly- used units 11Table A1: Suppliers of cryosurgical equipment suitable for cervical lesions 30.
# .
# Executive Summary.
Cervical cancer is a serious and growing global health issue. In 2008, there were approximately 274 000 deaths from the disease, about . This document seeks to assist programme managers, purchasing managers, and other .
# .
# Introduction.
Cervical cancer is a serious and growing global health issue.In 2008,there were an estimated 529 000 new cases of cervical cancer and approximately 274 000 deaths, making it the second most common cancer in women.About . Although it affects women worldwide, cervical cancer mortality is highest in low- resource settings where women have not traditionally had access to organized screening programmes. Infection with human papillomavirus (HPV), the virus that causes cervical cancer, is preventable through vaccination, but the vaccine should be given prior to infection, which often occurs within a few years of sexual debut. For those women already infected, development of cervical cancer is preventable using relatively simple, low- cost screening and treatment approaches that can be implemented at the district, if not primary, health care level. This is particularly true of visual inspection methods such as VIA (visual inspection with acetic acid) combined with cryosurgical treatment, although in certain cases more sophisticated treatment is needed2. In many areas, treatment is provided the same day as a positive screening test, or soon after. It is usually provided without histological confirmation because of the potential loss to followup that would result from the extra diagnostic step. Cervical cancer usually takes decades to . Cryosurgery is appropriate for use in low- resource settings because it is effective . The WHO Reproductive Health Strategy, adapted by Member States during the . That said, a successful programme requires confidence in both the screening method and the equipment necessary to treat lesions. Cryosurgical equipment has not always inspired such confidence. Failure to achieve freezing and gas line blockages are two problems that have been seen in the field. In response, the WHO Department of Reproductive Health and Research (WHO/RHR), in partnership with PATH and UNFPA, mobilized technical advisors, researchers, and manufacturers to develop procurement specifications for cryosurgical equipment, gas, and accessories, along with technical guidance for addressing operational.
# challenges and a consensus configuration of a standard cryosurgical package..
For more information about cervical cancer screening and treatment, consult WHO's [C4- GEP] and other documents which can be found in the "Screening" section of the RHO Cervical Cancer Library (www.rho.org).. Who is this document intended for?. This document is intended primarily for any policy- maker, manager, or procurement officer who has responsibility for procuring, supplying, and promoting the early prevention and management of cervical cancer. Individuals working in reproductive health care programmes, particularly STI/HIV/AIDS prevention and family planning programmes at the district and primary health care level, should also review this document to understand why it is vitally important to establish systems which ensure that a quality product is manufactured, procured, and used. Bulk procurement agencies and national regulatory authorities will also need to study this document in preparation for the manufacture, procurement, and supply of cryosurgical equipment and the appropriate . In addition to these primary users, the document will be useful to manufacturers, social marketing programmes, nongovernmental agencies, and policy- makers as they work to improve the acceptability and use of cryosurgery as a means to support cervical cancer prevention and management programmes in their target populations.. Purpose of the document. This document describes a technically sound, systematic process to support the procurement and distribution of cryosurgical equipment that can meet the needs of cervical cancer prevention and management programmes at the district and primary health care levels. It includes advice on technical specifications for purchasers, including the design and performance recommendations necessary to ensure the safety and efficacy of cryosurgical equipment. It also discusses issues related to the sources, storing, and handling of gases used by the equipment, and guidance on how to procure both the equipment and the gases..
# Chapter 1. Generic specification of cryosurgical equipment for the treatment of precancerous cervical lesions.
1.1 Scope. This Generic Specification specifies requirements and recommendations for cryosurgical equipment for the treatment of precancerous cervical lesions in low- resource settings. The specification is based on a series of meetings, surveys, reviews, and studies undertaken between 2008 and 2010 by WHO, PATH, and UNPFA<sup>4</sup>.. 1.2 Background to cryosurgical equipment. Cryotherapy, also known as cryosurgery, has been widely accepted as a practical and effective method of treating precancerous cervical lesions worldwide. Extreme cold is applied to the lesion using a cryoprobe (an extremely cold probe) to freeze the lesion. The World Health Organization Guidelines on the use of cryotherapy for cervical intraepithelial neoplasia strongly recommend the use of cryotherapy over no treatment.. Cryosurgical equipment (also known as cryotherapy equipment) is available from a number of manufacturers, mainly US- based, but with some types available from European and Indian manufacturers. Two main methods are used to cool the cryoprobe: the expansion of . Although current cryosurgical equipment relies on using a compressed gas or a cryogenic liquid to achieve the target probe temperature, new types of equipment with built- in freezer units are beginning to emerge. By eliminating the need for compressed gas supplies, units with built- in freezers may have clear advantages in low- resource environments despite their potentially higher initial purchasing costs. The suitability of this type of equipment for use in low- resource settings still has to be assessed but may well represent an opportunity for the future.. The most widely- used compressed gases for surgery are carbon dioxide and nitrous oxide, and most cryosurgical equipment manufacturers offer the option of using either. The choice of gas has to be made at the time of purchase of the equipment to ensure the proper fittings, and in some cases that the appropriate device is used. In low- resource settings carbon dioxide is often cheaper and more readily available than nitrous oxide.. Examples of some of the main suppliers that have been identified through internet and other searches are given in Table 1.. 1.3 Equipment requirements. Cryosurgical equipment operating on either compressed carbon dioxide or nitrous oxide may be used for the treatment of precancerous.
# cervical lesions. In low- resource settings carbon dioxide is generally more readily available and costs less. An example of a typical cryosurgical unit is shown in Figure 1..
The equipment comprises the following components:. A hand unit with a shaft to which detachable probe tips can be attached. The hand unit is made of a material that withstands routine sterilization or disinfection with hospital disinfectants, including bleach solutions or any other disinfectant for surgical instruments. The manufacturers' recommendations for sterilization and disinfection should be followed. The hand unit is fitted with one or more integrated triggers and other controls .
# 1. Probe
2. Trigger
3. Handle grip (fiberglass)
4. Yoke
5. Inlet of gas from cylinder
6. Tightening knob
7. Pressure gauge showing cylinder pressure
8. Silencer (outlet)
9. Gas-conveying tube
10. Probe tip.
o The trigger mechanism unit should be made of rigid plastic, of a type and grade that will insulate the hand of the user while providing durability. o The hand unit shall permit the removal and attachment of the cryotip and/or the cryoshaft to facilitate cleaning.. A hose assembly attaching the hand unit to a connector/pressure gauge assembly that connects to the high- pressure gas cylinder. The hose assembly comprises: o A high- pressure hose to conduct the gas to the hand unit and a return hose to carry the waste gas back to the pressure gauge assembly to be vented (venting of the gas within the handset is not acceptable). o The high- pressure hose, as required by ASTM F 882- 84 (Reapproved 2002) Standard Performance and Safety Specification for Cryosurgical Medical Instruments5, shall be rated for a pressure that is at least twice the maximum gas cylinder pressure (ca. 2000 psi). o Ideally the hose will comply with the requirements specified in ISO 21969 (2009) High- pressure flexible connections for use with medical gas systems6. o A minimum hose assembly length of . A connector/pressure gauge assembly that connects to the gas cylinder with the following features:. o A gas connector to permit the cryosurgical system to connect to the compressed gas cylinder. The connector is made of metal and should be appropriate for use with pressurized gases, specifically with carbon dioxide and nitrous oxide. Multiple types of connectors are available and compressed gas cylinder valves vary from country to country. It is essential that the proper.
# connector is used with the compressed gas cylinder valve. More information on gas fittings and gas supplies are given in Chapter 2. o A pressure gauge to indicate the pressure within the system. The gauge may be colour coded to indicate the safe working pressure range for the device. o A pressure relief valve designed to protect the device, the user and the patient from potentially excessive tank pressure. Typically the valve should have an internal rupture disk which bursts at a set pressure, preventing the device from becoming over- pressurized. The pressure relief valve should be designed to rupture if the maximum pressure rating of the pressure gauge, the hose assembly, or the trigger mechanism is reached. o An exhaust port to which a hose can be connected to vent the exhaust to a place with adequate air circulation. o Optionally the equipment may be fitted with a pressure regulator to maintain a relatively constant pressure within the unit. o Preferably a silencer unit to reduce noise levels. o Active defrosting mechanisms may or may not be incorporated into the operation of the unit. Both active and passive defrost systems are acceptable for the treatment of precancerous cervical lesions. If an active defrosting option is included, it will be integrated into the trigger function or the hand unit to facilitate single handed operation of the equipment. o Optionally the equipment may be fitted with temperature sensors to indicate the probe temperature and a timer to indicate the duration of tissue exposure..
probe shaft shall be removable at its base from the hand unit.. The cryotip shall be made from surgical- grade materials or the manufacturers shall provide evidence that the materials used for the cryotips have been assessed for cytotoxicity according to ISO 10993- 5 (2009), Biological evaluation of medical devices - Part 5: Tests for in vitro cytotoxicity, and for irritation and sensitization potential according to ISO 10993- 10 (2010), Biological evaluation of medical devices - Part 10: Tests for irritation and skin sensitization. Cryotips with a well- established history of safe use are acceptable.. The cryotip shall be made from materials capable of withstanding routine sterilization by autoclave or disinfection with hospital disinfectants, including bleach solutions or any other disinfectant for surgical instruments.. The surface of the cryotip that contacts the cervix should be smooth with no sharp edges.. Only cryotips conforming to the following requirements should be used for the treatment of precancerous cervical lesions:. The cryotips shall be of closed design. Open cryotips apply the cryogen directly to the target tissue and must not be used for treating cervical lesions because of the risk of damage to surrounding healthy tissue. The cryotips shall be rounded in shape and should be . 1.4 Cryotips. The cryotip will be removable to allow interchangeable tips to be used and to facilitate cleaning and disinfection after use. The cryotips may attach directly to the probe shaft or be integral to the probe shaft, in which case the. 1.5 Cryoshaft. The cryoshaft is made from materials capable of withstanding routine sterilization by autoclave or disinfection with hospital disinfectants, including bleach solutions or any.
# other disinfectant for surgical instruments. Manufacturers should include information on disinfectants that can be used with the shafts and warn about any that can cause damage. With some designs of equipment it may not be possible to detach the cryoshaft for sterilization. In such cases the manufacturers' procedures for disinfection should be followed..
The overall length of the cryoshaft and cryotip assembly should be between 170 and 200 mm. The cryoshaft should not freeze during normal use; its outer surface should be insulated to prevent accidental freezing of any tissue that it touches.. The cryoshaft should be rigid so that it does not flex during normal use.. The cryotip should provide safe and consistent delivery of gas to the tip as well as gas exhaust back through the interior body of the tube.. 1.6 Performance and safety standards. The cryosurgical equipment is capable of reaching and maintaining a cryotip temperature below . Ideally the cryosurgical system should conform to an appropriate national standard such as ASTM F882- 84 (Reapproved 2002), Standard Performance and Safety Specification for Cryosurgical Medical Instruments. All high- pressure gas fittings incorporated into the cryosurgical unit should comply with regulations for compressed gas fittings in the country where the equipment is manufactured.. 1.7 Regulatory status of cryosurgical equipment. In the US cryosurgical equipment is regulated as a Class II medical device. Before being.
# placed on the US market a 510(k) premarket notification has to be submitted to the Food and Drug Administration (FDA) providing information on the safety and effectiveness of the equipment. Manufacturers are required to demonstrate equivalence to a device that was on the US market prior to the introduction of the regulations (i.e. before May 28, 1976) or a device that has been shown to be substantially equivalent to such a device through a previous 510(k) submission. The previously- marketed device is known as the predicate device..
In Europe cryosurgical equipment falls into Class IIa according to classification rule 9 of the European Medical Device Directive (93/42/EEC as amended). Class IIa devices require prior clearance before being placed on the market in Europe by a Notified Body. Once the equipment is cleared for marketing the manufacturer must affix a CE Mark to the device to demonstrate that the product complies with the essential requirements of the directive. If the cryosurgical equipment includes any electrical components then the equipment may also be required to comply with other European regulations relating to the safety and compatibility of electrical equipment.. The regulation of medical devices in other countries and regions tends to vary considerably. Most low- resource countries have very limited, if any, regulation of most medical devices. It is therefore unlikely that product registration for cryosurgical equipment will be required in most low- resource countries but the national regulatory authority may insist on the product having US FDA 510(k) and/or European CE Mark clearance. National regulatory authorities may also require a certificate of free sale for the product in the country of manufacture and may want to review the documents submitted in support of 510(k) or CE mark approval.. A key stage in the procurement or purchase of cryosurgical equipment therefore is an assessment of local regulatory requirements, if any, in the recipient country or countries. Once the . - confirm with the national regulatory authorities whether there are any local regulatory or registration requirements for cryosurgical equipment;- source equipment that has US FDA 510(k) and/or European CE Mark clearance;- ensure that equipment which is not manufactured or distributed in the US or Europe, and does not have 510(k) or CE Mark clearance, has appropriate regulatory approval in the country of manufacture;- ensure, where applicable, that the equipment manufacturer has the appropriate export licences issued in the country of manufacture for the equipment;- ensure that the equipment manufacturers are prepared to supply any necessary documentation that may be required for local regulatory review in the recipient countries, including certificates of free sale.. 1.8 Gas cylinder connector. The connector between the gas cylinder valve and the cryosurgical unit is an integral part of the cryosurgical unit. The connector will be specified when the equipment is purchased and must be compatible with the cylinder valve fitment available in the country where the equipment is to be used. Further advice on gas cylinders and gas connectors is given in Chapter 2, including a list of some of the most common fitments.. Gas cylinder fitments are specific to the type and grade of gas being used as well as the cylinder size. It is essential to determine the type of fitments available in- country before ordering cryosurgical equipment.. Some manufacturers provide an empty gas cylinder with the equipment. In such cases it is essential to confirm that the local gas supplier.
# has the correct fittings to be able to refill the cylinder prior to purchase. It is also essential to confirm that the supplied cylinder is of adequate capacity for treating cervical lesions (for further information on gas cylinder fittings and cylinder capacity, refer to Chapter 2)..
1.9 Gas cylinders. A full review of gas supplies for cryosurgical equipment has been completed separately. This includes advice on the selection, procurement, storage, and handling of the gas cylinders (see Chapters 2 and 3).. 1.10 Spare parts. Essential spare parts such as the hose assembly, cryotips, cryoshafts, O- ring, and sealing washers should be purchased from the original equipment manufacturer. Manufacturers should provide a referenced list of spare parts to facilitate ordering..
# Chapter 2. Advice and guidance regarding gas supplies for cryosurgical treatment of precancerous cervical lesions.
2.1 Background. Cryosurgical equipment suitable for the in- clinic treatment of precancerous cervical lesions normally operates from a high- pressure gas cylinder. The most commonly- used gases are carbon dioxide and nitrous oxide. The probe tip is cooled by expansion of the gas through a nozzle, causing cooling by the Joule- Thomson effect. Both nitrous oxide and carbon dioxide have high Joule- Thomson coefficients, making them good gases for this application. Sourcing an appropriate supply of compressed gas can be problematic, especially in low- resource settings. This document provides advice and guidance to procurers and users of cryosurgical equipment in low- resource countries on obtaining, storing, and using suitable gases.. 2.2 Gas quality. Gases are available in many different "grades", including medical, food, industrial, ultrapure, and spectroscopic. Different manufacturers and/or distributors may use different designations for some of these grades.. Medical- grade gases are of very high quality and by necessity are free of any potentially problematic impurities. They are also more expensive than other grades.. Although with the types of cryosurgical equipment that are suitable for treatment of cervical lesions there is no direct contact between the gas and the patient, it is nevertheless recommended that medical- grade gas is used if available and affordable. This is to reduce the risk of equipment blockages due to impurities such as moisture or particulate material in the gas.. Ideally medical- grade gases should be used, but if these are not available locally then food, beverage (for carbon dioxide), or equivalent grades can be considered. Use of "industrial"-. grade gas is discouraged. Gases should never be mixed, nor should any other gas than that specified by the equipment manufacturer be used.. The type of connector between the cylinder valve (which is part of the gas tank and supplied by the distributor) and the device not only depends on the type of gas, but also the grade of gas. It may not be possible therefore to switch between different grades of gas without also changing the fitting on the device. Again this reinforces the need to check the local availability of gas supplies before purchasing cryosurgical equipment.. 2.3 Units used for gas pressure. Different units for pressure are in common use. The official SI (Système international d'unités) derived unit for pressure is the Pascal (Pa) but, to avoid excessively large numbers, it is normally more convenient to use the kilo Pascal (kPa) for gas pressures. A pressure of one Pa is equivalent to one Newton (a measure of force) per square metre. Other common units for pressure include pounds per square inch (psi), atmospheres, bar, and . The gauges used on cryosurgical equipment are commonly colour coded to indicate the acceptable operational range. Red indicates that the gas pressure is too high, green that it is within the acceptable operational range, and yellow that it is too low..
# 2.4 Properties of compressed gases.
The properties of compressed gases and the requirements for their safe transport and storage can be confusing and difficult to understand.Different standards, regulations, and requirements apply to gases and gas cylinders depending upon country, region, and application.Some gases turn into liquids when compressed and are stored in the tank in liquid form.Others remain as gases even under very high pressures.If the gas in the cylinder is liquefied, then there are important implications for the storage,handing,and use of the gas which are discussed later in this document.All gases under pressure are potentially hazardous. When dealing with compressed gases it is therefore essential to understand the basic principles behind the purchasing, storage, and use of gases and gas cylinders.. An important concept in understanding the behaviour of gases under pressure is the "critical point".The critical point is the combination of temperature and pressure at which separate liquid and gas or vapour phases effectively cease to exist.Above the critical temperature it is not possible to cause the gas to liquefy no matter how high a pressure is applied to it. In this state the gas is known as supercritical.The pressure required to cause a gas to liquefy at the critical temperature is known as the critical pressure.At temperatures below the critical temperature the gas can be liquefied if sufficient pressure is applied. This is why some gases liquefy at normal ambient temperatures and others do not.. Both carbon dioxide and nitrous oxide have critical temperatures that are a little higher than room temperature.For carbon dioxide the critical temperature is . 1. The pressure within the cylinders will remain largely constant as the gas is used until all the liquid is gone, at which point the gas pressure will start to drop. The gas pressure may also drop during use as the cylinder is approaching empty because the rate of evaporation of the liquid can no longer keep the pressure constant. However, once the treatment is stopped, the pressure may recover. The pressure gauge cannot therefore be relied upon to indicate the amount of gas remaining in the cylinder. If the gas pressure in the cylinder drops during use and then recovers, this should be taken as a warning that the cylinder is approaching empty.. 2. The vapour pressure of the liquid, and therefore the pressure in the cylinder, will depend on temperature to a much greater extent than for cylinders containing compressed gases only (i.e. no liquid). At typical storage temperatures in the range .
