Weaning Critically Ill Patients from Mechanical Ventilation: A Prospective Cohort Study Lin Pu, Bo Zhu, Li Jiang, Bin Du, Xi Zhu, Ang Li, Gang Li, Zhongjie He, Wei Chen, Penglin Ma, Jianguo Jia, Yuan Xu, Jianxin Zhou, Long Qin, Qingyuan Zhan, Wenxiong Li, Qi Jiang, Meiping Wang, Ran Lou, XiuMing Xi PII: DOI: Reference:

S0883-9441(15)00146-X doi: 10.1016/j.jcrc.2015.04.001 YJCRC 51796

To appear in:

Journal of Critical Care

Please cite this article as: Pu Lin, Zhu Bo, Jiang Li, Du Bin, Zhu Xi, Li Ang, Li Gang, He Zhongjie, Chen Wei, Ma Penglin, Jia Jianguo, Xu Yuan, Zhou Jianxin, Qin Long, Zhan Qingyuan, Li Wenxiong, Jiang Qi, Wang Meiping, Lou Ran, Xi XiuMing, Weaning Critically Ill Patients from Mechanical Ventilation: A Prospective Cohort Study, Journal of Critical Care (2015), doi: 10.1016/j.jcrc.2015.04.001

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Title Page

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Weaning Critically Ill Patients from Mechanical Ventilation: A Prospective Cohort Study Lin Pu#, Bo Zhu#, Li Jiang, Bin Du, Xi Zhu, Ang Li, Gang Li, Zhongjie He, Wei Chen, Penglin Ma, Jianguo

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Jia, Yuan Xu, Jianxin Zhou, Long Qin, Qingyuan Zhan, Wenxiong Li, Qi Jiang, Meiping Wang, Ran Lou, XiuMing Xi*

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Lin Pu:

Department of Critical Care Medicine, Fu Xing Hospital, Capital Medical University;

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Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University. Postal address: ICU Beijing Ditan Hospital, No. 8 Jingshundong Street, Chaoyang District, Beijing 100015, China. E-mail: [email protected] Bo Zhu

Department of Critical Care Medicine, Fu Xing Hospital, Capital Medical University.

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Postal address: ICU Fu Xing Hospital, No. 20 Fuxingmenwai Street, Xicheng District, Beijing 10038, China. E-mail: [email protected]

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Li Jiang

Department of Critical Care Medicine, Fu Xing Hospital, Capital Medical University.

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Postal address: ICU Fu Xing Hospital, No. 20 Fuxingmenwai Street, Xicheng District, Beijing 10038, China.

Bin Du

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E-mail: [email protected]

Medical Intensive Care Unit, Peking Union Medical College Hospital. Postal address: MICU Peking Union Medical College Hospital, No.1Shuaifuyuan, Wangfujing, DongCheng District, Beijing 100730, China. E-mail: [email protected] Xi Zhu Department of Critical Care Medicine, Peking University Third Hospital. Postal address: ICU Peking University Third Hospital, No. 49 Garden-North Road Haidian District, Beijing 100191, China. E-mail: [email protected] Ang Li

ACCEPTED MANUSCRIPT Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University. Postal address: ICU Beijing Friendship Hospital, No. 95 Yongan Road, Xicheng District, Beijing 100050, China. E-mail: [email protected]

Department of Critical Care Medicine, China-Japan Friendship Hospital.

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Gang Li

Postal address: ICU China-Japan Friendship Hospital, No. 2 Yinghuayuan east Street, Beijing 100029, China.

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E-mail: [email protected] Zhongjie He

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Department of Critical Care Medicine, The First Affiliated Hospital of General Hospital of People’s Liberation Army.

Postal address: ICU The First Affiliated Hospital of General Hospital of People’s Liberation Army, No. 51 Fucheng Road, Haidian District, Beijing 100048, China.

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E-mail: [email protected] Wei Chen

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Department of Critical Care Medicine, Beijing Shijitan Hospital, Capital Medical University. Postal address: ICU Beijing Shijitan Hospital, No. 10 Tieyi Road, Haidian District, Beijing 100038, China.

Penglin Ma

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E-mail: [email protected]

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Department of Critical Care Medicine, The 309th Hospital of Chinese People’s Liberation Army. Postal address: ICU The 309th Hospital of Chinese People’s Liberation Army, No. 17 Heishanhu Road Haidian District, Beijing 100094, China. E-mail: [email protected] Jianguo Jia Surgical Intensive Care Unit, Xuan Wu Hospital, Capital Medical University. Postal address: SICU Xuan Wu Hospital, No. 45 Changchun Street, Xicheng District, Beijing 100053, China. E-mail: [email protected] Yuan Xu Department of Critical Care Medicine, Beijing Tong Ren Hospital, Capital Medical University. Postal address: ICU Beijing Tong Ren Hospital, No.2 Chongwenmennei Street, Dongcheng District, Beijing 100730, China.

ACCEPTED MANUSCRIPT E-mail: [email protected] Jianxin Zhou Department of Critical Care Medicine, Beijing Tian Tan Hospital, Capital Medical University.

E-mail: [email protected] Long Qin

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Department of Critical Care Medicine, Beijing Haidian Hospital.

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Postal address: ICU Beijing Tian Tan Hospital, No.6 TianTan XiLi, Dongcheng District, Beijing 100050, China.

