High-dose, Criteria for Use

2020⼉童和青少年侵袭性成熟B细胞⾮霍奇⾦淋巴瘤诊疗专家共识（完整版）2020⼉童和青少年侵袭性成熟B细胞⾮霍奇⾦淋巴瘤诊疗专家共识（完整版）摘要成熟B细胞⾮霍奇⾦淋巴瘤（B-NHL）占⼉童和青少年⾮霍奇⾦淋巴瘤（NHL）的50%~60%。

以伯基特淋巴瘤（BL）/⽩⾎病（B-AL）和弥漫⼤B细胞淋巴瘤（DLBCL）最为常见。

现今⾼侵袭的⼉童和青少年成熟B-NHL已经成为可治愈性⼉童肿瘤性疾病。

本共识对近10年⼉童和青少年BL/B-AL和DLBCL的⼀线诊治⽅法进⾏汇总，以期为临床规范化治疗提供循证依据。

成熟B细胞⾮霍奇⾦淋巴瘤（B-cellnon-Hodgkinlymphoma,B-NHL）占⼉童和青少年⾮霍奇⾦淋巴瘤（non-Hodgkinlymphoma,NHL）的50%~60%。

以伯基特淋巴瘤（Burkittlymphoma,BL）/⽩⾎病（Burkittleukemia,B-AL）和弥漫⼤B细胞淋巴瘤（diffuselargeB-celllymphoma,DLBCL）最为常见。

2011年中华医学会⼉科学分会⾎液学组、中国抗癌协会⼩⼉肿瘤专业委员会和中华⼉科杂志编辑委员会发表了“⼉童⾮霍奇⾦淋巴瘤诊疗建议”［1］。

近10年来随着对疾病⽣物学特征认识的深⼊以及国际多中⼼临床研究证据的产⽣，⼉童和青少年成熟B-NHL的诊断治疗⽅法有了相应的调整。

本版专家共识汇总当前⼉童和青少年（疾病诊断时年龄6⽉龄~18岁）BL/B-AL和DLBCL的⼀线诊治⽅法（不对其他少见B-NHL做描述），为临床规范化治疗提供参考。

⼀、病理诊断要求及标准⾼质量的病理诊断是成功治疗的前提。

为保证有充⾜的肿瘤组织样本⽤于病理诊断，推荐采⽤切除、切取或空芯针穿刺活检的⽅法来获得可疑淋巴结或结外病变组织。

对于⼉童和青少年成熟B-NHL，外科⼿术的价值在于获取病变组织进⾏病理学诊断，所以⽆需完全切除病灶。

对⽆法获得肿瘤组织的病例，液态样本（如各种渗出液、⾻髓等）也可以作为检测样本。

耐药结核病的药物选择胡越凯;卢洪洲【摘要】Drug-resistant tuberculosis remains a difficult problem that threatens progress made in tuberculosis control. Man-agement strategies for drug-resistant tuberculosis rely on harnessing existing drugs in the best combinations and dosing schedules, together with adjunctive surgery in carefully selected cases. Immunotherapy may also play an important role in the future. This arti-cle focuses on drug selection of drug-resistant tuberculosis.%耐药结核病是结核病控制的难题，对其治疗依赖于现有药物的种类合理选择和剂量精心调整，部分患者需要外科辅助治疗，在未来免疫治疗可能起到重要作用。

本文对耐药结核病的药物选择进行阐述。

【期刊名称】《传染病信息》【年(卷),期】2014(000)003【总页数】4页(P139-142)【关键词】结核;药物耐受性;抗结核药;治疗学【作者】胡越凯;卢洪洲【作者单位】200040 上海，复旦大学附属华山医院感染科;200040 上海，复旦大学附属华山医院感染科; 201508，上海市复旦大学附属公共卫生临床中心感染科【正文语种】中文【中图分类】R52结核病是人类历史上的古老瘟疫之一，1944年链霉素和1946年对氨基水杨酸的相继问世，使得结核病有了真正的药物治疗，也从那时开始出现了耐药结核病。

1950年第一次链霉素或对氨基水杨酸单药以及联合应用的临床试验，奠定了结核病治疗的一个原则——联合用药，但同时2种药物的长期联合使用，也产生了第1例耐多药结核病病例。

P54-专业英语作业1. Drug Development is a very complex process requiring a great deal of coordination and communication between a wide range of different functional groups.中文翻译:药物开发是一个十分复杂的过程，需要在广泛的不同功能性团队之间进行大量的协调与沟通。

2. It is expensive, particularly in the later phases of clinical development, where studies involve hundreds of patients这个过程（药物开发）这是昂贵的，特别是在临床开发的后期阶段，其中涉及到对数百名患者的研究。

3. It is currently estimated that the development of a new drug costs about $230 million and takes somewhere between7and10years form initiation of preclinical development to first marketing.目前估计,一种新药的开发成本约为2.3亿美元,并且从启动临床前的开发阶段到首次上市，需要花费7到10年4. Drug development is a high-risk business; although the rate is increasing, only about one out of every ten new chemical entities studied in human beings for the first time will ever become a product.药物开发是一个高风险的业务，尽管比率在不断上升，但是在完成了首次在人体研究中的每十个新化学实体中，大约只有一个能成为产品。

