Gurusamy Kurinchi Selvan, Best Lawrence Mj, Tanguay Cynthia, Lennan Elaine, Korva Mika, Bussières Jean-François
Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UK, NW3 2PF.
Cochrane Database Syst Rev. 2018 Mar 27;3(3):CD012860. doi: 10.1002/14651858.CD012860.pub2.
Occupational exposure to hazardous drugs can decrease fertility and result in miscarriages, stillbirths, and cancers in healthcare staff. Several recommended practices aim to reduce this exposure, including protective clothing, gloves, and biological safety cabinets ('safe handling'). There is significant uncertainty as to whether using closed-system drug-transfer devices (CSTD) in addition to safe handling decreases the contamination and risk of staff exposure to infusional hazardous drugs compared to safe handling alone.
To assess the effects of closed-system drug-transfer of infusional hazardous drugs plus safe handling versus safe handling alone for reducing staff exposure to infusional hazardous drugs and risk of staff contamination.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, OSH-UPDATE, CINAHL, Science Citation Index Expanded, economic evaluation databases, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to October 2017.
We included comparative studies of any study design (irrespective of language, blinding, or publication status) that compared CSTD plus safe handling versus safe handling alone for infusional hazardous drugs.
Two review authors independently identified trials and extracted data. We calculated the risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models. We assessed risk of bias according to the risk of bias in non-randomised studies of interventions (ROBINS-I) tool, used an intracluster correlation coefficient of 0.10, and we assessed the quality of the evidence using GRADE.
We included 23 observational cluster studies (358 hospitals) in this review. We did not find any randomised controlled trials or formal economic evaluations. In 21 studies, the people who used the intervention (CSTD plus safe handling) and control (safe handling alone) were pharmacists or pharmacy technicians; in the other two studies, the people who used the intervention and control were nurses, pharmacists, or pharmacy technicians. The CSTD used in the studies were PhaSeal (13 studies), Tevadaptor (1 study), SpikeSwan (1 study), PhaSeal and Tevadaptor (1 study), varied (5 studies), and not stated (2 studies). The studies' descriptions of the control groups were varied. Twenty-one studies provide data on one or more outcomes for this systematic review. All the studies are at serious risk of bias. The quality of evidence is very low for all the outcomes.There is no evidence of differences in the proportion of people with positive urine tests for exposure between the CSTD and control groups for cyclophosphamide alone (RR 0.83, 95% CI 0.46 to 1.52; I² = 12%; 2 studies; 2 hospitals; 20 participants; CSTD: 76.1% versus control: 91.7%); cyclophosphamide or ifosfamide (RR 0.09, 95% CI 0.00 to 2.79; 1 study; 1 hospital; 14 participants; CSTD: 6.4% versus control: 71.4%); and cyclophosphamide, ifosfamide, or gemcitabine (RR not estimable; 1 study; 1 hospital; 36 participants; 0% in both groups).There is no evidence of a difference in the proportion of surface samples contaminated in the pharmacy areas or patient-care areas for any of the drugs except 5-fluorouracil, which was lower in the CSTD group than in the control (RR 0.65, 95% CI 0.43 to 0.97; 3 studies, 106 hospitals, 1008 samples; CSTD: 9% versus control: 13.9%).The amount of cyclophosphamide was lower in pharmacy areas in the CSTD group than in the control group (MD -49.34 pg/cm², 95% CI -84.11 to -14.56, I² = 0%, 7 studies; 282 hospitals, 1793 surface samples). Additionally, one interrupted time-series study (3 hospitals; 342 samples) demonstrated a change in the slope between pre-CSTD and CSTD (3.9439 pg/cm², 95% CI 1.2303 to 6.6576; P = 0.010), but not between CSTD and post-CSTD withdrawal (-1.9331 pg/cm², 95% CI -5.1260 to 1.2598; P = 0.20). There is no evidence of difference in the amount of the other drugs between CSTD and control groups in the pharmacy areas or patient-care areas.None of the studies report on atmospheric contamination, blood tests, or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction.None of the studies report short-term health benefits such as reduction in skin rashes, medium-term reproductive health benefits such as fertility and parity, or long-term health benefits related to the development of any type of cancer or adverse events.Five studies (six hospitals) report the potential cost savings through the use of CSTD. The studies used different methods of calculating the costs, and the results were not reported in a format that could be pooled via meta-analysis. There is significant variability between the studies in terms of whether CSTD resulted in cost savings (the point estimates of the average potential cost savings ranged from (2017) USD -642,656 to (2017) USD 221,818).
AUTHORS' CONCLUSIONS: There is currently no evidence to support or refute the routine use of closed-system drug transfer devices in addition to safe handling of infusional hazardous drugs, as there is no evidence of differences in exposure or financial benefits between CSTD plus safe handling versus safe handling alone (very low-quality evidence). None of the studies report health benefits.Well-designed multicentre randomised controlled trials may be feasible depending upon the proportion of people with exposure. The next best study design is interrupted time-series. This design is likely to provide a better estimate than uncontrolled before-after studies or cross-sectional studies. Future studies may involve other alternate ways of reducing exposure in addition to safe handling as one intervention group in a multi-arm parallel design or factorial design trial. Future studies should have designs that decrease the risk of bias and enable measurement of direct health benefits in addition to exposure. Studies using exposure should be tested for a relevant selection of hazardous drugs used in the hospital to provide an estimate of the exposure and health benefits of using CSTD. Steps should be undertaken to ensure that there are no other differences between CSTD and control groups, so that one can obtain a reasonable estimate of the health benefits of using CSTD.