Postal address: ICU Beijing Haidian Hospital, No.29 Zhongguancun Street, Haidian District, Beijing 100080,

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China. E-mail: [email protected] Qingyuan Zhan

Department of Respiratory, China-Japan Friendship Hospital.

100029, China.

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E-mail: [email protected]

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Postal address: Dept of Respiratory, China-Japan Friendship Hospital, No. 2 Yinghuayuan east Street, Beijing

Wenxiong Li

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Surgical Intensive Care Unit, Beijing Chao-Yang Hospital, Capital Medical University. SICU Beijing Chao-Yang Hospital, No. 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, 100020, China.

Qi Jiang

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E-mail: [email protected]

Department of Critical Care Medicine, Fu Xing Hospital, Capital Medical University. Postal address: ICU Fu Xing Hospital, No. 20 Fuxingmenwai Street, Xicheng District, Beijing 10038, China. E-mail: [email protected] Meiping Wang Department of Critical Care Medicine, Fu Xing Hospital, Capital Medical University. Postal address: ICU Fu Xing Hospital, No. 20 Fuxingmenwai Street, Xicheng District, Beijing 10038, China. E-mail: [email protected] Ran Lou Department of Critical Care Medicine, Fu Xing Hospital, Capital Medical University. Postal address: ICU Fu Xing Hospital, No. 20 Fuxingmenwai Street, Xicheng District, Beijing 10038, China.

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Corresponding Authors:

Prof. XiuMing Xi, Fu Xing Hospital, Capital Medical University, No. 20 Fuxingmenwai Street, Xicheng District,

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Beijing 10038, China. Phone numbers: +86-10-88062937. E-mail: [email protected] #

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These authors contributed equally to this work

ACCEPTED MANUSCRIPT Weaning critically ill patients from mechanical ventilation: a prospective cohort

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study

Abstract

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Purpose: A proposal was made at the International Consensus Conference to classify weaning of patients in intensive care units from mechanical ventilation into simple,

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difficult, and prolonged weaning groups based on the difficulty and length of the weaning process. The objective of the present study was to determine the incidence and outcome of weaning according to these new categories.

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Methods: We examined the weaning of patients in intensive care units from

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mechanical ventilation in a prospective multicentre cohort study. Results: In total, 343 patients were included in the final analysis. Simple, difficult,

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and prolonged weaning occurred in 200 (58%), 99 (29%), and 44 (13%) patients,

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respectively. Hospital mortality rates were higher for patients in the prolonged weaning group than in the simple and difficult weaning groups. Multivariate analysis revealed that a lower Glasgow Coma Scale (GCS) score (p < 0.014) and hypercapnia at the beginning of the first spontaneous breathing trial (p = 0.038) were independent predictors of prolonged weaning. Conclusions: Patients who experienced prolonged weaning had significantly higher mortality rates than patients who experienced either simple or difficult weaning. A lower GCS score and hypercapnia at the beginning of the weaning process were independent risk factors for prolonged weaning.

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Keywords: Epidemiology; Intensive care unit; Ventilation; Weaning.

ACCEPTED MANUSCRIPT Abbreviations MV: mechanical ventilation; ICC: International Consensus Conference; GCS:

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Glasgow Coma Scale; SBT: spontaneous breathing trial; ICU: intensive care unit; FiO2: inspired oxygen fraction; NIV: noninvasive ventilation; fC, cardiac frequency; fR,

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respiratory frequency; PSV: pressure support ventilation; APACHE-II: Acute Physiology and Chronic Health Evaluation II; PaO2: arterial oxygen tension; PaCO2:

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arterial carbon dioxide tension; RSBI: rapid shallow breathing index; COPD: chronic

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obstructive pulmonary disease; ARDS: acute respiratory distress syndrome

ACCEPTED MANUSCRIPT Introduction Successful weaning from mechanical ventilation (MV) is important in the treatment

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of patients requiring invasive MV. Weaning is part of the MV process and involves disconnection of the ventilator and withdrawal of the endotracheal tube. The weaning

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period accounts for 40% to 50% of the total duration of the MV support period [1, 2]. Prolonged weaning leads to prolonged MV and resultant increased MV-related

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complications, which affect patient survival [3].

During the 7th International Consensus Conference (ICC) in 2005, a weaning

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classification system was established that categorised weaning into simple, difficult,

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and prolonged based on the difficulty and length of the weaning process [4]. Patients who proceed from the initiation of weaning to successful extubation on the first

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attempt are considered to have experienced simple weaning. Patients who fail the

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initial weaning and require up to three spontaneous breathing trials (SBTs) or up to 7 days from the first SBT to achieve successful weaning are considered to have experienced difficult weaning. Prolonged weaning occurs in patients who fail at least three weaning attempts or require 7 days of weaning after the first SBT. However, this classification method is based on clinical experience, and its effectiveness requires validation through clinical studies.

It has been shown that prolonged weaning increases the incidence of MV-related complications and mortality in patients requiring MV in an intensive care unit (ICU).

ACCEPTED MANUSCRIPT Although difficult weaning increases the incidence of complications, it does not significantly influence hospital mortality [5, 6]. Furthermore, patients with critical

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respiratory illnesses who undergo simple or difficult weaning from MV show similar clinical characteristics and outcomes, whereas patients who undergo prolonged

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weaning have a poor prognosis.