缩略语英文全称中文全称ABE Average Bioequivalence 平均生物等效性AC Active control 阳性对照ADE Adverse Drug Event 药物不良事件ADR Adverse Drug Reaction 药物不良反应AE Adverse Event 不良事件AI Assistant Investigator 助理研究者ALB Albumin 白蛋白ALD Approximate Lethal Dose 近似致死剂量ALP Alkaline phosphatase 碱性磷酸酶ALT Alanine aminotransferase 丙氨酸转氨酶ANDA Abbreviated New Drug Application 简化新药申请ANOVA Analysis of variance 方差分析AST Aspartate aminotransferase 天冬氨酸转氨酶ATR Attenuated total reflection 衰减全反射法BA Bioavailability 生物利用度BE Bioequivalence 生物等效性BMI Body Mass Index 体质指数BUN Blood urea nitrogen 血尿素氮CATD Computer-assisted trial design 计算机辅助试验设计CDER Center of Drug Evaluation and Research 药品评价和研究中心CFR Code of Federal Regulation 美国联邦法规CI Co-Investigator 合作研究者CI Confidence Interval 可信区间COI Coordinating Investigator 协调研究者CRC Clinical Research Coordinator 临床研究协调者CRF Case Report/Record Form 病历报告表/病例记录表CRO Contract Research Organization 合同研究组织CSA Clinical Study Application 临床研究申请CTA Clinical Trial Application 临床试验申请CTP Clinical Trial Protocol 临床试验方案CTR Clinical Trial Report 临床试验报告CTX Clinical Trial Exemption 临床试验免责CHMP Committee for Medicinal 人用药委会Products for Human UseDSC Differential scanning 差示扫描热量计DSMB Data Safety and monitoring Board 数据安全及监控委员会EDC Electronic Data Capture 电子数据采集系统EDP Electronic Data Processing 电子数据处理系统EWP Europe Working Party 欧洲工作组FDA Food and Drug Administration 美国食品与药品管理局FR Final Report 总结报告GCP Good Clinical Practice 药物临床试验质量管理规范GCP Good Laboratory Practice 药物非临床试验质量管理规范GLU Glucose 葡萄糖GMP Good Manufacturing Practice 药品生产质量管理规范HEV Health economic evaluation 健康经济学评价IB Investigator’s Brochure 研究者手册IBE IndividualBioequivalence 个体生物等效性IC Informed Consent 知情同意ICF Informed Consent Form 知情同意书ICH International Conference on Harmonization 国际协调会议IDM Independent Data Monitoring 独立数据监察IDMC Independent Data Monitoring Committee 独立数据监察委员会IEC Independent Ethics Committee 独立伦理委员会IND Investigational New Drug 新药临床研究IRB Institutional Review Board 机构审查委员会ITT Intention-to –treat 意向性分析IVD In Vitro Diagnostic 体外诊断IVRS Interactive Voice Response System 互动语音应答系统LD50 Medial lethal dose 半数致死剂量LLOQ Lower Limit of quantitation 定量下限LOCF Last observation carry forward 最接近一次观察的结转LOQ Limit of Quantitation 检测限MA Marketing Approval/Authorization 上市许可证MCA Medicines Control Agency 英国药品监督局MHW Ministry of Health and Welfare 日本卫生福利部MRT Mean residence time 平均滞留时间MTD Maximum Tolerated Dose 最大耐受剂量ND Not detectable 无法定量NDA New Drug Application 新药申请NEC New Drug Entity 新化学实体NIH National Institutes of Health 国家卫生研究所（美国）NMR Nuclear Magnetic Resonance 核磁共振PD Pharmacodynamics 药效动力学PI Principal Investigator 主要研究者PK Pharmacokinetics 药物动力学PL Product License 产品许可证PMA Pre-market Approval (Application) 上市前许可（申请）PP Per protocol 符合方案集PSI Statisticians in the Pharmaceutical Industry 制药业统计学家协会QA Quality Assurance 质量保证QAU Quality Assurance Unit 质量保证部门QC Quality Control 质量控制QWP Quality Working Party 质量工作组RA Regulatory Authorities 监督管理部门REV Revision 修订SA Site Assessment 现场评估SAE Serious Adverse Event 严重不良事件SAP Statistical Analysis Plan 统计分析计划SAR Serious Adverse Reaction 严重不良反应SD Source Data/Document 原始数据/文件SD Subject Diary 受试者日记SDV Source Data Verification 原始数据核准SEL Subject Enrollment Log 受试者入选表SFDA State Food and Drug Administration 国家食品药品监督管理局SI Sponsor-Investigator 申办研究者SI Sub-investigator 助理研究者SIC Subject Identification Code 受试者识别代码SOP Standard Operating Procedure 标准操作规程SPL Study Personnel List 研究人员名单SSL Subject Screening Log 受试者筛选表T&R Test and Reference Product 受试和参比试剂T－BIL Total Bilirubin 总胆红素T－CHO Total Cholesterol 总胆固醇TG Thromboglobulin 血小板球蛋白Tmax Time of maximum concentration 达峰时间TP Total proteinum 总蛋白UAE Unexpected Adverse Event 预料外不良事件WHO World Health Organization 世界卫生组织WHO- WHO International Conference WHO 国际药品管理当局会议ICDR A of Drug Regulatory AuthoritiesAberrant result 异常结果Absorption phase 吸收相Absorption 吸收Accuracy 准确度Accurate 精密度Administer 给药Amendment修正案Approval 批准Assess 估计Audit Report 稽查报告Audit 稽查Auditor 稽查员Analytical run/batch：分析批Benefit 获益Bias 偏性，偏倚Bioequivalence 生物等效Biosimilar /Follow-on biologics 生物仿制药Blank Control 空白对照Blind codes 编制盲底Blind review 盲态检查 /盲态审核Blinding method 盲法Blinding/masking 盲法/设盲Block size 每段的长度Block 层 /分段BCS 生物药剂学分类系统Carryover effect 延滞效应Case history 病历Clinical equivalence 临床等效性Clinical study 临床研究Clinical Trial Report 临床试验报告Comparison 对照Compensation 补偿，赔偿金Compliance 依从性Concomitant 伴随的Conduct 行为Confidence level 置信水平Consistency test 一致性检验Contract/ agreement 协议／合同Control group 对照组Coordinating Committee 协调委员会Crossover design 交叉设计Cross-over Study 交叉研究Cure 痊愈Data management 数据管理Descriptive statistical analysis 描述性统计分析Dichotomies 二分类Dispense 分布Diviation 偏差Documentation 记录／文件Dosage forms 剂型Dose dumping 剂量倾卸（药物迅速释放入血而达到危险浓度）Dose-reaction relation 剂量－反应关系Double blinding 双盲Double dummy 双模Drop out 脱落Effectiveness 疗效Elimination phase 消除相Emergency envelope 应急信件Enantiomers 对映体End point 终点Endpoint criteria/ measurement 终点指标Enterohepatic recycling 肠肝循环Essential Documentation 必需文件Ethical 伦理的Ethics committee 伦理委员会Evaluate 评估Exclusion Criteria 排除标准Excretion 排泄Expedite 促进Extrapolated 外推的Essentially similar product：基本相似药物Factorial design 析因设计Failure 无效，失败Finacing 财务，资金Final point 终点First pass metabolism 首过代谢Fixed-dose procedure 固定剂量法Full analysis set 全分析集GC－FTIR 气相色谱－傅利叶红外联用GC－MS 气相色谱－质谱联用Generic drug 通用名药Gene mutation 基因突变Genotoxicity tests 生殖毒性试验Global assessment variable 全局评价变量Group sequential design 成组序贯设计Hypothesis test 假设检验Highly permeable：高渗透性Highly soluble：高溶解度Highly variable drug：高变异性药物Highly：Variable Drug 高变异性药物HVDP：高变异药物制剂Identification 鉴别，身份证Improvement 好转In vitro 体外In vivo 体内Inclusion Criteria 入选表准Information Gathering 信息收集Initial Meeting 启动会议Inspection 检察/视察Institution Inspection 机构检察Instruction 指令，说明Integrity 完整，正直Intercurrent 中间发生的，间发的Inter-individual variability 个体间变异性Interim analysis 期中分析Investigational Product 试验药物Investigator 研究者Involve 引起，包括IR 红外吸收光谱Innovator Product：原创药Ka 吸收速率常LC－MS 液相色谱－质谱联用logarithmic transformation 对数转换Logic check 逻辑检查Lost of follow up 失访Mask 面具，掩饰Matched pair 匹配配对Metabolism 代谢Missing value 缺失值Mixed effect model 混合效应模式Modified release products 改良释放剂型Monitor 监查员Monitoring Plan 监察计划Monitoring Report 监察报告MS－MS 质谱－质谱联用Multi-center Trial 多中心试验Negative 阴性，否定的Non-clinical Study 非临床研究Non-inferiority 非劣效性Non-Linear Pharmacokinetics 非线性药代动力学Non-parametric statistics 非参数统计方法NTID：窄治疗指数制剂Obedience 依从性Open-blinding 非盲Open-label 非盲Original Medical Record 原始医疗记录Outcome Assessment 结果评价Outcome measurement 结果指标Outlier 离群值OIP 经口服吸收药物Parallel group design 平行组设计Parameter estimation 参数估计Parametric statistics 参数统计方法Patient file 病人档案Patient History 病历Per protocol， PP 符合方案集Permeability 渗透性Pharmacodynamic characteristics 药效学特征Pharmacokinetic characteristics 药代学特征Placebo Control 安慰剂对照Placebo 安慰剂Polytomies 多分类Post-dosing postures 给药后坐姿Potential 潜在的Power 检验效能Precision 精密度Preclinical Study 临床前研究Precursor 母体前体Premature 过早的，早发Primary endpoint 主要终点Primary variable 主要变量Prodrug 药物前体Protocol amendment 方案补正Protocol Amendments 修正案Protocol 试验方案Quality Control Sample：质控样品Rapidly dissolving：快速溶出Racemates 外消旋物Randomization 随机 /随机化Range check 范围检Rating scale 量表Recruit 招募，新会员Replication 可重复Retrieval 取回，补修Revise 修正Risk 风险Run in 准备期Safety evaluation 安全性评价Safety set 安全性评价的数据集Sample Size 样本量、样本大小Sampling schedules 采血计划Scale of ordered categorical ratings 有序分类指标Secondary variable 次要变量Sequence 试验次序Seriousness 严重性Severity 严重程度Significant level 检验水准Simple randomization 简单随机Single Blinding 单盲Site audit 试验机构稽查Solubility 溶解度Specificity 特异性Specify 叙述，说明Sponsor-investigator 申办研究者Standard curve 标准曲线Statistical model 统计模型Statistical tables 统计分析表Steady state 稳态Storage 储存Stratified 分层Study Audit 研究稽查Study Site 研究中心Subgroup 亚组Sub-investigator 助理研究者Subject Enrollment Log 受试者入选表Subject Enrollment 受试者入选Subject Identification Code List 受试者识别代码表Subject Recruitment 受试者招募Subject Screening Log 受试者筛选表Subject 受试者Submit 交付，委托Superiority 检验Supplemental 增补的Supra-bioavailability 超生物利用度（试验药的生物利用度大于对照药）Survival analysis 生存分析System Audit 系统稽查SmPC：药品说明书Standard Sample：标准样品Target variable 目标变量Treatment group 试验组Trial error 试验误差Trial Initial Meeting 试验启动会议Trial Master File 试验总档案Trial Objective 试验目的Trial site 试验场所Triple Blinding 三盲Two one-side test 双单侧检验Therapeutic equivalence：治疗等效性Un-blinding 破盲/揭盲Verify 查证、核实Visual analogy scale 直观类比打分法Vulnerable subject 弱势受试者Wash-out Period 洗脱期Well-being 福利，健康Withdraw 撤回，取消药代动力学参数Ae(0-t)：给药到t时尿中排泄的累计原形药。