# high for use with some types of cryosurgical equipment until the cylinder has had time to cool to below .
3. The cylinders must be standing upright in order to deliver gas. If they are used on their side then liquid or a mixture of gas and liquid will be forced into the equipment. Cylinders may be stored upright or on their side, but before use they must be stood upright.. Some cylinders are fitted with a dip tube or siphon. These cylinders are intended to deliver liquid, not gas. Some manufacturers mark siphon cylinders with a white stripe running along the length of the cylinder. If there is any doubt about whether a cylinder contains a siphon tube the supplier should be consulted. Unless it is specifically stated for a specific piece of equipment that a siphon cylinder should be used, then never use a cylinder with a dip tube or siphon. Doing so could cause damage to the equipment leading to leaks, possible cold burns to the user, and even the risk of an explosion.. As gas is drawn from a cylinder containing a liquefied gas, some of the liquid evaporates in order to maintain the constant pressure. This has a cooling effect. If gas withdrawal is rapid this can cause a sufficient drop in temperature for moisture to condense and even for frost to appear on the outside of the cylinder.. If for any reason there is a rapid discharge of gas, for example if a valve leaks or a hose bursts, the valve itself can become very cold and there is a risk of frostbite if the valve is touched.. Gas suppliers always leave space in a cylinder containing liquefied gases, such as nitrous oxide and carbon dioxide, for expansion. Typically cylinders are only filled to about . of the available volume in temperate climates and . Overfilling could lead to excessive cylinder pressures during storage causing the pressure release valve to vent the entire contents of the cylinder. Always use a reputable gas supplier to reduce the risk of being supplied with overfilled cylinders.. If the gas pressure in a cylinder is too high for the specific type of cryosurgical equipment being used, the excess pressure can be vented using the following procedure:. - Close the main cylinder valve.- Ensure that the main cylinder valve opening is facing away from any people and slowly open the valve. Allow a small stream of gas to escape for 8-10 seconds.- Close the main cylinder valve.- Re-connect the cryosurgical system to the cylinder valve.- Open the main cylinder valve again. If the pressure is still too high, repeat the procedure.. If a cylinder containing gas at an excessively high pressure is attached to some types of cryosurgical equipment, the equipment may be damaged. If at all possible try and check cylinder pressures before attaching the cryosurgical unit.. 2.5 Gas cylinders. 2.5.1 General. Pressures within carbon dioxide and nitrous oxide cylinders can be extremely high, typically up to just over 1,000 psi. Cylinders are normally constructed of carbon steel or aluminium. Cylinders containing high- pressure gas are potentially very dangerous. Additionally, using an incorrect gas can cause serious injury and death due to asphyxiation, poisoning, fire, and explosion. For these reasons most countries have stringent regulations controlling the transport, supply, and use of compressed gas cylinders..
# Find out about the regulations regarding transport, supply, and use of compressed gas cylinders in your country..
Depending upon local or regional regulations, the cylinders have to be tested periodically to make certain that they can withstand the high pressures reached in service. The frequency of testing is determined by local regulations in most countries. In general a hydraulic pressure test is required every five to ten years depending upon the type of gas and local regulations. All cylinders should carry an indication of when they were last tested and when a re- test is required, although the code system used may not be obvious. If there is any doubt about the age or condition of a cylinder, consult with the gas supplier to determine when the cylinder was last tested and cleaned.. It is essential that the gas suppliers' recommendations relating to the safe transport, storage, and use of the cylinders are followed. Cylinders must be restrained by suitable chains or holders to prevent them falling over, both in storage and in use.. If a cylinder falls over and the valve is damaged or broken, it can turn the cylinder into a dangerous projectile causing extensive damage, serious injury, and even death. Some guidelines on handling cylinders are included at the end of this chapter.. 2.5.2 Identification of gas cylinders. To assist in the identification of gases, cylinders are usually colour- coded. Unfortunately there are different colour- coding systems in operation depending upon the country, the standards being used, and even the supplier of the gas. In some countries the colour code system may not even be followed.. Find out about the colour coding of gas cylinders used in your country.. Colour coding within the European Union is regulated under European Standard EN 1089- 37, Transportable gas cylinders. Gas cylinder identification (excluding LPG). This standard specifies colour coding for all types of gas cylinders. Colour coding can be related to the hazard properties of the gas or by specific gas contained in the cylinder. Carbon dioxide is indicated by a dusty grey on the cylinder and nitrous oxide by dark blue. Different countries use different colour- coding schemes, although attempts to standardize colours are being made. The colour coding of medical gases is covered by an international standard, ISO 32 (1977), Gas cylinders for medical use - marking for identification of content. This standard applies to medical gases only; not all countries use the standard.. It is therefore essential to check the label of any gas cylinder carefully to make sure the correct gas and the correct grade are being used. If there is any doubt about the contents of a gas cylinder, then either contact the supplier for confirmation or do not use it!. 2.5.3 Cylinder sizes. Cylinders are available in a wide range of sizes (see Figure 3). The size of gas cylinders can be specified by a letter code, by the water capacity expressed in pounds, by internal volume, or by the volume of gas at normal pressure and temperature contained in the cylinder. Common sizes for European medical gas cylinders are size C containing 450 ml of gas, size D containing 900 ml of gas, size E containing 1800 ml of gas, size F containing 3600 ml of.
# gas, size G containing 9000 ml of gas and size J containing 18 000 ml of gas..
- The most common and useful sizes for cryosurgery are D and E.. In the US, cylinder capacities are more commonly expressed in pounds (lbs). Commonly- used sizes for cryosurgery are 6 lbs and 20 lbs.. The number of cryosurgical sessions per cylinder will clearly depend upon the size of the cylinder, the type of equipment used, and the duration of the procedure. Wallach, in their sales literature, state that the LL100 Cryosurgical System using a 20 lb nitrous oxide cylinder should provide approximately 80 minutes of use. This would be sufficient for about 20 precancerous cervical lesion treatments. Practical experience, however, suggests that the number of treatments per 20 lb cylinder can vary widely. Contributors to this document commented that in some cases as few as two full treatment sessions have been possible with a 20 lb cylinder whereas in other . Smaller cylinders may only provide sufficient gas for a few procedures and should only be used for emergencies. When deciding on a cylinder size it is essential to take into account such factors as costs, caseload, frequency of use, convenience of resupply, and local transport, storage and handling issues. As a general rule, it is best to opt for the largest cylinder size available subject to practical considerations relating to storage and handling on site.. 2.5.4 Cylinder valves. All cylinders are fitted with a suitable valve to allow attachment to the equipment via an appropriate connector. To prevent the risk of an explosion, should a cylinder overheat during transport or storage, the valve assembly must have a pressure relief valve, normally in the form.
# of a rupture disc. These types of release valve do not reset; if for any reason the pressure limit is exceeded they will vent the entire contents of the cylinder..
For this reason transporting cylinders in enclosed vehicles can be extremely dangerous. If the rupture disc is activated then the entire contents of the cylinder will be vented into the vehicle.. 2.6 Connectors. Because of the significant risks associated with using the wrong gas - which include poisoning, asphyxiation, fire, and explosion - different types of cylinder valve connectors are used to prevent the accidental connection of the wrong type of gas cylinder to any equipment. Connectors can be of different types and sizes. Some connectors screw onto the valve directly but the size and shape of the union and the type of thread used vary to prevent connecting the wrong type of connector.. For medical gases the use of pin- indexed yoke connectors is common, particularly for the smaller cylinders (see Figure 4 for examples). The location of the pins determines whether the connector will fit on a specific valve. Larger cylinders of medical- grade gases may use other types of connectors meeting American, British, or French specifications.. Some connectors rely upon a direct fit between the metal parts to form a seal, whereas others contain washers and/or O- rings. Many connectors are designed to be tightened by hand only, whereas others require the use of a spanner or wrench.. It is important to never over- tighten the connection, since this can weaken the joint and eventually lead to failure. O- rings and washers need to be inspected every time the cylinder is changed and replaced regularly.. Figure 4: Examples of pin-indexed cylinder valves. Pin Indexed Cylinder Valves. Source: OHYG BOC Gas Cylindersafety.pdf, p. 10. Never apply any kind of lubricant to the thread or the connected thread; with oxidizing gases this could lead to an explosion.. Do not use Teflon (PTFE) tape to seal the connector to the cylinder valve unless this is a specific requirement for the type of connector used. Most connectors do not need tape or any kind of lubricant.. Open the cylinder valve slowly. Rapidly opening the valve can damage equipment attached to the cylinder and can cause the discharged gas to re- liquefy. This liquid can cause cold burns if in contact with the skin.. Unfortunately, different specifications and standards for connectors are in use around the world. The type of fitting can vary depending on the intended use of the gas and the size of the cylinder. In the US the regulation of the connector is governed by Compressed Gas Association (CGA). For example, carbon.
# dioxide connections in the US use CGA type320 connectors (applicable for pressures up to 3000 psi). In Europe, Africa, and much of Australia and New Zealand the connectors comply with British Standard BS431 No.8 (BS 431 is interchangeable with European equivalents DIN477 No.6, SN219505 type 7, French NFE29650 type C, and Australian AS2473 type 30). Similar differences apply to nitrous oxide connectors. For example, BS341 type 13 applies to larger cylinders supplied in the UK, whereas pin- index yoke type connectors apply to smaller D and E size cylinders. In the US CGA326 threaded connections and CGA910 yoke connections can be used, but for ultra- high purity nitrous oxide, CGA712 is used. Further information on gas fittings, cylinders, and suppliers by country is given in Annex 5..
2.6.1 Specifying connector requirements. Some suppliers of cryosurgical equipment provide a complete package including an empty gas cylinder, whereas others do not. Even in those cases where a cylinder is supplied, it is necessary to confirm that the cylinder can be refilled locally. If not, it may be necessary to obtain the cylinder from a local supplier and ensure that the equipment manufacturer supplies an appropriate connector with the equipment.. - Where a cylinder has to be obtained locally, it is essential to confirm that the cylinder valve fitting is compatible with the connector supplied by the cryosurgical equipment manufacturer.- The recommended procedure is to identify which size of cylinder and which type of fitting can be obtained locally and to provide detailed specification to the cryosurgical equipment manufacturer.. Some cylinders are provided with non- removable valve shields or collars. These shields or collars may interfere with the cryosurgical device connector supplied by the equipment manufacturer.. - It is essential therefore when conferring with gas suppliers to get a full specification of the cylinder including the dimensions of any fitted shield. A photograph would certainly help.. In some circumstances it may be necessary to use an adaptor between the cylinder valve and the cryosurgical device but this should only be done as a last resort. Should it prove necessary, it is essential to check local regulations to determine whether it is permitted.. - The fitting of any adaptors should only be carried out by individuals with the necessary skills and qualifications to undertake such work.- Any adaptors should be selected with great care to make sure that they are safe to use with the gas in question, and the pressures involved.- All materials must be compatible with the gas and all fittings compatible with the device and valve assembly.. 2.7 Gas cylinder maintenance. As already pointed out, the gas in a cylinder is under high pressure and extensive damage and injury can occur if a cylinder ruptures or bursts. It is essential that cylinders are managed carefully and not subjected to excessive heat, mechanical trauma, or misuse. All cylinders should be inspected carefully on receipt to make certain that they are not damaged in any way, and inspected periodically during use. Some degree of wear and tear can be expected - for example, the paint can become scuffed and scratched. But never use a cylinder that has dents, bulges, evidence of fire damage such as scorch marks, or significant signs of corrosion. Further advice on handling cylinders is given in Chapter 3..
# 2.8 Nitrous oxide.
Nitrous oxide is available in various sizes of high pressure cylinders. The cylinders are either made from carbon steel or aluminium. Under pressure at room temperature . The smaller sizes of nitrous oxide cylinder intended for medical use are fitted with pin index yoke fittings.Larger sizes will be fitted with a BS341- Type 13 fitting or a CGA326 threaded connector.The cylinders should have a working pressure of at least 137 bar.. Nitrous oxide is an anaesthetic. It can cause asphyxiation in high concentrations and is a strong oxidizing agent, strongly supporting vigorous combustion even with materials that do not normally burn in air. Exposure to the gas causes short- term decreases in mental performance and can cause disorientation, sedation, headache, nausea, vomiting, dizziness and loss of coordination, audio and vision problems, and loss of manual dexterity. The effects are rapidly reversible, but long- term exposure can cause vitamin B12 deficiency (megaloblastic anaemia), agranulocytosis, numbness, reduced fertility, reproductive side- effects in pregnant females, and other harmful side- effects.. Misuse of nitrous oxide, including its recreational use, can be dangerous.Do not play with it. Cylinders must be stored and used in well- ventilated areas. Good ventilation is essential when . performing cryosurgery in small rooms.. The long- term exposure limit (8- hour time- weighted average (TWA)) and workplace exposure limit recommended by the UK Health and Safety Executive in EH40/2005 (as consolidated with amendments 2007) is 100 ppm. The National Institute for Occupational Safety and Health (1992) recommended exposure limit for nitrous oxide is 25 ppm as a TWA for the duration of the exposure. The American Conference of Governmental Industrial Hygienists (1994) assigned nitrous oxide a threshold limit value of 50 ppm as a TWA for a normal 8- hour workday and a 40- hour workweek..
# suppliers. Ethylene propylene diene monomer (EPDM) O- rings, washes and gaskets are, for example, recommended for use with nitrous oxide..
2.9 Carbon dioxide. Carbon dioxide is a colourless, odourless gas that can cause the nose to sting in high concentrations. It is asphyxiant and toxic in high concentrations. Exposure to carbon dioxide may cause increased respiration, headache, nausea, vomiting, mild narcotic effects, increased blood pressure, increased heart rate, and occasionally unconsciousness. It is slightly corrosive in the presence of moisture. The gas is not combustible and does not support combustion (it is used in fire extinguishers).. - Carbon dioxide is heavier than air. It can therefore collect in ducts, drains, and low-lying areas. Entering a poorly. ventilated room in which carbon dioxide cylinders have been stored is therefore potentially hazardous.. As with nitrous oxide, carbon dioxide liquefies under pressures exceeding 73.8 bar at temperatures below . - It is very important to check any carbon dioxide cylinder to make certain that it does not contain a dip tube before connecting it to cryosurgical equipment. Cylinders containing a dip tube may be marked with a white stripe. If necessary check with the supplier of the cylinder.- Carbon dioxide cylinders should be stored or used in a well-ventilated area.- All O-rings, washers and gaskets must be compatible with the gas.- Only use components recommended by the equipment suppliers. EPDM O-rings, washes and gaskets are recommended for use with carbon dioxide..
# Chapter 3. Recommendations for handling gas cylinders<sup>10</sup>.
3.1 Main hazards from gas cylinders. The main hazards from gas cylinders include:. blast impact, including flying debris, from a gas cylinder explosion or rapid release of compressed gas (cylinder pressures can be as high as 300 bar); impact from parts of gas cylinders, regulators or valves that fail; contact with released gas or fluid which might be toxic or asphyxiating; fire resulting from the escape of flammable gases; impact from falling cylinders (they are very heavy- as much as . 3.2 Main potential causes of gas cylinder accidents. The main potential causes of gas cylinder accidents include:. inadequate training and supervision; poor installation; poor examination and maintenance; faulty equipment and/or design (e.g. badly fitted valves and regulators); poor handling or storage; inadequately- ventilated working conditions; incorrect filling procedure (only use reputable companies to refill cylinders); hidden damage.. 3.3 Inspection and training. All gas cylinders must be initially inspected by a competent person before they are put into service, to ensure they conform to the approved standards.. All gas cylinders must be periodically examined at appropriate intervals to ensure that they remain safe while in service. Anyone who examines or uses a gas cylinder should be suitably trained and have the necessary skills to carry out the job safely. They should understand the risks associated with the gas cylinder and its contents. Users should be able to carry out an external visual inspection of the gas cylinder and any attachments (e.g. valves and regulators) to determine whether they are damaged. Visible indication of damage includes dents, bulges, or evidence of fire damage (scorch marks). Gas cylinder users should satisfy themselves that the cylinders have been properly tested by examining either the written certificate accompanying the gas cylinder or the stamp or mark of relevant inspection body on the gas cylinder itself. The level of control over the quality of cylinders varies from country to country. In some countries certificates may not be routinely available and cylinders may not be stamped or marked. Users should nevertheless take whatever steps they can to confirm with the suppliers that the cylinders are safe and have been subject to testing. Gas cylinders must be clearly marked to show what they contain and the hazards associated with their contents.. 3.4 Handling and use. Gas cylinders should always be used in a vertical position, unless specifically designed to be used otherwise. Gas cylinders should always be securely restrained to prevent them from falling over (for example attached to a wall by a chain or strap). Always double check that the cylinder/gas is the right one for the intended use. Do not remove or discard any batch labels fitted to the cylinder if present. Before connecting a gas cylinder to equipment or pipework, make sure that the.
# regulators and pipework are suitable for the type of gas and pressure being used.- Gas cylinders can be heavy and difficult to handle. Wear appropriate personal protective equipment (such as safety shoes, protective overalls, or gowns and protective gloves) when handling gas cylinders, and safety spectacles when using them.- Carefully clean any connector with a clean, oil- free cloth before connecting the regulatory to the cylinder valve.- Never use excessive force when connecting equipment to the cylinder.- After connecting a cylinder, check for any leaks at the cylinder valve, regulator, hose, or any other location where there is potential for leakage to occur.- Should a leak occur between the valve outlet and the connector or manifold yoke, depressurise and remove the fitting and fit an approved sealing washer. Reconnect the fitting to the valve with moderate force only, fitting a replacement regulator or manifold tailpipe as required. If the leak persists, label the cylinder as leaking and return to the company. Sealing or jointing compounds must never be used to cure a leak.- Do not use gas cylinders for any other purpose than the transport and storage of gas.- Never drop, roll, or drag cylinders.- Close the cylinder valve and replace dust caps, where provided, when a gas cylinder is not in use.- Ensure that the valve is protected by a valve cap or collar that the valve has been designed to withstand impact if the cylinder is dropped..
3.5 Lifting and transport. - Avoid the need for manual handling of gas cylinders whenever possible, for example by using cylinder trolleys.- Do not lift cylinders by their valves, shrouds or caps unless they have been designed and manufactured for this purpose.. - Gas cylinders should not be raised or lowered unless adequate precautions are taken to prevent them from falling.- Fit suitable protective valve caps and covers to cylinders, when necessary, before transporting. This helps to prevent moisture and dirt from gathering in the valve of the cylinder, in addition to providing protection during transport.- Securely stay gas cylinders to prevent them from moving or falling. This is normally in the vertical position, unless instructions for transport state otherwise.- Avoid transport on vehicles where the load space is not separated from the driver's compartment.- Disconnect devices and hoses from cylinders when not being used.. 3.6 Storage. - Gas cylinders should not be stored for excessive periods of time. Only purchase sufficient quantities of gas to cover short-term needs.- Rotate stocks of gas cylinders to ensure first in is first used.- Store gas cylinder in a dry, safe place on a flat surface in the open air. If this is not reasonably practicable, store in an adequately-ventilated building or part of a building specifically designed for this purpose.- Gas cylinders containing flammable gas should not be stored in part of a building used for other purposes.- Protect gas cylinders from external heat sources that may adversely affect their mechanical integrity. This is particularly important in hot climates.- Store gas cylinders at room temperature (i.e. between 20-30 °C [68 - 86 °F]) and away from sunlight.- Gas cylinders should be stored away from sources of ignition and other flammable materials.- Warning notices prohibiting smoking and naked lights should be posted in the cylinder storage area..