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A number of factors contribute to weaning failure. Weaning outcomes are affected by respiratory, circulatory, and nervous system activities as well as the psychological and nutritional status of patients [7]. Hypercapnia after an SBT is an independent risk

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factor for prolonged weaning and patient death [8]. However, current research has

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shown discrepancies due to differences in experimental designs and study subjects. Thus, prospective and multicentre studies are required to identify factors that could

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lead to a poor prognosis.

In the ICC weaning classification system, weaning is categorised as simple or difficult based on the success of the initial SBT [4]. Therefore, determination of the timing of the first SBT is necessary to investigate the reasons for the initial SBT failure. The present study aimed to (1) conduct an epidemiological analysis of the weaning of patients who undergo invasive MV at local medical-surgical ICUs based on the ICC weaning classification system, (2) compare the clinical characteristics and outcomes of these patients, and (3) conduct a multifactor analysis of clinical data to determine factors related to prolonged weaning.

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Methods

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Study design

A prospective cohort study was performed at medical-surgical ICUs of 13 municipal

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hospitals in Beijing, China. The number of ICU beds ranged from 8 to 20 during the study period. Each ICU collected patient data from January to December 2012. Only

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investigative team members at each site were aware of the purpose and precise timing of the study. The research ethics board of each participating institution approved the

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study protocol with a waiver of informed consent.

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Patients

All patients who had been intubated and mechanically ventilated for more than 24 h

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were screened. We enrolled only those patients who underwent SBTs for the purpose

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of weaning. Patients who underwent tracheostomy prior or during the course of MV, died before they were ready to begin the weaning process, underwent noninvasive ventilation (NIV) during weaning, experienced unplanned extubation or withdrawal of treatment, or were transferred to another hospital before or during the weaning process were excluded from the study. We included consecutive patients who were weaned after successful SBTs according to established recommendations [4].

Study protocol At each centre, the onset of weaning was the time point at which the physician in

ACCEPTED MANUSCRIPT charge considered the patient likely to resume and sustain spontaneous breathing after the patient met the standard weaning criteria. The entire medical ICU team received

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detailed instructions regarding weaning recommendations and were trained to follow the steps of the weaning procedure. Questions regarding weaning procedures were

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coordinator was responsible for data entry.

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encouraged and were answered prior to and during the study. A local study

Weaning was considered as early as possible in the course of MV, and the physician in charge chose the method of weaning (including daily SBTs or gradual reduction of

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support) based on the habits and judgment of each ICU team. The performance of

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daily SBTs involved a two-step strategy. First, readiness for weaning from MV was assessed daily according to criteria in the panel statement [4]. Patients who fulfilled

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these criteria underwent an SBT as a diagnostic test to determine the likelihood of

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successful extubation. The initial SBT lasted for at least 30 min and involved breathing with a T-tube or continuous positive airway pressure (positive end-expiratory pressure of 5 cm H2O). Alternatively, a weaning trial using pressure support of 5 to 8 cm H2O with a positive end-expiratory pressure of 5 cm H2O was conducted. When a patient successfully passed the SBT [4], extubation was suggested. The physician in charge made the final decision to extubate. If a patient failed the initial SBT [4], MV was reinstituted, and the possible causes for failure were examined. The SBT was repeated the next day if it was determined that the patient was ready to be weaned.

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Definitions

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Readiness to wean was assessed based on the following criteria [2-4, 9]: (1) resolution of the acute phase of the disease for which the patient was intubated, adequate cough

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reflex, and absence of excessive tracheobronchial secretion; (2) stable cardiovascular status (cardiac frequency (fC) of ≤140 beats·min−1, systolic blood pressure of 90–160

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mmHg, and no or minimal vasopressors); (3) stable metabolic status; (4) adequate oxygenation (arterial oxygen saturation (SaO2) of >90% on an inspiratory oxygen fraction (FiO2) of ≤0.4 or oxygenation index of ≥150); (5) adequate pulmonary

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function (respiratory frequency (fR) of ≤35 beats·min−1, maximal inspiratory pressure of ≤20–25 cm H2O, tidal volume of >5 mL·kg−1, vital capacity of >5 mL·kg−1, rapid

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shallow breathing index (RSBI) of 8 mmHg; (5) arterial pH of 105 beats·min−1·L−1; (7) fR of >35 beats·min−1 or increased by ≥50%; (8) fC of >140 beats·min−1 or increased by ≥20%;

ACCEPTED MANUSCRIPT (9) systolic blood pressure of 180 mmHg, or increased by ≥20%; or (10)

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cardiac arrhythmias.

A patient was considered to be successfully weaned when he or she was extubated and

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breathing spontaneously without ventilator support for ≥48 h. Patients who had undergone a tracheotomy before they were ready to be weaned were considered to be

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successfully weaned when they were breathing spontaneously either through the tracheal cannula or directly through the tracheostoma for 48 h without support [4]. If a patient was reintubated after successful primary weaning and was subsequently

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successfully weaned, the primary weaning episode was used to define the patient’s

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weaning category. The total weaning duration was determined for patients who were successfully weaned at least once and calculated as the number of days between the

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time point at which a patient was first ready to begin the weaning process and the time

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point at which the patient was successfully weaned.

Outcome measures The primary outcome was 60-day mortality. Secondary outcome measures included hospital mortality, ICU mortality, ICU and hospital lengths of stay, ICU and hospital costs, reintubation rate, incidence of ventilator-associated pneumonia, and incidence of prolonged MV [12].

