chICAGO JOURNALS  芝加哥期刊

Effectiveness of Oral Rinse with Chlorhexidine in Preventing Nosocomial Respiratory Tract
;; 使用氯己定漱口液预防医院获得性呼吸道感染的有效性
Infections among Intensive Care Unit Patients -
重症监护病房患者中的感染情况 -
Author(s): Fernando Bellissimo-Rodrigues, MD, PhD; Wanessa Teixeira Bellissimo-Rodrigues,
作者：费尔南多·贝利西莫-罗德里格斯，医学博士，哲学博士；瓦内萨·特谢拉·贝利西莫-罗德里格斯，
DDS, PhD; Jaciara Machado Viana, MD, MS; Gil Cezar Alkmim Teixeira, MD; Edson Nicolini,
牙科博士，哲学博士；雅西亚拉·马查多·维亚纳，医学博士，理学硕士；吉尔·塞萨尔·阿尔克明·特谢拉，医学博士；埃德森·尼科利尼，
MD; Maria Auxiliadora-Martins, MD, PhD; Afonso Dinis Costa Passos, MD, PhD;
医学博士；Maria Auxiliadora-Martins，医学博士，哲学博士；Afonso Dinis Costa Passos，医学博士，哲学博士；
Edson Zangiacomi Martinez, Stat, PhD; Anibal Basile-Filho, MD, PhD; Roberto Martinez, MD, 
PhD 
Source: Infection Control and Hospital Epidemiology, Vol. 30, No. 10 (October 2009), pp. 952-
来源：《感染控制与医院流行病学》，第 30 卷，第 10 期（2009 年 10 月），第 952 页
958
Published by: The University of Chicago Press on behalf of The Society for Healtheare Epidemiology
出版者：芝加哥大学出版社代表美国医疗保健流行病学学会
of America  美国
Stable URL: http://www.jstor.org/stable/10.1086/605722
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овjective. To evaluate the effectiveness of the oral application of a $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% solution of chlorhexidine for prevention of respiratory tract infections among intensive care unit (ICU) patients.
目的。评估口服 0#氯己定溶液在预防重症监护病房（ICU）患者呼吸道感染中的有效性。
design. The study design was a double-blind, randomized, placebo-controlled trial.
设计。本研究采用双盲、随机、安慰剂对照试验设计。
setting. The study was performed in an ICU in a tertiary care hospital at a public university.
地点。研究在一所公立大学附属三级医院的 ICU 内进行。
patients. Study participants comprised 194 patients admitted to the ICU with a prospective length of stay greater than 48 hours, randomized into 2 groups: those who received chlorhexidine $(n=98)$$(n=98)$(n=98)(n=98) and those who received a placebo $(n=96)$$(n=96)$(n=96)(n=96).
患者。研究对象包括 194 名预计入住 ICU 时间超过 48 小时的患者，随机分为两组：一组接受 0#氯己定溶液，另一组接受 1#安慰剂。
intervention. Oral rinses with chlorhexidine or a placebo were performed 3 times a day throughout the duration of the patient’s stay in the ICU. Clinical data were collected prospectively.
干预措施。患者在 ICU 住院期间，每日三次使用氯己定或安慰剂进行口腔冲洗。临床数据为前瞻性收集。
results. Both groups displayed similar baseline clinical features. The overall incidence of respiratory tract infections (RR, 1.0 [ $95\mathrm{\%}$$95\mathrm{\%}$95%95 \% confidence interval [CI], 0.63-1.60]) and the rates of ventilator-associated pneumonia per 1,000 ventilator-days were similar in both experimental and control groups ( 22.6 vs $22.3;P=.95$$22.3;P=.95$22.3;P=.9522.3 ; P=.95 ). Respiratory tract infection-free survival time ( 7.8 vs 6.9 days; $P=.61$$P=.61$P=.61P=.61 ), duration of mechanical ventilation ( 11.1 vs 11.0 days; $P=.61$$P=.61$P=.61P=.61 ), and length of stay ( 9.7 vs 10.4 days; $P=.67$$P=.67$P=.67P=.67 ) did not differ between the chlorhexidine and placebo groups. However, patients in the chlorhexidine group exhibited a larger interval between ICU admission and onset of the first respiratory tract infection ( 11.3 vs 7.6 days; $P=.05$$P=.05$P=.05P=.05 ). The chances of surviving the ICU stay were similar (RR, $1.08[95\mathrm{\%}\mathrm{CI},0.72-1.63]$$1.08[95\mathrm{\%}\mathrm{CI},0.72-1.63]$1.08[95%CI,0.72-1.63]1.08[95 \% \mathrm{CI}, 0.72-1.63] ).
结果。两组患者基线临床特征相似。呼吸道感染总体发生率（相对风险 RR 1.0 [95%置信区间 CI 0.63-1.60]）及每 1000 个呼吸机日中的呼吸机相关肺炎发生率在实验组与对照组间无显著差异（22.6 例 vs 21 例）。呼吸道感染无病生存期（7.8 天 vs 6.9 天）、机械通气持续时间（11.1 天 vs 11.0 天）及住院天数（9.7 天 vs 10.4 天）在氯己定组与安慰剂组间均无统计学差异。但氯己定组患者从入住 ICU 到首次出现呼吸道感染的时间间隔更长（11.3 天 vs 7.6 天）。两组患者 ICU 存活率相近（RR 值未标注）。

CONCLUSION. Oral application of a $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% solution of chlorhexidine does not prevent respiratory tract infections among ICU patients, although it may retard their onset.
结论。使用未标注浓度的氯己定溶液进行口腔护理虽可能延迟呼吸道感染发生时间，但并不能预防 ICU 患者的呼吸道感染。