# Do not store gas cylinders containing flammable gases with cylinders containing oxidizing gases such as oxygen and nitrous oxide. Avoid storing gas cylinders so that they stand or lie in water or other liquid. Ensure the valves on empty cylinders are closed to prevent contamination entering the cylinder. Store gas cylinders securely when they are not in use. They should be properly restrained, unless designed to be freestanding. Store cylinders where they are not vulnerable to hazards caused by impact (e.g. from vehicles)..
3.7 Reference documents. Safe use of gas cylinders: Guidance issued by the Health and Safety Executive, Issue 1. London, Health and Safety Executive, June 2004. (www.hse.gov.uk). Medical Gas Data Sheet: Medical nitrous oxide, Essential safety information. BOC Healthcare Customer Service Centre, Priestley Road, Worsley, Manchester M128 2UT, UK.. Medical Gas Data Sheet: Medical carbon dioxide, Essential safety information. BOC Healthcare Customer Service Centre, Priestley Road, Worsley, Manchester M128 2UT, UK.. McIntosh N, Blumenthal P, Blouse A, eds. Cervical Cancer Prevention: Guidelines for low- resource settings. Baltimore, MD, Jhpiego Corporation, July 2000..
# Chapter 4. Procurement guidance.
This chapter provides information on procurement planning for procuring cryosurgical devices. Prioritizing and planning procurement activities upfront will avoid missed schedule milestones, the procurement of poorly specified equipment, and poor vendor relationships. These problems can cause delays and budget overruns. These are general guidelines and should be used as a complementary resource to local procurement and other regulations.. Procurement is a sequential process that includes seven major, interdependent steps, shown in Figure 6. An efficient and effective procurement procedure will include:. 1. estimating the quantities of cryosurgical equipment, spare parts and gas supplies needed and their costs;
2. defining and verifying the fitness of specifications (i.e. the physical characteristics and performance of the cryosurgical equipment to be procured), taking into account any national regulatory or registration requirements;. 3. preparing documents for competitive bidding and conducting the bidding process;
4. negotiating the details of the procurement with the selected supplier;
5. obtaining approvals and documentation;
6. completing the contract;
7. managing the supplier, delivery, and assuring quality.. 4.1 Planning. Estimating the quantities of cryosurgical equipment, spare parts, and gas supplies needed and their associated costs is a critical first step to initiating procurement actions. This step will define the scope of the procurement. Procurement processes often escalate in formality and time required depending on value and complexity. The quantity estimate is used in confirming financial considerations, procurement methods, and shipping methods..
# Consideration should be taken to calculate the number of facilities that will receive equipment and how many procedures per day will be performed. This information is important in determining the number of devices needed and the number of spare parts kits to include..
The required delivery date is also a critical piece of information that will inform when each procurement step needs to occur. The equipment should always arrive ahead of scheduled training with enough time to assemble and troubleshoot connections to gas. The procurement department will identify the amount of time needed for confirming specifications, conducting bidding, and other processes. Sufficient time should be allocated for the procurement process. Avoiding steps can lead to problems, ranging from bid protests to ordering incorrect or incomplete equipment. Transit time, customs processing, supplier manufacturing, contracting process, approval process, and negotiation should also be included in the timeline.. In some countries cryosurgical equipment may need to be approved and/or registered with the national regulatory authority as a medical device. A certificate of free sale in the country of manufacture may also be required for some recipient countries. In addition, some countries where the equipment is manufactured may required export certificates. Sufficient time and planning must be included to evaluate these regulatory needs and ensure that the manufacturers can supply all the documentation necessary to comply with local regulations where they exist. Failing to comply with this step can lead to the product being rejected or held in customs for long periods of time, and can also include severe penalties.. 4.2 Specifications. Specifications define the physical characteristics and the performance standards of the equipment to be procured. Earlier chapters provide information and guidance that can . Specifications include both minimum criteria for technical selection and optional considerations. If any area is considered optional, it must be clearly noted. Specifications must be clear and complete. When specifications are not complete, they often lead to offers that are difficult to compare and understand. In some cases, incomplete specifications can be considered an indication of a flawed procurement process and they leave the procurer open to a "protest" where suppliers can object to the final supplier selection. This creates delays and adds expense to the process. Specifications may also be used in pre- or post- shipment inspections (where applicable) and in overall acceptance of the final product.. 4.3 Competition. Competitive procurement is an accepted method in the public sector for obtaining the best value for a quality device. In most countries, the procurement of cryosurgical equipment would be conducted along with the procurement of other medical and surgical.
# devices. The processes used generally adhere to strict national requirements for bidding, including strict deadlines, evaluation by a procurement committee, and sealed bids. Local procurement regulations generally dictate the selected process and procedure; however, if cryosurgical equipment is procured through more informal methods, including those available to some vertically managed programmes, the process should ensure diligence in planning, competition to ensure a range of options, specification development, and technical evaluation of offers..
4.3.1 Requesting quotations (invitation to bid). The object of the Request for Quotation (RFQ) or Invitation to Bid is to solicit competitive offers that represent the best combination of technical and cost value. Typical orders for cryosurgical equipment will be under US$ 100 000 and can be procured using the simplified RFQ process described below. Should the procurement value be in excess of US$100 000 then a more formal process is generally required. The formal Invitation to Bid process requires an open invitation, a formal Request for Proposal document, and sealed bids, opened by a bid- opening committee on an established date and time.. The World Bank procurement guidelines offer an internationally accepted formal Invitation to Bid process<sup>11</sup>.. 4.3.2 Simplified request-for-quotation process. The RFQ communicates and establishes the technical requirements for the equipment, as well as all other criteria for awarding the final offer. It must be clear and structured, or resulting offers will lack the detail needed to evaluate the bids. At a minimum, the document should address equipment specifications, . All bids should be received sealed and only opened by the bid- opening committee at a specified time and date after the bid closing date and time. A bid analysis should be performed and documented. A template should be developed to indicate minimum technical and information requirements for the offers. This template should be developed at the same time as the RFQ and verified to ensure that the RFQ requests the required detail. Offers that do not meet the minimum requirements are rejected and only the remaining bids are reviewed for cost and other factors, such as supplier performance references, advantageous warranties, and other pre- established criteria. For a cryosurgical unit, it is appropriate to consider equipment cost, operating costs, delivery terms, warranty, and cost and availability of spare parts packages. Intangibles that would add to the assessment of each manufacturer, such as standardization with existing equipment, should also be included. All these variables should be put into a spreadsheet formatted for presentation to facilitate the analysis and support the final award.. 4.4 Negotiation. Subject to local procurement regulations, negotiation can occur once the evaluation is complete and the supplier has been selected. The ability to negotiate on the content of an offer varies depending on local procurement regulations, but is generally not allowed until after an initial selection as been made. Terms and conditions, delivery, spare parts packages, and service and warranty period are typically the areas where negotiation is considered. In some case, price may also be considered negotiable. The contract should reflect all terms included in the RFQ (noting that the procurer's standard terms and conditions should have been included), as well as any specially negotiated terms. Negotiation does.
# not occur without some level of risk. Clear and transparent documentation of any negotiation proceedings must be kept. If the negotiation takes place in a verbal meeting, minutes must be prepared. If it occurs via email, records of all negotiations must be maintained. When the procurer initiates negotiation, it is assumed at that point that the supplier may also attempt to negotiate certain terms. This should be allowed. In any case where negotiation is performed, trained procurement negotiators, attorneys, or contract specialists should always be involved..
4.5 Approval and documentation. Before releasing a final contract, all elements of the procurement process must be documented and presented for approval to the appropriate body. In most cases, procurement authorities require a system of checks and balances whereby the parties creating technical specifications and conducting bid evaluations are separate from those who review and approve the transaction. This practice safeguards against internal bias towards certain manufacturers and also ensures neutrality in reviewing the key risk elements of entering into a contract. Those who review and authorize the final transaction should be individuals within the procurement department who have the training and authority to commit their organization. The procurement process should document all steps along the way in preparation for this final step. Failing to produce documentation for a specific step in a procurement process is often assumed to imply that the step did not take place or was insufficiently managed. Returning to earlier phases to rework an element that was not properly documented or managed can create problems ranging from delays to cancelling and re- starting the entire process. Organized documentation is important in defending the decisions of the procurement authority and protects the procurer's decision in the event of any liability.. 4.6 Executing contracts. A purchase order (PO) or contract for goods and services is the final document that secures all terms and conditions of the transaction. The PO or contract is normally developed by the procurer and released to the supplier. It should represent all terms and conditions as agreed. The agreement would either be acceptance of all terms and conditions included in the RFQ, or all negotiated terms and conditions. When the PO is released, the supplier generally has a limited period (e.g. 3 working days) to accept or reject the purchase order. Rejection is rare and typically only occurs when the procurer does not accurately represent what has been agreed or adds significant terms that the supplier was not previously aware of.. Once the PO is accepted by the supplier, it represents a legally binding contract and governs the implementation of the transaction from that point forward. It is important to note that the PO governs the implementation of the transaction; however, the transaction must be actively managed to ensure compliance with the terms and conditions.. If a purchase order is altered in any way, a written amendment to the original purchase order must be created and signed by both procurer and supplier, and the documentation must be retained with other procurement documents related to the transaction. Once agreed to, any amendments are binding under the terms of the original purchase order.. 4.7 Managing the supplier delivery and assuring quality. The procurement process should build in steps to assure that the equipment will be of appropriate quality and performance when it finally arrives. POs and contracts have terms that allow them to not accept equipment that fails to meet the specifications, but avoiding such a situation is critical to maintaining timelines and avoiding extra costs. It is good practice to follow up with the supplier in advance of ship-.
# ping to ensure the agreed- upon delivery dates will be met. This will allow the receiving organization to properly plan for receipt inspection..
When necessary, equipment can be inspected prior to shipment or upon arrival in a country. This is referred to as pre- or post- shipment inspection and is conducted based on a subset of the specifications. It has limitations, but can be an effective safeguard when needed. An example of a limitation is that an inspector can confirm that contents meet the descriptions of the equipment, but they cannot test it to ensure that it meets performance standards without a specific testing protocol.. Pre- shipment factory testing is one way that many organizations assure the quality of their equipment purchases, particularly if certain tests need special test equipment that the buyer does not possess. In these cases, documentation of the test results is provided. The results are either inspected by an official inspector, or by a competent authority within the procurement agency. Verification that the documents are correct and bone fide is generally part of compliance with current Good Manufacturing Practices (cGMP). If a manufacturer is cGMP certified, the documents can be reasonably expected to be accurate and bone fide. If not, the procurer may opt to visit the factory and witness the testing or accept the documentation of the testing at their own risk.. Inspection criteria should be carefully used and developed. Excessive criteria can add costs, delays, and confusion if they are not implemented by qualified staff.. It is important to perform a comprehensive post- delivery inspection of the equipment after it is delivered to the receiving site. The inspection, which should be done immediately the equipment arrives, should document any damage or non- conformance to specifications. It should be reported immediately to the supplier and remedies should be sought.. A post- delivery inspection is a comprehensive, final inspection of the purchased equipment. The objective of the post- delivery inspection is to find any missing components, damage, or malfunctions.. Preparation for the inspection is done by developing a checklist based on the purchase order specifications. Include the equipment's original specifications in the purchase agreement. The inspection/receipt report should be documented as part of the procurement for the transaction.. If damage or problems are discovered, and the supplier cannot arrange for on- site remedy or repairs, then the equipment should be sent back to the manufacturer. If the schedule cannot accommodate the time required for the reworking, then the procurement department and the vendor will need to negotiate financial reparations or replacement. Payment for the shipment should only be made after the shipment has passed all inspections.. It is also important to track supplier's schedule and quality performance over time. Poorly- performing suppliers should be advised that expectations of their performance have not been met. Performance levels can also become evaluation criteria when considering future business.. Procurement is a crucial process. It ensures good stewardship of funds and supports quality medical care when medical equipment or supplies are involved. An appropriate and well- managed procurement process can take time and resources. The consequences of a poorly- managed procurement process can be devastating to programmes, ranging from delays to irreplaceable losses of limited funding. Procurement professionals are trained to work in conjunction with legal, financial, and technical departments. They work to coordinate a process that protects public funds and ensures the best possible results for those ultimately seeking health services that depend on supplies and equipment..
# Annex 1. Glossary of terms.
Active defrost - a mechanism within some cryosystems that accelerates the return of the cryotip towards ambient temperature.. Cryotip - an interchangeable tip designed to fit a specific anatomical site (cervix) for the purpose of freezing the tissue. A closed cryotip will not vent gas or cryogen in the vicinity of the tissue. An open cryotip directly jets the gas or cryogen onto the tissue and is not appropriate for use in treating cervical lesions.. Compressed gas cylinder - a container that is specifically designed to store a gas or liquid under elevated pressure conditions.. Compressed gas cylinder valve - a device specifically designed to receive a connector to the cryosystem. It is pre- attached to a gas cylinder to allow for the proper and safe release of its contents.. Connector to the cryosystem - the fitting between the compressed gas cylinder valve that connects the tank to the cryosystem.. Connection adapter - an extension placed between the compressed gas cylinder valve and the connector to the cryosystem, which is used in cases where there is mismatch between the valve tip and connector to the cryosystem, including the valve being too short, the wrong threading etc.. Cryo- adhesion - cryotip attachment to target tissue.. Cryogen - a substance, such as compressed gas or liquid, used to obtain reduced temperatures. Cryogens are usually classed by their boiling points and their grade. The most common cryogens for precancerous cervical lesions and their respective boiling points are as follows:. Cryonecrosis - destruction of tissue cells using cryogen (see clinical references for additional detail).. Cryoshaft - the component onto which the cryotip is attached. The cryoshaft may be detachable or fixed, and should be thermally insulated.. Cryosystem - collectively, all parts of system necessary to apply cryogen therapeutically, for the treatment of cervical precancer. It excludes the gas and its tank, the compressed gas cylinder valve, and the adaptor.. Defrost - the function of the cryosystem which allows the cryotip to return toward ambient temperature.. EPDM - ethylene propylene diene monomer rubber.. Exhaust hose - a hose that returns the exhaust gas from the cryogun to the regulator assembly for venting.. Exhaust port vent - the vent to which a tube can be attached to safely vent the exhaust gas from the room.. Gasket - a round, flat plastic or rubber ring (that looks like a washer) which is usually placed between the connector to the cryosystem and the compressed gas cylinder valve.. Handle - the part of the cryosystem that is gripped in the hand and that includes the trigger mechanism.. Hose assembly - polymer tubes that carry the cryogen from the regulator to the handle. In cryosystems, it is common to have an assembly in which there may be tubes inside a main hose.. Mechanical integrity - the ability of all components of a cryosystem to withstand the pressures and temperatures that may be encountered during use as recommended by the manufacturer.. Notified Body - in relation to medical devices, an organization authorized by a Competent.
# Authority of a European Member State to determine whether a medical device meets the essential requirements of the European Medical Device Directive..
O- ring - a ring of rubber or silicon usually inserted between the cryotip and the cryoshaft to ensure an effective seal to avoid leaking.. Passive defrost - a function of a cryosystem (without active defrost) to return towards ambient temperature. Passive defrost is typically a slower process of defrosting the cryotip than active defrost.. Regulator - a device for maintaining a constant gas pressure. Note that most cryosurgical devices are not equipped with a regulator.. Rupture disc - see safety valve.. Safety valve - a valve, usually a rupture disc, to release excessive pressure in the system. Can also be called a pressure relief valve.. Single- use disposable - any device which is designed to be discarded after one use.. Target tissue - the specific anatomical area of the cervix intended to be treated.. Thermal insulation - a material used to prevent unintended cryonecrosis, inflammatory responses, or cryo- adhesion to non- target tissues.. Thermocouple - a junction of two dissimilar metals that produce an output voltage proportional to the temperature of the junction. The output is directly correlated to the temperature to which the sensing junction is exposed.. Tractive force - the level of attraction between the cryotip and the target tissue during cryo- adhesion, i.e. when the tip freezes to the tissue.. Trigger mechanism - the mechanism that is activated (or squeezed, pressed, or pushed) to release the cryogen into the cryotip. Cryo- systems may also include triggers for active defrosting.. US FDA - United States Food and Drug Administration, an agency within the U.S. Department of Health and Human Services that protects public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products, medical devices, the food supply, cosmetics, dietary supplements, and products that give off radiation.. Washer - see gasket..
# Annex 2. Technical Basis Paper: Cryosurgical equipment for the treatment of precancerous cervical lesions.
A1 Introduction and scope. This technical basis paper reviews the types of cryosurgical equipment that are available and discusses some of the key issues in acquiring and using the equipment in low- resource countries. It is intended to summarize the technical discussions undertaken by the WHO Cryotherapy Technical Specification Working Group and provide background information supporting the recommendations made in the Cryotherapy Technical Specifications and Procurement Guidelines. It is not intended for circulation to users of the equipment, but to provide a record for future reference of the issues discussed and rationale for the recommendations made.. A1.1 Research methods. The paper is based on a literature search for information on cryosurgical equipment conducted online using the NML Gateway (a service of the US National Institutes of Health) which accesses multiple retrieval systems including MEDLINE/PubMed.. Information related to cryosurgical devices and equipment has also been collated from the following sources:. - The 2008 WHO/UNFPA/PATH Cryotherapy Market Survey.- Bench testing of four cryosurgical devices with nitrous oxide and carbon dioxide in Peru in 2009.- Discussion held by the Technical Specifications working group during the March 30-April 1, 2009: Building a consensus on approaches to improving cryotherapy service delivery to prevent cervical cancer.- Meeting on Procurement of Cryotherapy Equipment for Cervical Cancer Prevention. September 23rd and 24th, 2010.. A1.2 Cryosurgical equipment. Cryosurgical equipment is available from a number of manufacturers, mainly US- based but with some types available from European and. Indian manufacturers. The equipment is used to treat a wide range of medical conditions in dermatology, ophthalmology, gynaecology, and other disciplines. Not all cryosurgical equipment is suitable for the treatment of precancerous cervical lesions.. Two main methods are used to cool the cryoprobe: the expansion of a compressed gas through a nozzle, causing cooling by the Joule- Thomson effect; and the use of cryogenic liquids such as liquid nitrogen. Because of the risk of damaging surrounding tissue, cryosurgical equipment based on cryogenic liquids is never used in the treatment of precancerous cervical lesions. Additionally, the availability, transport, delivery, storage, and handling of liquid nitrogen can be problematic in low- resource countries. For these reasons this paper only considers cryosurgical equipment that operates on compressed gases such as nitrous oxide and carbon dioxide.. Both nitrous oxide and carbon dioxide have high Joule- Thomson coefficients making them good gases for this purpose. Most cryosurgical equipment manufacturers offer the option of carbon dioxide or nitrous oxide. The choice of gas has to be made at the time of purchase of the equipment to ensure the proper fittings, and in some cases the appropriate device. In low- resource settings carbon dioxide is often cheaper and more readily available.. The recommended temperature most widely cited in the literature for treating precancerous cervical lesions is .