ACCEPTED MANUSCRIPT Data collection The following data were collected from patients’ medical records and bedside flow

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charts at admission: baseline data, Acute Physiology and Chronic Health Evaluation II (APACHE-II) score [13], reasons for initiating MV, comorbidities, physiological

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parameters at initiation of the weaning process, method of weaning, use of sedation and vasopressors during weaning, ICU length of stay, MV duration before weaning,

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total MV duration, incidence of ventilator-associated pneumonia, and reintubation.

Statistical methods

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Statistical analyses were performed using SPSS version 19.0 software (SPSS Inc.,

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Chicago, IL, USA). Kruskal–Wallis ANOVA was used to compare continuous variables, and Dunn’s test was used for post-hoc testing. Categorical variables of the

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three weaning categories were compared using a chi-squared test for trends.

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Univariate and multivariate analyses were performed using logistic regression. The data are presented as mean ± standard deviation, median (interquartile range), or proportion, as appropriate. A two-sided p-value of ≤0.05 was considered statistically significant.

Results Patient characteristics In total, 840 patients who were admitted to the ICU and required intubation and MV were screened. Weaning was not initiated in 225 (27%) patients because of

ACCEPTED MANUSCRIPT tracheostomy, death, limited life-sustaining treatment, transfer to another hospital, or unplanned extubation. In the remaining 615 patients (73% of intubated patients),

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weaning was initiated according to the established recommendations. Patients were excluded from the analysis because of a gradual reduction of support to weaning (124

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patients), tracheostomy (61 patients), performance of NIV (78 patients), transfer to a different hospital (7 patients), and unplanned extubation during weaning (2 patients).

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In total, 343 patients were included in the final analysis (Figure 1). Simple, difficult, and prolonged weaning occurred in 200 (58%), 99 (29%), and 44 (13%) patients,

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respectively.

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The 343 patients included in the final analysis were stratified by weaning category, and their baseline characteristics were compared (Table 1). Sex, body mass index,

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smoking history, and prior episodes of MV did not differ greatly among the three

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groups. There were more surgical patients in the simple and difficult weaning groups. Patients in the prolonged weaning group were more likely to be from the medical ward and to have pneumonia as the reason for initiation of MV. Patients in the prolonged weaning group were older and had a higher APACHE-II score on admission to the ICU. More comorbidities were recorded in the prolonged weaning group. Patient characteristics were similar between the simple and difficult weaning groups.

The physiological parameters of the patients on the day of the first SBT are shown in

ACCEPTED MANUSCRIPT Table 2. Patients in the prolonged weaning group had a lower Glasgow Coma Scale (GCS) score at the start of the weaning process (p = 0.003). However, at the start of

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the SBT, the arterial carbon dioxide pressure was higher in the prolonged weaning group (p = 0.008). The mean arterial pressure, heart rate, RBSI, arterial pH, arterial

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oxygen pressure, and oxygenation index (PaO2/FiO2) at the beginning of the SBT did not differ significantly among the three groups; there was also no difference in the

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proportion of patients using a sedative or vasoactive drug during the weaning process. The SBT mode did not differ among the three groups. A T-piece was most commonly

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used in the SBTs.

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Length of stay and complications

The duration of MV prior to the initiation of weaning differed among the three groups

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(p = 0.001) (Table 3). The duration of MV prior to weaning was shortest in the

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difficult weaning group. Patients who experienced prolonged weaning had longer ICU and hospital stays as well as a longer total duration of MV (p < 0.001). The probability of weaning was significantly lower in the prolonged weaning group (Figure 2); no differences were observed between patients in the simple and difficult weaning groups. Additionally, the proportion of patients who required reintubation tended to be higher in the prolonged weaning group. Furthermore, the rates of subsequent ventilator-associated pneumonia and the proportion of patients who underwent prolonged MV were significantly higher in the prolonged weaning group. The ICU, hospital, and 60-day mortality rates for patients who underwent weaning

ACCEPTED MANUSCRIPT according to recommendations were 9%, 13%, and 14%, respectively. The ICU, hospital, and 60-day mortality rates were higher for patients in the prolonged than in

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the simple and difficult weaning groups (Table 3).

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Predictive factors for prolonged weaning

When patients in the prolonged weaning group were compared with those in the

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simple and difficult groups, significant differences in the ICU and 60-day mortality rates were observed. Univariate analysis showed that several variables were associated with prolonged weaning (Table 4). Multivariate analysis revealed that a

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lower GCS score (p = 0.014) and hypercapnia at the beginning of the first SBT (p =

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0.038) were independent predictors of prolonged weaning. Additionally, the weaning

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Discussion

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category significantly affected the 60-day mortality rate (Table 5).

The ICC classification considers weaning from MV to be an independent process, and patients undergoing MV are classified according to the duration and difficulty of weaning. Factors that affect weaning include the patient’s organ functional status and changes in physiological indicators before and after SBTs [4]. We performed a prospective cohort study at 13 local ICUs on patients requiring MV who were weaned according to ICC classification criteria. We found that in our cohort of patients undergoing MV, those in the prolonged weaning group had higher hospital mortality rates than those in the simple or difficult weaning groups. This indicates that patients

ACCEPTED MANUSCRIPT who fail at least three weaning attempts or require 7 days of weaning after the first

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of weaning were more likely to have prolonged weaning.