Infect Control Hosp Epidemiol 2009; 30:952-958
《感染控制与医院流行病学》2009 年第 30 卷，952-958 页

Respiratory tract infection is one of the most common types of nosocomial infection among intensive care unit (ICU) patients worldwide, ${}^{1-5}$${}^{1-5}$^(1-5){ }^{1-5} which leads to a substantial clinical and economic impact in this setting. ${}^{2,3,5-9}$${}^{2,3,5-9}$^(2,3,5-9){ }^{2,3,5-9} Chlorhexidine oral rinse has been demonstrated to be effective in the prevention of nosocomial respiratory tract infection among cardiac surgery patients, ${}^{10,11}$${}^{10,11}$^(10,11){ }^{10,11} although its effectiveness among ICU patients has been inconsistent. ${}^{12-16}$${}^{12-16}$^(12-16){ }^{12-16} Several meta-analyses of this subject have also produced conflicting results. ${}^{16-21}$${}^{16-21}$^(16-21){ }^{16-21} Beyond that, relevant technical limitations have been pointed out in these meta-analyses, as some of them combine data from distinct
呼吸道感染是全球重症监护病房（ICU）患者中最常见的医院感染类型之一， ${}^{1-5}$${}^{1-5}$^(1-5){ }^{1-5} 这在该环境中产生了重大的临床和经济影响。 ${}^{2,3,5-9}$${}^{2,3,5-9}$^(2,3,5-9){ }^{2,3,5-9} 洗必泰口腔冲洗已被证明在预防心脏手术患者的医院呼吸道感染方面有效， ${}^{10,11}$${}^{10,11}$^(10,11){ }^{10,11} 尽管其在 ICU 患者中的效果并不一致。 ${}^{12-16}$${}^{12-16}$^(12-16){ }^{12-16} 关于这一主题的几项荟萃分析也产生了相互矛盾的结果。 ${}^{16-21}$${}^{16-21}$^(16-21){ }^{16-21} 除此之外，这些荟萃分析中还指出了相关的技术局限性，因为它们中的一些将来自不同
study populations, including surgical patients, ICU patients, and general ward patients, as well as data from blinded and unblinded studies. Moreover, these meta-analyses have combined studies that use topical antibiotics or antiseptics, and some of them revealed a substantial preventive effect only when a fixed effect model was applied, regardless of the random model effect.
研究人群，包括手术患者、ICU 患者和普通病房患者，以及来自盲法和非盲法研究的数据。此外，这些荟萃分析结合了使用局部抗生素或消毒剂的研究，其中一些仅在应用固定效应模型时显示出显著的预防效果，而不管随机模型效应如何。

Of note, none of these studies have revealed a significant effect of chlorhexidine oral rinse on the duration of mechanical ventilation, length of stay, or mortality rates among ICU patients. Therefore, the role of chlorhexidine oral rinse
值得注意的是，这些研究均未显示洗必泰漱口液对 ICU 患者的机械通气时长、住院时间或死亡率有显著影响。因此，洗必泰漱口液的作用

in preventing nosocomial respiratory tract infections among ICU patients still remains controversial, which justifies further investigation. ${}^{20,22-26}$${}^{20,22-26}$^(20,22-26){ }^{20,22-26}
在预防 ICU 患者院内呼吸道感染方面仍存在争议，这证明需要进一步研究。 ${}^{20,22-26}$${}^{20,22-26}$^(20,22-26){ }^{20,22-26}

The main goal of this study was to evaluate the effectiveness of an oral application of chlorhexidine $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% solution in preventing the occurrence of respiratory tract infections among ICU patients. The primary outcome variable was the incidence of these infections, especially ventilator-associated pneumonia, during the ICU stay. We also evaluated the following secondary outcomes: respiratory tract infection-free survival time, time between ICU admission and onset of the first respiratory infection, duration of mechanical ventilation, length of stay in the ICU, total mortality, mortality attributable to respiratory infection, antimicrobial use for respiratory infections and for any other purpose, and microbial concentrations in tracheal secretions (only for patients receiving mechanical ventilation).
本研究的主要目的是评估口服洗必泰 $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% 溶液在预防 ICU 患者呼吸道感染发生方面的有效性。主要结局变量为 ICU 住院期间这些感染（尤其是呼吸机相关性肺炎）的发生率。我们还评估了以下次要结局：无呼吸道感染的生存时间、ICU 入院至首次呼吸道感染发作的时间间隔、机械通气持续时间、ICU 住院时长、总死亡率、归因于呼吸道感染的死亡率、用于呼吸道感染及其他目的的抗菌药物使用情况，以及气管分泌物中的微生物浓度（仅针对接受机械通气的患者）。

The Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo is a public university tertiary care hospital with 852 beds and 6 ICUs. The study was conducted in an ICU with 9 beds that provides general care for adult clinical and surgical patients.
圣保罗大学里贝朗普雷图医学院附属医院是一家公立大学三级医院，拥有 852 张病床和 6 个重症监护室。本研究在一个设有 9 张病床的重症监护室进行，该科室为成年内科及外科患者提供综合护理服务。

All patients admitted to the ICU with a prospective length of stay greater than 48 hours were considered eligible for the study, regardless of whether they received mechanical ventilation. Patients joined the study within the first 24 hours of their stay in the ICU from March 2006 to February 2008. Patients were excluded from the study on the basis of previous chlorhexidine hypersensitivity, pregnancy, formal indication for chlorhexidine use, or prescription of another oral topical medication.
所有入住重症监护室且预计住院时间超过 48 小时的患者均被视为符合研究条件，无论是否接受机械通气。患者需在 2006 年 3 月至 2008 年 2 月期间入住 ICU 后的 24 小时内加入研究。若患者既往对氯己定过敏、处于妊娠期、有正式使用氯己定的指征，或正在使用其他口腔局部药物，则被排除在研究之外。