UnitedHealthcare ® Community PlanViltepso ® (Viltolarsen)Policy Number : CS2023D0095KEffective Date : September 1, 2023 Instructions for Use Table of Contents Page Application ..................................................................................... 1 Coverage Rationale ....................................................................... 1 Applicable Codes .......................................................................... 2 Background ................................................................................... 2 Clinical Evidence ........................................................................... 3 U.S. Food and Drug Administration ............................................. 4 References ..................................................................................... 4 Policy History/Revision Information ............................................. 5 Instructions for Use ....................................................................... 5 This Medical Benefit Drug Policy does not apply to the states listed below; refer to the state-specific policy/guideline, if noted: State Policy/Guideline FloridaRefer to the state’s Medicaid clinical policy KansasNone LouisianaRefer to the state’s Medicaid clinical policy New JerseyViltepso ® (Viltolarsen) (for New Jersey Only) North CarolinaNone OhioViltepso ® (Viltolarsen) (for Ohio Only) PennsylvaniaViltepso ® (Viltolarsen) (for Pennsylvania Only) TexasRefer to drug-specific criteria found within the Texas Medicaid Provider Procedures ManualViltepso (viltolarsen) may be covered for the treatment of Duchenne muscular dystrophy (DMD) in patients who meet all of the following criteria :• For initial therapy , all of the following:o Diagnosis of Duchenne muscular dystrophy by, or in consultation with, a neurologist with expertise in the diagnosis of DMD; and o Submission of medical records (e.g., chart notes, laboratory values) confirming the mutation of the DMD gene is amenable to exon 53 skipping; ando One of the following: ▪ Submission of medical records (e.g., chart notes, laboratory values) confirming that the patient has a 6-MinuteWalk Test (6MWT) ≥ 300 meters while walking independently (e.g., without side-by-side assist, cane, walker,wheelchair, etc.) prior to beginning Viltepso therapy; or▪ Both of the following:Commercial Policy • Viltepso ® (Viltolarsen)Submission of medical records (e.g., chart notes) confirming that the patient is ambulatory without needing anassistive device (e.g., without side-by-side assist, cane, walker, wheelchair, etc.); and o One of the following:▪Patient has achieved a score of greater than 17 on the North Star Ambulatory Assessment (NSAA); or▪Patient has achieved a time to rise from the floor (Gower’s test) of less than 7 seconds;ando Viltepso is prescribed by, or in consultation with, a neurologist with expertise in the treatment of DMD; ando Viltepso dosing for DMD is in accordance with the United States Food and Drug Administration approved labeling; and o Viltepso is not used concomitantly with other exon skipping therapies for DMD; ando Initial authorization will be for no more than 6 monthsFor continuation of therapy, all of the following:o Patient has previously received Viltepso; ando Viltepso is prescribed by, or in consultation with, a neurologist with expertise in the treatment of DMD; ando Submission of medical records (e.g., chart notes) confirming that the patient is ambulatory without needing an assistive device (e.g., without side-by-side assist, cane, walker, wheelchair, etc.); ando Viltepso dosing for DMD is in accordance with the U.S. Food and Drug Administration (FDA) approved labeling; and o Viltepso is not used concomitantly with other exon skipping therapies for DMD; ando Reauthorization will be for no more than 12 monthsViltepso will not be covered for other forms of muscular dystrophy.The following list(s) of procedure and/or diagnosis codes is provided for reference purposes only and may not be all inclusive. Listing of a code in this policy does not imply that the service described by the code is a covered or non-covered health service. Benefit coverage for health services is determined by federal, state, or contractual requirements and applicable laws that may require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim payment. Other Policies and Guidelines may apply.HCPCS Code DescriptionJ1427 Injection, viltolarsen, 10 mgDiagnosis Code DescriptionG71.01 Duchenne or Becker muscular dystrophyDuchenne muscular dystrophy (DMD) is an X-linked disease that affects 1 in 3,600-6,000 live male births. DMD occurs as a result of mutations (mainly deletions) in the dystrophin gene. These mutations lead to an absence or a defect of the protein, dystrophin, resulting in progressive muscle degeneration, leading to loss of ambulation and additional respiratory, orthopedic, and cardiac complications. If left untreated, mean age of death is approximately 19 years of age.2-4Viltolarsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings found in natural DNA and RNA are replaced by a six-membered morpholino ring. Each morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the negatively charged phosphate linkage that is present in natural DNA and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA (adenine, cytosine, guanine, or thymine).1Viltolarsen is designed to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Approximately 8% of DMD patients have out of frame deletion mutations amenable to exon 53 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.1Eteplirsen (Exondys 51) was the first PMO approved by the U.S. Food and Drug Administration for treatment of DMD patients with confirmed genetic mutations amenable to exon 51 skipping. Approximately 13% of DMD patients have out of frame deletion mutations amenable to exon 51 skipping. This indication was approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with eteplirsen. A clinical benefit of eteplirsen has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.5Golodirsen (Vyondys 53) was the second PMO approved by the US Food and Drug Administration for treatment of DMD patients with confirmed genetic mutations amenable to exon 53 skipping, the same population as viltolarsen. Approximately8-10% of DMD patients have out of frame deletion mutations amenable to exon 53 skipping. This indication was also approved under accelerated approval based on an increase in dystrophin in skeletal muscle.6Casimersen (Amondys 45) is an antisense oligonucleotide that is designed to bind to exon 45 of dystrophin pre-messenger RNA, resulting in exon 45 skipping during messenger RNA processing in patients with amenable deletion mutations of the DMD gene. The FDA granted accelerated approval of casimersen for the treatment of patients with DMD who have a confirmed mutation of DMD that is amenable to exon 45 skipping, which is thought to cause approximately 8 percent of DMD cases.14Viltolarsen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.1A phase II study evaluated two doses of viltolarsen in 16 ambulatory boys aged 4 to 9 years with a DMD diagnosis and DMD gene amenable to exon 53 skipping over 24 weeks. Ambulatory boys on a stable corticosteroid regimen for at least 3 months who could complete time to stand from supine, time to run/walk 10 m, and time to climb four stairs assessments were included. The study was a multicenter, two period dose-finding clinical trial. The first study period, which corresponded to the first 4 weeks of treatment following enrollment, was double-blinded and placebo-controlled. Participants in both dose cohorts were randomized 3:1 to receive viltolarsen or placebo. The second study period began at week 5 for each participant. During this period, all participants received viltolarsen according to their cohort dose for a 20-week open-label treatment. Primary study outcomes included safety, tolerability, and pharmacokinetics of low-dose (40 mg/kg per week) and high-dose (80 mg/kg per week) viltolarsen in ambulant boys with DMD. Efficacy was assessed based on change from baseline in dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at week 25. Muscle dystrophin production was assessed as protein production by Western blot for the primary study efficacy outcome and as dystrophin mRNA splicing on RT-PCR, dystrophin protein production by MS, and dystrophin localization by IF staining for secondary study efficacy outcomes. Additional secondary efficacy outcomes were gross motor skill assessments of timed function tests, including time to stand from supine, time to run/walk 10 m, time to climb four stairs, North Star Ambulatory Assessment, and 6-minute walk test as well as quantitative muscle testing. These outcomes were compared with a matched natural history control group from the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS).In patients who received viltolarsen 80 mg/kg once weekly, mean dystrophin levels increased from 0.6% of normal at baseline to 5.9% of normal by week 25, with a mean change in dystrophin of 5.3% of normal levels (p = 0.01) as assessed by validated Western blot; the median change from baseline was 3.8%. All patients demonstrated an increase in dystrophin levels over their baseline values. As assessed by mass spectrometry, mean dystrophin levels increased from 0.6% of normal at baseline to 4.2% of normal by week 25, with a mean change in dystrophin of 3.7% of normal levels; the median change from baseline was 1.9%.Comparison of viltolarsen-treated participants with 65 age-matched and treatment matched natural history controls from CINRG DNHS suggested evidence of clinical benefit of viltolarsen treatment. Viltolarsen-treated participants showed improvement or stabilization of function over the 25-week period, whereas the CINRG DNHS external comparator group exhibited a decline in all timed function tests, except for time to climb four stairs. Velocity in the time to run/walk 10 m test significantly improved in viltolarsen-treated participants at weeks 13 and 25 compared with a decline in controls from CINRG DNHS (change at 25 weeks compared with baseline: viltolarsen, 0.23 m/s; control, −0.04m/s). The 6-minute walk test showed significant improvement at week 25 in viltolarsen treated participants, whereas results from CINRG DNHS controls declined over the same period (change at 25 weeks compared with baseline: viltolarsen, 28.9 m; control, −65.3 m). Significant improvements in time to stand from supine were observed (change at 25 weeks compared with baseline: viltolarsen, −0.19 s; control, 0.66 s). Velocity in the time toimprovement or stabilization, but the differences between viltolarsen treatment and external comparator controls were not significant. Measures of muscle strength by isometric testing showed no differences between viltolarsen-treated participants and the CINRG DNHS external comparator control group.7RACER53 is an ongoing 48-week, phase 3 double-blind, placebo controlled, randomized clinical trial that will evaluate the efficacy of viltolarsen in ambulatory DMD patients with out-of-frame deletion mutations amenable to skipping exon 53. The study will enroll 74 boys from 4 to 8 years of age with genotypically confirmed DMD on a stable dose of corticosteroids who can walk independently without assistive devices with a time to stand of less than 10 seconds. The primary endpoint is the change from baseline to week 48 in the time to stand. Secondary outcomes include the change in time to run/walk 10 meters, change in 6MWT, change in the NSAA, change in time to climb four steps, and change in muscle force contraction measured by dyanometry.8The SKIP-NMD trial of golodirsen is a U.S.-based, blinded, placebo-controlled, dose-escalation two-part Phase I/II RCT of male patients aged six to 15 years with a DMD diagnosis and DMD gene amenable to exon 53 skipping. Patients age 6 to 15 years with stable cardiac and pulmonary function, and on a stable dose of corticosteroids for at least six months were included. Additional inclusion criteria included a baseline six-minute walk test (6MWT) of greater than 250 m, a North Star Ambulatory Assessment (NSAA) score of greater than 17 or a rise time of less than 7 seconds. In part one, 12 patients were randomized to receive once-weekly intravenous infusions at escalating doses of 4, 10, 20, 30 mg/kg of golodirsen or matching placebo for 12 weeks. Part two consists of an open-label period of all patients from part one and 13 newly recruited patients who are receiving once-weekly infusions of 30 mg/kg of golodirsen for up to 168 weeks.Part one of the SKIP-NMD trial assessed safety and tolerability. In part two, the primary endpoints are change from baseline in 6MWT at 144 weeks and change in dystrophin protein levels at 48 weeks. Secondary endpoints include drug pharmacokinetics, change from baseline in FVC percent predicted, and change from baseline in dystrophin intensity at 144 weeks.At the time of pre-planned interim analysis, data from baseline and week 48 muscle biopsies, exon 53 skipping, and dystrophin localization were available for 25 patients on golodirsen. The study is ongoing, and results for the primary efficacy endpoint of 6MWT at week 144 are not yet available. Mean baseline of dystrophin in the trial was reported to be 0.095% of normal. At 48 weeks, the mean level of dystrophin had increased to 1.019% of normal resulting in an absolute increase of 0.918% of normal (p < 0.001). A clinically meaningful change in level of dystrophin has not yet been established in humans. As such, the clinical significance of these results is not clear. Among individual patients, dystrophin levels at week 48 ranged from 0.09% to4.30%.9-11ESSENCE is an ongoing 96-week, Phase 3, double-blind, placebo controlled, randomized clinical trial that will evaluate the efficacy of golodirsen and casimersen in DMD patients with out-of-frame deletion mutations amenable to skipping exon 53 and exon 45, respectively. The study will enroll 222 boys from 7 to 13 years of age with genotypically confirmed DMD and 6MWT ≥ 300 m and ≤ 450 m. The primary endpoint is the change from baseline to week 96 in 6MWT.12Viltolarsen or golodirsen have not been studied in DMD that is not amenable to exon 53 skipping, nor in other forms of muscular dystrophy (e.g., Becker muscular dystrophy).1,6This section is to be used for informational purposes only. FDA approval alone is not a basis for coverage.Viltepso is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with Viltepso. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.1.Viltepso [package insert]. Paramus, NJ; NS Pharma, Inc, March 2021.2.Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, et al. Diagnosis and management of Duchenne musculardystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol; 2010 Jan; 9(1):77 93.3.Bushby K, Finkel R, Birnkrant DJ, et al. (2010) Diagnosis and management of Duchenne muscular dystrophy, part 2:implementation of multidisciplinary care. Lancet Neurol; 2010 Jan; 9(2):177-189.4.Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis,and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol.2018;17(3):251-267. doi: 10.1016/S1474-4422(18)30024.5.Exondys 51 [package insert]. Cambridge, MA: Sarepta Therapeutics, Inc, January 2022.6.Vyondys 53 [package insert]. Cambridge, MA: Sarepta Therapeutics, Inc, February 2021.7.Clemens PR, Rao VK, Connolly AM, et al. Safety, tolerability, and efficacy of viltolarsen in boys with Duchenne musculardystrophy amenable to exon 53 skipping: a phase 2 randomized clinical trial. JAMA Neurol. 2020; 26;77(8):1-10. doi:10.1001/jamaneurol.2020.2025.8.Study to Assess the Efficacy and Safety of Viltolarsen in Ambulant Boys With DMD (RACER53)https:///ct2/show/NCT04060199?term=viltolarsen&draw=2&rank=1. Accessed June 5, 2023.9.Frank DE, Mercuri E, Servais, L, et al. Golodirsen induces exon skipping leading to sarcolemmal dystrophin expression inpatients with genetic mutations amenable to exon 53 skipping. Poster presented at: Annual Clinical Genetics Meeting of the American College of Medical Genetics and Genomics; April 2-6, 2019; Seattle, WA.10.Muntoni F, Frank DE, Morgan J, et al. Golodirsen induces exon skipping leading to sarcolemmal dystrophin expression inpatients with genetic mutations amenable to exon 53 skipping [abstract]. Neuromuscul Disord. 2018;28:S5. Abstract D01.11.Muntoni F, Frank DE, Sardone V, et al. SRP-4053 induces exon skipping leading to sarcolemmal dystrophin expression inDuchenne muscular dystrophy patients amenable to exon 53 skipping. Poster presented at: 22nd International Annual Congress of the World Muscle Society; October 3-7, 2017; Saint Malo, France.12.Study of SRP-4045 and SRP-4053 in DMD Patients (ESSENCE)https:///ct2/show/NCT02500381?term=golodirsen&cond=Duchenne+Muscular+Dystrophy&rank=3.Accessed June 5, 2023.13.Institute for Clinical and Economic Review (ICER). Deflazacort, eteplirsen, and golodirsen for Duchenne musculardystrophy: Effectiveness and value: Evidence Report. https:///wp-content/uploads/2020/10/Corrected_ICER_DMD-Final-Report_042222.pdf. April 22, 2022. Accessed June 5, 2023. 14.Amondys 45 [package insert]. Cambridge, MA; Sarepta Therapeutics, Inc.: March 2023.Date Summary of Changes09/01/2023 ApplicationLouisianaReplaced reference link to the state-specific policy version with instruction to refer to the state’sMedicaid clinical policySupporting InformationArchived previous policy version CS2023D0095JThis Medical Benefit Drug Policy provides assistance in interpreting UnitedHealthcare standard benefit plans. When deciding coverage, the federal, state, or contractual requirements for benefit plan coverage must be referenced as the terms of the federal, state, or contractual requirements for benefit plan coverage may differ from the standard benefit plan. In the event of a conflict, the federal, state, or contractual requirements for benefit plan coverage govern. Before using this policy, please check the federal, state, or contractual requirements for benefit plan coverage. UnitedHealthcare reserves the right to modify its Policies and Guidelines as necessary. This Medical Benefit Drug Policy is provided for informational purposes. It does not constitute medical advice.UnitedHealthcare may also use tools developed by third parties, such as the InterQual® criteria, to assist us in administering health benefits. The UnitedHealthcare Medical Benefit Drug Policies are intended to be used in connection with the independent professional medical judgment of a qualified health care provider and do not constitute the practice of medicine or medical advice.。