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SBT have higher mortality. Patients with a low GCS score and hypercapnia at the start

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Using data from previous clinical studies, the ICC estimates that approximately 69% of patients experience simple weaning and 15% experience prolonged weaning [4,

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14-17]. In our study, we found that 58% of patients experienced simple weaning and 13% of patients experienced prolonged weaning. This is in agreement with the previous study results. However, patients who underwent tracheotomy, NIV during

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weaning, and gradual reduction of supporting pressure were all excluded in light of

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our research objective. This led to a lower proportion of patients with late weaning than shown by the actual clinical observations. Tracheostomy improved patients’

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comfort and communication, reduced sedative use, and may have contributed to

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earlier weaning. The status of the patients who underwent tracheotomy and intubation might have varied, influencing the weaning process. Therefore, all patients who underwent tracheotomy were excluded. However, we observed that the weaning process in these patients took much longer than that in the simple and difficult weaning groups. Additionally, patients who require NIV support following extubation should not be defined as successfully weaned [4]. These patients were also excluded from our study (9% of all patients undergoing MV). However, previous studies have shown that NIV can expedite weaning in specific patient groups, including patients with hypercapnia and chronic obstructive pulmonary disease (COPD) [18, 19].

ACCEPTED MANUSCRIPT Moreover, although previous studies have confirmed that weaning by SBTs can shorten the weaning process and improve the success rate [1, 20], the clinicians still

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chose to gradually lower the support conditions of MV for some patients who were difficult to be weaned. Peñuelas et al. [21] observed a similar phenomenon. This may

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suggest that some patients could have been weaned more quickly if they had undergone an SBT. Our study design and patient exclusion criteria may explain the

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lower proportion of patients who experienced prolonged weaning in the present study.

Similar to what has been previously observed, our study confirmed that the ICC

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classification is closely related to the 60-day, ICU, and hospital mortality rates [5, 6, 8,

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22]. In our study, patients in the prolonged weaning group had a higher mortality rate. A longer duration of MV is associated with a higher incidence of related

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complications [23]. We found that patients in the prolonged weaning group had a

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longer MV duration; 18% of these patients required prolonged MV. Additionally, the incidences of reintubation, ventilator-related pneumonia, and mortality were significantly higher in this group. In contrast, the total MV duration did not differ significantly between the simple and difficult weaning groups; the clinical outcomes of these two groups were similar. Peñuelas et al. [21] found that the weaning time did not appear to affect ICU mortality until the patient reached 7 days of weaning. The baseline characteristics of the patients in the simple and difficult weaning groups were similar. Although the weaning duration showed some differences, the patients could be weaned from MV successfully within 7 days. There was no evident difference in

ACCEPTED MANUSCRIPT the total MV time, occurrence of ventilator-associated pneumonia, or reintubation rate. This is why the two groups had similar clinical outcomes. We found that the duration

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of ventilator support before weaning in the difficult weaning group was shorter than that in the simple weaning group. Therefore, we believe that the earlier initiation of

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due to selection bias rather than a causal effect.

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SBT in the difficult weaning group than in the simple weaning group may have been

Although it has been suggested that the GCS score cannot be applied to the prediction of extubation failure [24], several studies have found that the patient’s consciousness

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level and mental status affect the success of weaning [25–27]. Our study showed the

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same finding. Delirium, anxiety, depression, and other neurological disorders reduce weaning success [28]; therefore, adequate evaluation and treatment of patients’

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consciousness level and mental condition contribute to successful weaning from MV

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[29]. The use of dexmedetomidine pyridine to reduce delirium was recently shown to reduce the duration of MV [30].

Higher PaCO2 levels at the initial SBT were independently related to prolonged weaning in our study. This finding is consistent with that obtained by Sellares et al. [8]. Previous studies have shown that patients develop increased cardiopulmonary stress during an unsuccessful SBT [31–33]. Most patients undergoing weaning still have considerable gas exchange disturbances during the weaning process and may develop hypoxemia, hypercapnia, or both during an SBT. Patients who experience

ACCEPTED MANUSCRIPT failed weaning are frequently unable to increase their minute ventilation in response to a high PaCO2 because of weakness of the respiratory muscles, altered respiratory

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mechanics, and other factors. In these patients, it is important to limit the instrumental

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dead space as much as possible [34].

Previous studies have shown that pneumonia as the reason for initiating MV was

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associated with an increased risk of extubation failure [35]. In the present study, patients in the prolonged weaning group were more likely to have pneumonia as the reason for initiation of MV. Our hypothesis is that these patients may not have fully

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cleared the microbial load from their pneumonia and therefore require longer

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ventilatory support. Other reasons associated with prolonged weaning were acute exacerbation of COPD or acute respiratory distress syndrome (ARDS). These patients

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have substantially longer weaning times than patients who require MV as a result of

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other diseases. Approximately 46% to 59% of patients undergoing prolonged MV reportedly have COPD. Jubran and Tobin [10] showed that airway resistance in patients with COPD who failed an SBT was significantly higher than that in patients who passed an SBT, indicating that the lower airway resistance in patients with COPD might promote weaning success. In the present study, 74 patients underwent MV because of acute exacerbation of COPD. However, 69% these patients were excluded from the final cohort because they underwent tracheostomy prior to or during the course of MV, died before they were ready to begin the weaning process, underwent NIV during weaning, or met other exclusion criteria. Patients with ARDS were also

ACCEPTED MANUSCRIPT faced with the same problem. A total of 79 patients underwent MV due to ARDS, accounting for 9% of the total patients intubated and ventilated. Among these 79

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patients, only 18 (23%) were included in the final cohort. Among the remaining patients, 28 (35%) died before weaning or received withdraw therapy, 16 (20%) were

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weaned by gradually lowering the support conditions, 8 (10%) underwent tracheotomy, and 6 (8%) underwent NIV. We believe that the failure to find

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significant differences can be attributed to the limited sample size.