Written informed consent was obtained from the patient or from an appropriate surrogate if the patient was unable to provide consent. This work fulfilled resolution no. 196/ 1996 from the Brazilian National Health Council for research involving humans and was approved by the Ethical Committee of Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo.
已从患者或其无法提供同意时的适当代理人处获取书面知情同意书。本研究符合巴西国家卫生委员会关于涉及人类研究的第 196/1996 号决议要求，并获得了圣保罗大学里贝朗普雷图医学院医院伦理委员会的批准。

This was a double-blind, randomized, placebo-controlled trial. It has not been registered as a clinical trial because this registration is not available in Brazil.
这是一项双盲、随机、安慰剂对照试验。由于巴西未提供临床试验注册服务，本研究未进行临床试验注册。

Chlorhexidine solutions and placebo solutions were prepared at the study hospital by a pharmacist. Solutions of $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% chlorhexidine and solutions containing a placebo were manipulated to be indistinguishable in color, consistency, smell,
研究医院的药剂师配制了氯己定溶液和安慰剂溶液。浓度为 $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% 的氯己定溶液与安慰剂溶液经过调配，在颜色、质地、气味上均无法区分，
and taste. They were packed in $500-\mathrm{mL}$$500-\mathrm{mL}$500-mL500-\mathrm{mL} bottles, which were sent to the ICU; each one was identified by an exclusive blind code number. Until all data were collected, only the pharmacist knew which code numbers corresponded to which kind of solution.
且口感一致。溶液分装于 $500-\mathrm{mL}$$500-\mathrm{mL}$500-mL500-\mathrm{mL} 瓶中送往重症监护室，每瓶标有唯一的盲法编号。在数据收集完成前，仅药剂师知晓编号对应的溶液种类。

Once consent had been obtained, a code number was selected from a box and the corresponding numbered bottle was placed beside the patient’s bed. Randomization was not stratified. Then the patient’s physician prescribed the study solution to be applied orally 3 times a day (once every 8 hours). Fully conscious patients who were not receiving ventilation were instructed to rinse the mouth with 15 mL of the study solution for at least 1 minute and discharge it after that. For patients who were unconscious and/or receiving ventilation, oral hygiene was performed by nurses who were specially trained in the study protocol. After mechanical cleaning, 15 mL of study solution was applied in the mouth with the intent of reaching all internal surfaces of the oral cavity. The applications of the study solutions were continued as long as the patient remained in the ICU. Compliance was assessed through a review of the patient’s medical records.
在获得同意后，从盒子中随机选取一个编码数字，并将对应编号的瓶子放在患者床边。随机化过程未进行分层处理。随后，由患者的主治医师开具处方，要求每日口服研究溶液 3 次（每 8 小时一次）。对完全清醒且未接受通气的患者，指导其用 15 毫升研究溶液漱口至少 1 分钟后吐出。对于无意识和/或接受通气的患者，则由经过研究方案专门培训的护士进行口腔护理。机械清洁后，将 15 毫升研究溶液涂抹于口腔内，力求覆盖所有内表面。只要患者仍在重症监护室，就持续使用研究溶液。通过审查患者病历记录来评估依从性。

Clinical data were collected prospectively on the basis of medical records and physical examination of patients, as necessary; all data were collected by the same investigator. At admission to the ICU, demographic data and medical history were registered and an Acute Physiology and Chronic Health Evaluation (APACHE) II score calculated. ${}^{27}$${}^{27}$^(27){ }^{27}
前瞻性地收集临床数据，依据患者病历及必要时的体格检查；所有数据均由同一研究者采集。患者入住 ICU 时，登记人口统计学资料和既往病史，并计算急性生理与慢性健康评分（APACHE II）。 ${}^{27}$${}^{27}$^(27){ }^{27}

While the patient was in the ICU, potential risk factors for developing respiratory tract infections were monitored, including receipt of mechanical ventilation and tracheostomy; thoracic or abdominal surgery; semirecumbent positioning; receipt of enteral nutrition; use of inhibitors of gastric acid secretion, antimicrobial drugs, corticosteroids, and other immunosuppressive drugs; and aspiration of gastric contents.
患者在 ICU 期间，监测了发生呼吸道感染的潜在风险因素，包括接受机械通气与气管切开术；胸腹部手术；半卧位姿势；接受肠内营养；使用胃酸分泌抑制剂、抗菌药物、皮质类固醇及其他免疫抑制剂；以及胃内容物误吸等情况。

We registered the occurrence of respiratory tract infections at any time during the ICU stay and until 48 hours after discharge from the ICU. Infection diagnosis was based on Centers for Disease Control and Prevention criteria. ${}^{28}$${}^{28}$^(28){ }^{28}
我们记录了患者在 ICU 住院期间及转出后 48 小时内任何时间发生的呼吸道感染情况。感染诊断依据美国疾病控制与预防中心标准。 ${}^{28}$${}^{28}$^(28){ }^{28}

The safety of the application of the study solution was clinically evaluated. Special attention was given to hypersensitivity reactions, irritation of oral mucosa, discoloration of teeth, and claims of unpleasant taste.
本研究溶液应用的安全性进行了临床评估，特别关注了过敏反应、口腔黏膜刺激、牙齿变色及口感不佳的主诉。