ICH 的论题主要分为四类，因此ICH 根据论题的类别不同而进行相应的编码分类：1.“Q”类论题：Q 代表QUALITY，指那些与化工和医药，质量保证方面的相关的论题。

Q1/Q2...Q10 都属于这种。

2.“S”类论题：S 代表SAFETY，指那些与实验室和动物实验，临床前研究方面的相关的论题。

3.“E”类论题：E 代表EFFICACY ，指那些与人类临床研究相关的课题。

4.“M”类论题：M 代表MULTIDISCIPLINARY，指那些不可单独划入以上三个分类的交叉涉及的论题。

1. Q1A(R2): Stability Testing of New Drug Substances and Products新原料药和制剂的稳定性试验2. Q1B: Photostability Testing of New Drug Substances and Products新原料药和制剂的光稳定性试验3. Q1C: Stability Testing for New Dosage Forms新剂型的稳定性试验4. Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and DrugProducts原料药和制剂稳定性试验的交叉和矩阵设计5. Q1E: Evaluation of Stability Data稳定性数据的评估6. Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV在气候带III 和IV，药物注册申请所提供的稳定性数据7. Q2(R1): Validation of Analytical Procedures: Text and Methodology分析程序的验证：正文及方法论8. Q3A(R2): Impurities in New Drug Substances新原料药中的杂质9. Q3B(R2): Impurities in New Drug Products (Revised Guideline)新制剂中的杂质10. Q3C(R5): Impurities: Guideline for Residual Solvents杂质：残留溶剂指南11. Q3C(R6): Impurities: Guideline for Residual SolventsPDE for Triethylamine and PDE for Methylisobutylketone杂质：残留溶剂指南三乙胺的日允许接触剂量及甲基异丁基酮的日允许接触剂量12. Q3D: Guideline for Elemental impurities主要杂质指南13. Q4A: Pharmacopoeial Harmonisation 药典的协调14. Q4B: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH RegionsICH 地区使用的药典正文评估和建议15. Q4B Annex1(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Residue on Ignition/Sulphated Ash General Chapter附录1 ICH 地区使用的药典正文评估和建议灼烧残渣/灰分通则16. Q4B Annex2(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Test for Extractable Volume of Parenteral Preparations General Chapter附录2 ICH 地区使用的药典正文评估和建议注射剂可提取体积测试通则17. Q4B Annex3(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Test for Particulate Contamination: Sub-Visible Particles General Chapter 附录3 地区使用的药典正文评估和建议颗粒污染物测试:不溶性微粒通则18. Q4B ANNEX 4A(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use inthe ICH Regions on Microbiological Examination of Non-sterile Products ：Microbial Enumerations Tests General Chapter附录4A(R1) 地区使用的药典正文评估和建议非无菌产品微生物检验:微生物计数法通则19. Q4B ANNEX 4B(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use inthe ICH Regions on Microbiological Examination of Non-sterile Products ：Test for Specified Micro-organisms General Chapter附录4B(R1) 地区使用的药典正文评估和建议非无菌产品微生物检验:控制菌检查法通则20. Q4B ANNEX 4C(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use inthe ICH Regions on Microbiological Examination of Non-sterile Products ：Acceptance Criteria For Pharmaceutical Preparations and Substances for Pharmaceutical Use General Chapter附录4C(R1) 地区使用的药典正文评估和建议非无菌产品微生物检验:药物制剂及原料药的认可标准通则21. Q4B ANNEX 5(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Disintegration Test General Chapter附录5(R1) ICH 地区使用的药典正文评估和建议崩解试验通则22. Q4B ANNEX 6 Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Uniformity of dosage units General Chapter附录6 ICH 地区使用的药典正文评估和建议含量均匀度通则word 格式-可编辑-感谢下载支持23. Q4B ANNEX 7(R2) Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Dissolution Test General Chapter附录7(R2) ICH 地区使用的药典正文评估和建议溶解度测试通则24. Q4B ANNEX 8(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Sterility Test General Chapter附录8(R1) ICH 地区使用的药典正文评估和建议无菌检查通则25. Q4B ANNEX 9(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Tablet Friability General Chapter附录9(R1) ICH 地区使用的药典正文评估和建议片剂脆碎度检查通则26. Q4B ANNEX 10(R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use inthe ICH Regions on Polyacrylamide Gel Electrophoresis General Chapter附录10(R1) ICH 地区使用的药典正文评估和建议聚丙烯酰胺凝胶电泳通则27. Q4B ANNEX 11 Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Capillary Electrophoresis General Chapter附录11 ICH 地区使用的药典正文评估和建议毛细管电泳通则28. Q4B ANNEX 12 Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Analytical Sieving General Chapter附录12 ICH 地区使用的药典正文评估和建议分析筛选通则29. Q4B ANNEX 13 Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Bulk Density and Tapped Density of Powders General Chapter附录13 ICH 地区使用的药典正文评估和建议粉末的松密度与密切度30. Q4B ANNEX 14 Evaluation and Recommendation of Pharmacopoeial Texts for Use in theICH Regions on Bacterial Endotoxins Test General Chapter附录14 ICH 地区使用的药典正文评估和建议细菌内毒素检测通则31. Q5A(R1): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines ofHuman or Animal Origin来源于人或者动物细胞系的生物技术产品的病毒安全性评估32. Q5B: Quality of Biotechnological Products: Analysis of the Expression Construct in CellsUsed for Production of r-DNA Derived Protein Products生物技术产品的质量：rDNA 衍生蛋白质产品生产细胞的表达构建体分析33. Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/BiologicalProducts生物技术产品的质量：生物技术产品/生物制品的稳定性试验34. Q5D: Derivation and Characterization of Cell Substrates Used for Production ofBiotechnological/Biological Products用于生产生物技术产品/生物制品的细胞基质的来源和鉴定35. Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in TheirManufacturing Process生产工艺变更后生物技术产品/生物制品的可比性质量标准36. Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances andNew Drug Products: Chemical Substances (including decision trees)规范：新原料药和新制剂的检测方法和可接收标准：化学物质(包括决定过程)37. Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/BiologicalProducts规范：生物技术产品/生物制品的检验方法和可接收标准38. Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients药物活性成份的GMP 指南39. Q8(R2): Pharmaceutical Development药物开辟40. Q9: Quality Risk Management质量风险管理41. Q10: Pharmaceutical Quality System药物质量体系42. Q11:Development and Manufacture of Drug Substances (Chemical Entities andBiotechnological/Biological Entities)原料药的开辟与创造(化学实体与生物技术/生物制品实体)1. S1A: Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals药物致癌试验的必要性2. S1B: Testing for Carcinogenicity of Pharmaceuticals药物致癌试验3. S1C(R2): Dose Selection for Carcinogenicity Studies of Pharmaceuticals药物致癌试验的剂量选择4. S2(R1) : Guidance on Genotoxicity Testing and Data Interpretation for PharmaceuticalsIntended for Human Use人用药物的遗传毒性试验和数据分析指导原则5. S3A: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in ToxicityStudies毒物代谢动力学指南的注释：毒性研究中全身暴露的评价6. S3B: Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies药物代谢动力学：重复给药的组织分布研究指导原则7. S4: Duration of Chronic Toxicity Testing in Animals (Rodent and Non Rodent ToxicityTesting)动物体内慢性毒性持续时间的检验(啮齿类和非啮齿类毒性试验)8. S5(R2) : Detection of Toxicity to Reproduction for Medicinal Products and Toxicity to MaleFertility药品的繁殖毒性检测及雄性生育力毒性9. S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals生物技术药品的临床前安全性试验10. S7A: Safety Pharmacology Studies for Human Pharmaceuticals人用药物的安全性药理研究11. S7B: The Non-clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QTInterval Prolongation) by Human Pharmaceuticals 人用药延迟心室复极化(QT 间期延长) 潜在作用的非临床评价指导原则12. S8: Immunotoxicity Studies for Human Pharmaceuticals人用药品的免疫毒理学研究13. S9: Nonclinical Evaluation for Anticancer Pharmaceuticals抗癌药物的临床前评价14. S10: Photosafety Evaluation of Pharmaceuticals药物的光安全评价1. E1: The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended forLong-Term Treatment of Non-Life-Threatening Conditions对非危及生命的疾病的长期治疗药物进行临床安全性评估的人群暴露程度2. E2A: Definitions and Standards for Expedited Reporting快速报告的定义和标准3. E2C(R2): Periodic Benefit-Risk Evaluation Report上市药品定期风险效益评估报告4. E2D: Post-Approval Safety Data Management: Definitions and Standards for ExpeditedReporting 批准后安全性数据管理：快速报告的定义和标准5. E2E: Pharmacovigilance Planning 药物警戒计划6. E2F: Development Safety Update Report 安全性更新报告7. E3: Structure and Content of Clinical Study Reports临床研究报告的结构与内容8. E4: Dose-Response Information to Support Drug Registration新药注册所需量-效关系的资料9. E5(R1): Ethnic Factors in the Acceptability of Foreign Clinical Data对国外临床研究资料的种族因素的可接受性10. E6(R1): Good Clinical Practice: Consolidated Guideline药品临床研究规范(GCP)一致性指导原则11. E6(R2): Integrated Addendum to ich E6(R1): Guideline for Good Clinical Practice E6(R1)整合的附录：药品临床研究规范指南12. E7: Studies in Support of Special Populations: Geriatrics老年人群的临床研究13. E8: General Considerations for Clinical Trials临床研究总则14. E9: Statistical Principles for Clinical Trials临床研究统计原则15. E10: Choice of Control Group and Related Issues in Clinical Trials临床研究对照组的选择及相关问题16. E11: Clinical Investigation of Medicinal Products in the Pediatric Population儿童人群的临床研究17. E12: Principles for Clinical Evaluation of New Antihypertensive Drugs抗高血压新药的临床评价指导原则18. E14: The Clinical Evaluation of QT/QTc Interval Prolongation and ProarrhythmicPotential for Non-Antiarrhythmic Drugs非抗心律失常药物致QT/QTc 间期延长及潜在心律失常作用的临床评价19. E15: Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, GenomicData and Sample Coding Categories基因组生物标记物、药物基因组学、遗传药理学、基因组数据和样本编码分类的定义20. E16: Biomarkers Related to Drug or Biotechnology Product Development: Context, Structureand Format of Qualification Submissions与药物或者生物技术产品相关的生物标记物研发: 申请资料的内容、结构和格式21. E17: General principle on planning/designing Multi-Regional Clinical Trials规划多地区临床试验的普通原则22. E18: Guideline on Genomic Sampling and Management of Genomic Data基因组数据采集与管理的指导原则1. M3: Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials andMarketing Authorization for Pharmaceuticals药物进行人体临床试验和上市许可申请的临床前安全性研究指导原则2. M4(R3): Organisation of the Common Technical Document for the Registration ofPharmaceuticals for Human Use人用药物注册申请的通用技术文件组织结构3. M4E(R1): The Common Technical Document for Registration of Pharmaceuticals for HumanUse Clinical人用药物注册申请的通用技术文件：临床4. M4E(R2): Revision of M4E Guideline on Enhancing Format and Structure of Benefit-riskInformation in ICH EfficacyM4E 指南修订，优化临床研究风险评估的格式与结构5. M4Q(R1): The Common Technical Document for the Registration of Pharmaceuticals forHuman Use: Quality人用药物注册申请的通用技术文件：质量6. M4S(R2): The Common Technical Document for the Registration of Pharmaceuticals forHuman Use: Safety人用药物注册申请的通用技术文件：安全性7. M4E(R1): The Common Technical Document for the Registration of Pharmaceuticals forHuman Use: Efficacy人用药物注册申请的通用技术文件：有效性8. M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals toLimit Potential Carcinogenic Risk为限制潜在致癌风险而对药物中DNA 活性(诱变性)杂质进行的评估和控制。