T-tube methods were most commonly used for weaning in our cohort. However,

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consistent with previous reports, weaning outcomes did not vary with the weaning

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method used [36, 37]. New ventilator modes have recently been used for the weaning process, including automatic tube compensation, adaptive support ventilation, and

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automated weaning systems such as SmartCare (Dräger, Lübeck, Germany). However,

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whether these new modes help patients to wean as soon as possible remains unknown [38–41].

There are limitations to this study. First, although a number of pathological and physiological factors affect weaning, not all such factors were examined in this study because of the limited sample size. Second, our study did not identify the GCS score and arterial carbon dioxide tension threshold that affect prognosis. Third, the study endpoint was 60-day and hospital mortality; however, 1-year mortality is a more valuable endpoint. Finally, the cohort was limited to local patients; thus, the study

ACCEPTED MANUSCRIPT results are not representative of other populations.

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Conclusions

In this study, we analysed patients undergoing MV in local medical-surgical ICUs

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according to the ICC weaning classification guidelines. A total of 13% of patients experienced prolonged weaning; these patients had significantly increased 60-day and

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hospital mortality rates. In contrast, patients in the simple and difficult weaning groups showed similar clinical characteristics and outcomes. A low GCS score and hypercapnia at the start of weaning were independent risk factors for prolonged

Acknowledgments

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weaning.

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This study was a Beijing Health Science and Technology Joint Research Project and

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was funded by the Research Fund of Capital Medical Development (No. H020920020530).

Conflicts of interest None.

ACCEPTED MANUSCRIPT References 1. Kollef MH, Shapiro SD, Silver P, St John RE, Prentice D, Sauer S, Ahrens TS,

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Shannon W, Baker-Clinkscale D. A randomized, controlled trial of protocol-directed versus physician-directed weaning from mechanical ventilation. Crit Care Med 1997;

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25: 567–574.

2. Ely EW, Baker AM, Dunagan DP, Burke HL, Smith AC, Kelly PT, Johnson MM,

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Browder RW, Bowton DL, Haponik EF. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996; 335: 1864–1869.

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3. Coplin WM, Pierson DJ, Cooley KD, Newell DW, Rubenfield GD. Implications of

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extubation delay in brain-injured patients meeting standard weaning criteria. Am J Respir Crit Care Med 2000; 161: 1530–1536.

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Dembinski R. Outcome and mortality risk factors in long-term treated ICU patients: a retrospective analysis. Minerva Anestesiol 2011; 77: 427–438.

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P, Margolis BD, Byrne DW, Ely EW, Rocha MG; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301: 489–499. 31. Grasso S, Leone A, De Michele M, Anaclerio R, Cafarelli A, Ancona G, Stripoli T, Bruno F, Pugliese P, Dambrosio M, Dalfino L, Di Serio F, Fiore T (2007) Use of N-terminal probrain natriuretic peptide to detect acute cardiac dysfunction during weaning failure in difficult-to-wean patients with chronic obstructive pulmonary disease. Crit Care Med 35:96–105.

ACCEPTED MANUSCRIPT 32. Jubran A, Tobin MJ (1997) Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit

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Care Med 155:906–915.

33. Jubran A, Mathru M, Dries D, Tobin MJ (1998) Continuous recordings of mixed

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venous oxygen saturation during weaning from mechanical ventilation and the ramifications thereof. Am J Respir Crit Care Med 158:1763–1769.

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34. Le Bourdellès G, Mier L, Fiquet B, et al. Comparison of the effects of heat and moisture exchangers and heated humidifiers on ventilation and gas exchange during weaning trials from mechanical ventilation. Chest 1996, 110:1294-1298.

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Gonza´ lez M, Hill NS, Nava S, D’Empaire G, et al. Risk factors for extubation failure in patients following a successful spontaneous breathing trial. Chest

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2006;130:1664–1671.

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36. Brochard L, Rauss A, Benito S, Conti G, Mancebo J, Rekik N, Gasparetto A, Lemaire F. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med 1994; 150: 896–903. 37. Farias JA, Retta A, Alia I, Olazarri F, Esteban A, Golubicki A, Allende D, Maliarchuk O, Peltzer C, Ratto ME, Zalazar R, Garea M, Moreno EG. A comparison of two methods to perform a breathing trial before extubation in pediatric intensive care patients. Intensive Care Med 2001; 27: 1649–1654. 38. Cohen J, Shapiro M, Grozovski E, Fox B, Lev S, Singer P. Prediction of

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39. Chen CW, Wu CP, Dai YL, Perng WC, Chian CF, Su WL, Huang YC. Effects of implementing adaptive support ventilation in a medical intensive care unit. Respir

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automatic tube compensation and continuous positive airway pressure during spontaneous breathing trials. Respir Care 2010; 55: 549–554. 41. Karci A, Duru S, Hepağuşlar H, Ciftçi L, Yilmaz O. Comparison of the effect of

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sevoflurane and propofol on oxygenation during gradual transition to one-lung

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ventilation. Braz J Anesthesiol 2014; 64: 79–83.