The microbiological effectiveness of chlorhexidine was evaluated by obtaining samples of tracheal secretions for semiquantitative culture from a randomly selected group of patients who underwent endotracheal intubation on days 1 , 4 , and 7 of mechanical ventilation. The specimens that were collected were immediately sent to the microbiology laboratory of the study facility, where they were weighed and homogenized with 2 mL of sterile saline in a vortex mixer (Whirlimixer) for 1 minute. After that, samples were rediluted
通过随机选取一组接受气管插管的患者，在机械通气第 1、4、7 天采集气管分泌物样本进行半定量培养，评估了氯己定的微生物学效果。采集的标本立即送至研究机构的微生物实验室，称重后与 2 毫升无菌生理盐水在涡旋混合器（Whirlimixer）中匀浆 1 分钟，随后进行再稀释处理。
table 1. Demographic and Clinical Characteristics and Exposure to Potential Risk Factors for Developing Respiratory Tract Infection during an Intensive Care Unit (ICU) Stay for Patients Treated with Chlorhexidine or Placebo
表 1. 使用氯己定或安慰剂治疗的患者在重症监护病房（ICU）期间发生呼吸道感染的人口统计学特征、临床特征及潜在危险因素暴露情况

note. Data are no. (%) of patients, unless otherwise indicated. APACHE II, Acute Physiology and Chronic Health Evaluation II; COPD, chronic obstructive pulmonary disease; LOS, length of stay.
注：数据为患者人数（%）表示，除非另有说明。APACHE II，急性生理与慢性健康评分 II；COPD，慢性阻塞性肺疾病；LOS，住院时长。
in sterile saline to produce concentrations varying from $1/10$$1/10$1//101 / 10 to $1/(1\times {10}^{10})$$1/\left(1\times {10}^{10}\right)$1//(1xx10^(10))1 /\left(1 \times 10^{10}\right); these were then spread over blood agar plates and incubated for 24 hours at ${35}^{\circ }\mathrm{C}$${35}^{\circ }\mathrm{C}$35^(@)C35^{\circ} \mathrm{C}. Colonies were counted on the plates that contained samples diluted to the lowest concentration that exhibited microbial growth, so the presumptive number of colony-forming units per gram of tracheal secretion was determined.
用无菌生理盐水配制浓度从 $1/10$$1/10$1//101 / 10 到 $1/(1\times {10}^{10})$$1/\left(1\times {10}^{10}\right)$1//(1xx10^(10))1 /\left(1 \times 10^{10}\right) 不等的溶液，随后将其均匀涂布于血琼脂平板上，在 ${35}^{\circ }\mathrm{C}$${35}^{\circ }\mathrm{C}$35^(@)C35^{\circ} \mathrm{C} 条件下孵育 24 小时。对稀释至最低浓度仍显示微生物生长的样本平板进行菌落计数，由此推定每克气管分泌物所含的菌落形成单位数。

From 1999 to 2005, the ventilator-associated pneumonia rate at the study ICU was 21.8 episodes per 1,000 ventilator-days (data not published). To have sufficient power to detect a $69\mathrm{\%}$$69\mathrm{\%}$69%69 \% reduction in this incidence, as reported before, ${}^{21}$${}^{21}$^(21){ }^{21} with
1999 年至 2005 年间，研究 ICU 内呼吸机相关肺炎发生率为每 1000 个呼吸机日 21.8 例次（数据未发表）。为具备足够统计效力检测出此前报道的 $69\mathrm{\%}$$69\mathrm{\%}$69%69 \% 发病率降幅，需 ${}^{21}$${}^{21}$^(21){ }^{21} 配合
$\alpha =5\mathrm{\%}$$\alpha =5\mathrm{\%}$alpha=5%\alpha=5 \% and $B=20\mathrm{\%}$$B=20\mathrm{\%}$B=20%B=20 \%, we estimated that we had to include 96 patients in each group. Because we expected some patients to drop out of the study, we decided to include 100 patients in each group. The statistical analysis was conducted unblinded with a ${\chi }^2$${\chi }^2$chi^(2)\chi^{2} test with the Yates correction, 2-tailed Fisher exact test, Wilcoxon test, binomial regression, and a random effects regression model with Stata (version 9.0) or SAS (version 9).
基于 $\alpha =5\mathrm{\%}$$\alpha =5\mathrm{\%}$alpha=5%\alpha=5 \% 与 $B=20\mathrm{\%}$$B=20\mathrm{\%}$B=20%B=20 \% ，我们估算每组需纳入 96 例患者。考虑到可能存在病例脱落，最终决定每组纳入 100 例患者。统计分析采用非盲法，运用经 Yates 校正的 ${\chi }^2$${\chi }^2$chi^(2)\chi^{2} 检验、双尾 Fisher 精确检验、Wilcoxon 检验、二项回归分析，以及通过 Stata（9.0 版）或 SAS（9 版）构建的随机效应回归模型。

Of the 200 patients initially included, 6 (3%) were ultimately excluded for the following reasons: 1 patient (in the control
在最初纳入的 200 名患者中，最终有 6 名（3%）因以下原因被排除：1 名患者（对照组
table 2. Characteristics and Incidence of Respiratory Tract Infection in Patients Who Received Chlorhexidine or a Placebo
表 2. 接受氯己定或安慰剂治疗患者的特征及呼吸道感染发生率