# that the equipment is capable of achieving tip temperatures of .
Examples of some of the main suppliers that have been identified through internet searches are given in Table A1.. A1.3 Description of a typical cryosurgical unit. A typical cryosurgical unit consists of a hand unit with a shaft to which detachable probe tips can be attached. The hand unit is fitted with one or more triggers and other controls to regulate the temperature and control the freezing/thaw cycle. It is designed such that the controls can be used with just one hand. Some models are fitted with temperature sensors to indicate . The hand unit is attached to a pressure gauge assembly that conducts the high pressure gas to the unit and returns waste gas to be vented.. A1.4 Cryotips. Most manufacturers offer a wide range of interchangeable cryosurgical probe tips (cryotips). These are interchangeable and can be cleaned and disinfected between patients. In some cases the cryotips can be changed without depressurising the system. Some cryotips can be autoclaved whereas others can only be disinfected by treatment with chemical disinfectants. The manufacturers' instruction must.
# be followed when determining the cleaning and disinfection cycle for any probe type..
Only closed cryotips can be used for treating cervical lesions. Open cryotips apply the cryogen directly to the target tissue and must not be used for treating cervical lesions because of the risk of damage to surrounding healthy tissue.. The cryotips are usually made from surgical- grade interchangeable metal fittings. Some designs are covered with a plastic sleeve which is removable for cleaning. Based on an assessment of the type and duration of exposure to the cryotips according to ISO 10993- 1 (2009), Biological evaluation of medical devices, it is recommended that the cryotips should be assessed by the manufacturers for cytotoxicity, irritation, and sensitization potential. If medical- grade materials are used for the cryotips, then actual testing may not be necessary. Cryotips with a well- established history of safe use also do not need to be subjected to testing according to ISO 10993- 1.. The cryotip must be removable to allow interchangeable tips to be used and to facilitate cleaning and disinfection after use. In some configurations, the cryotip attaches to the probe shaft with internally threaded surfaces inside the metal tube. Other configurations combine the probe shaft and the cryotip. These are detachable at the base of the probe. Both configurations provide the same intended result and there are no technical reasons to select one over the other, although detachable cryotips may be easier to sterilize by boiling or autoclaving.. Cryotips used for treating precancerous cervical lesions should be rounded in shape and be 19 mm in diameter .
# The surface of the cryotip should be smooth with no sharp edges. The material should withstand routine sterilization or disinfecting with hospital disinfectants. It is recommended that the manufacturers' recommendations for cleaning and disinfection are followed. Not all cryotips can be autoclaved or disinfected with some hospital disinfectants..
A1.5 Cryoshaft. The cryoshaft connects the cryotip to the trigger unit. It does not have a required minimum or maximum length but typically the overall length of the cryoshaft and cryotip assembly should be between . The materials used for its construction must be able to withstand routine sterilization or disinfecting with hospital disinfectants, including bleach dilutions or any other disinfectant for surgical instruments.. A1.6 Trigger mechanism. The hand unit should have an integrated trigger or other mechanism to activate the flow of gas. The trigger mechanism should be designed to give the user sensory feedback indicating whether the device is in the on or off position. There should be a latching or ratchet mechanism allowing the user to lock the trigger in the on position. The trigger must also have a release mechanism to unlock the trigger and return the device to the off position.. The trigger mechanism activates the internal valves and switches required to deliver the gas from the attached hose though the gas delivery tube to the cryotip and exhaust gas.
# back through the exhaust tube. The trigger mechanism unit should be made of rigid plastic, of a type and grade that will insulate the hand of the user while providing durability..
The material must withstand routine sterilization or disinfecting with hospital disinfectants, including bleach dilutions or any other disinfectant for surgical instruments. The handle should be of a design that allows the user to hold and control the device in one hand, either the left or the right.. Active defrosting mechanisms may or may not be incorporated into the operation of the unit. If an active defrosting option is included, it may be integrated into the trigger function or the handle. Both active and passive defrost systems are acceptable. Whatever system is used, it must be capable of being operated by one hand.. A1.7 Hose assembly. The hose assembly connects the trigger mechanism to the gas supply, both delivering the gas and venting the exhaust gas. The hose assembly should be of sufficient length for comfortable operation while the tank is appropriately secured to a nearby wall or safe portable stand. A minimum of . The hose connection should be integrated into the handle and not designed for removal by the user. The other end of the hose should securely connect to the pressure gauge. The hose assembly should be capable of being pressured to at least twice the maximum cylinder pressure13(ca 2,000 psi).Ideally, hoses complying with the requirements specified . Due to the constant flexing, pressure, and movement during use, the hose assembly should be checked periodically for and signs of damage including leaks or cracks. If damaged, cracked or leaking, the hose assembly must be replaced with replacement part provided by the manufacturer. Most manufactures supply a step- by- step instruction on how to replace the hose assembly.. A1.8 Pressure gauge. The pressure gauge is a visual indicator of the pressure in the tank and should clearly indicate whether the gas pressure is within the appropriate range (minimum to maximum) for the device to function properly. For many cryosurgical devices, the pressure gauges are colour- coded to indicate the safe operational range.. A1.9 Pressure relief valve. The pressure relief valve is designed to protect the device and the user from potential excessive tank pressure. It typically works by having an internal rupture disc which bursts at a set pressure, preventing the device from becoming over- pressurized. The pressure relief valve should be designed to rupture if the maximum pressure rating of the pressure gage, the hose assembly, or the trigger mechanism is reached. Once triggered, the relief valve will completely empty the cylinder.. A1.10 Exhaust port. Since both carbon dioxide and nitrous oxide can be hazardous, cryosurgical units should have an exhaust port that allows the operator to attach a hose to vent the exhaust to a place with adequate air circulation.. A1.11 Gas connector. The gas connector connects the cryosurgical system to the compressed gas cylinder..
# It should be made of metal and should be appropriate for use with pressurized gases, specifically with carbon dioxide and nitrous oxide. There are multiple types of connectors (compressed gas cylinder valves vary from country to country). It is essential that the proper connector is used with the compressed gas cylinder valve. More information on gas fittings and gas supplies are given later in this document and in the document on gas supplies..
A1.12 Performance and Safety Standards. Ideally cryosurgical systems should conform to appropriate standards such as F882- 84 (reapproved 2002) Standard Performance and Safety Specification for Cryosurgical Medical Instruments. This specification covers standards a manufacturer must meet in the designing, manufacturing, testing, labelling, and documenting of cryosurgical medical instruments, but does not cover factors such as production methods, quality control techniques, manufacturer's lot release criteria, or clinical recommendations.. A1.13 Training. All equipment should be fit for the intended purpose of treating precancerous cervical lesions. Each unit should be accompanied by training materials specifying basic operation of all components, assembling the equipment, risks of use, and maintenance.. A1.14 Spare parts. It is imperative that spare parts such as the hose assembly, cryotips and cryoshafts be purchased from the original equipment manufacturer. Due to varying design, replacement parts from other manufactures are not acceptable replacements. Similar comments apply to parts that require inspection and replacement on a regular basis. These include O- rings and sealing washers. A supply of these components should be purchased with and maintained with the equipment.. A2. Bench testing of cryosurgical devices and equipment. Bench testing was conducted in Peru using four different makes of cryosurgical devices and locally obtained nitrous oxide and medical- and industrial- grade carbon dioxide. The temperatures reached by each device when used with each gas were compared using a thermocouple to continuously monitor the temperature of the cryotip. Comparisons across the devices were based on the mean and lowest temperatures reached. The study found that all of the devices tested reached temperatures below . One- way analysis of variance identified the device as the dominant factor determining the differences in temperature, whereas the gas was not a significant determinant of temperature reached. The study concluded that both nitrous oxide and medical- and industrial- grade carbon dioxide reach appropriate freezing temperatures with some cryosurgical devices and that performance of some cryosurgical devices is suboptimal. Given that carbon dioxide is likely to be the preferred gas in low- resource countries since it is generally more readily available and cheaper, the outcome of this study suggest that the choice of a device that can reach the recommended temperature of . A3. Recommendations on gas supplies. A full review of gas supplies for cryosurgical equipment has been completed separately. This includes advice on the selection, procurement, storage and handling of the gas cylinders (See Chapter 2 and 3). Both carbon dioxide and nitrous oxide are liquid at the typical pressures.
# found in commercial gas cylinders. This significantly increases the capacity of gas that can be stored in an equivalent- sized cylinder compared to the amount of a gas that does not liquefy under normal cylinder pressure..
Carbon dioxide and nitrous oxide can be obtained in a number of different purity grades and in a wide variety of cylinder sizes. In general, the purer the grade the less likely is the risk of the cryosurgical equipment becoming clogged during use. For this reason medical- grade gases are preferred, with food/beverage grades being acceptable as an alternative.. Cylinders are available in a wide range of sizes. The size of gas cylinders can be specified by a letter code, by the water capacity expressed in pounds, by internal volume, or by the volume of gas at normal pressure and temperature contained in the cylinder. Common sizes for European medical gas cylinders<sup>14</sup> are size C containing . The number of cryosurgical sessions per cylinder will clearly depend upon the size of the cylinder, the type of equipment used and the duration of the procedure. Walach, in their sales literature, state that the LL100 Cryosurgical System using a 20 lb nitrous oxide cylinder should provide approximately 80 minutes of use, i.e. sufficient for about 20 precancerous cervical lesion treatments. Practical experience, however, suggests that the number of treatments per 20 lb cylinder can vary widely ranging from as few as two full treatments per 20 lb cylinder to over 20 treatments. Local temperature conditions and the filling policies of local gas suppliers may have a significant impact on . A3.1 Specifying connector requirements. A major potential problem in using cryosurgical equipment in low- resource settings is ensuring that the fitting on the equipment matches the fitting on the gas cylinder. Different standards apply to gas cylinder connectors in different countries. To prevent accidental use of the wrong gas, cylinder fittings are deliberately designed differently for different gases. Additionally, the type of fitting can change depending upon the grade of gas and the size of the cylinder. All of these factors complicate the purchase and use of cryosurgery in low- resource settings where the availability of gas cylinder fittings may be different to that in the country where the equipment is manufactured. Guidance on the choice of the correct fitting is provided in the document on gas supplies for cryosurgical equipment (See Annex 5).. A3.2 Gas safety. Both carbon dioxide and nitrous oxide can be hazardous if leaks occur or the exhaust from the cryosurgical unit is not vented properly. Additionally, the gas cylinders are under high pressure and can be hazardous in their own right. Appropriate precautions for working with the gases and handling the cylinders are given in Chapters 2 and 3.. A4. Operational procedures. Cryosurgical treatment is a medical procedure that should only be performed by trained clinical providers. Appropriate clinical training should be provided in advance of using the equipment.. Clinical guidelines on the use of cryosurgical equipment are available in the WHO guidelines on cryotherapy (Annex 3)..
# General guidelines on the operation of cryosurgical equipment in the treatment of precancerous cervical lesions are given in the Jhpeigo Cervical Cancer Prevention Guidelines for Low- Resource Settings<sup>15</sup>. The guidelines are based on the Wallach LL100 cryotherapy system but nevertheless can be generalized to most equipment types. The general steps required to set up, test, use, clean, and troubleshoot the equipment are described. When using equipment from other manufacturers, however, reference must be made to the manufacturer's own instructions for specific guidelines on setting up, testing, using, cleaning, disinfecting and troubleshooting the equipment..
The guidelines recommend that when using carbon dioxide, the risk of the unit becoming blocked by ice particles can be reduced by using the freeze- clear- freeze technique. Basically this consists of beginning the freeze cycle for 15 seconds and then very briefly pressing the defrost trigger for a second or less before reapplying freezing. This cycle is repeated through the whole of the freezing procedure. This procedure is also known as the cough technique.. Seamans et al<sup>16</sup> demonstrated, however, that when using the cough technique with the Wallach LL100 cryotherapy system (with a T- 2500 2.5 cm diameter flat probe) the minimum tissue temperatures achieved using either nitrous oxide or carbon dioxide were greater than the . Winkler et al<sup>17</sup> reported very similar results, again using the Wallach LL100 cryotherapy system. The temperature of the cryotip did not drop below . In an attempt to overcome blockages due to icing, Seamans et al.<sup>18</sup> reported on the use of a gas conditioner to filter and dry the gas before it enters the cryogun. The conditioner was placed in the in the gas supply line between the cylinder and the Cryogun. It contained a commercial calcium sulphate laboratory desiccant, Drierite (W. A. Hammond Drierite Co. Ltd, Xenia, Ohio). The authors concluded that the gas conditioner showed promise in reducing the incidence of blocking, but it has not yet been made commercially available. Follow up work by Winkler et al.<sup>19</sup>, however, showed that the device only helped with the Wallach LL100,.
# which as stated in the previous paragraph has since been recalled and modified. Using the conditioner with other makes of cryosurgical equipment led to increased tip temperatures. The use of a gas conditioner is therefore not recommended..
A5. Cleaning and disinfection. The cryosurgical unit, cryoshaft and cryotip will all require cleaning and disinfection between patients. Disinfection can present a major problem in low- resource countries. WHO recommends that a solution of sodium hypochlorite with . When cleaning equipment without a detachable cryoshaft, special care has to be taken to prevent damage to the hand unit. Such units cannot, for example, be immersed in disinfectant.. Alternative chemical disinfection options are severely limited. Treatment with . Other options for disinfecting the cryotips include boiling or steaming to 20 minutes, autoclaving at . Whatever methods of cleaning and disinfection are used, it is essential that the manufacturers' instructions are followed, otherwise the cryotips could be damaged. Not all manufacturers make cryotips that can be heated or autoclaved and some might be damaged by the chemicals that are used. Read the manufacturers' instructions before use..
# Annex 3. WHO guidelines on cryotherapy.
PS 12: Cryotherapy. PRACTICE SHEET 12: CRYOTHERAPY. Cryotherapy is the freezing of the abnormal areas of the cervix by the application of a very cold disc to them. It takes only a few minutes and usually only causes some cramping.. The following materials and equipment are needed for cryotherapy:. speculum, high- level disinfected (it need not be sterile); disposable or high- level disinfected examination gloves (need not be sterile); cotton swabs for wiping the cervix; normal saline solution; colposcope, if used in the particular venue; cryosurgery unit with adequate gas supply (Figure PS12.1).. For basic equipment to perform a pelvic examination refer to PS7.. Source: Sellors JW, Sankaranarayanan R. Colposcopy and treatment of cervical intraepithelial neoplasia: a beginners' manual. Lyon, IARCPress, 2002..
# PERFORMING CRYOTHERAPY.
Before the procedure. 1. Explain the procedure, and why it is important to return for further management as requested. Ensure that the woman has understood and obtain informed consent.. PS6 Informed consent PS7 Pelvic exam. 2. Show her the cryotherapy equipment and explain how you will use it to freeze the abnormal areas on the cervix.. 3. Prepare the patient for a gynaecological examination, and perform a speculum examination (see Practice Sheet 7).. 4. If there is no evidence of infection, proceed with cryotherapy.. 5. If there is a cervical infection, provide treatment as described in Annex 8. You may proceed with the cryotherapy, or you may give the patient an appointment to return once the infection is cured.. Procedure. 6. Wipe the cervix with a saline-soaked cotton swab and wait a few minutes.
7. Apply acetic acid to outline the abnormality and wait a further few minutes.
8. Tell the woman she might feel some discomfort or cramping while you are freezing the cervix.
9. Wipe the cryoprobe surface with saline to ensure optimum effectiveness.
10. Apply the cryoprobe tip in the centre of the os and make sure the probe adequately covers the lesion (Figure PS12.2). If the lesion extends more than 2 mm beyond the probe, discontinue the procedure. Explain to the woman why you are doing this and what needs to be done for her as an alternative.
11. Ensure that the vaginal wall is not in contact with the cryoprobe or you may cause a freezing injury to the vagina.
12. Set the timer and release the gas trigger to cool the probe.
13. You will observe the ice forming on the tip of the cryoprobe and on the cervix (Figure PS12.2). When the frozen area extends 4-5 mm beyond the edge of the cryoprobe, freezing is adequate..
# Figure PS12.2 Position of cryoprobe on the cervix and ice forming.
14. Allow two cycles of freezing and thawing: 3 minutes freezing, followed by 5 minutes thawing, followed by a further 3 minutes freezing.
15. Once the second freezing is complete, allow time for thawing before attempting to remove the probe from the cervix. Removing it before it is fully thawed will pull tissue off the cervix.
16. Gently rotate the probe on the cervix to remove it. The area you have frozen will appear white.
17. Examine the cervix for bleeding. If bleeding is noted, apply Monsel's paste.
18. Do not pack the vagina.
19. Remove the speculum.. After the procedure. 20. Provide a sanitary pad.. 21. Instruct the woman to abstain from intercourse and not to use vaginal tampons for 4 weeks, until the discharge stops completely. This to avoid infection.. 22. Provide condoms for use if she cannot abstain from intercourse as instructed. Teach her how to use them.. 23. Invite her to return in 2-6 weeks to be checked for healing, and again in 6 months for a repeat Pap smear and possible colposcopy..
# 24. inform her of possible complications and ask her to return immediately if she notes:.
a. fever with temperature higher than . 25. Clean and disinfect the cryoprobe and decontaminate the cryogun, tubing, pressure gauge and gas tank:17. a. Decontaminate the cryotherapy unit, hose and regulator by wiping them with alcohol.
b. Wash the cryotip and the plastic sleeve with soap and water until visibly clean.
c. Rinse the cryotip and plastic sleeve thoroughly with clean water.
d. High-level disinfect (HLD) the cryotip and plastic sleeve by one of the following methods: - boil in water for 20 minutes; or - steam for 20 minutes; or - soak in chemical disinfectant (0.1% chlorine solution or 2-4% glutaral) for 20 minutes and then rinse with boiled water.. e. It is critical that the hollow part of the cryotip is completely dry when next used, otherwise the water will freeze and the probe could crack or the treatment not work.. f. Either use a rubber cap to seal off the hollow part of the cryoprobe during processing, or thoroughly dry the cryoprobe before it is reused.. g. If none of the high-level disinfection options are available, the cryotip and sleeve may be disinfected by soaking in 70-90% ethanol or isopropanol for 20 minutes. Allow to air-dry and then reassemble.. Follow-up. 26. Perform a pelvic examination to check for healing 2-6 weeks after the cryotherapy.. Flowchart precancer. 27. At 6 and 12 months, do a Pap test and a colposcopy and take a biopsy if necessary. Follow up as described in Annex 5..