REVIEWCritical Care Management of Patients Following Aneurysmal Subarachnoid Hemorrhage:Recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus ConferenceMichael N.Diringer•Thomas P.Bleck•J.Claude Hemphill III•David Menon•Lori Shutter•Paul Vespa•Nicolas Bruder•E.Sander Connolly Jr.•Giuseppe Citerio•Daryl Gress•Daniel Ha¨nggi•Brian L.Hoh•Giuseppe Lanzino•Peter Le Roux•Alejandro Rabinstein•Erich Schmutzhard•Nino Stocchetti•Jose I.Suarez•Miriam Treggiari•Ming-Yuan Tseng•Mervyn D.I.Vergouwen•Stefan Wolf•Gregory ZipfelPublished online:20July2011ÓSpringer Science+Business Media,LLC2011Abstract Subarachnoid hemorrhage(SAH)is an acute cerebrovascular event which can have devastating effects on the central nervous system as well as a profound impact on several other organs.SAH patients are routinely admitted to an intensive care unit and are cared for by a multidisciplinary team.A lack of high quality data has led to numerous approaches to management and limited guidance on choos-ing among them.Existing guidelines emphasize risk factors, prevention,natural history,and prevention of rebleeding,but provide limited discussion of the complex critical care issues involved in the care of SAH patients.The Neurocritical Care Society organized an international,multidisciplinary con-sensus conference on the critical care management of SAH to address this need.Experts from neurocritical care,neuro-surgery,neurology,interventional neuroradiology,and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise.A jury of four experienced neurointensivists was selected for their experience in clinical investigations and development of practice guidelines.Recommendations were developed based on literature review using the GRADE system,dis-cussion integrating the literature with the collective experience of the participants and critical review by an impartial jury.Recommendations were developed using the GRADE system.Emphasis was placed on the principle thatDisclaimer This statement is provided as an educational service of the Neurocritical Care Society.It is based on an assessment of current literature and the consensus of the opinions of the attendees and jury of the conference.It is not intended to include all possible proper methods of care for SAH patients.Neither is it intended to exclude any reasonable alternative methodologies.The Neurocritical Care Society recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved.No formal practice recommendations should be inferred.The Organizer,Members of the Jury,and Conference participants in the International Multi-disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage are listed in Appendix.M.N.Diringer(&)Neurology/Neurosurgery Intensive Care Unit,Washington University,St.Louis,MO,USAe-mail:diringerm@T.P.BleckRush Medical College,Chicago,IL,USAJ.Claude Hemphill IIIUniversity of California at San Francisco,San Francisco, CA,USAD.MenonUniversity of Cambridge,Cambridge,UK L.ShutterUniversity of Cincinnati,Cincinnati,OH,USAP.VespaUniversity of California at Los Angeles,Los Angeles,CA,USA N.BruderUniversite´de la Me´diterrane´e,Marseille,FranceE.S.Connolly Jr.Columbia University,New York,NY,USANeurocrit Care(2011)15:211–240 DOI10.1007/s12028-011-9605-9recommendations should be based not only on the quality of the data but also tradeoffs and translation into practice. Strong consideration was given to providing guidance and recommendations for all issues faced in the daily man-agement of SAH patients,even in the absence of high quality data.Keywords Subarachnoid hemorrhageÁCritical careÁAneurysmÁVasospasmÁAnticonvulsantsÁHyponatremiaÁEndovascularÁFeverIntroductionSubarachnoid hemorrhage(SAH)is an acute cerebrovas-cular event which can have devastating effects on the central nervous system as well as a profound impact on several other organs.The course of the disease can be prolonged,with considerable secondary brain injury due to delayed cerebral ischemia(DCI).Systemic manifestations affecting cardiovascular,pulmonary,and renal function are common,and complicate the management of DCI.Due to the profound effects of the hemorrhage itself and the risk of early rebleeding and hydrocephalus,SAH patients are routinely admitted to an intensive care unit and are cared for by a multidisciplinary team including neurosur-geons,(neuro)intensivists,(neuro)anesthesiologists and interventional neuroradiologists.The ICU course of SAH patients ranges from a few days to a few weeks and is fre-quently accompanied by multiple medical complications.Despite considerable effort,only one intervention—the use of nimodipine—for this complex multifaceted disorder has been proven to improve outcome in prospective ran-domized controlled trials[1].This lack of high quality definitive data has led to numerous approaches to manage-ment and provides limited guidance on choosing among them.There have been relatively few guidelines developed for SAH management.They emphasize risk factors,preven-tion,natural history,and prevention of rebleeding,but provide limited discussion of the critical care issues involved in the care of SAH patients.In order to provide a comprehensive review of those issues the Neurocritical Care Society organized a multidisciplinary consensus conference on the critical care management of SAH. Topics were chosen based on their relevance to the critical care management of patients with aneurysmal SAH.Pro-cedures used to repair aneurysms were not addressed.Statement of PurposeThe purpose of the consensus conference was to develop recommendations for the critical care management of patients following acute SAH.The complex multi-organ pathophysiology of SAH presents a multitude of clinical challenges which demand attention.For each situation decisions must be made about if,when,and how to inter-vene.Ideally,each decision would be made based on high quality data;yet the reality is that such data rarely exist. Still,decisions about management must be made.Recom-mendations were developed based on the literature,a robust discussion regarding the interpretation of the liter-ature,the collective experience of the members of the group and review by an impartial jury.G.CiterioSan Gerardo Hospital,Monza,ItalyD.GressUniversity of Virginia,Charlottesville,VA,USAD.Ha¨nggiHeinrich-Heine University,Du¨sseldorf,GermanyB.L.HohUniversity of Florida,Gainesville,FL,USAnzinoÁA.RabinsteinMayo Clinic,Rochester,MN,USAP.Le RouxUniversity of Pennsylvania,Philadelphia,PA,USAE.SchmutzhardUniversity Hospital Innsbruck,Innsbruck,AustriaN.StocchettiFondazione IRCCS Ca`Granda–Ospedale Policlinico,Milan University,Milan,Italy J.I.SuarezBaylor College of Medicine,Houston,TX,USA M.TreggiariUniversity of Washington,St.Louis,MO,USA M.-Y.TsengNottingham University Hospitals,Nottingham,UK M.D.I.VergouwenUniversity of Utrecht,Utrecht,The Netherlands S.WolfFreie Universita¨t Berlin,Berlin,GermanyG.ZipfelWashington University,St.Louis,MO,USAProcessTopics were identified based on clinical decision points in the critical care management of SAH patients.Experts drawn from Europe and North America from thefields of neurosurgery, neurocritical care,neurology,interventional neuroradiology, and neuroanesthesiology were recruited based on their expertise related to each topic.A jury of four experienced neurointensivists was selected for their expertise in clinical investigation and development of practice guidelines.Each participant performed a critical literature review.The findings were summarized in tables and a summary was pre-pared which reviewed the data and provided specific management recommendations.These were submitted in draft form before the conference and distributed to all participants.The quality of the data was assessed and recommenda-tions developed using the GRADE system[2].The quality of the evidence was graded as:•High=Further research is very unlikely to change our confidence in the estimate of effect.•Moderate=Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.•Low=Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.•Very low=Any estimate of effect is very uncertain.The GRADE system classifies recommendations as strong or weak,according to the balance among benefits,risks, burden,and cost,and according to the quality of evidence. Keeping those components explicitly separate constitutes a crucial and defining feature of this grading system.An advantage of the GRADE system is that it allows for strong recommendations in the setting of lower quality evidence and thus it is well suited to this situation.Recommendations were either strong or weak and based on the following:•The trade-offs,taking into account the estimated size of the effect for the main outcomes,the confidence limits around those estimates,and the relative value placed on each outcome•The quality of the evidence•Translation of the evidence into practice in a specific setting,taking into consideration important factors that could be expected to modify the size of the expected effectsThe conference took place on October22–23,2010.Each participant presented a summary of the data and recom-mendations to the jury and other participants.Presentations were followed by discussion focused on refining the pro-posed management recommendations.Approximately1/3of the conference time was utilized for discussion.The jury met for2days after the conference and again at a subsequent2-day meeting and held several conference calls.They reviewed selected key studies,the recommen-dations made by the primary reviewers and the discussion that took place at the conference.Strong consideration was given to providing guidance and recommendations for all issues faced in the daily management of SAH patients, even in the absence of high quality data.Medical Measures to Prevent RebleedingQuestions Addressed•Do any medical interventions reduce the incidence of rebleeding in patients awaiting definitive management of their ruptured aneurysm?•Do alterations in investigative approaches reduce the incidence of rebleeding in patients awaiting definitive management of their ruptured aneurysm?•Does stringent blood pressure reduction reduce the incidence of rebleeding in patients awaiting definitive management of their ruptured aneurysm?Summary of the LiteratureRebleeding following aneurysmal SAH is common.Its incidence is highest immediately following the initial hemorrhage(5–10%over thefirst72h)[3],is higher in patients with poor-grade SAH,larger aneurysms,sentinel bleeds,and those who undergo catheter angiography within 3h of the ictus.Immediate repair of the ruptured aneurysm by either coil embolization or microsurgical clip ligation markedly reduces the risk of rebleeding,with microsurgical exclusion being slightly more efficacious[4].Nevertheless, some patients are either too sick for immediate repair or require transport to a center where repair can be performed. Repair procedures have significant risks and require experienced teams to minimize the serious procedural side effects of repair.This fact can lead to further delay in repair,and increase the risk of rebleeding.We considered three interventions that might modulate this risk:antifi-brinolytic therapy,catheter vs.CT angiography,and blood pressure control.Nine studies of antifibrinolytic therapy prior to2002 involving1399patients showed no benefit on poor out-come or death despite a marked significant reduction in rebleeding,probably due to a significantly higher incidence of cerebral ischemia in the treated patients[5].It is note-worthy that all of these studies continued therapy for weeks (into the period when the risk of vasospasm was high),and at least one of these studies initiated therapy as late as 4days post-ictus,when the risk of rebleeding wassubstantially reduced.More recently,one randomized trial (involving505patients)[6]and two case control studies (involving428patients)[7,8]examined whether an early short course of antifibrinolytic therapy can reduce the risk of rebleeding while early,safe repair is being arranged.A third study also found a reduction in rebleeding but noted an increased incidence of DVTs[8].These studies suggest a uniform reduction in rebleeding rates from*11to *2.5%,but the studies were not adequately powered to determine the effect of antifibrinolytic therapy on overall patient outcome.Several case reports or case series report aneurysmal rebleeding when catheter angiography is undertaken very early(less than3–6h)following aneurysmal SAH.Specific rebleeding rates are difficult to compute,as many of these are individual case reports,and the denominator in case series (i.e.,the total number of patients undergoing early angiog-raphy)is poorly defined.However,rates as high as20–38.5% have been quoted[9–13].It seems unwarranted to conclude this is a specific risk attributable to DSA for several reasons. First,where a clear denominator is provided to assess the incidence of rebleeding,figures are much lower(*5%)[11]. Second,it is unclear whether these instances of rebleeding with DSA actually reflect a risk of the procedure,or are simply a manifestation of the high rebleeding rates known to occur after initial aneurysm rupture.Third,there is no sat-isfactory direct comparison of rebleeding with and without DSA or to CTA within thefirst6h post-SAH;the one case series that does report a twofold risk with DSA included only a small number of patients[12].Intriguingly,reports of contrast extravasation during ultra-early CTA[14,15]have heretofore been interpreted as the investigation being able to image the process of early rebleeding[13],rather than being a cause of such rebleeding.There are no systematic data that address blood pressure levels in patients with unsecured aneurysms in relation to the risk of rebleeding.Some early studies of hypervolemic–hypertensive therapy reported aneurysmal rebleeding or hemorrhagic transformation of hypodense lesions with ele-vation of systolic blood pressure to160–200mmHg. However,more recent series do not report rebleeding at systolic blood pressure in this range,and the clear consensus of the participants at the workshop was that modest blood pressure elevation(mean arterial pressure<110mmHg; systolic blood pressure<160mmHg)was not associated with rebleeding.DiscussionFurther definitive evidence of benefit from antifibrinolytic agents will require a trial with very early identification of patients and early administration of tranexamic acid or aminocaproic acid,a large sample size and sufficient power to detect an effect on functional outcome.Patients in good neurological condition with evidence of sentinel hemor-rhage,loss of consciousness at ictus and who harbor larger aneurysms on initial CTA are likely to be the best popu-lation for study.There appears to be sufficient equipoise in the USA for such a trial to be conducted,and we would underline the fact that our recommendations in this area would need to be revised when data from such a study were available.Given the less-than-definitive evidence on which we have based our recommendation for early antifibrino-lytic therapy,we have explicitly stated several cautionary recommendations that would mitigate against side effects of the intervention.We did not feel that the data available provided a clear basis for attributing an increased rebleeding risk to ultra-early DSA.Formal assessment of catheter vs.CT angiog-raphy in the hyperacute phase would require further collection of epidemiological data in thefirst instance,and a large trial comparing the two would be needed to provide definitive recommendations.Given that CTA is now well established,it seems unlikely that a large RCT comparing DSA and CTA will ever materialize.However,pending the continued collection of epidemiological data,it was felt that choosing CTA over DSA for ultra-early angiography was a reasonable option where both options are available, the technical quality of CTA was good,and an endovas-cular intervention was not planned at the time of angiography.However,in the setting of SAH,the over-whelming aim is to detect and secure a culprit aneurysm, and there is no case for delaying investigation(either CTA or DSA)to reduce any theoretical risk of rebleeding.There appears to be little concern that rebleeding with modest blood pressure elevation is a significant clinical issue,and there was no enthusiasm for a study addressing this issue.Recommendations•Early aneurysm repair should be undertaken,when possible and reasonable,to prevent rebleeding(High Quality Evidence;Strong Recommendation).