NOTE. Data are no. (%) of cases, unless otherwise indicated. CI, confidence interval; RR, relative risk; VAP, ventilatorassociated pneumonia.
注：除非另有说明，数据均为病例数（%）。CI，置信区间；RR，相对风险；VAP，呼吸机相关性肺炎。
${}^{\text{a}}$${}^{\text{a }}$^("a "){ }^{\text {a }} For the $P$$P$PP value, Yates-corrected ${\chi }^2$${\chi }^2$chi^(2)\chi^{2} or 2-tailed Fisher exact test, as appropriate. For the RR value, binomial regression model analysis adjusted for sex, age, and LOS.
对于 ${}^{\text{a}}$${}^{\text{a }}$^("a "){ }^{\text {a }} 值，采用 Yates 校正 ${\chi }^2$${\chi }^2$chi^(2)\chi^{2} 或双尾 Fisher 精确检验（视情况而定）。对于 RR 值，采用经性别、年龄和住院时间（LOS）调整的二项回归模型分析。
group) developed postchemotherapy mucositis, which is a formal indication for oral chlorhexidine use, and among the other 5 the study protocol was not followed correctly (2 patients in the experimental group and 3 in the control group). Overall, 194 patients participated, 98 of them in the chlorhexidine (experimental) group and 96 in the placebo (control) group. Although most of the patients included in the study received mechanical ventilation (133/194), only 20 ( $15.0\mathrm{\%}$$15.0\mathrm{\%}$15.0%15.0 \% ) underwent placement of endotracheal tubes in the ICU and had used the study solution before endotracheal tube placement, while the other $113(85.0\mathrm{\%})$$113(85.0\mathrm{\%})$113(85.0%)113(85.0 \%) were admitted to the ICU with endotracheal tubes already in place, and placement had occurred under various conditions.
组）出现了化疗后黏膜炎（这是使用口腔氯己定的正式适应症），其余 5 例未正确遵循研究方案（实验组 2 例，对照组 3 例）。共有 194 名患者参与研究，其中 98 名属于氯己定（实验）组，96 名属于安慰剂（对照）组。尽管大多数纳入研究的患者接受了机械通气（133/194），但仅有 20 例（ $15.0\mathrm{\%}$$15.0\mathrm{\%}$15.0%15.0 \% ）在 ICU 内进行了气管插管并在插管前使用了研究溶液，其余 $113(85.0\mathrm{\%})$$113(85.0\mathrm{\%})$113(85.0%)113(85.0 \%) 患者在入院时已置入气管插管，且插管操作是在不同条件下完成的。

Analysis of baseline clinical features revealed that, despite lower age in the control group, both groups showed an equivalent sex distribution and similar medical conditions of similar severity, on the basis of the APACHE II score, as presented
基线临床特征分析显示，尽管对照组年龄较低，但两组性别分布相当，且基于 APACHE II 评分显示的医疗条件严重程度相似。
in Table 1. The reasons for ICU admission and the rates of respiratory failure and shock were also similar between the 2 groups, although compromised mental status was more common among placebo patients. The rate of exposure to potential risk factors for developing nosocomial respiratory tract infections during the ICU stay was also similar for the chlorhexidine and placebo groups.
如表 1 所示，两组患者入住 ICU 的原因、呼吸衰竭和休克发生率也相似，但安慰剂组患者精神状态受损更为常见。在 ICU 住院期间，洗必泰组与安慰剂组接触可能导致院内呼吸道感染的危险因素的比率也相近。

During the study, 46 episodes of respiratory tract infection were diagnosed among 39 patients, comprising 21 episodes among 19 (19.4%) of 98 patients who received chlorhexidine and 25 episodes among $20(20.8\mathrm{\%})$$20(20.8\mathrm{\%})$20(20.8%)20(20.8 \%) of 96 patients who received the placebo. Almost half the episodes diagnosed (22/ 46 [47.8%]) were microbiologically confirmed ( 11 microbiologically confirmed episodes in patients in the chlorhexidine group and 11 in patients in the placebo group).
研究期间，39 名患者共发生 46 例次呼吸道感染，其中洗必泰组的 98 名患者中有 19 人（19.4%）发生 21 例次，安慰剂组的 96 名患者中有 $20(20.8\mathrm{\%})$$20(20.8\mathrm{\%})$20(20.8%)20(20.8 \%) 人发生 25 例次。确诊的感染中近半数（22/46 [47.8%]）经微生物学确认（洗必泰组患者 11 例，安慰剂组患者 11 例）。

The comparison of respiratory tract infection characteristics and incidence between the study groups is presented in
各研究组之间呼吸道感染特征和发病率的比较见表 2。
table 3. Clinical Outcome after and Temporal Data Obtained during Intensive Care Unit (ICU) Stay of Patients Treated with Chlorhexidine or Placebo
表 3. 使用氯己定或安慰剂治疗的患者在重症监护病房（ICU）期间的临床结果及时间数据

${}^{\text{a}}P$${}^{\text{a }}P$^("a ")P{ }^{\text {a }} P values for patient counts were calculated with a Yates-corrected ${\chi }^2$${\chi }^2$chi^(2)\chi^{2} or a 2-tailed Fisher exact tests, as appropriate. $P$$P$PP values for mean durations were calculated with a Wilcoxon test.
患者计数的 ${}^{\text{a}}P$${}^{\text{a }}P$^("a ")P{ }^{\text {a }} P 值采用 Yates 校正 ${\chi }^2$${\chi }^2$chi^(2)\chi^{2} 或双尾 Fisher 精确检验（视情况而定）进行计算。 $P$$P$PP 平均持续时间的值则通过 Wilcoxon 检验得出。
table 4. Differences in Microbial Concentration (Bacteria and Yeasts) in Tracheal Secretion Samples Collected during Mechanical Ventilation in Intensive Care Unit Patients Treated with Chlorhexidine, Compared with Patients Treated with a Placebo
表 4. 重症监护病房接受氯己定治疗与安慰剂治疗患者机械通气期间气管分泌物样本中微生物浓度（细菌与酵母菌）差异对比

nоте. CI, confidence interval. 
${}^{\text{a}}$${}^{\text{a }}$^("a "){ }^{\text {a }} In colony-forming units per gram of tracheal secretion.
（ ${}^{\text{a}}$${}^{\text{a }}$^("a "){ }^{\text {a }} 以每克气管分泌物中的菌落形成单位计）
${}^{\mathrm{b}}$${}^{\mathrm{b}}$^(b){ }^{\mathrm{b}} Random effects regression model. 