# Annex 4. WHO universal precautions for infection prevention.
Annex 1: Universal precautions for infection prevention. ANNEX 1: UNIVERSAL PRECAUTIONS FOR INFECTION PREVENTION24. Universal precautions are simple measures that help prevent the spread of infection. All health care providers must use universal precautions to protect patients, themselves and other health care workers from the spread of infectious diseases.. The current epidemic spread of bloodborne viruses, including hepatitis B, C and D, and HIV, underscores the importance of paying scrupulous attention to preventing infection in clinical practice. Many transmissible infections are asymptomatic, and it is not always possible to know who is infected. Therefore, precautions against spreading infection should be used with all patients, whether they appear sick or well, and whether their HIV or other infection status is known or not.. Quality control and supervision are essential to ensure that infections are prevented. A pelvic infection after a clinical procedure is an indicator of poor infection- prevention measures.. Infection prevention: universal precautions. Wear latex gloves whenever:. - you handle items or body surfaces that might be contaminated;- you perform clinical examinations or procedures (cryotherapy, biopsy, endocervical curettage and LEEP), or give injections;- you clean the area where the patient has been;- you handle used instruments.. Remember:. - If gloves get damaged, remove them, wash your hands thoroughly, and then put on new gloves.- Gloves are not a substitute for handwashing.. Wash your hands with soap and water for at least 30 seconds:. - before and after contact with each client or patient;- if you touch blood or body fluids;- immediately after you take off latex gloves..
# Handle contaminated disposable items and clinic surfaces as follows:.
Discard disposable items that are soiled with blood or body fluids in a tightly sealed plastic bag. Disposable needles need special handling; use your health facility's protocols. Wash linen and reusable cloth items. Use detergent, dry them in the sun, and iron them if possible. Clean and disinfect surfaces such as examination tables and floors.. Process reusable instruments and gloves after each use, as follows:. All instruments that have been in contact with the vagina or cervix (e.g. specula, biopsy forceps, gloves, etc.) should be decontaminated, cleaned, and sterilized or high- level disinfected. Cryoprobes should be decontaminated, cleaned, and high- level disinfected. The examination or procedure table must be decontaminated after each patient. Other instruments (e.g. colposcope, cryogun, torch lights) must be decontaminated at least once a day, and more often if visibly soiled.. Processing instruments25. There are three basic steps for processing instruments used in clinical and surgical procedures, before they can be reused: (1) decontamination, (2) cleaning, and (3) sterilization or high- level disinfection (HLD).. Decontamination. Decontamination is the process by which used instruments and gloves are made safe for handling; this step inactivates hepatitis B and HIV. To decontaminate instruments and gloves immediately after use, immerse them in a large plastic bucket containing . Cleaning. Soon after decontamination, instruments should be cleaned by a person wearing heavy gloves and glasses or goggles. Use a brush to scrub instruments with water and detergent, and rinse thoroughly with boiled water. Special attention must be given to instruments with teeth, joints and screws..
# Sterilization.
Sterilization Sterilization destroys all microorganisms and must be used for all instruments that come into contact with sterile parts of the body, e.g. that penetrate the skin or enter the womb.. Sterilization can be achieved by one of the following:. Expose instruments to superheated steam in an autoclave: 20 minutes for unwrapped instruments and 30 minutes for wrapped instruments. Autoclaving is the preferred method of sterilization. Soak instruments in either . High-level disinfection. HLD destroys all organisms except bacterial spores, and is used when sterilization equipment is not available or the instrument is too delicate to be sterilized. One of the following processes can be used for HLD:. Boil instruments for at least 20 minutes in plain tapwater, which is changed at least daily. Make sure that instruments are fully covered by the water, and start timing after the water with the instruments is fully boiling. Do not add anything to the pot once you have started to time. Soak instruments in . Supplies and equipment. The following supplies and equipment are needed for infection prevention (depending on the processing methods used):. clean and boiled water; detergent; household bleach or commercial chlorine powder; one or more sterilizing chemicals (2- 4% glutaral, 8% formaldehyde); one or more HLD chemicals (0.1% chlorine, 2% glutaral, 6% hydrogen peroxide); 60- 90% ethanol or isopropanol; sterile clothes; plastic bucket,. (continued next page).
# scrubbing brush; large jars for storage of solutions; heavy gloves for cleaning; sterile or high- level disinfected gloves and long- handled forceps for handling processed instruments; autoclave or vessels for boiling and soaking instruments; closet with light closure to prevent entrance of dust, for storage of processed instruments and supplies..
#
#
# Additional information on gas suppliers.
The following companies supply gases, including medical- grade carbon dioxide, and have local distribution centres around the world:. Linde AG: gas.de/international/web/lg/de/like35lgde.nsf/docbyalias/homepage. Messer: . Tyczka: . Praxair: .
# .
# For more information, please contact: Department of Reproductive Health and Research World Health Organization Avenue Appia 20, CH- 1211 Geneva 27, Switzerland Fax: +41 22 791 4171 E- mail: reproductivehealth@who.int www.who.int/reproductivehealth.
|
None
|
None
|
None
|
7deade3b54c74cf4bf972c5b708fb825
|
2022+JASTRO共识指南
|
妇科癌症腔内和间质联合近距离放射治疗
|
# Japanese Society for Radiation Oncology Consensus Guidelines of combined intracavitary and interstitial brachytherapy for gynecological cancers.
Naoya Murakami<sup>1</sup>, Tatsuya Ohno<sup>2,3,*</sup>, Takafumi Toita<sup>4</sup>, Ken Ando<sup>2</sup>, Noriko Ii<sup>5</sup>, Hiroyuki Okamoto<sup>6</sup>, Toru Kojima<sup>7</sup>, Kayoko Tsujino<sup>8</sup>, Koji Masui<sup>9</sup>, Ken Yoshida<sup>10</sup> and Hitoshi Ikushima<sup>11</sup>. <sup>1</sup>Department of Radiation Oncology, National Cancer Center Hospital, Tokyo 104- 0045, Japan <sup>2</sup>Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma 371- 8511, Japan <sup>3</sup>Gunma University Heavy Ion Medical Center, 3- 39- 22 Showa- machi, Maebashi 371- 8511, Japan <sup>4</sup>Radiation Therapy Center, Okinawa Chubu Hospital, Okinawa 904- 2293, Japan <sup>5</sup>Department of Radiation Oncology, Ise Red Cross Hospital, Mie 516- 8512, Japan <sup>6</sup>Radiation Safety and Quality Assurance Division, National Cancer Center Hospital, Tokyo 104- 0045, Japan <sup>7</sup>Department of Radiation Oncology, Saitama Cancer Center, Saitama 362- 0806, Japan <sup>8</sup>Department of Radiation Oncology, Hyogo Cancer Center, Hyogo 673- 8558, Japan <sup>9</sup>Department of Radiology, Kyoto Prefectural University of Medicine, Kyoto 602- 8566, Japan <sup>10</sup>Institute of Radiology, Kansai Medical University Medical Center, Osaka 573- 1191, Japan <sup>11</sup>Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770- 8503, Japan *Corresponding author. Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma 371- 8511, Japan. tohno@gunma- u.ac.jp (Received 12 December 2021; revised 25 January 2022; editorial decision 23 February 2022). ABSTRACT. It has been postulated that the combination of intracavitary and interstitial brachytherapy (IC/IS) is effective and safe for large and irregularly shaped uterine cervical cancer patients. However, due to its invasiveness compared to conventional intracavitary brachytherapy (ICBT), it has to be said that the implementation speed of IC/IS is slow. Until now, there have been no guidelines for required equipment, human resources, and procedural guide focusing solely on IC/IS. The purpose of this guideline is to provide radiation oncologists and medical physicists who wish to start IC/IS with practical and comprehensive guidance for a safe IC/IS introduction and to help accelerate the spread of the utilization of IC/IS nationwide. This is the English translation of the Japanese IC/IS Guidelines, and it was created in an effort to share the Japanese approach to the management of locally advanced uterine cervical cancer worldwide.. Keywords: JASTRO Guidelines; intracavitary and interstitial brachytherapy (IC/IS); cervical cancer; brachytherapy; consensus guidelines; gynecologic cancers. INTRODUCTION. In the management of uterine cervical cancer with primary radiotherapy, brachytherapy plays a central role that cannot be replaced by other treatment modalities [1]. The point A prescription calculated by orthogonal 2D X- ray images based on the Manchester method became the standard method, and favorable clinical results have been reported [2]. This 2D treatment plan was summarized in detail in the Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee' published by the Japanese Brachytherapy Society of the Japanese Society for Radiation. Oncology (JASTRO) in 2013 [3], and has greatly contributed to the standardization and equalization of 2D- based intracavitary brachytherapy (ICBT) for cervical cancer. However, point A was not based on the individual tumor morphology. As a result, 2D methods cannot control a large or irregularly shaped tumor. Additionally, dose evaluation of organs at risk (OARs) had not been adequately performed, and only the point dose evaluation had been performed.. Since 2000, 3D image- guided brachytherapy (3D- IGBT) has been introduced in which dose calculation has been performed based on 3D images such as magnetic resonance images (MRI) or.
# computed tomography (CT) with intra- uterine/vagina brachytherapy applicators in place [4]. In 3D- IGBT, clinical target volume (CTV) and OARs were delineated, and dose prescription and/or evaluation have been performed based on dose- volume histograms (DVHs). The 3D- IGBT has been rapidly and widely adopted also in Japan, with accumulating reports indicating that it not only enhanced local control but also decreased late toxicities when compared to the 2D era [4, 5]. The Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee' published in 2013 provided details on standard techniques and dose calculation for 3D- IGBT in cervical cancer [6]. In 2018, the Guidelines for the Introduction of Image- Guided Brachytherapy In .
On the other hand, even with the use of 3D- IGBT, it has been elucidated that it is difficult to deliver an adequate tumoricidal dose while sparing surrounding DARs for bulky or irregularly shaped tumors. For such tumors, it is obvious that multi- catheter interstitial brachytherapy (MC- ISBT) should be appropriate due to the superior dose coverage and conformity compared to conventional ICBT. However, because MC- ISBT is highly invasive and requires expertise, the widespread use of this method has been limited. In such circumstances, combined intracavitary and interstitial brachytherapy (IC/IS BT) has been introduced to compensate for the disadvantage of ICBT while integrating the benefits of MC- ISBT. In IC/IS, additional interstitial needles are inserted into the area that cannot be adequately covered by the conventional ICBT, and increasing the ratio of CTV covered by the prescribed dose can be achieved while sparing OARs. IC/IS has also been gradually adopted in several Japanese hospitals, and favorable clinical outcomes have been reported not only from Western countries but also from Japanese hospitals [5, 8, 9]. This method can be adopted not only for cervical cancer but also for other gynecologic malignancies such as endometrioid carcinoma or vaginal cancer, and international recommendations advocate applying IC/IS for selective other gynecologic malignancies [10- 13].. Although IC/IS is less invasive compared to MC- ISBT, several interstitial needles are used. Therefore, appropriate preparation and additional attention should be paid to avoid adverse events related to needle insertion. In addition, extra attention should be paid to dose calculations specific to IC/IS. As a result, it could be said that the speed of the spread of implementation of IC/IS is rather slow compared to the effectiveness of this method. It can easily be imagined that radiation oncologists who can perform ICBT hesitate to start IC/IS due to its invasiveness, as mentioned above. In such circumstances, there exist no guidelines for required equipment, human resources, or procedural guide focusing solely on IC/IS. It is true that there are many institutions which can perform ICBT. The purpose of this guideline is to provide radiation oncologists and medical physicists who wish to start IC/IS with practical and comprehensive guidance for a safe IC/IS introduction and help to accelerate the spread of the utilization of IC/IS nationwide.. This guideline was approved by JASTRO in July 2021. This is the English translation of the Japanese IC/IS Guidelines, and it was created in an effort to share the Japanese approach to the management of locally advanced uterine cervical cancer worldwide.. MATERIALS AND METHODS. The members involved in the development of this guideline are radiation oncologists who specialize in gynecologic malignancies and medical physicists. A thorough literature review regarding IC/IS for gynecologic malignancies was initially performed by two radiation oncologists. Two hundred three papers were extracted by PubMed between January 2000 and December 2020 using the following keywords; 'uterine cervical neoplasms,' 'endometrial neoplasms,' vaginal neoplasms,' vulval neoplasms,' image- guided brachytherapy' or 'image- based brachytherapy,' 'intracavitary and interstitial,' and 'guideline.' Among the 203 papers, 33 papers were further carefully selected, which were deemed highly important.. Definition of IC/IS. Based on the conventional ICBT, additional interstitial needles are inserted to cover the area where adequate doses cannot be delivered only by ICBT.. Patient selection. IC/IS should be adopted for uterine or vaginal tumors in which an adequate dose cannot be delivered to the entire high- risk CTV . Preparation. - Pelvic examination preferably performed under anesthesia should be done by the start of IC/IS, and it is recommended that the obtained information be drawn using a drawing template (Fig. 1).- Pelvic MRI soon before the start of IC/IS- Electrocardiogram- Blood tests including blood count, biochemistry, coagulation, and cross-match for transfusion. Note the bleeding tendency in patients with platelets less than .
# Antibiotics may be considered if there is a retained pyometra and postoperative infection is highly anticipated or if a postoperative infection has occurred during previous treatment..
Equipment required for pain control and sedation General anesthesia or lumber spinal anesthesia managed by an anesthesiologist is preferable. Even if such anesthesia is not available, a moderate level of sedation should be performed because interstitial needle insertion is applied. It is recommended that a sedation/analgesia plan be prepared after conducting a pre- patient evaluation in advance, referring to 'the 2020 Guidelines for Sedation and Anesthesia in Gynecologic Brachytherapy' [16] and that the patient's consent for sedation be obtained beforehand. The following is the equipment required for pain control and sedation.. Sedative agents (benzodiazepines, propofol, etc.) Analgesics (pentazocine, opioids, etc.) Equipment for continuous measurement of patient vitals during the procedure Essential: continuous blood pressure monitor, pulse oximeter, electrocardiogram. Recommended: Capnometer (measuring end- expiratory carbon dioxide . Items to be used in an emergency. Respiratory support/artificial respiration: nasal airway, Ambu bag, endotracheal tube, etc. Medications: Flumazenil, naloxone, catecholamine, etc., which are antagonists for an overdose of sedative/analgesic drugs.. Equipment and applicators used. Transrectal ultrasound (TRUS), transabdominal ultrasound (TAUS). X- ray fluoroscopy X- ray in the same room or in a separate room, or MRI in a separate room:. If patients need to be moved to the other room to take images, care must be taken in fixing the applicators and interstitial needles, and in the way of transferring the patient to prevent displacement of the applicators and interstitial needles. The use of a patient transfer system dedicated to brachytherapy is also beneficial.. Applicator for intracavitary irradiation:. When performing MRI- based 3D- IGBT, use an MRI- compatible applicator; even for CT- based 3D- IGBT, an MRI- compatible applicator has fewer CT artifacts than a metal applicator. There is also an applicator for IC/IS that is equipped with an interstitial needle insertion template and with holes for interstitial needles in vaginal voids/ring.. Interstitial needle:. Interstitial needles are either made of metal (reusable) or plastic (disposable). The characteristics of each material are described later.. Examples of combined use: Tandem + ovoid + interstitial needles Tandem + interstitial needles Tandem + vaginal cylinder + interstitial needles Applicator dedicated for IC/IS, etc.. Personnel requirements for performing IC/IS. Because IC/IS involves a more invasive technique than conventional ICBT, at least the personnel required by the guidelines for the introduction of 3D- IGBT should be secured [7]. When performing IC/IS, it is necessary to have sufficient experience with 3D- IGBT for gynecologic tumors or to perform the procedure under the supervision of a person who is proficient in 3D- IGBT..
# In addition to the above, it is desirable to assign a full- time physician or nurse (person in charge of the management of sedation and analgesia) who continuously manages and monitors the patient's condition separately from the brachytherapists..
The medical safety system. Vaginal bleeding during and after procedures can often be stopped with tamponade with gauze. However, it is important to establish a system to obtain the cooperation of gynecologists and interventional radiologists (IVR) in advance, assuming that suturing for vaginal wall lacerations . IC/IS procedure. 1. Pretreatment. To prevent vomiting during sedation, abstain from food for 6 hours and water for 2 hours before the treatment. Also, explain that the patient should have defecated beforehand.. 2. Sedation and analgesia. Start sedation and analgesia based on the sedation and analgesia plan prepared before treatment. Since the depth of sedation and analgesia changes over time, check the depth of sedation, analgesia, and vital signs as treatment progresses.. 3. Insertion of the irradiation needle into the tissue. A) Selection of insertion route. There are two routes for insertion of the intratissue irradiation needle: the transvaginal approach and the transperineal approach (Fig. 2). The advantages and disadvantages of each are shown in Table 1. To prevent postoperative infection, thoroughly disinfect the vaginal (or perineal) site of insertion.. A-1) Transvaginal approach. The advantage of the transvaginal approach is that the distance until the needle reaches the tumor is shorter than that of the transperineal approach, the penetration into the tumor is much easier, and it does not require a high degree of analgesia compared to the transperineal approach. Therefore, it is a relatively easy technique to obtain. On the other hand, there is a limit to the reach of the interstitial needle due to the space limitation of the vagina, and there are cases where it is difficult to treat large tumors or tumors with complex shapes. In addition, there is interference between other vaginal applicators and the interstitial needles, which can make insertion difficult, especially in patients with narrow vaginas.. A-2) Perineal approach. The advantage of this approach is that it has high flexibility in terms of the reach and angulation of the interstitial needles and the extent to which they can be inserted. It can easily be used even for large tumors and tumors with complex shapes. However, because it requires a high degree of sedation, such as saddle block, and the path to the tumor is long, it should be performed under the supervision of an experienced brachytherapist at least in the beginning.. B) Selecting an interstitial needle. There are two types of materials for interstitial needles: plastic and metal. Each has advantages and disadvantages as shown in Table 2, and should be selected according to the preference of each brachytherapist and their level of proficiency in the method. Regardless of which type of needle is used, visually confirm that there is no damage to the interstitial needle before insertion, and use an appropriate obturator to maintain needle strength during insertion.. B-1) Plastic needle. There are two types of plastic needles (sharp and round). Because it has only been short period of time since round plastic needles were available in Japan and not so much information or experience has accumulated regarding the round plastic needle, only sharp plastic needles are described in this guideline. When MRI- based 3D- IGBT is performed, metallic needles cannot be used unless they are made of.