•An early,short course of antifibrinolytic therapy prior to early aneurysm repair(begun at diagnosis;continued up to the point at which the aneurysm is secured or at72h post-ictus,whichever is shorter)should be considered (Low Quality Evidence;Weak Recommendation).•Delayed(>48h after the ictus)or prolonged(>3days) antifibrinolytic therapy exposes patients to side effects of therapy when the risk of rebleeding is sharply reduced and should be avoided(High Quality Evidence;Strong Recommendation).•Antifibrinolytic therapy is relatively contraindicated in patients with risk factors for thromboemboliccomplications(Moderate Quality Evidence;Strong Recommendation).•Patients treated with antifibrinolytic therapy should have close screening for deep venous thrombosis(Moderate Quality Evidence;Strong Recommendation).•Antifibrinolytic therapy should be discontinued2h before planned endovascular ablation of an aneurysm (Very Low Quality Evidence;Weak Recommendation).•When CTA and DSA are both available and CTA is of high technical quality,CTA should be performed preferentially if endovascular intervention is not planned at the time of angiography(Very Low Quality Evidence;Weak Recommendation).•Treat extreme hypertension in patients with an unse-cured,recently ruptured aneurysm.Modest elevations in blood pressure(mean blood pressure<110mmHg) do not require therapy.Pre-morbid baseline blood pressures should be used to refine targets;hypotension should be avoided(Low Quality Evidence;Strong Recommendation).Seizures and Prophylactic Anticonvulsant Use Questions Addressed•What is the incidence and impact of convulsive and non-convulsive seizures after SAH?•Does anticonvulsant prophylaxis influence this incidence?Summary of the LiteratureAbnormal movements that may appear seizure-like are common at the onset of SAH,but it is usually unclear whether this is a true seizure or represents posturing at the time of aneurysm rupture[16,17].Clinical seizures are uncommon after the initial aneurysm rupture(occurring in 1–7%of patients)and when they occur in patients with an unsecured aneurysm,they are often the manifestation of aneurysmal re-rupture[4,18].Risk factors for the development of seizures in SAH are surgical aneurysm repair in patients>65years of age,thick subarachnoid clot,and possibly intraparenchymal hematoma or infarc-tion[16,17].Prophylactic treatment with anticonvulsants in SAH patients without seizures has previously been commonplace,although no randomized trials specifically addressing this issue have been performed.Recent studies have suggested that anticonvulsant use is associated with worsened long-term outcome after SAH,although most of the patients in these studies were treated with phenytoin [19,20].Thus,prophylactic anticonvulsant therapy with phenytoin may worsen outcome,although the impact of other anticonvulsant medications is less clear.Also,in patients with no history of seizure,a short course(72h) of anticonvulsant prophylaxis seems as effective as a more prolonged course in preventing seizures[21].In comatose(poor-grade)SAH patients,non-convulsive sei-zures may be detected on continuous EEG(cEEG)in 10–20%of cases[22–24].While patients with non-con-vulsive seizures have a worsened outcome,the impact of successful treatment of these non-convulsive seizures has not been studied.Also,the influence of anticonvulsant prophylaxis on the occurrence of non-convulsive seizures has not been studied.DiscussionThere was general agreement among the participants that current evidence raises concern that anticonvulsants,spe-cifically phenytoin,may worsen outcome after SAH. Therefore,there was consensus that routine prophylactic phenytoin use should not be undertaken after SAH.There was,however,controversy regarding use of other anti-convulsant medications and the unknown potential for anticonvulsants to lessen the impact of non-convulsive seizures.Also,the possibility that certain subgroups,such as elderly patients undergoing craniotomy,may have a higher seizure risk led the group to consider that a short course(3–7days)of anticonvulsant prophylaxis might still be considered in certain situations,especially if an agent other than phenytoin was used.There was also agreement that patients who suffer a clear clinical seizure after the period of aneurysmal rupture should be treated with anti-convulsants,but that if seizures do not recur,these anticonvulsants should be discontinued after3–6months. There was disagreement about whether an EEG should be performed at that time and,if so,whether seizure-free patients with an epileptic focus should be continued on anticonvulsants.There was consensus that cEEG is prob-ably underutilized in poor-grade SAH patients and that non-convulsive seizures are common.However,there was concern regarding whether these non-convulsive seizures represented markers of disease severity or a target for treatment.Thus,there was modest disagreement on the aggressiveness with which to pursue treatment of non-convulsive seizures.There was a general agreement that one or perhaps two anticonvulsants should be used to attempt to treat non-convulsive seizures identified on cEEG,but disagreement about whether to pursue more aggressive means such as benzodiazepine or barbiturate infusions if initial measures were unsuccessful.Recommendations•Routine use of anticonvulsant prophylaxis with phe-nytoin is not recommended after SAH(low quality evidence—strong recommendation).•Routine use of other anticonvulsants for prophylaxis may be considered(very low quality evidence—weak recommendation).•If anticonvulsant prophylaxis is used,a short course (3–7days)is recommended(low quality evidence—weak recommendation).•In patients who suffer a seizure after presentation, anticonvulsants should be continued for a duration defined by local practice(low quality evidence—weak recommendation).•Continuous EEG monitoring should be considered in patients with poor-grade SAH who fail to improve or who have neurological deterioration of undetermined etiology(low quality evidence—strong recommendation).Cardiopulmonary ComplicationsQuestions Addressed•What monitoring should be utilized in SAH patients with cardiovascular instability?•Are there recommendations regarding managing car-diopulmonary complications in patients with SAH? Summary of the LiteratureMyocardial injury occurs following SAH and is thought to be related to sympathetic stimulation and catecholamine discharge.Elevations of troponin I levels occur in approximately35%[25,26],arrhythmias in35%[27],and wall motion abnormalities on echocardiography in about 25%of patients with SAH[28].Echocardiographic abnormalities are more frequent in patients with elevated troponin levels.The terms‘‘Neurogenic Stress Cardiomy-opathy’’and‘‘Stunned Myocardium’’have been applied to the clinical syndrome of chest pain;dyspnea;hypoxemia, and cardiogenic shock with pulmonary edema and elevated cardiac markers that occurs within hours of SAH.This syndrome has a wide spectrum of severity,and it may contribute to sudden death in12%of patients.The mani-festations are usually transient lasting1–3days after which myocardial function returns to normal.Management should focus on supportive care that balances cardiac needs with the neurological goals[29].In general,cardiac abnormalities are more common in patients who later develop DCI and have worse outcomes [30].Although several mechanisms have been proposed to explain the cardiac abnormalities,the evidence seems strongest for a catecholamine induced process[29].Mon-itoring of cardiac function may be beneficial in the setting of hemodynamic instability or myocardial dysfunction,but there is no evidence that it improves outcome.Manage-ment of cardiac complications is heterogeneous,and interventions should reflect current best medical practices.Symptomatic pulmonary complications occur in over 20%of patients after SAH[31,32],although evidence of impaired oxygenation occurs in up to80%[33].These complications are associated with worse clinical grade SAH and higher mortality[34–36].Patients may develop pulmonary edema(cardiac or neurogenic),acute lung injury or acute respiratory distress syndrome.The mecha-nism of pulmonary injury may also be related to sympathetic hyperactivity or cardiac failure.Management of pulmonary issues follows general principles of pul-monary management,however,with careful attention to avoid hypovolemia.DiscussionThe participants all agreed that cardiopulmonary compli-cations are common after SAH,and have a significant impact on clinical care.They frequently complicate management by increasing procedural risk and exacerbate brain oxygen delivery by lowering perfusion pressure and arterial oxygenation saturation.It was generally agreed that a baseline assessment of cardiac function with echocardiography may be beneficial,especially if there are any signs of myocardial dysfunction.Although there is limited evidence,the panel strongly felt that cardiac output should be monitored(invasively or non-invasively) in those patients with myocardial dysfunction or hemo-dynamic instability.The participants voiced the opinion that management of these complications may vary based on the patient’s clin-ical status and in the setting of vasospasm.There was strong agreement that cardiopulmonary issues are wors-ened in the event of hypervolemia,thus the goal of therapy should be euvolemia.The panel also strongly recom-mended that management of cardiopulmonary issues should reflect current best medical practice,while balanc-ing the needs of the underlying neurological condition. RecommendationsMonitoring•Baseline cardiac assessment with serial enzymes, electrocardiography,and echocardiography is recom-mended,especially in patients with evidence ofmyocardial dysfunction(Low quality evidence;Strong Recommendation).•Monitoring of cardiac output may be useful in patients with evidence of hemodynamic instability or myocar-dial dysfunction.(Low quality evidence;Strong Recommendation).Treatment•In case of pulmonary edema or evidence of lung injury,the goal of therapy should include avoiding excessivefluid intake and judicious use of diuretics targeting euvolemia (Moderate quality evidence;Strong recommendation).•Standard management of heart failure is indicated with the exception that CPP/MAP should be maintained as appropriate for the neurological condition.(Moderate quality evidence;Strong recommendation). Monitoring Intravascular Volume StatusQuestions Addressed•What is the role of monitoringfluid balance and central venous pressure(CVP)?•What measurements should be used to assess blood volume?•Is there a role for non-invasive hemodynamic monitoring?•Is there a role for pulmonary artery catheters(PACs)? Summary of the LiteratureSAH patients frequently develop hypovolemia and hypo-natremia.Retrospective studies have identified a relationship between hypovolemia and an increased inci-dence of cerebral infarcts and worse outcome[37,38]; especially whenfluid administration is restricted.For this reason,assessment of intravascular volume in patients after SAH is essential to daily management.Therefore,guidance is needed regarding the mechanism and impact of altera-tions influid balance,and the methods for monitoring volume status.Available literature describes multiple fac-tors that may contribute to changes in volume status [39,40].Fluid balance may not accurately reflect intravascular volume[41–44],therefore invasive and non-invasive methods have been used as possible alternatives to monitor volume status.Although all methods provide information to guide patient management,none have demonstrated superiority over vigilantfluid management[45–47].In fact,CVP appears to be an unreliable indicator of intravascular volume[45,46],and,although PACs may have a role in hemodynamically unstable patients,the complications associated with their routine use appear to outweigh any potential benefit[48–50].DiscussionThe participants generally agreed that volume status of patients should be monitored after SAH even though it may not accurately reflect intravascular volume,nor is there evidence that close monitoring has a beneficial impact on outcome.The panel discussed multiples methods to monitor vol-ume status,and weighed the evidence regarding potential risk versus benefit of each.It was generally felt that both physicalfindings and clinical data must be integrated into assessment of volume status.Although there was not a preferred method of monitoring volume status,a hierar-chical approach is often used.The primary assessment should be close monitoring offluid input and output.Other invasive and non-invasive modalities may be used to pro-vide supplemental information based on the clinical scenario,but no one tool should be used in isolation.The panel did voice strong agreement against the routine use of invasive PACs or dependence on CVP targets. Recommendations•Monitoring of volume status may be beneficial(Mod-erate quality evidence;weak recommendation).•Vigilantfluid balance management should be the foundation for monitoring intravascular volume status.While both non-invasive and invasive monitoring technologies are available,no specific modality can be recommended over clinical assessment(Moderate quality evidence;weak recommendation).•Central venous lines should not be placed solely to obtain CVP measures andfluid management based solely on CVP measurements is not recommended (Moderate quality evidence;strong recommendation).•Use of PACs incurs risk and lacks evidence of benefit.Routine use of PACs is not recommended(Moderate quality evidence;strong recommendation). Managing Intravascular Volume StatusQuestions Addressed•Should prophylactic hypervolemia be employed in the management of SAH patients?。