医护人员职业接触危险药物会降低生育能力，并导致流产、死产和癌症。有几种推荐的做法旨在减少这种接触，包括防护服、手套和生物安全柜（“安全操作”）。与仅采用安全操作相比，除安全操作外使用密闭式药物转移装置（CSTD）是否能降低输注危险药物时的污染及工作人员接触风险，目前仍存在很大不确定性。
评估输注危险药物时采用CSTD加安全操作与仅采用安全操作相比，对减少工作人员接触输注危险药物及降低工作人员污染风险的效果。
我们检索了截至2017年10月的Cochrane对照试验中心注册库（CENTRAL）、MEDLINE、Embase、职业安全与健康更新数据库（OSH-UPDATE）、护理学与健康领域数据库（CINAHL）、科学引文索引扩展版、经济评估数据库、世界卫生组织国际临床试验注册平台及美国国立医学图书馆临床试验数据库（ClinicalTrials.gov）。
我们纳入了任何研究设计的比较研究（无论语言、是否设盲或发表状态），这些研究比较了CSTD加安全操作与仅采用安全操作在输注危险药物方面的差异。
两位综述作者独立识别试验并提取数据。我们使用固定效应模型和随机效应模型计算风险比（RR）和平均差（MD）及其95%置信区间（CI）。我们根据干预性非随机研究的偏倚风险（ROBINS-I）工具评估偏倚风险，使用0.10的组内相关系数，并使用GRADE评估证据质量。
本综述纳入了23项观察性整群研究（358家医院）。我们未找到任何随机对照试验或正式的经济评估。在21项研究中，使用干预措施（CSTD加安全操作）和对照措施（仅安全操作）的人员为药剂师或药房技术员；在另外两项研究中，使用干预措施和对照措施的人员为护士、药剂师或药房技术员。研究中使用的CSTD有PhaSeal（13项研究）、Tevadaptor（1项研究）、SpikeSwan（1项研究）、PhaSeal和Tevadaptor（1项研究）、多种类型（5项研究）以及未说明（2项研究）。各研究对对照组的描述各不相同。21项研究为本系统评价提供了一项或多项结局的数据。所有研究均存在严重偏倚风险。所有结局的证据质量都非常低。对于仅使用环磷酰胺的情况，CSTD组和对照组尿液检测呈阳性的暴露人员比例没有差异（RR = 0.83，95%CI为0.46至1.52；I² = 12%；2项研究；2家医院；20名参与者；CSTD组：76.1%，对照组：91.7%）；对于环磷酰胺或异环磷酰胺，没有差异（RR = 0.09，95%CI为0.00至2.79；1项研究；1家医院；14名参与者；CSTD组：6.4%，对照组：71.4%）；对于环磷酰胺、异环磷酰胺或吉西他滨，没有差异（RR无法估计；1项研究；1家医院；36名参与者；两组均为0%）。除5-氟尿嘧啶外，对于任何药物，药房区域或患者护理区域表面样本污染比例在CSTD组和对照组之间均无差异，5-氟尿嘧啶在CSTD组中的污染比例低于对照组（RR = 0.65，95%CI为0.43至0.97；3项研究，106家医院，1008个样本；CSTD组：9%，对照组：13.9%）。CSTD组药房区域中环磷酰胺的含量低于对照组（MD = -49.34 pg/cm²，95%CI为-84.11至-14.56，I² = 0%，7项研究；282家医院，1793个表面样本）。此外，一项中断时间序列研究（3家医院；342个样本）表明，在使用CSTD之前和使用CSTD期间斜率发生了变化（3.9439 pg/cm²，95%CI为1.2303至6.6576；P = 0.010），但在使用CSTD期间和停用CSTD之后没有变化（-1.9331 pg/cm²，95%CI为-5.1260至1.2598；P = 0.20）。在药房区域或患者护理区域，CSTD组和对照组之间其他药物的含量没有差异。没有研究报告大气污染、血液检测或其他输注危险药物暴露指标，如尿液致突变性、染色体畸变、姐妹染色单体交换或微核诱导。没有研究报告短期健康益处，如皮疹减少，中期生殖健康益处，如生育能力和生育次数，或与任何类型癌症或不良事件发生相关的长期健康益处。五项研究（六家医院）报告了使用CSTD可能节省的成本。这些研究使用了不同的成本计算方法，结果未以可通过Meta分析合并的格式报告。在CSTD是否能节省成本方面，各研究之间存在显著差异（平均潜在成本节省的点估计范围为2017年美元-642,656至2017年美元221,818）。
目前没有证据支持或反驳在输注危险药物的安全操作之外常规使用密闭式药物转移装置，因为没有证据表明CSTD加安全操作与仅采用安全操作在暴露或经济效益方面存在差异（证据质量极低）。没有研究报告健康益处。根据暴露人群的比例，精心设计的多中心随机对照试验可能可行。次优的研究设计是中断时间序列研究。这种设计可能比无对照的前后研究或横断面研究提供更好的估计。未来的研究可能涉及除安全操作之外的其他减少暴露的方法，作为多臂平行设计或析因设计试验中的一个干预组。未来的研究应采用能够降低偏倚风险并能够测量除暴露之外直接健康益处的设计。使用暴露指标的研究应针对医院使用的相关危险药物进行测试，以估计使用CSTD的暴露情况和健康益处。应采取措施确保CSTD组和对照组之间没有其他差异，以便能够合理估计使用CSTD的健康益处。