Table 2. The data analysis reveals that rates of ventilatorassociated pneumonia were similar between the study groups, with 22.6 episodes per 1,000 ventilator-days $(16/708)$$(16/708)$(16//708)(16 / 708) in the chlorhexidine group and 22.3 episodes per 1,000 ventilatordays (17/763) in the placebo group ( $P=.95$$P=.95$P=.95P=.95 ). The overall incidence of respiratory tract infection did not differ between the study groups, which demonstrates the ineffectiveness of chlorhexidine as a preventive measure, with a relative risk of 1.00 ( $95\mathrm{\%}$$95\mathrm{\%}$95%95 \% confidence interval [CI], $0.63-1.60$$0.63-1.60$0.63-1.600.63-1.60 ) after adjustment for sex, age, and length of stay in the ICU.
表 2. 数据分析显示，研究组间呼吸机相关肺炎发生率相似，洗必泰组为每 1000 个呼吸机日 22.6 例次（0#），安慰剂组为每 1000 个呼吸机日 22.3 例次（17/763）（1#）。两组间呼吸道感染总体发生率无差异，表明洗必泰作为预防措施无效，经性别、年龄和 ICU 住院时间调整后的相对风险为 1.00（2#置信区间[CI]，3#）。

The results regarding the secondary clinical outcomes are presented in Table 3. No significant differences between the 2 groups were observed for respiratory tract infection-free survival time, duration of mechanical ventilation, antimicrobial use either for respiratory infections or for any purpose, or length of stay in the ICU (Table 3). The chances of surviving the stay in the ICU were also similar in the 2 study groups. The relative risk, after adjustment for sex and age, was 1.08 ( $95\mathrm{\%}$$95\mathrm{\%}$95%95 \% CI, $0.72-1.63$$0.72-1.63$0.72-1.630.72-1.63 ). Moreover, patients who had a respiratory infection did not have an increased risk of death (RR, 1.32 [95% CI, 0.87-2.0]) (data not shown). Conversely, patients in the chlorhexidine group experienced a larger time gap between ICU admission and onset of the first respiratory tract infection than those in the placebo group (11.3 vs 7.6 days; $P=.05$$P=.05$P=.05P=.05 ).
关于次要临床结局的结果见表 3。两组在呼吸道感染无病生存时间、机械通气持续时间、针对呼吸道感染或任何目的的抗菌药物使用、以及 ICU 住院时长方面均未观察到显著差异（表 3）。两组患者在 ICU 存活几率也相近。经性别和年龄调整后的相对风险为 1.08（ $95\mathrm{\%}$$95\mathrm{\%}$95%95 \% 置信区间， $0.72-1.63$$0.72-1.63$0.72-1.630.72-1.63 ）。此外，发生呼吸道感染的患者并未显示死亡风险增加（RR=1.32 [95% CI, 0.87-2.0]）（数据未展示）。相反，洗必泰组患者从入住 ICU 到首次出现呼吸道感染的时间间隔较安慰剂组更长（11.3 天 vs 7.6 天； $P=.05$$P=.05$P=.05P=.05 ）。

A comparison of the concentration of bacteria or yeast isolated from cultures grown from samples of tracheal secretions collected periodically throughout the ICU stay did not reveal any difference between the study groups (Table 4).
对 ICU 住院期间定期采集的气管分泌物样本培养所得的细菌或酵母菌浓度进行比较，未显示两组间存在差异（表 4）。

No severe adverse event related to study participation was identified. However, 3 patients in the experimental group and 5 in the placebo group complained about the unpleasant taste of the solution $(P=.50)$$(P=.50)$(P=.50)(P=.50). One patient discontinued use of the study solution (chlorhexidine, in this case) after complaining of dysgeusia (data not shown).
未发现与研究参与相关的严重不良事件。然而，实验组中有 3 名患者和安慰剂组中有 5 名患者抱怨溶液的难闻味道 $(P=.50)$$(P=.50)$(P=.50)(P=.50) 。一名患者因抱怨味觉障碍（数据未显示）而停止使用研究溶液（本例中为氯己定）。

Our data clearly indicate that oral application of a $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% solution of chlorhexidine was not superior to a placebo for the prevention of respiratory tract infection among ICU pa-
我们的数据明确表明，口服 $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% 氯己定溶液在预防 ICU 患者呼吸道感染方面并不优于安慰剂。
tients. This is corroborated by the fact that no differences were detected between the study groups in most results, including the incidence of respiratory tract infection, the total mortality rate and that attributable to respiratory tract infection, respiratory tract infection-free survival time, the duration of mechanical ventilation, antimicrobial use either for respiratory tract infection or for any purpose, the length of stay in the ICU, and the microbial concentrations detected in the semiquantitative cultures of tracheal secretions. However, the time between ICU admission and onset of the first respiratory tract infection was longer in the chlorhexidine group than in the placebo group, which suggests that chlorhexidine application was not totally inert.
这一观点得到了以下事实的支持：在研究组之间，大多数结果未检测到差异，包括呼吸道感染发生率、总死亡率及与呼吸道感染相关的死亡率、无呼吸道感染生存时间、机械通气持续时间、用于呼吸道感染或任何目的的抗菌药物使用、ICU 住院时间以及气管分泌物半定量培养中检测到的微生物浓度。然而，洗必泰组从入住 ICU 到首次发生呼吸道感染的时间比安慰剂组长，这表明洗必泰的应用并非完全无效。