Needle-based injection systems for medical use 医用针基注射系统— Requirements and test methods要求和测试方法—Part 2: Needles第二部分：针INTERNATIONAL STANDARDISO 11608-2Second edition2012-04-01Contents 目录PageForeword (iv)Introduction (v)1 Scope (1)2 Normative references (1)3 Terms and definitions (1)4 Requirements (3)4.1 Materials (3)4.2 Dimensions (3)4.3 Determination of flow rate through the needle... ... ... . (3)4.4 Bond between hub and needle tube (3)4.5 Needle points (4)4.6 Freedom from defects (4)4.7 Lubrication (4)4.8 Dislocation of measuring point at patient end (4)4.9 Determination of functional compatibility with needle-based injection systems (4)4.10 Ease of assembly and disassembly (4)4.11 Sterility (4)5 Sampling (4)6 Pre-conditioning of needles (5)6.1 Pre-conditioning in a dry-heat a tmosphere (5)6.2 Pre-conditioning in a cold-storage atmosphere (5)6.3 Pre-conditioning in a cyclical atmosphere (5)7 Standard atmosphere and apparatus for tests (6)7.1 General (6)7.2 Standard test atmosphere (6)7.3 Test gauge (6)8 Determination of dislocation of measuring point at patient end (7)9 Bond between hub and needle tube (8)10 Packaging (8)11 Test method for validating the compatibility of needles and injector systems (8)11.1 Principle (8)11.2 Apparatus and equipment (9)11.3 Sample quantity requirements (9)11.4 Procedure (9)11.5 Acceptance criteria (11)11.6 Test report (12)12 Information supplied by the manufacturer (12)12.1 General (12)12.2 Marking (12)12.3 Instructions for use (14)Annex A (normative) Determination of flow rate through needle (15)Bibliography (17)Foreword前言ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.The main task of technical committees is to prepare International Standards. Draft International Standards adopted by the technical committees are circulated to the member bodies for voting. Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote.Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights.ISO 11608 -2 was prepared by Technical Committee ISO/TC 84, Devices for administration of medicinal products and intravascular catheters.This second edition cancels and replaces the first edition ( ISO 11608 -2:2000), which has been technically revised.ISO 11608 consists of the following parts, under the general title Needle-based injection systems for medical use — Requirements and test methods:ISO 11608由以下部分组成，共用标题医用针基注射系统-要求和测试方法—Part 1: Needle-based injection systems 针基注射系统—Part 2: Needles 针—Part 3: Finished containers 最终包装—Part 4: Requirements and test methods for electronic and electromechanical pen-injectors 电动笔式注射器的要求和测试方法—Part 5: Automated functions 自动化功能Needle-based injection systems for medical use医用针基注射系统— Requirements and test methods要求和测试方法—Part 2: Needles第二部分：针1 ScopeThis part of ISO 11608 specifies requirements and test methods for single-use, double-ended, sterile needles for needle-based injection systems (NISs) that fulfil the specifications of ISO 11608-1.本部分的ISO 11608规定了，与NIS（符合ISO11608-1要求）配合的一次性使用双头无菌针的要求和检测方法。