# titanium. Plastic needle has the advantage of being less artifactual, even when CT- based. They are disposable, but at the time of the development of this guideline, Japanese public insurance does not cover plastic needle costs. To determine the first stopping point in the treatment planning system, the offset value (distance from the applicator tip to the closest stopping point) obtained by the dummy source or the value obtained from commissioning performed in advance is used..
B-2) Metallic needle. Although the metallic needle has the advantage of easy puncture and better real- time ultrasound visualization during needle insertion, it has a sharper tip, so be careful of the risk of damaging blood vessels or bowels. In addition, the offset value is longer than that of the plastic needle, so care must be taken with the depth of the needle. To determine the first stopping point in the treatment planning system, use the offset value obtained from the dummy source or commissioning performed in advance.. C) Interstitial needle insertion procedure. The interstitial needle is inserted aiming at the tumor portion where the dose is insufficient in the dose distribution of normal ICBT. For insertion, it is essential to have an image in mind of the insertion site, angle, depth, etc., in advance using MRI images before IC/IS and TRUS or TAUS while inserting a sonde into the uterine cavity, as described before. In addition, pelvic examination findings on the day of the procedure and modalities to assist the insertion as described below are used as appropriate. The insertion is performed with the utmost care. The following is an overview of the insertion method by different approaches.. C-1) Transvaginal approach. First, the regular ICBT applicator insertion is performed, followed by the insertion of the interstitial needles. Although needle insertion after insertion of the ovoid is easy and the ovoid serves as a guide for the insertion site, it has the disadvantage of limiting the space and range of needle insertion due to interference with the ovoid. If the interstitial needle is inserted into the tissue before inserting the ovoid, there is more freedom in the needle insertion site and direction, but the needle must be inserted from the side of the vagina to avoid interference so that the ovoid can be inserted after insertion.. There are two methods of needle insertion from the vaginal wall: freehand insertion and insertion using the applicator for IC/IS as a template. Freehand needle insertion offers a wide range of applicability with a high degree of freedom in the insertion site and angulation, but it is difficult to ensure reproducibility. When a template (ring or ovoid with holes) is used, the insertion site and direction are restricted according to the template, but it has the advantage of high reproducibility.. When puncturing the vaginal wall, it is recommended that the vaginal wall be sufficiently stretched after the insertion of the ICBT applicator and that the needle be inserted into the vaginal wall as vertically as possible in order to avoid vaginal wall lacerations caused by the interstitial needle penetrating the vaginal wall at an angle.. C-2) Transperineal approach. The patient should be in the extended lithotomy position to avoid pubic bone interference. Because the ovoid and the interstitial needle.
# may interfere with each other in the transperineal approach, it is often possible to perform the procedure smoothly by inserting the interstitial needles first and then the ICBT applicators. In some cases, the interstitial needle may be excessively bent by the ovoid inserted after the interstitial needles. In such a case, confirm that the source path is not blocked by using a dummy source and consider replacing it with a smaller size ovoid. Meanwhile, inserting the tandem first may make it easier to insert the interstitial needle because it serves as an indicator of the insertion site of the interstitial needle..
In the transperineal approach, there is a risk that the needle tip may point in an unexpected direction due to the high degree of flexibility in the angle of the interstitial needle in the tissues, so it is recommended that the needle tip be confirmed in real- time by TRUS during insertion. If TRUS is not used, it is safer to use a perineal template where the needle angle is prefixed.. To avoid damage to the vaginal wall due to the long penetration route, be careful not to expose the interstitial needle in the vagina. If the position of the needle tip cannot be confirmed by TRUS, it is safer to insert a finger into the vagina and use the finger to palpate and guide the needle tip under the vaginal mucosa as it moves deeper. If it is necessary to insert the needle into a deeper plane against the vaginal wall surface, the needle under the vaginal mucosa serves as a marker, making it easier to insert the needle into the deeper planes.. When the ICBT applicator is inserted after insertion of the interstitial needles, the interstitial needles may come out slightly. Check and modify the tip of the interstitial needle again with TRUS before vaginal gauze packing is performed.. C-3) Modalities that can assist interstitial needle insertion. When freehand needle insertion is performed, it is possible that the needle will go in an unintended direction. Since organ damage associated with the insertion of an interstitial needle can lead to serious adverse events such as bleeding, infection, and bowel perforation, it is necessary to perform the insertion under real- time image guidance such as TRUS with X- ray assistance or frequent use of CT to avoid unnecessary normal organ injury and to always pay attention to the position of the needle tip while inserting the needle and keeping it inside the . TAUS guidance: Inject about . TRUS guidance: Real- time confirmation of needle position and depth is safer and has the advantage of completing the procedure more quickly than CT guidance, but unlike prostate brachytherapy under TRUS guidance, experience is required to recognize the TRUS images in the female pelvis. The range of images is limited to the depth of the transrectal probe, so the needle tip needs to be confirmed by CT or TAUS for deeper needle insertion.. CT- guided . C-4) Precautions after needle insertion. When multiple interstitial needles are used, it is possible to mistake the channel number of the transfer tube to be connected or to misidentify the channel number when the applicator is reconfigured in the treatment planning system. When multiple interstitial needles cross each other or the needle passes the air cavity of the vagina, and it is difficult to identify them, insert a dummy source that helps indicates the source path and confirm it. In addition, it is desirable to take measures such as attaching number stickers to all interstitial needles so that they can be easily identified.. If it takes a long time until the start of irradiation after the insertion is completed, consider inserting an obturator into the interstitial needle to prevent blood or disinfectant contamination. If the connection point of the interstitial needle is faulty, or if blood or other substances have contaminated the inside of the catheter and cannot be removed, cut the faulty point of the needle using a dedicated instrument. In such a case, measure the length of the interstitial needle again and reflect it in the applicator reconstruction of the treatment plan.. Needle retraction or displacement can happen, especially when patients need to be moved to another room for image acquisition. To avoid such circumstances, when needed, needle fixation using a button sutured to the skin could be considered.. D) Treatment plan image acquisition. After implantation and insertion of the ICBT applicator and the interstitial needles are completed, CT and/or MRI for treatment planning should be taken. When image acquisition is required in a room separate from the brachytherapy room, care should be taken to ensure that the positional relationship between the applicators and the interstitial needle is not displaced or retracted during transportation, such as by fixing the applicators with tape, etc. During MRI imaging, care should be taken to ensure that the interstitial needle does not move due to the weight or pressure of the MRI coil. After confirming the obtained images and confirming that the applicators and interstitial needles are in the appropriate locations and depths and that there are no excessively bent parts in the interstitial needles, move on to treatment planning.. E) Treatment Planning/Dose calculation. Dose calculation of IC/IS is performed based on the Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee [6] or Guidelines for the Introduction of Image- Guided Brachytherapy in 2018 [7]. In particular, in the case of IC/IS, the length to the first stopping point and the offset value differ depending on the type of interstitial needle. Therefore, attention should be paid to using the correct offset value, which is acquired with commissioning in advance.. For contouring of high- risk CTV . Calculate and record the bilateral point A doses, .
# \mathbf{D}_{2\mathrm{cm3}}.
Evaluate the International Commission on Radiation Units and Measurements (ICRU) recto- vaginal reference point dose [22] (Figure 3). Vaginal . In calculating dose distributions, the standard Manchester method dose distribution based on the point A prescription is first prepared. Then, the dose distribution is modified by adding doses to the areas in the . The biological equivalent dose is calculated using the LQ model to add the dose from each IC/IS session . \mathrm{D_{90\%}}. In the standard external radiation schedule in Japan, central shielding (CS) is used as the tumor shrinks. According to the definition of . If sedation and analgesia are not sufficiently obtained, the position of the applicator and the interstitial needle may shift due to the patient's unintentional body movement. Therefore, monitor the patient carefully during treatment planning, and connect the applicator to the transfer tube immediately before treatment.. (F) Indication. When connecting the interstitial needle to the transfer tube, be careful because the weight of the transfer tube can pull the interstitial needle toward the outside of the body. It would be helpful to use some kind of support stand to prevent needle displacement due to the transfer tube weight.. When multiple interstitial needles are inserted, be careful not to connect the wrong transfer tube to the wrong interstitial needle. Use a dummy source to confirm the applicator passage in advance to avoid errors during irradiation.. Visually confirm that there is no significant change in the applicator position before and after treatment.. G) Needle removal. Bleeding often occurs during needle removal, so paramount attention should be paid to bleeding during the removal of the interstitial needle.. In general, the transvaginal approach is more likely to cause bleeding than the transperineal approach because of the abundant blood flow in the vaginal wall. However, if the point of bleeding is well identified and pressure is applied to the bleeding point for a sufficient time, hemostasis can often be achieved. In addition to focused hemostasis, filling the vagina with gauze (or iodoform gauze) and applying continuous pressure to the entire vagina is also effective. If the outside of the gauze does not turn red after a while, it is likely that hemostasis has been obtained.. Even in cases where minor bleeding persists, and multiple gauze changes are required, overnight tamponade with gauze will almost always stop bleeding the next day. However, if arterial bleeding or bleeding of more than moderate severity is suspected, do not attempt to handle the situation alone, but do not hesitate to ask for help from a gynecologist or IVR physician..
# Note that intra- abdominal hemorrhage may occur in rare cases when the tip of the needle is beyond the .
Confirming the position of uterine arteries by prior MRI is also useful in avoiding bleeding. Intraoperative Doppler ultrasonography is also helpful in identifying vessels in a real- time manner.. The above description focuses on IC/IS for curative cases of uterine cervical cancer. However, it is possible to apply the same procedure for other gynecological malignancies, such as postoperative vaginal recurrences thicker than . Effectiveness and safety of IC/IS. In 3D- IGBT for cervical cancer, randomized controlled trials comparing ICBT versus IC/IS have not yet been reported.. A large retrospective multicenter study comparing the results of both treatment methods has been conducted by the External beam radiochemotherapy and MRI- based adaptive brachytherapy in locally advanced cervical cancer (EMBRACE) group [8]. In this study, the local control rate, late adverse events, and DVH were evaluated in 300 patients in the IC/IS group and 310 patients in the ICBT group. The 5- year local control rate was . In the EMBRACE study mentioned above, DVH parameters were compared between the tandem plus ovoid group and the tandem plus ring applicator group, and in both groups, . A case with severe bleeding treated by transcatheter arterial embolization was reported in which an obturator artery was injured by an interstitial needle inserted using an ovoid with holes as a template. The lessons learned from this case include inserting the needle under image guidance and, if CT preplanning is used to determine needle position beforehand, paying attention to anatomical changes during the treatment period, such as tumor shrinkage due to treatment [18].. The initial treatment results of a novel applicator dedicated to IC/IS were reported from the United States. The median . The results of 42 cases of IC/IS using the standard radiotherapy schedule in Japan were reported [9]. The median . In conclusion, IC/IS has clear advantages in terms of dose distribution compared to ICBT. It is recommended because of its clinical advantages in cases in which the conventional ICBT does not provide sufficient dose to cover the entire . QA/QC. A) Quality assurance and control of treatment devices, treatment planning systems, and applicators. For quality control and commissioning of treatment devices and treatment planning systems, refer to the Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee [3, 35], and for quality assurance required for the initiation of IGBT, refer to the Guidelines for the Introduction of Image- Guided Brachytherapy (IGBT) [7].. B) Applicator and catheter quality control. The novel applicator dedicated to IC/IS has a complex structure with many components, so it should be checked periodically for missing or damaged parts. Since applicators such as disposable plastic interstitial needles cannot be sterilized at their own facility, it is not possible to confirm the position of the radiation source using an actual radiation source beforehand. Therefore, before the start of clinical use, an applicator for QA that is not used for actual patients must be introduced separately to confirm the source anchorage position (referring to the commissioning of applicator reconstruction).. It is advisable to visually confirm that there are no abnormalities such as bends or indentations each time it is used.. DISCUSSION. Since the introduction of 3D- IGBT, the clinical outcome has dramatically improved compared to the 2D era [19, 36]. However, it was elucidated that even with 3D- IGBT, it is challenging to achieve the recommended dose constraints for .
# due to its invasiveness. Although the clinical results of IC/IS have been reported, until now, there have been no guidelines for required equipment, human resources, and procedural guides focusing solely on IC/IS. Therefore, to help spread IC/IS, JASTRO decided to create a practical and comprehensive guide dedicated to IC/IS. Because IC/IS is more invasive than conventional ICBT and deeper sedation is required, when the conditions in each institution allow, it is recommended that radiation oncologists conduct sedation, at least initially, in collaboration with anesthesiologists. This guideline deals with practical patient selection, preparation, procedures, and evidence supporting the effectiveness and safety of IC/IS. The authors hope that this article will help radiation oncologists and medical physicists who wish to start IC/IS and contribute to improving the clinical outcomes of patients suffering from this devastating disease..
Even though the incidence of uterine cervical cancer could be reduced by human papillomavirus vaccination [37], it will be long before most countries are fullvaccinated and it will be one of the major health problems for the next several decades in most countries. In such circumstances, this guideline will help promote IC/IS and increase the curative rate of definitive radiotherapy.. The limitations of this guideline are that most of the information described above is not based on phase III clinical trials but on expert opinions or retrospective studies. However, because of the paucity of phase III clinical trials in the field of brachytherapy, the authors believe that collecting such expert opinions and results from retrospective studies and creating this kind of clinical guideline is valuable.. ACKNOWLEDGEMENT. The authors appreciate Takahito Chiba for drawing the figures for this article.. FUNDING. This work was supported by Research Funding of Gunma University Heavy Ion Medical Center.. CONFLICT OF INTEREST. Dr. Yoshida reports personal fees from Chiyoda Technol, outside the submitted work. The other authors have no conflict of interest to declare.. REFERENCES. 1. Chino J, Annunziata CM, Beriwal S et al. Radiation therapy for cervical cancer: executive summary of an ASTRO clinical practice guideline. Pract Radiat Oncol 2020;10:220-34.
2. Nakano T, Kato S, Ohno T et al. Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix. Cancer 2005;103:92-101.
3. Japanese Brachytherapy Society, Japanese Society for Radiation Oncology (JASTRO). Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee. KANEHARA & CO, LTD, 2013.
4. Potter R, Tanderup K, Kirisits C et al. The EMBRACE II study: the outcome and prospect of two decades of evolution within the. GEC- ESTRO GYN working group and the EMBRACE studies. Clin Transl Radiat Oncol 2018;9:48- 60. 5. Ohno T, Noda SE, Okonogi N et al. In- room computed tomography- based brachytherapy for uterine cervical cancer: results of a 5- year retrospective study. J Radiat Res 2017;58: 543- 51. 6. Ohno T, Japanese Brachytherapy Society, Japanese Society for Radiation Oncology (JASTRO). Chapter 6. Gynecologic Malignancies, B. Intracavitary Brachytherapy for Cervical Cancer (3D), Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee. KANEHARA & CO, LTD, 2013; 83- 91. 7. Japanese Brachytherapy Society Working Group, Japanese Society for Radiation Oncology (JASTRO). Guidelines for the Introduction of Image- Guided Brachytherapy (IGBT), Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee. 2017. 8. Fokdal L, Sturdza A, Mazeron R et al. Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: analysis from the retroEMBRACE study. Radiother Oncol 2016;120:434- 40. 9. Murakami N, Kobayashi K, Shima S et al. A hybrid technique of intracavitary and interstitial brachytherapy for locally advanced cervical cancer: initial outcomes of a single- institute experience. BMC Cancer 2019;19:221- 228. 10. National Cancer Comprehensive Network' (NCCN). Clinical Practice Guidelines in Oncology (NCCN Guidelines) Cervical Cancer Version 4.2019- 2019. 11. Cibula D, Potter R, Planchamp F et al. The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer. Radiother Oncol 2018;127:404- 16. 12. Concin N, Matias- Guiu X, Vergote I et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer 2021;31:12- 39. 13. National Cancer Institute (NCI). Vaginal Cancer Treatment (PDQ)- Health Professional Version. 2021. treatment- pdq#cit/section_5.10 14. Gonzalez Y, Giap F, Klages P et al. Predicting which patients may benefit from the hybrid intracavitary- interstitial needle (IC/IS) applicator for advanced cervical cancer: a dosimetric comparison and toxicity benefit analysis. Brachytherapy 2021;20: 136- 45. 15. Takami A, Matsushita T, Ogata M et al. The Japan Society of Transfusion Medicine and Cell Therapy (JSTMCT). Guideline for the use of platelet transfusion concentrates based on scientific evidence: update 2019. Jpn J Transfus Cell Ther 2019;65: 544- 61. 16. Japanese Society for Radiation Oncology (JASTRO), Japanese Society of Anesthesiologists (JSA). Guidelines for Sedation and Anesthesia in Gynecologic Brachytherapy. 2020. 17. Gupta P, Aich RK, Deb AR. Acute complications following intracavitary high- dose- rate brachytherapy in uterine cancer. J Contemp Brachytherapy 2014;6:276- 81..
# 18. Aggarwal V, Chuprin A, Aggarwal A et al. Bleeding after interstitial brachytherapy for cervical cancer requiring embolization. Radiol Case Rep 2018;13:1141-5.
19. Pötter R, Haie-Meder C, Van Limbergen E et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67-77.
20. Ohno T, Wakatsuki M, Toita T et al. Recommendations for high-risk clinical target volume definition with computed tomography for three-dimensional image-guided brachytherapy in cervical cancer patients. J Radiat Res 2017;58:341-50.
21. Ohno T, Ii N, Ikushima H et al. A multi-institutional study on high-risk CTV (HR-CTV) in CT-based image-guided brachytherapy (IGBT) for cervical cancer. JASTRO NEWSLETTER 2017;1-6.
22. Kirchheiner K, Nout RA, Lindegaard JC et al. Dose-effect relationship and risk factors for vaginal stenosis after definitive radio(chemo)therapy with image-guided brachytherapy for locally advanced cervical cancer in the EMBRACE study. Radiother Oncol 2016;118:160-6.
23. Murakami N, Kasamatsu T, Sumi M et al. Vaginal tolerance of CT based image-guided high-dose rate interstitial brachytherapy for gynecological malignancies. Radiat Oncol 2014;9:31.
24. Susko M, Craciunescu O, Meltsner S et al. Vaginal dose is associated with toxicity in image guided tandem ring or ovoid-based brachytherapy. Int J Radiat Oncol Biol Phys 2016;94:1099-105.
25. Tanderup K, Nielsen SK, Nyvang GB et al. From point a to the sculpted pear: MR image guidance significantly improves tumour dose and sparing of organs at risk in brachytherapy of cervical cancer. Radiother Oncol 2010;94:173-80.