One important difference between ICU patients and cardiac surgery patients is that endotracheal tubes are placed in the latter on an elective basis, which makes it possible to clean their teeth and apply oral antiseptic before tubes are placed. Endotracheal tubes are frequently placed in ICU patients on an emergency basis, without any preparation, which means that the bacterial inoculum of the lower respiratory tract may be great enough for an infection to start developing. This may be part of the explanation for the discrepancies between the inefficacy of a $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% chlorhexidine solution when used in ICU patients and its efficacy when used in surgical patients. ${}^{10,11,13}$${}^{10,11,13}$^(10,11,13){ }^{10,11,13}
ICU 患者与心脏手术患者的一个重要区别在于，后者是在择期基础上插入气管插管，这使得在插管前能够清洁牙齿并使用口腔消毒剂。而 ICU 患者的气管插管往往是在紧急情况下进行的，没有任何准备，这意味着下呼吸道的细菌接种量可能足以引发感染。这或许可以部分解释为何 0.02%洗必泰溶液在 ICU 患者中无效，而在手术患者中却有效。

Our findings may also be associated with the dose of chlorhexidine used. Although $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% chlorhexidine exhibits a very potent in vitro germicidal effect against most potential pathogens of the respiratory tract, this may not occur in vivo. ${}^{29}$${}^{29}$^(29){ }^{29} Redilution of chlorhexidine by saliva may reduce the in vivo antiseptic concentration, and the presence of biofilm on the teeth may increase the minimum inhibitory concentration for chlorhexidine to bacteria and yeasts living in that microenvironment. ${}^{17,30}$${}^{17,30}$^(17,30){ }^{17,30} The postponement of infection episodes in the chlorhexidine group may indicate that, at this concentration, chlorhexidine partially inhibited microbial proliferation, delaying but not preventing respiratory tract infection, which suggests that a possible dose-response effect should be further investigated. This hypothesis is in agreement with previous findings of preventive benefits when $2\mathrm{\%}$$2\mathrm{\%}$2%2 \% chlorhexidine was used ${}^{15,16}$${}^{15,16}$^(15,16){ }^{15,16} and also with findings that did not reveal any clinical benefit when $0.2\mathrm{\%}$$0.2\mathrm{\%}$0.2%0.2 \% chlorhexidine was used. ${}^{13}$${}^{13}$^(13){ }^{13}
我们的发现也可能与所使用的氯己定剂量有关。虽然 $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% 氯己定在体外对大多数呼吸道潜在病原体表现出极强的杀菌效果，但在体内可能不会发生这种情况。 ${}^{29}$${}^{29}$^(29){ }^{29} 唾液对氯己定的再稀释可能会降低体内的抗菌浓度，而牙齿上生物膜的存在可能会增加氯己定对生活在该微环境中的细菌和酵母菌的最低抑菌浓度。 ${}^{17,30}$${}^{17,30}$^(17,30){ }^{17,30} 氯己定组感染事件的推迟可能表明，在此浓度下，氯己定部分抑制了微生物增殖，延迟但未预防呼吸道感染，这表明应进一步研究可能的剂量-效应关系。这一假设与先前使用 $2\mathrm{\%}$$2\mathrm{\%}$2%2 \% 氯己定 ${}^{15,16}$${}^{15,16}$^(15,16){ }^{15,16} 时发现的预防益处一致，也与使用 $0.2\mathrm{\%}$$0.2\mathrm{\%}$0.2%0.2 \% 氯己定 ${}^{13}$${}^{13}$^(13){ }^{13} 时未显示任何临床益处的研究结果一致。

Cardiac surgery experience also reaffirms the possibility that our findings are associated with the dose of chlorhexidine used, since cardiac surgery patients receive mechanical ventilation for only 12-24 hours in most cases. ${}^{10,11}$${}^{10,11}$^(10,11){ }^{10,11} In such a situation, chlorhexidine at $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% concentration would be enough to minimize oral and tracheal microbial proliferation until the patient leaves mechanical ventilation, which is the most relevant risk factor for respiratory tract infections. ${}^{24-26}$${}^{24-26}$^(24-26){ }^{24-26} This is, unfortunately, not the case for ICU patients, who frequently receive mechanical ventilation for days or weeks.
心脏手术的经验也再次证实，我们的发现可能与所使用的氯己定剂量有关，因为大多数情况下，心脏手术患者仅接受 12 至 24 小时的机械通气。 ${}^{10,11}$${}^{10,11}$^(10,11){ }^{10,11} 在这种情况下， $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% 浓度的氯己定足以在患者脱离机械通气前（这是呼吸道感染最相关的风险因素）最大限度地减少口腔和气管内微生物的繁殖。 ${}^{24-26}$${}^{24-26}$^(24-26){ }^{24-26} 遗憾的是，ICU 患者的情况并非如此，他们往往需要接受数天或数周的机械通气。