ACCEPTED MANUSCRIPT Table 1. Baseline characteristics of mechanically ventilated patients.

Simple weaning

Difficult weaning

Prolonged weaning

(N = 200)

(N = 99)

(N = 44)

p-value Comparison

T

Comparison

Comparison

Comparison

between

between

between

simple and

difficult and

difficult

prolonged

prolonged

weaning

weaning

weaning

0.003

0.636

0.001

0.004

simple and

Age (years)

62±19

63±19

73±14

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between the

Gender, N (% female)

84(42%)

37(37%)

21(48%)

0.807

0.444

0.488

0.246

24±4

24±5

26±16

0.070

0.629

0.051

0.045

0.474

0.789

0.295

0.321

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BMI (kg/m2)

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3 groups

Type of ICU admission, N (%) 18(9%)

11(11%)

12(27%)

0.003

0.562

0.001

0.016

Surgery ward

128(64%)

62(63%)

18(41%)

0.017

0.817

0.005

0.016

Emergency department

48(24%)

18(18%)

12(27%)

0.924

0.254

0.649

0.219

8(8%)

2(5%)

0.238

0.051

0.603

0.446

15±7

18±7

0.001

0.237

＜0.001

0.018

6(3%)

Others admission

14±6

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APACHE-II score at ICU admission

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Medical ward

70(35%)

34(34%)

15(34%)

0.889

0.911

0.909

0.977

Prior episode of MV, N (%)

18(9%)

8(8%)

8(18%)

0.165

0.791

0.075

0.078

0.015

0.945

0.003

0.006

Cause for initiation of MV, N (%)

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History of smoking, N (%)

4(4%)

7(16%)

0.097

0.479

0.027

0.014

12(6%)

4(4%)

2(5%)

0.537

0.479

0.708

0.890

17(9%)

15(15%)

12(27%)

0.001

0.080

0.001

0.088

Septic shock

12(6%)

4(4%)

1(2%)

0.253

0.479

0.320

0.597

Cardiovascular disease

15(8%)

6(6%)

1(2%)

0.216

0.647

0.206

0.334

Neurological disease

4(2%)

1(1%)

2(5%)

0.525

0.531

0.325

0.175

116(58%)

62(63%)

16(36%)

0.072

0.444

0.009

0.004

12(6%)

3(3%)

3(7%)

0.782

0.269

0.838

0.299

0.003

0.287

0.001

0.029

ARDS Pneumonia

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12(6%)

AECOPD

Postoperative respiratory failure Others Number of Co-morbidities#, N (%) None

76(38%)

34(34%)

8(18%)

0.022

0.538

0.012

0.051

One

60(30%)

26(26%)

11(25%)

0.410

0.502

0.509

0.874

ACCEPTED MANUSCRIPT 64(32%)

39(39%)

25(57%)

0.003

0.206

0.002

Data are presented as mean ± standard deviation or number (percentage). N, number; BMI, body mass index; ICU, intensive care unit; APACHE-II, acute physiology and chronic health evaluation II; MV, mechanical ventilation; AECOPD, acute exacerbation of chronic obstructive pulmonary disease; ARDS, acute respiratory distress

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syndrome; NYHA: New York Heart Association functional classification.

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#Co-morbidities included hypertension, insulin-dependent diabetes, chronic renal failure, heart failure (NYHA III-IV), chronic respiratory

CE

PT

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failure, cirrhosis, tumor, and brain stroke.

AC

Two or more

0.054

ACCEPTED MANUSCRIPT Table 2. Physiological characteristics of patients at the start of the weaning process.

Simple weaning

Difficult weaning

Prolonged weaning

(N = 200)

(N = 99)

(N = 44)

p-value Comparison

T

Comparison

Comparison

Comparison

between

between

between

3 groups

simple and

difficult and

difficult

prolonged

prolonged

weaning

weaning

weaning

15(13-15)

15(11-15)

15(10-15)

0.003

0.006

0.007

0.364

MAP (mmHg)

83±13

85±13

84±12

0.658

0.363

0.837

0.671

Cardiac frequency (beats·min-1)

90±15

89±13

89±14

0.850

0.615

0.717

0.997

RSBI (beats·min-1·L-1)

43±14

39±13

44±16

0.077

0.056

0.454

0.117

7.43±0.05

7.43±0.05

7.41±0.05

0.154

0.967

0.060

0.090

39±7

37±6

41±8

0.008

0.027

0.109

0.003

PaO2 (mmHg)

126±42

130±42

118±59

0.293

0.352

0.310

0.146

Oxygenation index

314±100

321±103

299±147

0.517

0.568

0.401

0.295

Use of vasoactive drugs, N (%)

31(16%)

18(18%)

11(25%)

0.145

0.556

0.131

0.351

Use of sedative drug, N (%)

10(5%)

3(7%)

0.497

0.468

0.628

0.957

0.111

0.014

0.509

0.239

PSV

7(7%)

142(71%)

80(81%)

33(75%)

0.225

0.068

0.595

0.433

6(3%)

5(5%)

2(5%)

0.447

0.376

0.603

0.898

52(26%)

14(14%)

9(21%)

0.103

0.020

0.443

0.345

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CPAP

CE

SBT mode, N (%) T-tube

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PT

PaCO2 (mmHg)

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Arterial PH

SC

simple and

Glasgow score

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between the

Data are presented as median (interquartile range), mean ± standard deviation, or number (percentage). N, number; MAP, mean arterial pressure; RSBI, rapid shallow breathing index; PaO2, arterial oxygen tension; PaCO2, arterial carbon dioxide tension; SBT, spontaneous breathing trial; T-tube, T-tube trial; CPAP, continuous positive airway pressure with 5 cm H2O positive end-expiratory pressure (PEEP); PSV, weaning trial using 5–8 cm H2O pressure support with 5 cm H2O PEEP.