26. Fokdal L, Tanderup K, Hokland SB et al. Clinical feasibility of combined intracavitary/interstitial brachytherapy in locally advanced cervical cancer employing MRI with a tandem/ring applicator in situ and virtual preplanning of the interstitial component. Radiother Oncol 2013;107:63-8.
27. Viswanathan AN, Erickson BA. Seeing is saving: the benefit of 3D imaging in gynecologic brachytherapy. Gynecol Oncol 2015;138:207-15.
28. Tamaki T, Noda SE, Ohno T et al. Dose-volume histogram analysis of composite IQD2 dose distributions using the central shielding technique in cervical cancer radiotherapy. Brachytherapy 2016;15:598-606..
29. Tanderup K, Nesvacil N, Kirchheiner K et al. Evidence-based dose planning aims and dose prescription in image-guided brachytherapy combined with Radiochemotherapy in locally advanced cervical cancer. Semin Radiat Oncol 2020;30:311-27.
30. Viswanathan AN, Beriwal S, De Los Santos JF et al. American brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part II: high-dose-rate brachytherapy. Brachytherapy 2012;11:47-52.
31. Yaegashi N, Nagase S, Eniomoto T et al. The general rules for clinical and pathological management of uterine cervical cancer: clinical edition (the .
|
None
|
None
|
None
|
efe878c001314c1bb82293693e7ad37f
|
2024+AAN／AES／SMFM实践指南
|
子宫内暴露于抗癫痫药物后的畸形、围产期和神经发育结局
|
# Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication.
Practice Guideline From the AAN, AES, and SMFM. Alison M. Pack, MD, MPH, Maryam Oskoui, MD, MSc, Shawniqua Williams Roberson, MEng, MD, Diane K. Donley, MD, Jacqueline French, MD, Elizabeth E. Gerard, MD, David Gloss, MD, MPH&TM, Wendy R. Miller, PhD, RN, CCRN, Heidi M. Munger Clary, MD, MPH, Sarah S. Osmundson, MD, MS, Brandy McFadden, Kaitlyn Parrott, MBBS (Hons 1), Page B. Pennell, MD, George Saade, MD, Don B. Smith, MD, Kelly Sullivan, PhD, Sanjeev V. Thomas, MD, DM, Torbjörn Tomson, MD, Mary Dolan O'Brien, MLIS, PMP, Kylie Botchway- Doe, Heather M. Silsbee, MWC, and Mark R. Keezer, MDCM, PhD. Neurology 2024;102:e209779. doi:10.1212/WNL.0000000000209279. Abstract. This practice guideline provides updated evidence- based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic- clonic or focal- to- bilateral tonic- clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least . Correspondence American Academy of Neurology guidelines@aan.com.
# Glossary.
\mathbf{AAN} =. Epilepsy is one of the most common neurologic disorders, affecting more than 50 million people worldwide. One in 5 of those affected are people of childbearing potential, based on extrapolations from the proportion of the 2022 US female population aged 15- 45 years. Infants born to people with epilepsy are at increased risk of major congenital malformations (MCMs), adverse perinatal outcomes, and adverse neurodevelopmental outcomes. Multiple factors are associated with this risk, including genetic differences, environmental factors, seizure control, and intrauterine exposure to antiseizure medications (ASMs). The role of folic acid supplementation in mitigating these risks is unclear. Optimizing the treatment of epilepsy is necessary to achieve the most favorable outcomes for persons with epilepsy and their offspring.. In 2009, the American Academy of Neurology (AAN) published the guideline "Practice Parameter update: Management issues for women with epilepsy- Focus on pregnancy: Teratogenesis and perinatal outcomes." The authors concluded that treatment with valproic acid carries a higher risk of MCMs in the offspring of women with epilepsy than treatment with carbamazepine, phenytoin, and phenobarbital, especially if taken in polytherapy. The risk associated with other commonly used ASMs, such as levetiracetam or topiramate, was not evaluated because of limited available evidence. The authors concluded that treatment with valproic acid carried the highest risk of adverse cognitive outcomes in the offspring of women with epilepsy as compared with carbamazepine, although the risk of autism spectrum disorder (ASD) was not addressed because this association was not yet reported in the literature. Infants exposed to any ASM in utero had a higher risk of being born small for gestational age (SGA), but there was no evidence of an increased risk of fetal death.. A separate 2009 practice guideline recommended that preconception folic acid supplementation "may be considered to reduce the risk of MCMs," but did not provide further guidance on supplementation dosage. Since 2009, new studies have been published related to the risk of MCMs associated with several ASMs, the association between different ASMs and adverse perinatal or neurodevelopmental outcomes, and the effect of folic acid supplementation.. While the 2009 guidelines described the affected population as "women with epilepsy," this phrasing does not recognize the important difference between biological sex and sociocultural gender. In this update, we refer to the affected population with the gender- neutral language, "people with epilepsy of childbearing potential" (PWECP).. In this practice guideline update, we aim to provide guidance to clinicians when choosing an ASMs in monotherapy or polytherapy, in this patient population. We also aim to clarify the potential role of folic acid supplementation among PWECP. This guideline specifically addresses the following 4 clinical questions:. 1. What is the prevalence of MCMs associated with intrauterine exposure to specific ASMs, and how does this vary between ASMs in monotherapy vs polytherapy, and at high doses vs low-medium doses of ASMs, in children born to PWECP?
2. What is the prevalence of adverse perinatal outcomes associated with intrauterine exposure to specific ASMs, and how does this vary between ASMs in monotherapy vs polytherapy, and at high doses vs low-medium doses of ASMs, in children born to PWECP?
3. What is the prevalence of adverse neurodevelopmental outcomes associated with intrauterine exposure to specific ASMs, and how does this vary between ASMs in monotherapy vs polytherapy, and at high vs low-medium doses of ASMs, in children born to PWECP?
4. What is the effect of intrauterine exposure to folic acid on the prevalence of MCMs, adverse perinatal outcomes, and neurodevelopmental outcomes, and how does this vary by folic acid dose in children born to PWECP treated with ASMs?. Description of the Analytic Process. The development of this practice guideline followed the 2017 edition of the AAN's guideline development process manual. In March 2018, a multidisciplinary panel was recruited to develop the protocol for this guideline. The authors include content experts, methodologists, Guidelines Subcommittee members, an AAN epilepsy quality measure workgroup representative, physician representatives for the American Epilepsy Society and the Society for Maternal- Fetal Medicine, and patient advocates. In accordance with AAN policy, the current lead developer (A.M.P.), and the majority of the panel, has no conflicts of interest (COIs). Five of the 19 guideline developers (J.F., E.G., K.P., G.S., and T.T.) were determined to have COIs, but each COI was judged to be not significant enough to preclude authorship. These 5 developers were not permitted to review or rate the evidence; they served in an advisory capacity to help with the validation of the key.
# questions, the scope of the literature search, and the identification of seminal articles. They also participated in the recommendation development process. The full author panel was solely responsible for final decisions about the design, analysis, and reporting of this guideline..
This article is a summary of the key findings of the guideline. The complete guideline, including the literature search strategy, details about evidence classification, and the full systematic review of the evidence, is available in eAppendix 1.. Systematic Review of the Evidence. The panel searched Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Ovid Embase, CINAHL, the Database of Abstracts of Reviews of Effects, ClinicalTrials.gov, and the US Food and Drug Administration literature databases from June 1, 2007, to February 15, 2019, for relevant peer- reviewed articles that met inclusion criteria. The initial search after duplicates were removed yielded 4,039 articles. Using a systematic process detailed in the AAN's guideline development process manual,5 2 review panel members (not the same pair for all articles) independently reviewed the article titles and abstracts for relevance and then reviewed the full text of the articles determined to be relevant. (Figure). Disagreements about inclusion were resolved through discussion between the 2 panelists, with a third reviewer included to break ties when necessary. One hundred eighty- three articles were selected and rated for risk of bias by 2 panel members using the AAN criteria for the classification of causation studies. Class I studies have the lowest risk of bias, and Class IV studies have the highest risk of bias. As per predefined exclusion criteria that are laid out in the process manual,5 the panel excluded articles that were assessed as Class IV . An updated literature search was completed to identify additional relevant articles published between February 15, 2019, and August 1, 2022. The initial search after duplicates were removed yielded 128 articles. The abstracts and full- text articles were reviewed following the same process as the first literature review, which resulted in 13 articles being added to the systematic review (Figure). The primary findings of the systematic review are summarized in Tables 1- 7. Additional data are presented in eTables 1 and 2.. As detailed in the AAN's guideline development process manual, a modified version of the grading of Recommendations.
# Assessment, Development and Evaluation process was used to develop conclusions after the analysis of evidence. The evidence was analyzed based on parameters pertaining to risk of bias, .
#
#
# Continued.
# different studies) and, at best, classified as Class III evidence to address causation, the initial confidence rating for most conclusions was anchored as low if at least 2 Class III or at least 1 Class I or II studies informed each estimate used in the comparisons. The initial confidence rating was set to very low if one of the contributing estimates was informed by a single Class III study..
In the second step, the classification of evidence was upgraded or downgraded according to criteria specified in the process manual (e.g., upgraded for large magnitude of effect, downgraded for lack of statistical precision). For estimates obtained through indirect comparisons, confidence in the evidence was downgraded for precision when the width of the .
#
# statistical significance were not upgraded for magnitude of effect..
The authors formulated a rationale for each recommendation based on the evidence systematically reviewed and stipulated axiomatic principles of care, related evidence, and inferences. The recommendation development process is described in further detail in the complete guideline (eAppendix 1) and the AAN's guideline development process manual.5. Clinical Context. The goal of this guideline is to assist clinicians (e.g., physicians, nurses, and advanced practice providers) in the pharmacologic management of PWECP to limit risk of adverse congenital, perinatal, and neurodevelopmental outcomes. Given the many variables that may confound the outcomes we examined (e.g., genetic conditions, pregnancy conditions, and socioeconomic contexts), we weighted evidence more strongly where analyses could be adjusted for these and other potential confounders (i.e., Class I studies). Demonstration of . The available evidence on the association between in utero ASM exposure and neurodevelopmental outcomes is rapidly expanding. Although valproic acid exposure shows a strong effect, data from our preplanned analyses on adverse neurodevelopmental outcomes were insufficient to demonstrate an effect; thus, caution in counseling is warranted. While we could not extract sufficient data on topiramate exposure, the SCAN- AED study49 found even higher prevalences of ASD and intellectual disability with exposure to topiramate than.
# valproic acid. Their adjusted hazard ratios (aHRs), however, used prevalence in the general population of children as a comparator group (aHRs for ASD and intellectual disability after topiramate exposure were 2.8 .
Folic acid prescribing practices for PWECP are variable.. Practice Recommendations. General. Recommendation 1 Rationale. The overarching goals of care for PWECP are to optimize health outcomes both for individuals and their future offspring. In many cases, in utero ASM exposure may be associated with increased risks to the fetus. There are also risks associated with discontinuing or changing ASMs in PWECP.. Recommendation 1 Statements. 1(A) Clinicians should engage in joint decision- making with PWECP, taking individual preferences into account when selecting ASMs and monitoring their dosing (Level B).. 1(B) When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally (e.g., at the time of starting an ASM in a person post- menarche) (Level B).. Recommendation 2 Rationale. The odds of mortality during pregnancy is 5- 12 times greater among PWECP as compared with pregnant people without epilepsy, according to an analysis of a Danish cohort of more than 2 million pregnancies and a US cohort of more than 20 million participants.. In an analysis of the EURAP study including 1,956 pregnancies among 1,882 participants, there was no statistical association between seizures during pregnancy and spontaneous abortion or stillbirth. However, the 1 stillbirth that occurred soon after a seizure was an episode of convulsive status epilepticus.. Valproic acid is one of the most effective ASMs at obtaining adequate seizure control among people with idiopathic generalized epilepsy.. The serum concentration of most ASMs has a defined therapeutic window for effective seizure control. The serum concentration of some ASMs (in particular, lamotrigine and levetiracetam) decreases during pregnancy. These decreases may occur at any point during the pregnancy.. There are limited data available on epilepsy- related outcomes during pregnancy among PWECP for numerous ASMs, including but not limited to acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin..
# Recommendation 2 Statements.
2A. Clinicians must minimize the occurrence of convulsive seizures (generalized tonic-clonic seizures and focal-tobilateral tonic-clonic seizures) in PWECP during pregnancy to minimize potential risks to the birth parent (e.g., seizurerelated mortality) and to the fetus (Level A).. 2B. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-tobilateral tonic-clonic seizures, even if it is not an optimal choice with regards to the risk to the fetus (e.g., valproic acid) (Level B).. 2C. Clinicians should monitor ASM levels in PWECP throughout pregnancy as guided by individual ASM pharmacokinetics and patient clinical presentation (Level B).. 2D. Clinicians should adjust the dose of ASMs at their clinical discretion during the pregnancy in response to (1) decreasing serum ASM levels or (2) worsening seizure control (observed or anticipated based on the clinician's judgment and known pharmacokinetics of ASMs in the pregnant state) (Level B).. 2E. Clinicians treating PWECP using acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, or vigabatrin should counsel their patients that there are limited data on pregnancy-related outcomes for these drugs (Level B).. Antiseizure Medications: Major Congenital Malformations. Recommendation 3 Rationale. The unadjusted birth prevalence of any MCM among children born to people without epilepsy is approximately . Valproic acid is associated with the highest unadjusted birth prevalence of neural tube defects (NTDs) . A detailed anatomical ultrasound of the fetus can enable earlier diagnosis of MCMs,e20- e24 Early detection of severe . Recommendation 3 Statements. 3A. Clinicians must counsel their patients with epilepsy that the birth prevalence of any MCM in the general population is approximately . 3B. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs (Level A).. 3C. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs (composite outcome) or NTDs, if clinically feasible (Level A).. 3D. Clinicians must counsel PWECP who are treated with, or are considering starting, valproic acid that the risk of any MCM is the highest with valproic acid as compared with other studied ASMs (Level A).. 3E. To reduce the risk of cardiac malformations, clinicians must avoid the use of phenobarbital in PWECP, if clinically feasible (Level A).. 3F. To reduce the risk of oral clefts, clinicians should avoid the use of phenobarbital and topiramate in PWECP, if clinically feasible (Level B).. 3G. To reduce the risk of urogenital and renal malformations, clinicians should avoid the use of valproic acid in PWECP, if clinically feasible (Level B).. 3H. To enable early detection and timely intervention of MCMs, obstetricians should recommend fetal screening for MCMs (e.g., a detailed anatomical ultrasound, where available) for PWECP who are treated with any ASM during pregnancy (Level B).. 3I. To enable early detection and timely intervention of congenital heart defects, obstetricians should recommend screening cardiac investigations of the fetus among PWECP who are treated with phenobarbital during pregnancy (Level B).. Antiseizure Medications: Perinatal Outcomes. Recommendation 4 Rationale. Among children exposed to ASMs in utero and born to PWECP, the prevalence of intrauterine death is highly likely.
# not to differ across ASMs when used in monotherapy and the prevalence of prematurity is possibly no different across ASMs when used in monotherapy (eTable 2). The risk of intrauterine death is likely higher with polytherapy exposure compared with monotherapy exposure. Fetal growth restriction increases the risk of perinatal morbidity and mortality..
Recommendation 4 Statements. 4A. Clinicians should counsel PWECP that the prevalence of intrauterine death does not differ among different ASM exposures in monotherapy (Level B).. 4B. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born SGA, if clinically feasible (Level B).. 4C. To enable early identification of fetal growth restriction, obstetricians should recommend screening of fetal growth throughout pregnancy among PWECP who are treated with valproic acid or topiramate (Level B).. Antiseizure Medications: Neurodevelopmental Outcomes. Recommendation 5 Rationale. Among children born to PWECP, in utero exposure to valproic acid is likely associated with a decrease in full scale IQ at age 6 years compared with gabapentin and lamotrigine in monotherapy; valproic acid is possibly associated with a decrease as compared with carbamazepine, levetiracetam, and topiramate in monotherapy; and there is possibly no difference in full scale IQ with valproic acid as compared with phenytoin in monotherapy.. Among children born to PWECP, in utero exposure to valproic acid is likely associated with a decrease in verbal IQ at age 6 years compared with gabapentin, lamotrigine, levetiracetam, and phenytoin in monotherapy, and possibly associated with a decrease as compared with carbamazepine and topiramate in monotherapy.. Among children born to PWECP, in utero exposure to valproic acid is possibly associated with a decrease in non- verbal IQ at age 6 years compared with carbamazepine and phenytoin in monotherapy, but there is possibly no difference as compared with gabapentin, lamotrigine, levetiracetam, and topiramate in monotherapy.. Among children born to PWECP, in utero exposure to valproic acid throughout the pregnancy is possibly associated with an increased risk of ASD and autistic traits compared with other studied ASMs (i.e., carbamazepine, clonazepam, lamotrigine, and levetiracetam) used in monotherapy.. Numerous ASMs have limited available data on neurodevelopmental outcomes. These neurodevelopmental outcomes are determined during both early and later stages of pregnancy.. Recommendation 5 Statements. 5A. To reduce the risk of poor neurodevelopmental outcomes, including ASD and lower . 5B. Clinicians must counsel PWECP who are treated with, or are considering starting, valproic acid that in utero exposure to valproic acid is likely or possibly associated with a decrease in full scale, verbal, and non-verbal . 5C. Clinicians must counsel PWECP who are treated with, or are considering starting, valproic acid that in utero exposure to valproic acid is possibly associated with an increased risk of ASD as compared with other studied ASMs (i.e., carbamazepine, clonazepam, levetiracetam, and lamotrigine) (Level A).. 5D. Clinicians should implement age- appropriate developmental screening in children exposed to any ASM in utero born to PWECP (Level B).. Folic Acid. Recommendation 6 Rationale. The optimal dosing and timing of folic acid supplementation are unknown in PWECP. There is likely no demonstrated benefit of folic acid supplementation (at least .
# Preconception folic acid supplementation is possibly associated with better neurodevelopmental outcomes among children born to PWECP. Folic acid supplementation of at least .