The baseline oral health of the patients who participated in the study and the appropriateness of the oral hygiene per-
参与研究的患者基线口腔健康状况及口腔卫生的适宜性
formed by nurses on ICU patients may be a complementary explanation for the results presented here and the inconsistencies detected among previous similar studies. Poor oral health and an insufficient oral hygiene program could act to confound the analysis of the effectiveness of chlorhexidine application. Dental plaque, dental caries, and periodontal disease may be a major reservoir of pathogens that is not substantially affected by the application of chlorhexidine. ${}^{31,32}$${}^{31,32}$^(31,32){ }^{31,32}
由 ICU 护士执行的操作可能是对本文结果及先前类似研究中发现的不一致性的补充解释。口腔健康状况不佳和口腔卫生计划不充分可能会混淆氯己定应用效果的分析。牙菌斑、龋齿和牙周病可能是病原体的主要储存库，而氯己定的应用对其影响有限。 ${}^{31,32}$${}^{31,32}$^(31,32){ }^{31,32}

Note that the oral health of many patients who participated in our study was poor. Although oral health was not systematically evaluated in our study, a recent national oral health survey that analyzed oral health data collected from 108,921 persons revealed that periodontal disease was present in $78\mathrm{\%}$$78\mathrm{\%}$78%78 \% of Brazilian adults and that the Decayed/Missing/Filled Teeth index (DMFT) was 20.1 for adults and 27.8 for elderly people. ${}^{33}$${}^{33}$^(33){ }^{33}
需注意的是，参与我们研究的许多患者口腔健康状况不佳。尽管本研究未系统评估口腔健康，但近期一项覆盖 108,921 人的全国口腔健康调查显示，巴西成年人中牙周病患病率达 $78\mathrm{\%}$$78\mathrm{\%}$78%78 \% ，且成年人与老年人的龋失补牙指数（DMFT）分别高达 20.1 和 27.8。 ${}^{33}$${}^{33}$^(33){ }^{33}

We think that future studies should address whether oral health influences chlorhexidine’s germicidal effect in the oral cavity and, as a consequence, its ability to prevent respiratory tract infections. It would also be of interest to analyze the effect of dental care provided by a dental surgeon or a dental hygienist, combined with oral application of chlorhexidine, on ICU patients with caries or periodontal disease.
我们认为未来研究应探讨口腔健康是否影响洗必泰在口腔内的杀菌效果，进而影响其预防呼吸道感染的能力。同时，分析由牙科医生或洁牙师提供的口腔护理服务，结合洗必泰口腔用药，对患有龋齿或牙周病的 ICU 患者的效果也颇具研究价值。

Beyond not having evaluated the oral health of patients, our study is subject to at least 2 other limitations. First, the sample size was chosen to detect a $69\mathrm{\%}$$69\mathrm{\%}$69%69 \% reduction in infection rates; the power of the study was not sufficient to identify more modest reductions, although smaller reductions could still be important from a clinical perspective. Second, compliance with the study protocol was assessed by checking medical records and not by direct observation of the application of the study solution. If the study solution was actually applied inadequately, the results in the experimental group would be at a disadvantage.
除了未评估患者的口腔健康状况外，我们的研究至少还存在另外两项局限性。首先，样本量的选择旨在检测感染率降低 $69\mathrm{\%}$$69\mathrm{\%}$69%69 \% 的效果；研究效力不足以识别更小幅度的降低，尽管从临床角度看，较小的降低仍可能具有重要意义。其次，研究方案的依从性是通过检查医疗记录而非直接观察研究溶液的使用情况来评估的。若研究溶液实际应用不当，实验组的结果将处于不利地位。

In conclusion, our results demonstrate that oral application of a $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% solution of chlorhexidine does not prevent respiratory tract infections in ICU patients, although it may retard their onset.
总之，我们的结果表明，虽然可能延迟发病时间，但口腔应用 $0.12\mathrm{\%}$$0.12\mathrm{\%}$0.12%0.12 \% 浓度的氯己定溶液并不能预防 ICU 患者的呼吸道感染。

We thank Marlene M. Hattori, Luiz M. Sakamoto, Dalva Bó, Therezinha J.O. Resuto, Renzo E.C. Bianchi, Alessandra Tomiati, Elisângela B. Deus, Giani P. Moraes, Lucilaine de Oliveira, Ronaldo V. Martins, Rosa H.A.R. Gironi, Lúcia H. Vitali, Larissa A.S. Serveli, Kenia C.T. Zanetti, Marília O. Andrade, Leila P.P. Silva, Mirley M. Frontaroli, and Vanessa M.C.F. Bráulio for their assistance in the study implementation. We also thank Olindo Assis MartinsFilho, PhD , who assisted us on the revision of the manuscript.
我们感谢 Marlene M. Hattori、Luiz M. Sakamoto、Dalva Bó、Therezinha J.O. Resuto、Renzo E.C. Bianchi、Alessandra Tomiati、Elisângela B. Deus、Giani P. Moraes、Lucilaine de Oliveira、Ronaldo V. Martins、Rosa H.A.R. Gironi、Lúcia H. Vitali、Larissa A.S. Serveli、Kenia C.T. Zanetti、Marília O. Andrade、Leila P.P. Silva、Mirley M. Frontaroli 和 Vanessa M.C.F. Bráulio 在研究实施过程中提供的协助。同时感谢 Olindo Assis MartinsFilho 博士在稿件修订过程中给予的帮助。

Potential conflicts of interest. All authors report no conflicts of interest relevant to this article.
潜在利益冲突声明。所有作者均声明不存在与本文相关的利益冲突。

Address reprint requests to Fernando Bellissimo-Rodrigues, Avenida dos Bandeirantes, 3900, Campus Universitário-Monte Alegre, CEP 14048-900, Ribeirão Preto, São Paulo, Brazil (fbellissimo@ig.com.br).
重印请求请寄至巴西圣保罗州里贝朗普雷图市蒙特阿莱格里大学校园班代兰特斯大道 3900 号，邮编 14048-900，Fernando Bellissimo-Rodrigues 收（电子邮箱：fbellissimo@ig.com.br）。

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