ACCEPTED MANUSCRIPT Table 3. Length of hospital and ICU stay and outcome of weaning.

Simple weaning

Difficult weaning

Prolonged weaning

(N = 200)

(N = 99)

(N = 44)

p-value Comparison

Comparison

Comparison

between the

between

between

between

3 groups

simple and

simple and

difficult and

difficult

prolonged

prolonged

weaning

weaning

weaning

0.001

0.001

0.158

0.003

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T

Comparison

47(33-86)

39(20-66)

60(38-119)

Total duration of MV (hours)

53(36-95)

62(38-112)

286(196-433)

＜0.001

0.265

＜0.001

＜0.001

5(3-8)

6(3-11)

18(10-21)

＜0.001

0.522

＜0.001

＜0.001

Hospital Stay (days)

22(15-31)

20(13-31)

26(17-42)

0.082

0.211

0.131

0.028

Re-intubation, N (%)

12(6%)

5(5%)

13(30%)

＜0.001

0.739

＜0.001

＜0.001

VAP, N (%)

13(7%)

9(9%)

14(32%)

＜0.001

0.420

＜0.001

0.001

PMV, N (%)

4(2%)

2(2%)

8(18%)

＜0.001

0.991

＜0.001

＜0.001

ICU mortality, N (%)

6(3%)

5(5%)

20(46%)

＜0.001

0.376

＜0.001

＜0.001

Hospital mortality, N (%)

13(7%)

10(10%)

20(46%)

＜0.001

0.407

＜0.001

＜0.001

16(8%)

11(11%)

21(48%)

＜0.001

0.378

＜0.001

＜0.001

4.1(2.1-7.1)

3.5(1.5-8.6)

11.0(6.5-13.7)

＜0.001

0.402

＜0.001

＜0.001

7.8(4.2-13.5)

12.8(8.5-19.0)

0.001

0.265

＜0.001

＜0.001

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ICU stay (days)

60-day mortality, N (%)

Hospital costs (10,000 RMB$)

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ICU costs (10,000 RMB$)

SC

Duration of MV before weaning (hours)

8.9(5.6-14.9)

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Data are presented as median (interquartile range), mean ± standard deviation, or number (percentage). N, number; MV, mechanical ventilation; ICU, intensive care unit; VAP, ventilator-associated pneumonia; PMV, prolonged mechanical ventilation; RMB$, Chinese Yuan

ACCEPTED MANUSCRIPT Table 4. Logistic multivariate analysis for the identification of predictors of difficult weaning

95% Confidence Odds ratio

p-value interval

1.022

0.998-1.047

APACHE-II score on admission ICU

1.038

0.984-1.096

Glasgow score

0.840

PaCO2 (mmHg)

1.050

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1.676

Number of Co-morbidities 1.238

Two or more

0.173

0.731-0.966

0.014

1.002-1.100

0.038

0.703-3.995

0.244

0584-2.623

0.578

SC

Causes for initiating MV Pneumonia – any cause

0.071

T

Age (years)

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MV, mechanical ventilation; APACHE-II, acute physiology and chronic health evaluation II; PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; RSBI, rapid shallow breathing index; AECOPD, acute exacerbation of chronic obstructive pulmonary disease.

Table 5. Logistic regression analysis of weaning category and 60-day mortality.

1

Difficult weaning

1.438

Prolonged weaning

10.500

AC

CE

PT

Simple weaning

ED

Odds ratio

95% Confidence interval

p-value

0.640-3.227

0.379

4.806-22.942

＜0.001

ACCEPTED MANUSCRIPT Fig. 1. Study flow chart detailing the inclusion and exclusion of patients.

Intubated and ventilated patients

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(N = 840)

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Died before ready to wean (N = 111)

Limit life-sustaining treatment before ready to wean

Tracheostomy before ready to wean

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(N = 62) Transferred to another hospital before ready to wean

(N = 41)

Unplanned extubation before ready to wean

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(N = 7)

(N = 4)

Initiated weaning (N = 615)

Received noninvasive ventilation during weaning

Tracheostomy during weaning

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(N = 78) Didn’t use spontaneous breathing trial to wean

Unplanned extubation during weaning

(N = 124) Transferred to another hospital during

PT

(N = 61)

(N = 2)

weaning

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CE

(N = 7)

Final patient cohort (N = 343)

Simple weaning

Difficult weaning

Prolonged weaning

(N = 200)

(N = 99)

(N = 44)

ACCEPTED MANUSCRIPT Fig. 2. The duration of mechanical ventilation and the probability of weaning. The probability of weaning was significantly lower in the prolonged weaning group. No differences were observed between patients in the simple

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CE

PT

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SC

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and difficult weaning groups.