Recommendation 6 Statements. 6A. Clinicians should prescribe at least . 6B. Clinicians must prescribe at least . 6C. Clinicians should counsel PWECP treated with an ASM that adherence to recommended folic acid supplementation preconceptionally and during pregnancy is important to minimize the risk of MCMs and poor neurodevelopmental outcomes (Level B).. Suggestions for Future Research. The findings of this systematic review highlight several knowledge gaps that should be addressed in future research to . There is considerable practice variation in the dosing of folic acid supplementation. High- quality studies, including randomized controlled trials where possible, will be required to definitively clarify the optimal dose and timing with respect to conception.. The impact of screening for fetal anomalies and growth restriction on perinatal outcomes needs to be established. Clarification of the impact of socioeconomic status on pregnancy outcomes in PWECP will inform social service priorities. To better clarify the potentially diverse needs of underrepresented groups, future studies should work to include diverse ethnic and racial groups, people from low and middle- income countries, as well as transgender, nonbinary, and intersex PWECP. Altogether, these lines of research will help identify pregnancies at greatest risk of adverse outcomes and inform new, targeted interventions to improve parental, fetal, perinatal, and neurodevelopmental outcomes.. Disclaimer. Clinical practice guidelines, practice advisories, systematic reviews, and other guidance published by the American Academy of Neurology (AAN) and its affiliates are assessments of current scientific and clinical information provided as an educational service. The information (1) should not be considered inclusive of all proper treatments or methods of care or as a statement of the standard of care; (2) is not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is developed and when it is published or read); (3) addresses only the question(s) specifically identified; (4) does.
# not mandate any particular course of medical care; and (5) is not intended to substitute for the independent professional judgment of the treating provider because the information does not account for individual variation among patients. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. The AAN provides this information on an "as is" basis and makes no warranty, expressed or implied, regarding the information. The AAN specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. AAN assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions..
Conflict of Interest. The American Academy of Neurology (AAN) is committed to producing independent, critical, and trustworthy clinical practice guidelines (CPGs) and evidence- based documents. Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this evidence- based document. Management and disclosure of document developer relationships is conducted in compliance with the 2017 AAN process manual section titled, "Implementing the AAN Conflict of Interest Policy for Guidelines and Case Definitions," which can be viewed at aan.com.. Acknowledgment. Coauthor Sanjeev V. Thomas, MD, died February 4, 2024. The authors are grateful for his contributions to this guideline and to the field of neurology. The authors thank former lead developer Cynthia L. Harden, MD, for drafting the protocol and clinical questions and former AAN staff member Shannon Merillat, MLIS, for her assistance during the guideline development process.. Study Funding. This practice guideline was developed with financial support from the American Academy of Neurology (AAN). Authors who have served as AAN subcommittee members (A.M.P., M.O., S.W.R., D.K.D., J.F., K.S., M.K.), or as methodologists (M.O., D.B.S.), or who are or were AAN staff members (M.D.O., K.B.D., H.M.S.) were reimbursed by the AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were reviewed.. Disclosure. A.M. Pack serves on the editorial board for the journal Epilepsy Currents, receives royalties from UpToDate, receives funding from the NIH for serving as coinvestigator and site PI for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, and receives funding from Bayer for serving as a co-investigator on a study on women with epilepsy initiating a progestin IUD. An immediate family member of
A.M. Pack has received personal compensation for serving as an employee of. REGENEXBIO. M. Oskoui has received personal compensation in the range of .
# Consortium, the Epilepsy Foundation, Angelini Pharma, Biohaven Pharmaceuticals, Cerebral Therapeutics, Neurelis, Neurocrine, Praxis, Rapport, SK Life Science, Stoke, Takeda, and Xenon. E.E. Gerard has received personal compensation in the range of .
Parratt receives funding from Zynebba for serving as a subinvestigator for the study Cannabidiol ZYNN2- CL- 04 and ZYNN2- CL- 04 for arterial onset seizures, receives funding from SK Life Science for serving as a subinvestigator for the study Cenobamate YKP3089C021 for partial onset seizures, has received funding from Eisai Inc. for the study Perampanel E2007- G00- 335 for partial onset seizures, has received funding from Marinus Pharmaceuticals for the study Ganaxolone 10420603 for partial onset seizures, and has received honoraria from Eisai for a dinner meeting lecture. P.B. Pennell's institution has received research support from the NINDS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development for observational studies of people with epilepsy of childbearing potential and their children. The institution of an immediate family member of P.B. Pennell has received research support from the U.S. Department of Defense, the Environmental Protection Agency, the NIH, and Advanced Energy Consortium. P.B. Pennell has received publishing royalties from UpToDate, a publication relating to health care. P.B. Pennell has received honoraria and/or travel reimbursements from the AES, the AAN, and various academic medical institutions for CME lectures. She has received honoraria for grant reviews from the NIH and Harvard Catalyst. She has received honoraria for serving on the scientific advisory board for BRAINS, an NIH- funded study. G. Saade has received personal compensation in the range of .
# India, and served on the editorial board of the journal Epilepsy Research. T. Tomson's institution has received personal compensation in the range of .
Publication History. Received by Neurology October 17, 2023. Accepted in final form February 21, 2024. Submitted and externally peer reviewed. The handling editor was Editor- in- Chief Jose Merino, MD, MPhil, FAAN..
# References.
1. US Census Bureau. National Population by Characteristics: 2020-2022 [online]. Accessed January 3, 2022. census.gov/data/tables/time-series/demo/popest/2020s-national-detail.html.
2. Stephen LJ, Harden C, Tomson T, Brodie MJ. Management of epilepsy in women. Lancet Neurol. 2019;18(5):481-491. doi:10.1016/S1474-4422(18)30495-2
3. Harden C, Pennell P, Koppel B, et al. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73 (2):133-141. doi: 10.1212/WNL.0b013e3181a6b312
4. Harden CL, Pennell PB, Koppel BS, et al. Practice parameter update: management issues for women with epilepsy: focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the. American Academy of Neurology and American Epilepsy Society. Neurology. 2009; 73(2):142- 149. doi:10.1212/WNL.0b013e3181a6b325 5. Gronseth GS, Cox J, Gloss D, et al. Clinical Practice Guideline Process Manual, 2nd ed. American Academy of Neurology; 2017. 6. Tomson T, Battino D, Bonizzoni E, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018;17(6):530- 538. doi:10.1016/S1474- 4422(18)30107- 8 7. Meador K, Baker G, Finnell R, et al. In utero antiepileptic drug exposure: fetal death and malformations. Neurology. 2006;67(3):407- 412. doi:10.1212/01. wnl.00000227918.1208. b2 8. Artama M, Auvinen A, Randaskoski T, Isojvari I, Isojvari J. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology. 2005; 64(11):1874- 1878. doi:10.1212/01. wNL.0000063771.96962.1F 9. Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med. 2001;344(15):1132- 1138. doi:10.1056/NEJM200104123441504 10. Samren EB, van Duijn CM, Lieve Christiaens GCM, Hofman A, Lindhout D. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol. 1999;46(5):739- 746. doi:10.1002/1531- 8249(199911)46:5<739::aid- ana9>3.0. co:2- 2 11. Hernandez- Diaz S, Smith CR, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012;78(21):1692- 1699. doi:10.1212/WNL.0b013e3182574f59 12. Ban L, Fleming KM, Doyle P, et al. Congenital anomalies in children of mothers taking antiepileptic drugs with and without peri- conceptional high dose folic acid use: a population- based cohort study. PLoS One. 2015;10(7):e0131130. doi:10.1371/ journal.pone.0131130 13. Campbell E, Kennedy F, Russell A, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry. 2014;85(9):1029- 1034. doi: 10.1136/jnnp- 2013- 306318 14. Olafsson E, Hallgrimsson JT, Hauser WA, Ludvigsson P, Gudmundsson G. Pregnancies of women with epilepsy: a population- based study in Iceland. Epilepsia. 1998; 39(8):887- 892. doi:10.1111/j.1528- 1157.1998.001186. x 15. Vajda FJE, Graham JE, Hitchcock AA, Lander CM, OBrien TJ, Eadie MJ. Antiepileptic drugs and foetal malformation: analysis of 20 years of data in a pregnancy register. Seizure. 2019;65(1- 11. doi:10.1016/j.seizure.2018.12.006 16. Scolnik D, Nulman I, Rovet J, et al. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA. 1994;271(10):767- 770. doi: 10.1001/jama.1994.03510340057034 17. Kaaja E, Kaaja R, Hüllesmaa V. Major malformations in offspring of women with epilepsy. Neurology. 2003;60(4):575- 579. doi:10.1212/01. wnl.0000044157.28073. dc 18. Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy. J Neurol. 2014; 261(3):579- 588. doi:10.1007/s00415- 013- 7239- x 19. Mawer G, Briggs M, Baker G, et al. Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study. Seizure. 2010;19(2):112- 119. doi:10.1016/ j.seizure.2009.11.008 20. Samren EB, van Duijn CM, Koch S, et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia. 1997;38(9):981- 990. doi: 10.1111/j.1528- 1157.1997. tb01480. x 21. Canger R, Battino D, Canevini MP, et al. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia. 1999;40(9):1231- 1236. doi:10.1111/j.1528- 1157.1999. tb00851. x 22. Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nationwide, population- based register study. Acta Paediatr. 2004;93(2):174- 176. doi: 10.1080/08035250310021118 23. Charlton RA, Weil JG, Cunnington MC, Ray S, de Vries CS. Comparing the General Practice Research Database and the UK epilepsy and Pregnancy Register as tools for postmarketing teratogen surveillance: anticonvulsants and the risk of major congenital malformations. Drug Saf. 2011;34(2):157- 171. doi:10.2165/11584970- 000000000- 00000 24. Thomas SV, Jeemon P, Pillai R, et al. Malformation risk of new anti- epileptic drugs in women with epilepsy; observational data from the Kerala registry of epilepsy and pregnancy (KREP). Seizure. 2021;93:127- 132. doi:10.1016/ j.seizure.2021.10.005 25. Holmes LB, Mittendorf R, Shen A, Smith CR, Hernandez- Diaz S. Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations. Arch Neurol. 2011;68(10):1275- 1281. doi:10.1001/archneurol.2011.133 26. Vajda FJ, Hitchcock A, Graham J, et al. Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry. Eur J Neurol. 2006;13(6):645- 654. doi:10.1111/j.1468- 1331.2006.01359. x 27. Molgaard- Nielsen D, Hvid A. Newer- generation antiepileptic drugs and the risk of major birth defects. JAMA. 2011;305(19):1996- 2002. doi:10.1001/jama.2011.624 28. Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neuro Neurosurg Psychiatry. 2006;77(2):193- 98. doi:10.1136/jnnp.2005.074203 29. Cunnington MC, Weil JG, Messenheimer JA, Ferber S, Yerby M, Tennis P. Final results from 18 years of the International Lamotrigine Pregnancy Registry. Neurology. 2011;76(21):1817- 1823. doi:10.1212/WNL.0b013e31821cc1d18 30. Meador KJ, Pennell PB, May RC, et al. Fetal loss and malformations in the MONEAD study of pregnant women with epilepsy. Neurology. 2020;94(14):e1502- e1511. doi: 10.1212/WNL.0000000000008687.
# 31. Mawhinney E, Craig J, Morrow J, et al. Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology. 2013;80(4):400-405. doi:10.1212/WNL.0b013e31827f087432. Vajda F, O'brien T, Graham J, Hitchcock A, Lander C, Eadie M. Anti-epileptic drug exposure and risk of foetal death in utero. Acta Neurol Scand. 2018;137(1):20-23. doi: 10.1111/ane.1281633. Scheuerle AE, Holmes LB, Albano JD, et al. Levetiracetam Pregnancy Registry: final results and a review of the impact of registry methodology and definitions on the prevalence of major congenital malformations. Birth Defects Res. 2019;111(13): 872-887. doi:10.1002/bdr.2.152634. Lv H, Zhao X, Yu J. Analysis of the clinical effects of sodium valproate and levetiracetam in the treatment of women with epilepsy during pregnancy. Evid Based Complement Alternat Med. 2021;2021:5962200. doi:10.1155/2021/596220035. Sharma SR, Sharma N, Hussain M, Moping H, Hynniewta Y. Levetiracetam use during pregnancy in women with active epilepsy: a hospital-based, retrospective study from a tertiary care hospital in North Eastern India. Neurol India. 2021;69(3): 692-697. doi:10.4103/0028-4886.31923436. Tripathi NK. A retrospective research asses the usage of levetiracetam during pregnancy in epileptic mothers. Int J Toxicol Pharmacol Res. 2021;11:79-8837. Putignano D, Clavenna A, Campi R, et al. Perinatal outcome and healthcare resource utilization in the first year of life after antiepileptic exposure during pregnancy. Epilepsy Behav. 2019;92:14-17. doi:10.1016/j.yebeh.2018.09.03338. Tomson T, Battino D, Bonizzoni E, et al. Antiepileptic drugs and intrauterine death: a prospective observational study from EURAP. Neurology. 2015;85(7):580-588. doi: 10.1212/WNL.0000000000184039. Vajda FJ, Hitchcock A, Graham J, O'Brien TJ, Lander CM, Eadie MJ. The teratogenic risk of antiepileptic drug polytherapy. Epilepsia. 2010;51(5):805-810. doi: 10.1111/j.1528-1167.2009.01336.x40. McCluskey G, Kinney MO, Russell A, et al. Zonisamide safety in pregnancy: data from the UK and Ireland epilepsy and pregnancy register. Seizure. 2021;91:311-315. doi: 10.1016/j.seizure.2021.07.00241. Dolk H, Jentink J, Loane M, Morris J, de Jong-van den Berg LT, EUROCAT Antiepileptic Drug Working Group. Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? Neurology. 2008;71(10):714-722. doi: 10.1212/wl.wnl.000003161948475.d842. Holmes LB, Baldwin EJ, Smith CR, et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology. 2008;70(22 pt 2): 2152-2158. doi:10.1212/wl.wnl.0000304343.45104.d643. Martinez Ferri M, Pena Mayor P, Perez Lopez-Fraile I, et al. Malformations and fetal death in the Spanish antiepileptic drug and pregnancy registry: results at 6 years [in Spanish]. Neurologia. 2009;24(6):360-365.44. Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent teratogenicity of valproate in mono- and polytherapy: an observational study. Neurology. 2015;85(10):866-872. doi:10.1212/WNL.000000000000177245. Mawhinney E, Campbell J, Craig J, et al. Valproate and the risk for congenital malformations: is formulation and dosage regime important? Seizure. 2012;21(3): 215-218. doi:10.1016/j.seizure.2012.01.005.
46. Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Pregnancy, delivery, and outcome for the child in maternal epilepsy. Epilepsia. 2009;50(9):2130-2139. doi:10.1111/j.1528-1167.2009.02147.x47. Hernandez-Diaz S, Huybrechts KF, Desai RJ, et al. Topiramate use early in pregnancy and the risk of oral clefts: a pregnancy cohort study. Neurology. 2018;90(4): e342-e351. doi:10.1212/WNL.000000000000485748. Dolk H, Wang H, Loane M, et al. Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology. 2016;86(18):1716-1725. doi: 10.1212/WNL.000000000000254049. Bjork MH, Zoega H, Leinonen MK, et al. Association of prenatal exposure to antiseizure medication with risk of an autorellectual disability. JAMA Neurol. 2022; 79(7):672-681. doi:10.1001/jamneumol.2022.126950. Nadebaum C, Anderson VA, Vajda F, Reutens DC, Barton S, Wood AG. Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology. 2011;76(8):719-726. doi:10.1212/WNL.0b013e31820d62c751. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013;12(3):244-252. doi:10.1016/S1474-4422(12)70323-X52. Gaily E, Kantola-Sorsa E, Hilemsma V, et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology. 2004;62(1):28-32. doi:10.1212/wnl.62.1.2853. Adab N, Kini U, Vinten J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2004;75(11):1575-1583. doi:10.1136/jnnp.2003.02913254. Eriksson K, Vinikainen K, Monkkonen A, et al. Children exposed to valproate in utero: population based evaluation of risks and confounding factors for long-term neurocognitive development. Epilepsy Res. 2005;65(3):189-200. doi:10.1016/j.eplepsyres.2005.06.00155. Baker GA, Bromley RL, Briggs M, et al. IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study. Neurology. 2015;84(4):382-390. doi: 10.1212/WNL.000000000000118256. Bromley RL, Calderbank R, Cheyne CP, et al. Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate. Neurology. 2016;87(18): 1943-1953. doi:10.1212/WNL.000000000000315757. Christensen J, Gronborg TK, Sorensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorder and childhood autism. JAMA. 2013;309(16):1696-1703. doi:10.1001/jama.2013.227058. Bromley RL, Mawer GE, Briggs M, et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry. 2013;84(4):637-643. doi:10.1136/jnnp-2012-30427059. Veiby G, Daltveit AK, Schjolberg S, et al. Exposure to antiepileptic drugs in utero and child development: a prospective population-based study. Epilepsia. 2013;54(8): 1462-1472. doi:10.1111/epi.1222660. Wiggs KK, Rickert ME, Sujan AC, et al. Antisense medication use during pregnancy and risk of ASD and ADHD in children. Neurology. 2020;95(24):e3232-e3240. doi: 10.1212/WNL.0000000000010993Access eReferences online at Neurology.org..
|
None
|
None
|
None
|
b617694dff3640acb36c4975008f87f1
|
2024+AIRO意见书
|
妇科恶性肿瘤放疗相关毒性的预防和管理
| "# Prevention and management of radiotherapy-related toxicities in gynecological malignancies. Posit(...TRUNCATED)
|
None
|
None
|
None
|
a81ae2a7e46f4208b08f22e652700d85
|
2024+AIUM实践参数
|
女性盆腔的超声检查表现
| "# AIUM Practice Parameter for the Performance of Ultrasound of the Female Pelvis, 2024 Revision. \n(...TRUNCATED)
|
None
|
None
|
None
|
e679156e66de43f28ac061e1a62ff3da
|
2024+BFS实践指南
|
卵巢过度刺激综合征的预防
| "# Prevention of ovarian hyperstimulation syndrome (OHSS): British Fertility Society policy and prac(...TRUNCATED)
|
None
|
None
|
None
|
3394f4d63ab04c6fb4e12f35ab59bedb
|
2024+BGCS／BMS指南
|
妇科癌症治疗后更年期症状的管理
| "# British Gynaecological Cancer Society and British Menopause Society guidelines: Management of men(...TRUNCATED)
|
None
|
None
|
None
|
1e4bc7b7bb754fc59eb222c768af2f04
|
2024+ESGAR／ESUR／PSOGI／EANM联合建议
|
卵巢癌和结直肠癌腹膜转移的影像学检查
| "# Imaging of peritoneal metastases of ovarian and colorectal cancer: joint recommendations of ESGAR(...TRUNCATED)
|
None
|
None
|
None
|
b135c2442c534843becb13a7ed6d3d91
|
2024+ESGE实践建议
|
肌瘤切除的外科技术—第1部分
| "# European Society for Gynaecological Endoscopy (ESGE) Good Practice Recommendations on surgical te(...TRUNCATED)
|
None
|
None
|
None
|
6e93c96cae504e28af1564f10c60809e
|
2024+ESGE实践建议
|
肌瘤切除的外科技术—第2部分
| "# European Society for Gynaecological Endoscopy (ESGE) Good Practice Recommendations on surgical te(...TRUNCATED)
|
None
|
None
|
None
|
End of preview. Expand
in Data Studio
- Downloads last month
- 8