BiRd方案治疗多发性骨髓瘤(附5例报告)王韵;朱彦;费小明【摘要】目的:观察来那度胺联合地塞米松、克拉霉素的BiRd方案治疗复发难治性多发性骨髓瘤(MM)的疗效和不良反应.方法:本组5例复发难治性MM患者,平均年龄56.2岁(44～71)岁.在为期4周的疗程内来那度胺口服每日25 mg,首个疗程从第3日～第21日,后续的疗程为第1～第21日;地塞米松口服每日40 mg,首个疗程第1,2,3,8,15,22日,后续的疗程第1,8,15,22日;克拉霉素每次500 mg,每日2次.患者分别接受2～7个疗程的治疗.采用IMWG标准观察疗效,并按NCICTCAE(第4版)标准判断不良反应.结果:4例患者对治疗有效,其中1例完全缓解,3例部分缓解,1例病情进展.不良反应方面,1例患者出现腹胀及便秘,对症治疗后好转.2例患者出现白细胞减少,未发生发热及感染.2例患者发生短暂血小板减少,未发生出血,予以对症治疗后好转.2例患者骨痛缓解,1例患者肾功能不全改善,所有患者贫血症状得到改善.结论:BiRd方案治疗复发难治性多发性骨髓瘤是一种新的治疗选择,不良反应少且易于控制.【期刊名称】《淮海医药》【年(卷),期】2016(034)001【总页数】3页(P12-14)【关键词】多发性骨髓瘤;复发难治性;来那度胺;克拉霉素;地塞米松【作者】王韵;朱彦;费小明【作者单位】江苏大学附属医院血液内科,江苏镇江212001;江苏大学附属医院血液内科,江苏镇江212001;江苏大学附属医院血液内科,江苏镇江212001【正文语种】中文【中图分类】R733.3多发性骨髓瘤(MM)是浆细胞恶性增生性疾病，约占全部恶性肿瘤的1%，血液恶性肿瘤的10%。

目前在我国联合化疗仍然是其治疗的主要手段，自1969年被用于治疗MM以来，马法兰联合泼尼松(MP)的联合化疗方案，仍是MM的标准方案之一。

近十年来，由于造血干细胞移植技术的成熟，长春新碱、阿霉素联合地塞米松(VAD)的联合化疗方案成为MM行自体移植前的标准方案之一[1-3]。